Medicine

How can cancer be targeted without killing healthy cells?
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How can cancer be targeted without killing healthy cells?

Targeted Therapy: a tremendous solution

Abstract: Targeted therapy is a relatively new method of curing cancer that uses drugs to attack targets on which cancer cells’ growth closely depend. [1] By attacking the proteins or enzymes responsible for their abnormal growth, its effects are amplified. Targeted therapy is successful in curing many cancer patients, it has fewer effects on healthy cells and causes fewer long-term conditions or complications than other chemotherapy treatments [1]; although the side effects it can cause, such as hand-foot syndrome, are very complicated. [2]

Tracing Targeted Therapy

Targeted Therapy is a new way of curing cancer by using drugs that target specific proteins or enzymes in addition to blocking signals that help the cancer cells to grow and spread through the body’s systems. Targeted therapy has fewer side effects on the normal dividing cells and causes fewer long-term conditions than other chemotherapies. A significant factor in the functioning of other cancer treatments, like radiotherapy, is cytotoxicity, meaning they function to slow the spreading of or to kill the cancerous cells. This impacts the cells’ dividing routine: the cell cycle. [1]

Figure 2

The Cell Cycle

The cell cycle is the normal growth routine of cells. It has 5 phases [1] (as seen in Figure 2):

Cells in the G0 phase are not dividing nor preparing for dividing, and are in an inactive state. This stage can lasts for a few hours or for years depending on the cell type.

Specific signalling will allow progression to G1. In this stage normal metabolic processes occur (e.g. respiration and protein synthesis) and cells are preparing to progress to the next phase.

Next is stage S: now DNA is being replicated for the daughter cells that will form. There is then a second G phase (G2), before finally mitosis (the cell division) in stage M. [1]

Radiotherapy has been successful in targeting actively dividing cells (those not in G0) but has led to killing healthy cells as well. To avoid killing healthy cells, a new solution was needed: a cytostatic(meaning stopping tumor cells’ proliferation), targeted therapy. [3]

Targeted therapy differs from standard chemotherapy in several ways, including:

• Most standard chemotherapies act on all dividing cells, while targeted therapies act on specific molecular targets associated with cancer.

• Targeted therapies are designed to interact or change something involving the genes within cancer cells that causes further growth to be inhibited. Thus the tumour stays the same size and they are cytostatic. However many chemotherapies kill cells to decrease the size of tumours and therefore are cytotoxic. [1][2]

Targeted therapy can cause different reactions inside the cell such as:

• Preparing and developing immune systems to kill the cancer cells

• Carrying a toxin to the cancer cell to kill it without harming normal cells [4]

• Blocking or turning off the signals that tell cancer cells to grow and divide

• Keeping cells from living longer than normal [4.1]

• Changing proteins within the cancer cells so the cells die

• Stopping to make new blood vessels to feed the cancer cells [4.2]

Different cancers propagate through the body differently. Identifying the target of the targeted therapy is one of the most important factors in using this kind of method to cure cancer, as each type of cancer has its own target that needs to be identified to have a successful treatment.

Detailed Action of certain types of Targeted Therapy

Enzyme Inhibitors

One of the main goals of targeted therapy is the slowing down of the infected cells’ growth and spread, which can be targeted through enzyme inhibitors. In the human body, there are many enzymes that function to keep the body normal and some of these are enzymes give “spreading” and “growing” signals to infected cancer cells. Some targeted therapies block these signals, which results in the interruption of the infected cells’ cell cycles. However it does not distinguish cancerous cells from normal cells. [2]

In new research published on 21 March 2016 by Cornell researchers from Ithaca and Weil Cornell Medicine campuses, a promising new inhibitor which showed effectiveness most noticeably against several types of difficult and complicated cancer types, such as leukemia, breast and colorectal cancer was described. “This started from basic science, and the basic study led us to this path, which looks very promising. We have high hope that in a few years, we can develop an effective anti-cancer drug,” said co-lead author Hening Lin, professor of chemistry and chemical biology in the College of Arts and Sciences and a Howard Hughes Medical Institute investigator. [5] An important role in the survival of several types of cancer, and one of the major factors in this research was played by the oncoprotein c-Myc, which is found in almost half of all human tumors and on the enzyme SIRT2. Experimenting on a laboratory breast cancer mouse model, the tumor growth in the breast cancer was inhibited by the group of researchers in addition to inhibiting SIRT2 and decreasing the c-Myc protein level by using a compound known as TM, which is a thiomyristoyl lysine compound. [5]

Apoptosis-inducing drugs

Many cancer treatments, including radiotherapy, cause changes in cells which lead to apoptosis (programmed cell death). Targeted therapy drugs in this treatment, apoptosis-inducing drugs, cause the cancer cells to die. In some situations, the “signals” for cell death do not work properly and drugs such as Olaparib (Lynparza) try to restore them in addition to:

• Blocking poly ADP-ribose polymerase (PARP) enzymes so that the cancer cells’ DNA cannot be repaired, causing the cells to die [6]

• Making the cells more easily destroyed

• Blocking BCL2 which promotes cancer call survival resulting in more sensitivity to anti cancer drugs [1] [6]

Angiogenesis inhibitors

Tumors and cancer cells need blood and nutrients to grow and spread– if they get insufficient amounts of nutrients they will not be able to grow. Angiogenesis is the process of making new blood vessels, which is a healthy and normal process; it may not be much needed for healthy adults but is very useful and important in remaking blood vessels when injured for example. So, one way of stopping the growth of cancer tumors is stopping the supply of nutrients needed for their growth. Cancerous cells use VEGF, vascular endothelial growth factor, which is a family of protein growth factors made by some tumors: the VEGF proteins attach to their receptors in blood vessel cells and cause new blood vessels to form around the tumor, allowing it to become more massive. Some angiogenesis inhibitors work to block VEGF. [1]

Figure 3: Man-made targeted antibody drugs

Figure 4: Small-molecule drugs for inner cell treatments.

 

Types of Targeted Therapy Drugs:

Most targeted therapy drugs are divided into two main types:

•Antibody drugs: Man-made versions of immune system proteins (as seen in Figure 3) called antibodies that have been designed to attack certain targets on cancer cells, mostly around the surface of infected cells as they are more massive than others drugs. Normally the body itself makes antibodies to fight harmful microbial attackers.

• Small-molecule drugs: Such drugs are smaller and can easily go inside cells and therefore are assigned to do tasks inside cancer cells and that can be noticed in Figure 4. [2]

Some drugs that have noticeably great usage today:

Gleevec: There are many different kinds and types of targeted therapy drugs, one of the first to be used to cure cancer was Gleevec (imatinib mesylate) which is usually used to treat gastrointestinal  stromal tumor, a rare type of cancer in the gastrointestinal area known as GIST, and specific kinds of leukemia. This drug, imatinib, is a tyrosine kinase inhibitor meaning it targets tyrosine kinase proteins that are used for growth signaling of cells [7] and a type of small molecular drug that normally targets abnormal proteins or enzymes that form on and inside cancer cells and provide the key to the uncontrolled growth of dividing cells. Blocking these enzymes inhibit the growth of these cells, that is one of the main goals of targeted therapy. [2]

Iressa (gefitinib): One way to treat advanced non-small cell lung cancer is the targeting of epidermal growth factor receptors– (EGFR) which are found on the surface of many normal cells, but specific cancer cells have an abnormally high number of them on their surface which helps in giving more signals to the infected cells to grow and spread. Using gefitinib to stop the signals by blocking them  results in slowing or stopping of abnormal cell growth [2].

Sutent: One of the multi-functioning targeted therapy drugs available for treating both advanced kidney cancer and some gastrointestinal stromal tumors (GIST), which is very useful and impressive, is Sutent (sunnitinib). It is considered as a multi-targeted kinase inhibitor as it is a kind of vascular endothelial growth factor receptor inhibitor and an angiogenesis inhibitor. It stops the source of nutrients for cancer tumors, in addition to blocking the well-known tyrosine kinase enzyme. By succeeding in performing all these tasks, this useful drug not only slows cancer growth but it keeps tumors from making their own blood vessels to help the growth of them throughout the body. [2]

Velcade (bortezomib): This kind of drug, which is a small molecular drug, is necessary to treat multiple myeloma when other drugs have not responded to previous treatments. This proteasome inhibitor, bortezomib, stops the proteasome (which is a complex of enzymes that helps destroy proteins no longer necessary to the cell, including those regulating cell function and growth) from breaking down these proteins which in turn causes cancer cells to die. [2] Velcade has been used to treat an estimated number of 550000 atients worldwide which is very hopeful for a brighter future. [8]

Figure 5: Different kinds of side effects from targeted therapy, such as hand-foot syndrome (shown in the bottom-centre image)

Targeted Therapy Side Effects

One of the main benefits of targeted therapy is that it has fewer side effects on the body than other standard chemo treatments, although it can have side effects that are deeply dependent on the target that the drugs are used to attack. [2] Some drugs have more targets on cancer cells but also some on healthy cells that can cause negative impacts. The side effects increase in severity as the number of drug targets increase, especially drugs that play an important role in angiogenesis inhibition, as that affects new blood vessel formation all over the body, not just those near the infected cancer cells and tumors, meaning they can lead to complications, such as those seen in Figure 5.

Some people get few, if any side effects and it really depends on the person that uses the drugs; even the severity of the effects varies greatly from person to person and how long the drug was used. The side effects usually are not long-term as most side effects go slowly after treatment and the healthy cells recover however it really depends on the patient’s overall health conditions and the consumed drugs’ specifications. [2]  Some types of medicines may be given to the patient to control the side effects after or even before the medication. These are some of the most common side effects of targeted therapy:

Skin problems:

The most common skin problem after the treatment is rash: more than half of patients who chose this type of treatment are affected by it. Its severity depends on the type of cancer and the dose used to treat it, although it is mild for most people. It is often similar to acne but without blackheads as seen in Figure 6, and usually appears on the scalp, face, neck, chest and upper back by about the fourth week of the treatment, when the skin usually crusts and gets very dry and red (dryness of the skin which can even crack open is another side effect which is more difficult to handle than rash) and after that, flat or raised spots appear on the skin which can itch, burn, sting and may even be painful to touch (some patients may be needed to use drugs such as diphenhydramine to get relief); the rash usually should completely go away about after a month of the treatment [9].

Figure 6: Rash is the most common side effect of this therapy

These problems usually develop slowly over days to weeks and are not the signs of drugs allergy – which includes serious symptoms such as dizziness, trouble in breathing, tightness in the chest and throat, swelling of lips or tongue, intense itching or hives that usually becomes noticeable suddenly a few minutes to hours after taking the drug– but problems like lack of skin moisture, which is the result of some of the specialized drugs that target the epidermal growth factor receptor (EGFR) protein which sends growth and division signals to cancer cells, like Iressa (geftinib); as explained above, it affects the normal skin cells which do have a lot of EGFR on their surfaces making it harder to maintain skin moisture [10].

Figure 7: Hand-Foot syndrome can result in swelling of the soles and hands.

Other problems that are a result include the hand-foot syndrome –its cause is not known yet but is probably because of the damage to the tiny blood vessels in the hands and feet or the drugs themselves leaking out from the blood vessels and into tissues, leading to tissue damage that targets proteins such as the vascular endothelial growth factor (VEGF) which helps tumors build and maintain a blood supply. Some patients who reach severe levels of pain both in the hands and feet may be given medicine for relief as it can cause swelling in the palms of the hands and soles of the feet, which can be seen in Figure 7, redness which may even blister and open up and become painful sores and can even affect the ability to walk and doing normal activities. Scientists have reached the conclusion that patients getting radiotherapy, as well as targeted therapy, have more skin problems in the area where the radiotherapy treatment has been focused on as well. [2]

Another side effect caused by some targeted therapies is swollen, red, open and painful skin sores around fingernails and toenails which can superficially look like an infection or an ingrown nail as can be seen in Figure 5 (bottom right image). It happens mostly to the big toes and thumbs and may get infected, brittle and grow slowly.

Other types of side effect include changes in hair growth, affecting both men and women, can be noticed including the hair becoming thin, dry, curly and even brittle. Bold patches or complete loss of scalp hair may as well be observed when using targeted therapy for a long time. Some drugs may even affect the colour of the hair, in addition to a change of the skin colour; the skin usually tends to turn to a yellowish shade and in rare situations hair becomes darker. These effects usually fade away as the treatment ends.

Targeted therapy may even cause damage to the clear part of the eye, which can result in injury, pain, or infection as in few people the eyelids may turn inwards or outwards as seen in Figure 5, get tender, swollen or inflamed and crusts may be seen in the eyelashes. [2] The eye itself can become dry and red and burn painfully. Problems with wound healing like the opening up of old wounds and new ones not closing, perforations, which are holes opening up in the digestive system organs, can also be observed.

Complications with bleeding and clotting because of angiogenesis inhibitors’ interference in the formation of new blood vessels can occur and result in bruising. Throwing up blood may also be a sign that the patient is facing inner bleeding in the intestines and stomach, which is very severe. These drugs may even cause clots in the lungs and legs, heart attacks and strokes – of which  symptoms include sudden swelling, pain, or tenderness in the arm or leg. These symptoms should always be reported immediately to a doctor as they may lead to death. [2]

In conclusion, targeted therapy is a very useful treatment for many types of cancer, with fewer side effects on normal, healthy cells than other therapies. [1]  Specific drugs can attack their targets in many different ways to decrease the number of cancerous cells in the body, but inevitably do lead to complications (such as blood clots). The difficulties a patient may go through because of their treatments can include rare but possibly long-term diseases [3]; however, because these techniques are still young compared with other chemo treatments, there are still many more studies to be done and improvements to be made. The very best is wished to all victims of cancer, a deadly killer, in the hope of the best use of targeted therapy to cure them.

 

By Anne-Rosa Bilal

 

 

References:

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A New Look At Pancreatic Cancer
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A New Look At Pancreatic Cancer

Inhibitory Effects of Flufenamic Acid on YAP-TEAD Activity through the Hippo Signaling Pathway in Murine Pancreatic Adenocarcinoma Cells (LTPA)

Robin Hu

Abstract

Pancreatic adenocarcinoma, accounting for about 85% of pancreatic cancer cases, has poor prognosis and survival rates; novel therapies are needed [1,2]. A core pathway in cancer development is the Hippo Signaling Pathway: a signal cascade that inhibits protein kinases such as the Yes-Associated Protein (YAP) and transcription cofactors such as TEAD, to control organ size and growth through regulation of cell proliferation and apoptosis [3,4]. Deactivation of the Hippo Signaling Pathway leads to uncontrolled cell proliferation, and hence cancer. Previous studies have identified Flufenamic Acid, an anti-inflammatory medicine, as an effective drug in modulating growth in aortic smooth muscle cells [5]. This study illustrates that Flufenamic Acid is also effective in murine pancreatic adenocarcinoma cells (LTPA cell line) by inhibiting the YAP- TEAD interactions that are key to the deactivation of the Hippo Signaling Pathway. This study confirms the efficacy of Flufenamic Acid in inhibiting YAP-TEAD activity, indicating the pathway’s direct role in cancer pathogenesis. YAP-TEAD complexes are promising molecular targets and Flufenamic Acid has clinical potential for pancreatic cancer treatment development.

Introduction

Pancreatic cancer is the fourth most common cause of death from cancer [1]. Because there are no specific, cost-effective tests that can easily and reliably detect early-stage pancreatic cancers, pancreatic cancer is difficult to diagnose [2]. Symptoms normally do not appear until later stages when the cancer has already progressed to a stage that makes the few options available impossible [2]. While more therapies and clinical studies are being implemented to improve patient outcomes and find a cure for this difficult-to-treat cancer, novel treatments are sorely needed.

The Hippo Signaling Pathway is a key signaling cascade involved in the regulation of organ size and tissue growth [3,4]. Originally discovered in Drosophila, its core protein regulators are highly conserved in mammals [4]. The pathway consists of a protein kinase cascade where the

transcription coactivators YAP and TAZ are phosphorylated, sequestered in the cytoplasm and degraded [7]. However, once the Hippo Signaling Pathway is dysregulated, YAP and TAZ are dephosphorylated and translocate into the nucleus where they interact with TEAD1-4 and other transcription factors to induce gene expression [7] (Figure 1). The YAP-TEAD heterodimer complex activates expression of transcription genes crucial for tissue growth [7].


Figure 1. The Hippo Signaling Pathway: upper half illustrates normal functioning of pathway inhibiting cell proliferation; bottom half illustrates dysregulation of pathway leading to uncontrolled growth

Flufenamic Acid is an inexpensive, non-steroidal anti-inflammatory drug (NSAID) first known to have anti-inflammatory properties in the 1960s [8]. Since then, it has been shown to act as an ion channel modulator [8]. Additionally, Flufenamic Acid has been proven effective in inhibition of cell proliferation, clonogenic activity, migratory ability and gene expression in aortic smooth muscle cells [5]. Due to the high rate of gastrointestinal side effects, Flufenamic Acid has not been used in the US. However recent research studies confirm the efficacy of Flufenamic Acid in bladder cancers in mice, re-paving the way for a new path for cancer therapy research [9].

Despite these studies, the efficacy of Flufenamic Acid against pancreatic cancer cells has not previously been researched. This study shows that rather than binding directly to the YAP binding site on TEAD transcription factors and preventing YAP from interacting with TEAD, Flufenamic Acid has a higher affinity for a separate pocket on the TEAD surface, disrupting YAP-TEAD from activating target transcription genes after YAP and TEAD have already interacted. This study examines the potential of the Hippo Signaling Pathway by targeting the YAP- TEAD complex with Flufenamic Acid and establishes a foundation for future treatment studies.

Materials and Methods

Cell culture and cell lines: The murine pancreatic adenocarcinoma cell LTPA (ATCC CRL-2389) line was purchased from American Type Culture Collection (ATCC, www.atcc.org). The cell line was cultured in EMEM media (Invitrogen/ThermoFisher, Carlsbad, CA) with 10% FBS (Invitrogen/ThermoFisher, Carlsbad, CA), 2mM glutamine (Invitrogen, Carlsbad, CA) and 100 U penicillin/0.1 mg/ml streptomycin (Invitrogen, Carlsbad, CA). Cell line was maintained at 37 °C in 5% CO2.

Antibodies and therapeutic reagents: The antibodies used include: YAP mouse monoclonal antibody 63.7 (cat. sc-101199, Santa Cruz Biotechnology, Santa Cruz, CA), Alexa Fluor 488 conjugated anti-mouse antibody G-6 (Jackson, ImmunoResearch, West Grove, PA), biotinylated goat anti-mouse IgG secondary antibody (Vector Laboratories, Burlingame, CA), and DAPI cat. D1306 counterstain (Invitrogen/ ThermoFisher, Carlsbad, CA). Flufenamic Acid was purchased from Sigma. An 320 μM stock solution of Flufenamic Acid was prepared by dissolving in DMSO (Sigma) and stored at 4 °C.

Cell viability assays: To determine percent cell viability, a WST-8 Cell Viability assay (CCK-8 Dojindo Molecular Technologies, Rockville, MD) was used. 100 μL of cell suspension (5000 cells/well) were incubated in a 96-well plate for 24 hours at 37 °C, 5% CO2.

Eight two-fold dilutions were carried out from the Flufenamic Acid stock solution and was added to each specified well with one control well containing cells with no Flufenamic Acid, and another control well containing media only. After 48 hours of continuous drug exposure at 37 °C, 10 μL of WST-8 Viability Assay Reagent (Dojindo Molecular Technologies, Rockville, MD) was added into each well and the plate was incubated for 2 hours at 37 °C. In order to calculate relative cell viability, absorbance value from the wells with WST-8 and no cells was subtracted from the absorbance values of all other wells and these values were divided by the absorbance value of the negative control wells (cells only). Values were obtained from iMark Microplate Reader. Each concentration was tested 3 times in replicate wells and average cell viability assay percentages were calculated.

Immunofluorescence: LTPA cells were fixed with 4% formaldehyde diluted in PBS for 15 minutes at room temperature and rinsed. After permeabilization with 0.1% Triton X-100 and blocking in 1% BSA in PBS for 1 hour, diluted 1:200 primary mouse YAP antibody (cat. sc 101199, Santa Cruz) was applied and incubated overnight at 4 °C. Cells were washed and incubated with Alexa Fluor 488 conjugated anti-mouse antibodies G-6 (Jackson, ImmunoResearch) diluted 1:1000 for 2 hours at room temperature in the dark. DNA was stained with DAPI counterstain cat. D1306 (Invitrogen) diluted 1:1000 in PBS. Cells were washed and mounted. Slides were analyzed using Olympus fluorescence microscope (DP 80).

Immunocytochemistry: In a 6 well plate containing cover slips, LTPA cells were trypsinized, centrifuged, and resuspended in 500 μL EMEM media with approximately 5000 cells/well. Cells were fixed onto coverslips using 400 μL of 4% formaldehyde, washed with PBS, covered with 400 μL of wash buffer and permeabilized with PBS containing 0.1% Triton X-100. After rewashing, 400 μL of blocking buffer (10% normal goat serum, 0.3% Triton X-100) was added and stored for 45 mins at room temperature before removing blocking buffer. 400 μL of diluted 1:50 YAP mouse monoclonal primary antibody 63.7 (cat. sc-101199, Santa Cruz Biotechnology, Santa Cruz, CA) was added and incubated overnight at 4 °C. Coverslips were washed and incubated for 1 hour with biotinylated goat anti-mouse IgG secondary antibody (Vector Laboratories, Burlingame, CA). Coverslips were rinsed with PBS and Streptavidin- HRP (ThermoFisher) was added to each well and incubated for 30 minutes at room temperature before washed again. DAB peroxidase substrate solution (Vector Laboratories, Burlingame, CA) was added and incubated for 5 minutes at room temperature. Samples were washed with PBS to stop development of color reaction and mounted for light microscopy analysis.

Computational Protein and Molecular Modeling: Flufenamic Acid and TEAD/YAP structures were modeled and analyzed using the UCSF Chimera Modeling Application with PDB, PubChem, and UniProt molecular codes. Druggability probability was calculated using PockDrug. PDB codes used for computational modeling: 3KYS (YAP-TEAD), 3L15 (TEAD2), 5DQ8 (Flufenamic Acid-TEAD) [16,17].

 

Results

Target-ability of YAP-TEAD complexes with Flufenamic Acid Monomer:

YAP-TEAD binding activity involves certain pocket surfaces and residue structures (Figure 2A). There are three major binding interfaces on the TEAD transcription factor structure in the YAP binding domain [13]. Interface 1 binds YAP residues 51-58 to TEAD residues 318-324; Interface 2 binds YAP residues 65-69 to TEAD residues 346-370 and 314; Interface 3 binds YAP residues 86-99 to TEAD residues 240-249, 404-406, 272-276, and 391 (Figure 2B). There are 4 possible methods of inhibiting YAP-TEAD complexes in the dysregulated pathway: inhibition at one of the three interfaces or the central pocket of the YAP binding domain.

Structural Models of YAP-TEAD binding domains:

Figure 2. YAP-TEAD complex structural models: (A) Overall structure of YAP-TEAD complex with residues labeled (B) YAP-TEAD complex with YAP outlined in blue, Interface 1 indicated in white, Interface 2 in red, Interface 3 in green, and central pocket of YAP binding domain in yellow

Druggability Probabilities of YAP Binding Domains on TEAD factors:

Two factors considered were volume of the pocket and druggability probability. The volume of the central pocket was significantly larger than the other surfaces, and thus contains more surface residues to bind an inhibiting small molecule drug (Figure 3). The druggability probability is defined as the the likelihood for a small molecule drug to bind to a pocket surface in order to inhibit protein function. Residues were matched between models created in Chimera and the TEAD2 in PockDrug in order to determine which four of the 20+ possible pockets generated on PockDrug contained the corresponding YAP binding domains in Chimera (Figure 4). The druggability probabilities of the four were formulated. The central pocket surface (Pocket 1) had the highest possible druggability probability value of 1.0 with standard deviation value of 0.0. The other three pockets had smaller druggability probabilities and larger standard deviation values.

Figure 3. Pocket Surfaces for YAP binding data: Pocket number, druggability probability value, standard deviation for the probability, volume hull, and number of residues for each pocket surface (interface area)

 

Figure 4. PockDrug (Left Panels) and Chimera (Right Panels) Structures of binding domains: Left panel contains figures of the pocket surfaces that contain YAP binding residues; Right panel contains figures of the actual surface of TEAD that binds to YAP (A) Interface (IF) 1 bright green pocket area (B) IF 1 actual YAP binding surface dark blue (C) IF 2 forest green pocket area (D) IF 2 actual YAP binding surface pink (E) IF 3 light blue pocket area (F) IF 3 actual YAP binding surface light green (G) Central Pocket dark yellow pocket area (H) Central Pocket actual YAP binding surface white

Flufenamic Acid Inhibits YAP-TEAD Function through Interface 3 or Central Pocket

The above data indicates higher potential for druggability in Interface 3 and the central pocket. Flufenamic Acid structure fits both locations when modeled in Chimera; however Flufenamic Acid more probably binds to the central pocket instead of Interface 3 based on the central pocket’s higher druggability probability and larger volume hull (Figure 5). Interface 3 has smaller volume available, 736.55, that is on the outer surface of the TEAD2 factor. This would not fit the Flufenamic Acid drug molecule structurally as effectively as a pocket surface embedded in the center of the TEAD2 factor with larger binding volume. The degree of significance of Interface 3 in Flufenamic Acid-TEAD-YAP complex binding is further researched with immunostaining processes and cell viability assay below.

Flufenamic Acid Inhibits LTPA Cell Proliferation without Disrupting YAP Expression:

Flufenamic Acid effectively inhibited LTPA cell proliferation seen in the cell viability assay results (Figure 6A). At a 160 μM concentration, approximately 52.7% of the cells survived. Among the three trials tested, this concentration had a low standard deviation of 4.15. The dose- response curve generated for the viability assay is similar to the first half of the expected backwards S-shaped curve. A top plateau, sharp decline in the middle, and approach towards a bottom plateau is seen (Figure 6B). In all three trials, cell viability noticeably decreased with Flufenamic Acid treatment, while YAP expression locations did not change.

Figure 5. Structural models of Flufenamic Acid bound to TEAD at the two potential sites: (A) Focus: Flufenamic Acid bound at Interface 3 in the cyan and magenta (B) Focus: Flufenamic Acid bound at central pocket in green and magenta (C) Surface model of Flufenamic Acid bound only at Interface 3 (D) Surface model sliced and capped of Flufenamic Acid bound only at the central pocket (E) Sequence with residues for Flufenamic Acid- TEAD2 binding at Interface 3 highlighted in cyan (F) Sequence with residues for Flufenamic Acid-TEAD2 binding at central pocket highlighted in green

Figure 6. Cell Viability Assay and Dose Response Curve: (A) Two fold dilutions of stock solution of Flufenamic Acid and % cell viability data of 3 different trials including standard deviation of overall results for each concentration (B) Dose-response curve plotting concentration with mean % cell viability and standard deviation bars and modeled mathematical equation for curve

Immunocytochemistry was performed to compare the pattern and levels of YAP in LTPA cells with and without Flufenamic Acid treatment, after observing a dramatic decrease in cell viability after treatment dropping as low as 38.57%. Increased levels of YAP in the pancreatic adenocarcinoma cells before and after Flufenamic Acid treatment are indicated by the arrowheads (Figure 7A and 7B). Pattern of staining with Flufenamic Acid treatment indicate the specific TEAD2-Flufenamic Acid binding analyzed in Discussion. Immunofluorescence was then performed to determine whether YAP remained in the cytoplasm, was translocated to the nucleus, or both, with Flufenamic Acid treatment. YAP staining is present in both but appears in higher concentrations in the nuclear area (Figure 7E and 7H). Density of YAP presence increased after drug treatment as seen by the brighter green fluorescence in the nucleus.

Figure 7. Immunostainings of YAP in LTPA cells: (A) Immunocytochemistry without Flufenamic Acid treatment- elevated patterns of YAP indicated by yellow arrows (B) Immunocytochemistry after Flufenamic Acid treatment- elevated patterns of YAP still apparent with minimal to no change (C) Immunofluorescence stain of YAP (green) in LTPA cells without Flufenamic Acid treatment (D) Immunofluorescence stain of DAPI (blue) nucleus in LTPA cells without Flufenamic Acid treatment (E) Merged image of C and D- YAP detected in LTPA cells with concentration in the nuclear areas but still maintained in the cytoplasm (F) Immunofluorescence stain of YAP (green) in cells after Flufenamic Acid treatment (G) DAPI immunofluorescence of cells after Flufenamic Acid treatment (H) Merged image of G and H- YAP expressed in both nuclear areas and cytoplasm

Discussion

Computational and structural analysis of the YAP-TEAD complex in relation to Flufenamic Acid presented two possibilities:

1) Flufenamic Acid attaches to TEAD2 at Interface 3, preventing YAP from completely binding to TEAD2 and turning off transcription.

2) Flufenamic Acid attaches to a separate site- the central pocket- and YAP still binds to TEAD2 but protein function is inhibited and transcription is turned off.

The former possibility inhibits YAP binding to TEAD2 while the latter still allows YAP-TEAD2 binding but inhibits its functioning afterwards. The latter was more probable due to the larger volume and more residues available for binding in the central pocket, in addition to its higher druggability probability.

The cell viability assay illustrated the efficacy of Flufenamic Acid in inhibiting pancreatic adenocarcinoma cell proliferation by approximately 50% with a concentration of 160 μM. The immunocytochemistry results confirmed the elevated presence of YAP and its staining pattern [10]. The immunofluorescence results elucidate the differences in nuclear and cytoplasmic retention of YAP that were not apparent from the immunocytochemistry. If Flufenamic Acid only attached at Interface 3, YAP would not bind to TEAD in the first place and increased unbound YAP would be present in the nucleus with an appreciable amount of YAP remaining in the cytoplasm. If Flufenamic Acid only attached to the central pocket, YAP would still translocate to the nucleus and bind to TEAD but transcription would not be turned on and there would be a much higher density of YAP retained in the nucleus. The concentrated clusters of YAP apparent in the nucleus from the immunofluorescence in comparison to the cytoplasm after drug treatment suggest that Flufenamic Acid interacts with the central pocket. Additionally the increase in density after drug treatment confirms the more probable dominant manner that Flufenamic Acid would act on the central pocket.

This suggests a novel role that Flufenamic Acid plays in the Hippo Signaling Pathway, preventing cancer cell proliferation in pancreatic cells. By binding to the central pocket, Flufenamic Acid inactivates proper functioning of the YAP-TEAD complexes. In turn, although this would not reverse the dysregulated pathway completely, it would assist in preventing metastasis and pancreatic cancer progression by inhibiting the unchecked cell proliferation that occurs after YAP-TEAD functioning [15]. Some other targets of the Hippo Signaling Pathway in past research include inhibition of YAP nuclear translocation, upstream regulators and YAP binding to other transcription factors [11,12]. However the small volume of space available at the YAP binding domains poses a difficulty in developing drugs that can effectively inhibit binding activity. Flufenamic Acid takes advantage of the larger and highly druggable central pocket space to inhibit YAP-TEAD in a different manner. Many common drugs and their analogs have been tested to regulate the Hippo Signaling Pathway but have failed due to limitations.

Conclusion

This study illustrates that Flufenamic Acid is effective in murine pancreatic adenocarcinoma cells by inhibiting the YAP-TEAD interactions that are key to the deactivation of the Hippo Pathway. The exact underlying mechanisms of how Flufenamic Acid acts on the pathway are poorly understood and yet to be thoroughly researched. The Hippo Signaling Pathway itself is also poorly understood in mammals. Structural analogs of Flufenamic Acid could be studied to determine how to reduce side effects by altering the drug’s mechanism of inhibiting pancreatic cancer progression or investigating a synergistic effect for more targeted inhibition in the Hippo Signaling Pathway. It’s impossible to completely rule out the possibility that Flufenamic Acid partially binds to Interface 3 to inhibit YAP-TEAD binding when the mechanisms of Flufenamic Acid and the pathway are not fully understood. However the efficacy of Flufenamic Acid points to an unresearched potential for targeting pancreatic cancer. With the growing interest in the Hippo Pathway, Flufenamic Acid is a novel avenue for future studies.

References

  1. Jemal A., Bray F., Center M. M., Ferlay J., Ward E. & Forman D. Global cancer statistics. CA Cancer J

Clin 61, 69–90 (2011).

  1. Witt H., Apte M. V., Keim V. & Wilson J. S. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 132, 1557–1573 (2007).
  2. Yu, F.X.; Zhao, B.; Guan, K.L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 2015, 163, 811–828.
  3. Zhang, L.; Ren, F.; Zhang, Q.; Chen, Y.; Wang, B.; Jiang, J. The tead/tef family of transcription factor

scalloped mediates hippo signaling in organ size control. Dev. Cell 2008, 14, 377–387.

  1. Schober W, Wiskirchen J, Kehlbach R, et al: Flufenamic acid: growth modulating effects on human aortic smooth muscle cells in vitro. J Vasc Interv Radiol. 13:89–96. 2002.
  2. Zeng Q, Hong W. The emerging role of the hippo pathway in cell contact inhibition, organ size control,

and cancer development in mammals. Cancer Cell 2008; 13: 188–192. doi: 10.1016/j.ccr.2008.02.011. pmid:18328423

  1. Hong W, Guan K-L. The YAP and TAZ transcription coactivators: key downstream effectors of the mammalian Hippo pathway. Seminars in Cell & Developmental Biology. 2012;23(7):785-793. doi: 10.1016/j.semcdb.2012.05.004.
  2. Guinamard R, Simard C, Negro CD. Flufenamic acid as an ion channel modulator. Pharmacology &

therapeutics. 2013;138(2):272-284. doi:10.1016/j.pharmthera.2013.01.012.

  1. “Flufenamic Acid Slows Spread of Bladder Cancer in Mouse Model.” Biotechdaily.com. Globe Tech

Media, 26 Oct. 2016. Web. 16 Dec. 2016. <http://www.biotechdaily.com/genomics-proteomics/articles/ 294766558/flufenamic-acid-slows-spread-of-bladder-cancer-in-mouse-model.html>.

  1. Morvaridi S, Dhall D, Greene MI, Pandol SJ, Wang Q. Role of YAP and TAZ in pancreatic ductal

adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis. Scientific Reports. 2015;5:16759. doi:10.1038/srep16759.

  1. Zhao B, Wei X, Li W, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & Development. 2007;21(21):2747-2761. doi:10.1101/ gad.1602907.
  2. Pobbati AV, Han X, Hung AW, et al. Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy. Structure (London, England  : 1993). 2015;23(11):2076-2086. doi: 10.1016/j.str.2015.09.009.
  3. Li Z, Zhao B, Wang P, Chen F, Dong Z, Yang H, Guan KL, Xu Y: Structural insights into the YAP and TEAD complex. Genes Dev 24: 235-240, 2010.
  4. Kang W, Cheng AS, Yu J, To KF. Emerging role of Hippo pathway in gastric and other gastrointestinal cancers. World Journal of Gastroenterology. 2016;22(3):1279-1288. doi:10.3748/wjg.v22.i3.1279.
  5. George NM, Day CE, Boerner BP, Johnson RL, Sarvetnick NE. Hippo Signaling Regulates Pancreas

Development through Inactivation of Yap. Molecular and Cellular Biology. 2012;32(24):5116-5128. doi: 10.1128/MCB.01034-12.

  1. Hiba Abi Hussein, Alexandre Borrel, Colette Geneix, Michel Petitjean, Leslie Regad, Anne-Claude Camproux. PockDrug-Server: a new web server for predicting pocket druggability on holo and apo proteins. Nucleic Acids Research. May 8, 2015.
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History of Arabic Alchemy
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History of Arabic Alchemy

While reading Jim Al-Khalili’s book “Pathfinders: The Golden Age of Arabic Science” it became apparent that scientific collaboration is essential to achieve meaningful progress. Great advances were made in the medical profession during the Golden Age. The Golden Age occurred during the Abbasid rule which was between the 8th century and the 12th century CE. I would like to focus on two academics, Al-Razi and Al-Zahrawi, who published a great deal of work in this period. My reading of this coincided with the recent decision for Britain to leave the EU and led me to question the potential impact this has on scientific research with regards to both funding and partnerships, which I will continue to discuss.

 

The Golden Age in Context:

Developments made within medical practises, including alchemy and the ethical progress achieved by scientists in this period are of great significance. Although the status of alchemy as a scientific discipline is disputed by modern researchers, as Al-Khalili states “there is no ambiguity about its meaning today as an irrational, pseudo-scientific belief.” [1] However, the advances made in practical techniques are considered to be a vital aspect in the development of modern day chemistry. Similarly, it is hard to ignore the impact that previous civilisations had on the development of academia throughout the Golden Age. For example, much of the initial alchemical theories were learned from Egyptian traditions which were then further developed. To distinguish Arabic science from its forerunners, I will use the same definition of Arabic science as Al-Khalili. He considers it to be science performed under the Abbasid rule and written in Arabic, the official language of the empire. Throughout the book, Al-Khalili suggests there is a greater need for widespread knowledge and appreciation of the progress made in that era.

During the Abbasid rule Baghdad became the centre of scholarship and scientific research for a range of reasons, including the construction of the House of Wisdom called the “Bayt al-Hikma” in the 8th century. It is often pointed out that during this era Europe was considered to be in the Dark Ages and experienced limited progress in comparison, further emphasising the progressive nature of the region. The Abbasid Empire was formed in 750CE. Due to its size it had contact with neighbouring regions such as India, China and the Byzantine Empire which enabled the adoption of culture and academic information. Jean Cooper in her book “Chinese Alchemy: Taoism, the Power of Gold and the Quest for Immortality” argues that trade routes and other military conquests were vital for the exchange of knowledge between various civilizations to take place. One such example is the technique for making paper taught by Chinese tradesmen that enabled cheaper production of books.

 

Al-Razi’s Impact on Arabic Science

Al-Razi, a medical alchemist, developed several practical techniques which he placed in two categories. The first included methods of melting metals with apparatus such as a hearth (kur) and crucibles (bawtaqa). The second involved the preparation of other substances and used flasks (quorua) and water baths (qudr) amongst other equipment. The first form of distillation is thought to have been developed by him using an alembic (the etymology of which is thought to go back to the Arabic “al-anbīḳ” meaning cup or beaker) although there are disagreements as to what an alembic was: “often made of glass to enable observation, but can also be ceramic or copper, and they have two palchemyarts. The bottom sits over a heat source and contains the substance to be distilled, and at the top is a bulb with a tube sloping down and out”.[2]

Al-Razi also contributed to the progress made regarding medical ethics, as he emphasised the obligation and responsibility doctors and medical professionals held to their patients and society. Several other Arabic scholars were also influential in this area, most notably Ibn Sina, sometimes referred to as the “Prince of Physicians”, who introduced a holistic approach to medicine, considering both physical and psychological aspects when treating patients. This was greatly influenced by the beliefs of Hippocrates, who produced the Hippocratic Oath for physicians to take, written between the 3rd and 5th century BC, and still used to this day.

Al-Razi also made significant progress as he published “The Book of Secrets” (Kitab al-Asrar) within which he categorizes minerals according to experimental properties and observation in a similar system to that of the modern periodic table. This was divided into metals and non-metals, which is remains to be an aspect of our periodic table.

 

Al-Zahrawi’s Impact on Arabic Science 

Another notable academic and surgeon is Al-Zahrawi who wrote several encyclopaedias such as the “Kitab al-Tasrif”, which describes the use of cauterization in surgeries to reduce tissue damage. This was widely used for amputations. Al-Zahrawi also introduced the use of catgut in surgical stitching; this is of vital importance as catgut can be absorbed by the body which prevents the need for a second surgery to remove the stitches made. Al-Zahrawi also includes observations of the effect that several compounds had on the body, such as alcohol which he observed to cause “disturbances of the liver which causes tumors and obstructions which is a definite cause of ascites and general ill health” [3] Al-Zahrawi was also an innovator in terms of patient comfort; he introduced the use of concealed knives to ensure that patients were more at ease when undergoing surgery.  As we have seen, academics had a great awareness regarding the importance for medical practises to be carried out with the patient in mind. In addition to this the profession was becoming more regulated during the Abbasid era, hospitals kept a record of patients and their treatments, and began a system for recognising qualified physicians. To become qualified one would have to be trained and have a pre-clinical period, often including the study of pharmacology or toxicology. This would lead to clinical training and finally they could specialise in a certain field of practise.

 

Impact of Arabic Science on Western Science:

The House of Wisdom was of huge value to the West, here Jabir ibn Hayyan wrote “The Great Book of Mercy” (Kitâb al-Rahma al-Kabir) which was a convergence of Greek and Indian knowledge along with some other indigenous theories. In addition to this, translators worked to translate treatises into Arabic to remove language barriers and make them more accessible. This resulted in the ability to harness previous research and build on the achievements of the Greeks, such as Zosimos of Panapolic who was writing in the 3rd Century CE. This was something utilised by Western scholars who then translated the Arabic texts into Latin so they could learn and develop them further. The House of Wisdom was built in the 8th century in Baghdad near the River Tigris which enabled relatively cheap access to paper due to trade with China along the river. This was another factor that ensured research and academic progress could flourish. The House of Wisdom and a significant number of books and academic papers were destroyed in the Mongol invasion of 1258 CE as accounts suggest they were thrown into the River Tigris. This has resulted in the Latin translations rather than the original Arabic texts remaining today.

However, there are several theories behind the etymology of a variety of words we use in science in Romance languages, and these include Arabic origins. For example “chemistry”, which is potentially derived from “kimiya”, the Arabic for “alchemy”. At a basic level, this shows some influence on the development of Western science. We can also trace back other chemical terms such as “alkali” which is thought to have come from the Arabic “al-qili” meaning ashes of the saltwort plant. Alkalis were in demand as they were required to make glass and soap, some of the first hard soap recipes being written by Al-Razi.

 

Possible Implications of Brexit on the Sharing of Scientific Knowledge:

I would like to end by bringing this discourse a little closer to home, both geographically and historically, and discuss the potential impacts of ‘Brexit’, which are still surrounded by uncertainty.

The ability to exchange theories has been crucial to scientific development. As we have seen, in the past the existence of an Empire and trade had huge benefits during the Golden Age and enabled scholars to learn from a variety of traditions. Al-Khalili emphasised the necessity of translators throughout history as they successfully removed language barriers and made information more accessible. Today these collaborations are more direct and explicit due to the improvement in technology, allowing their potential impact to be even greater.

There are several impacts of Brexit to consider. The uncertainties of Brexit itself are causing harm to research as many researchers are reluctant to accept posts in Britain until policies have been officially decided. So far, scientists have been reassured that they will continue to have access to Horizon 2020 until the current framework for EU funding changes. H2020 is a funding scheme from the EU that began in 2014 and will continue until 2020, with the aim of increasing science research within Europe by streamlining the process of accessing funds.  However, there can be no guarantee of the funding structure that will take place once H2020 has ended and a new framework has been established. One suggestion has been for Britain to become an associated country, such as Norway, however this would reduce our influence as to where funding goes because we would no longer be part of the European Council or Parliament. The funding we currently receive from bodies supported by the EU is hard to ignore; for example, in 2014 we received 24% of the European Research Council (ERC) grant, which will be hard to replenish by other means. Some believe leaving the EU will enable Britain to have greater power as to the distribution of funding which will negate the impact of its reduction, in line with the slogan “Vote Leave – Take Control.” The anti-EU supporters suggested that the £350 million a week we contribute to the EU could be directed into the areas of scientific research we require or the NHS , hence increasing our control over what our funding supports. However, as has already become evident the government is unable to guarantee additional funding for the health service among other sectors that would have supposedly benefited from leaving the EU.

There are also questions regarding freedom of movement which will affect the ability for partnerships as it will add an administrative barrier, decreasing the ease for projects such as the European Cooperation in Science and Technology (COST) which aids short-term exchanges. As a member state, we are fortunate to have access to a variety of infrastructure enabling a wide breadth of research to take place, such as the European Synchrotron Radiation Facility (ESRF) situated in Grenoble, France where funds are provided to cover travel for EU members. These relations and agreements may be time consuming to rewrite and re-establish post-Brexit, limiting Britain’s ability to remain a front-runner in research.

Another aspect to consider is the European Research Association’s (ERA) ambition to maximise research by avoiding duplication of both research projects and infrastructure which will lead to improved effectiveness. This would be made more tedious once we leave the European Parliament and other bodies.

An aspect that is not often discussed is the European Health Insurance Card, another feature currently in place to make travel, and hence partnerships, easier and more efficient.  It remains to be seen what will become of science funding, and collaboration, but I believe isolating ourselves from the valuable knowledge and infrastructure would be unwise. We can see how much Arabic scientists gained from previous research and civilisations and the great effect this then had on medicine and science after the fall of the Abbasid Empire from the introduction of medical records to the numerous treatises that were then translated into Latin. Some of al-Razi’s treatises were being used as late as the 19th century CE.  James Wilsdon from the University of Sheffield told Buzzfeed, “I think there will be a brain drain”[4], but it remains to be seen what the outcome and agreements of leaving will be.

 

References

Dow, Travis J. “Jabir ibn Hayyan (Geber).” History of Alchemy. July 6, 2013. Accessed April 22, 2017. http://historyofalchemy.com/list-of-alchemists/jabir-ibn-hayyan-geber/.

“The Abbasid Dynasty”. Saylor Academy. Accessed April 22, 2017. http://www.saylor.org/site/wp-content/uploads/2012/07/HIST101-9.3.1-AbbasidDynasty-FINAL.pdf·

Bengoechea, Isabella. “Iraq’s Golden Age: The Rise and Fall of The House of Wisdom”. Culture Trip. http://www.saylor.org/site/wp-content/uploads/2012/07/HIST101-9.3.1-AbbasidDynasty-FINAL.pdf.

Syed, Ibrahim B. PhD. “Islamic Medicine: 1000 years ahead of its times” Published February 2002. Accessed April 22, 2017. http://www.ishim.net/ishimj/2/01.pdf

Samir S. Amr, Arab and Muslim Physicians and Scholars, 2007·

Majeed, Azeem. “How Islam Changed Medicine”. PubMed Central. Published 24 December 2005. Accessed April 22, 2017.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1322233/

Royal Society of Chemistry. “The Relationship between EU Membership and the Effectiveness of Science, Research and Innovation in the UK”. Published  November 2015.  http://www.rsc.org/globalassets/04-campaigning-outreach/policy/research-innovation/eu-membership-uk-science-consultation.pdf

[1] Al-Khalili, Jim. “Pathfinders: The Golden Age of Arabic Science”, page 51, Penguin Books, Published 2010

[2]Massey, Laura. “What’s an Alembic: Alchemy, the History of Science and our Logo” Published 2016 https://alembicrarebooks.com/blogs/alembic-rare-books-blog/94965830-whats-an-alembic-alchemy-the-history-of-science-our-logo

[3] Awadain, M. Reda. “A Recent Look and Study of Some Papers of al-Zahrawi’s Book “al-Tasrif”.” IslamSet. N.p.. Web. Published 16 Dec 2012

[4] Vence, Tracey. “Brexit’s Effects on Science” Published 2016. http://www.the-scientist.com/?articles.view/articleNo/46415/title/Brexit-s-Effects-on-Science/

anosh01
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How Positron Emission Tomography works

This post aims to explain what positron emission tomography (PET) is and how it works.

PET is a unique type of medical imaging that reveals information about the physiology of organs and tissues, unlike CT or MRI machines which only yield images of anatomy. By doing this, PET scans can often detect irregularities such as cancer significantly earlier than other diagnostic tests. The scan works by injecting a radioactive tracer into the patient which is taken up in different parts of the body by varying amounts; the positron decay of the tracer is detected and an image of the body is reconstructed from this data. A specialised radiologist looks at these images and forms a diagnosis.

Synthesis of radiotracers:

The radiotracers used in a PET scan are synthesised in a cyclotron. The synthesis of radiotracers can be summarised into two stages: firstly a radioactive isotope with a short half-life is created by proton bombardment, and then this radioisotope is chemically incorporated into a biological molecule. The radioactively labelled biological molecule is taken up by the body, and higher concentrations of it show up as hot spots on the scan. The most commonly used radiotracer in PET is fluorodeoxyglucose[1] (FDG), for which this article will mainly be focussed on.

~CyclotronDiagram showing how a cyclotron works.

The purpose of a cyclotron in PET is to create a β+ (positron) emitting radioisotope that has a short half-life that can be substituted quickly into a molecule such as glucose. A cyclotron achieves this by accelerating protons to bombard a stable target isotope.

A cyclotron works on the principle of using the magnetic force to bend moving charges[2] (protons in our case). It consists of two metal ‘dees’ separated by a gap that has a rapidly reversing electric field across it. When a proton is placed near the centre, it accelerates away from the electric field in the centre. The electric field is then reversed, so the proton turns back on itself and accelerates back towards the centre – this reversing of the electric field repeats itself, and each time the proton gains more kinetic energy[3]. Once the proton has sufficient kinetic energy to enter the nucleus of the target, it is released out of its spiral and bombardment occurs.

DeesAerial view of the two ‘dees’

For FDG synthesis, the target used is enriched water (H218O). Protons accelerated by the cyclotron knock and replace neutrons from the isotope of oxygen, forming radioactive F-18:

image005

Since the half-life of F-18 is only 110 minutes, it has to be incorporated into glucose to form FDG very quickly. This is done via a complicated chemical process that is usually automated[4]. The end product, FDG is identical to glucose, except that the second OH group has been replaced by the radioactive F-18 made in the cyclotron:

image008 image009

Skeletal formula of FDG (bottom) and glucose (top). The second OH group is replaced by radioactive F-18.

Decay and distribution of FDG:

When FDG taken up into a cell, it is phosphorylated into FDG-phosphate[5], and this molecule cannot be broken down further, so is therefore trapped in the cell. Cancerous cells divide much faster than normal body cells, so their energy needs are much higher. This means that more FDG would be taken up by a cancer cell as compared to a normal cell; resulting in a hot spot on the scan.

Atoms decay when the ratio of protons to neutrons in the nucleus is skewed – a proton enriched nucleus like in F-18 would try to lose its extra proton to become O-18. It does this by positron emission:

image012

Essentially, a proton in the nucleus of F-18 turns into a neutron, releasing a high-speed positron (β+) and a neutrino (read up on the weak interaction to find out more). When this decay is complete, the FDG becomes glucose-phosphate, which can be metabolised normally[6].

Annihilation and Detection:

A positron is the anti-matter match to an electron – it has identical properties but an opposite charge. This means that when an electron and a positron meet, they annihilate and their combined mass is completely converted into energy; i.e. high frequency photons. Since momentum is always conserved in collisions, the two photons produced must travel 180 degrees apart in opposite directions.

image014

Image credit: astronomy.swin.edu.au

The positron emitted from the decay of FDG usually meets and annihilates an electron within a very short distance (usually much smaller than 1mm)[7]; this distance has little effect on the accuracy of the scan.

In a PET machine, the photons emitted by the positron-electron are sensed by multiple rings of detectors that surround the object being scanned. These detectors are comprised of two parts; a scintillator crystal optically coupled to a photomultiplier tube (PMT)[8].

As a high energy photon from annihilation passes through the scintillator, it interacts with an electron in one of the atoms of the crystal, energising it according to the photoelectric effect. This excited electron (known as a photo-electron) moves through the scintillator, exciting many other electrons in the process and causing them to ‘jump’ energy levels. When these electrons return to their ground state, they re-emit the absorbed energy as even more photons. The photons produced by the scintillator are then converted into an electrical signal by the PMT, which is processed by a computer in order to form an image.[9]

image015Image credit: ILC-Sefuri

Image Reconstruction:

The annihilation of a positron and electron result in two photons being emitted at the same time and energy at 180 degrees apart. In effect, this does not always happen due to scattering and attenuation of photons as well as the time lag inherent in most scintillator detectors. Therefore parameters for time difference and energy of two photons detected are decided – if a pair of photons meet these criteria, it is assumed that they came from the same annihilation (termed as a ‘coincidence’)[10]. A line of response (LOR) is drawn between where the two photons are detected; somewhere along this line an annihilation occurred (assuming it is a true coincidence).

image017

Diagram showing LOR and coincidences. Credit: depts.washington.edu

One method for forming an image from this data is to back-project from where signals were detected in order to determine a space in which higher concentrations of annihilation reactions would have occurred:

image019

Each shaded line represents a LOR between two detectors. (Image Credit: depts.washington.edu)

Points where more LOR’s intersect are shown up as hot spots on the scan where higher concentrations of the tracer are (cancerous and rapidly dividing cells when using FDG).[11]

However, the image formed by doing this is two-dimensional, to form a 3D image many of these cross-section images are taken and stacked onto each other.

In reality, this method of image reconstruction is not so simple – complicated computer programs are employed in order to mitigate the inaccuracies caused by scattering, absorption of photons, and other sources of error. Despite this, the back-projection method often produces noisy images. Better ways of reconstructing images are constantly being developed; some involve measuring the difference in time-of-flight between coincident photons in order to extrapolate their origin, others relying on iterative reconstruction techniques. [12]

Since PET images do not provide as much anatomical detail as other imaging techniques, they are often used in conjunction with a CT scan. These images are superimposed onto each other to give more precise information and therefore a more accurate diagnosis.

image020

Image showing a PET scan, a CT scan, and a PET/CT scan from left to right. The orange and green areas represent high concentrations of tracer. Credit: SEELA, UCLA

Conclusion:

PET’s major drawbacks are its expense and poor resolution compared to CT or MRI scans. The requirement of an on-site cyclotron to produce radioisotopes and facilities to incorporate them into biological molecules mean that PET is incredibly expensive. The poor resolution of PET also means that irregularities less than 1mm are not usually detected; although this disadvantage is lessened by the development of PET/CT.

PET’s greatest strength lies in its versatility. There are many different tracers that can be used in order to measure a range of activity such as blood flow, oxygen usage, tissue pH, and cell metabolism. For example, a radioactive oxygen tracer is used to measure blood flow in the brain, allowing for various neurological diseases such as Alzheimer’s, Parkinson’s, and epilepsy to be investigated. This information about physiology of the body often enables a diagnosis to be formulated much earlier than with other medical scans. In addition, it allows for physicians to assess the effectiveness of certain treatments such as chemotherapy. However, the largest application of PET is in detecting and differentiating malignant from benign cell growths, meaning early detection and therefore higher chances of survival in cancer patients.

[1] cancerquest.org

[2] hyperphysics.phy-astr.gsu.edu

[3] webphysics.davidson.edu

[4] Radionuclides: Guidance on Facility Design and Production of [18F]Fluorodeoxyglucose (FDG) – International Atomic Energy Agency

[5] med.harvard.edu

[6] med.harvard.edu

[7] Michael E. Phelps (2006). PET: physics, instrumentation, and scanners

[8] med-ed.virginia.edu

[9] Introduction to PET Physics, Section 5 – Ramsey Badawi – depts.washington.edu

[10] med-ed.virginia.edu

[11] owlnet.rice.edu

[12] Tomographic Image Reconstruction. An Introduction. – Milan Zvolský (Lecture)

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Sudden Cardiac Arrest in Young Athletes

Sudden Cardiac arrest in the young may seem uncommon (2 deaths per 100,000 people) but is a fatal end for many passionate athletes. These tragedies appear to be unexpected as they are asymptomatic leading fans and spectators to wonder how a perfectly ‘healthy’ football player could suddenly collapse.

Athletes under the age of 35 predominantly have structural heart disease. This means that the defect or deformity is inherited or congenital. Whilst athletes over the age 35 usually have ischemic heart disease, meaning that the blood supply to their heart muscles is reduced.

According to a large study on 1866 deaths among athletes in the USA the most frequent causes are:

Hypertrophic Cardiomyopathy (HCM)

This is when the heart muscle (myocardium) becomes abnormally thick (hypertrophied) subsequently causing a difficulty for the heart to pump blood. Abnormal inherited genes usually cause the disease. Along with HCM these genes cause an abnormal arrangement of heart muscle cells called myofibre disarray. This disarray of muscle cells can lead to arrhythmia (abnormal heart beat) in some people. The majority of people with HCM have a form of the disease in the septum between the ventricles causing it to become enlarged and impede blood flow out of the heart (this condition can be called obstructive hypertrophic cardiomyopathy). Occasionally the HCM occurs without significant blockage of blood flow, nevertheless the left ventricle may become stiff. This limits the amount of blood the ventricle can hold and consequently the amount of blood pumped out to the body with each heartbeat (this condition can also be called non-obstructive cardiomyopathy)

image

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
This is a disorder causing the myocardium to break down over time, increasing the risk of arrhythmia and sudden death.
ARVC is a result of the mutation of at least 8 genes. The majority of these genes are involved in the function of desmosomes (structures that connect muscle cells to one another). Desmosomes strengthen the myocardium and contribute to signaling between neighboring cells.
The mutations in the genes that result in ARVC often disable the desmosomes causing the muscle cells to detach from one another and subsequently die, especially when the heart muscle is under stress such as during vigorous exercise. The damaged myocardium (around the right ventricle) is gradually replaced by fat and scar tissue, which in turn stretch the wall of the ventricle preventing the heart from pumping blood normally. These changes can also alter the electrical signals that regulate the heartbeat, which can lead to arrhythmia. This arrhythmia may also lead to ion channelopatheis meaning that the muscle fibers no longer function normally due to an abnormal amount of ions.

Dilated Cardiomyopathy

This disease affects both the hearts ventricles and atria. It often begins in the left ventricle (the hearts main pumping chamber) and is when the myocardium begins to stretch and become thinner (dilate). This causes the chamber to enlarge meaning that the heart can no longer contract normally, thus cannot pump blood very well. Over time the problem usually spreads to the right ventricle and eventually the atria as the problem worsens. Furthermore the heart becomes weaker and the probability of heart failure increases exponentially. Dilated cardiomyopathy may also lead to heart valve problems, arrhythmias and blood clots in the heart caused by stagnant blood.

image

Wolff-Parkinson-White Syndrome
Those with this congenital syndrome have an extra electrical pathway between their atria and ventricles, which results in a rapid heartbeat (tachycardia).
A normal heart possesses a sinus node (a mass of tissue in the right atrium) that produces electrical impulses that generate a heartbeat. These electrical impulses pass across the atria resulting in muscle contractions that pump blood in the ventricles. The impulses then arrive at a cluster of cells known as the atrioventricular node (AV node), this is the only bridge for the signals to travel from the atria to the ventricles. The AV node slows down the signal before passing it to the ventricles, this in turn creates a slight delay which allows the ventricle to fill with blood. Eventually when the electrical impulses reach the ventricle, muscle contractions pump the blood to the rest of the body.
However the heart of a person affected by WPW has an extra electrical pathway between the atria and ventricles, allowing the electrical impulses to bypass the AV node. When the electrical impulses travel through the extra pathway they are not slowed down thus the ventricles are activated too early (pre-excitation).
-Looped electrical impulses – In WPW the heart’s electrical impulses travel down one pathway and up another. This results in an electrical loop of signals called AV reentrant tachycardia, which sends impulses to the ventricles at a rapid rate causing them to pump very quickly, causing rapid heartbeat.
-Deorganized electrical impulses – If the electrical impulses don’t begin correctly in the right atrium, they may cross the atria in a disorganized way. This results in the atria beating quickly and not in time with each other (atrial fibrillation). These disorganized signals coupled with an extra pathway can cause ventricles to beat faster subsequently not allowing enough time for the ventricles to fill up with blood. As a result not enough blood is pumped to the body.

HCM, ARVC and DCM can all be diagnosed using a magnetic resonance imaging (MRI) scanner. Additionally WPW syndrome can be detected using an electrocardiography (ECG).

In conclusion all these conditions are diagnosable and the many sudden deaths caused by them could have been avoided if thorough cardiac screening was given to these athletes.

http://www.mayoclinic.org/diseases-conditions/hypertrophic-cardiomyopathy/symptoms-causes/dxc-20122103

http://ghr.nlm.nih.gov/condition/arrhythmogenic-right-ventricular-cardiomyopathy

http://www.heart.org/HEARTORG/Conditions/More/Cardiomyopathy/Dilated-Cardiomyopathy_UCM_444187_Article.jsp#.Vl4ZAGThAy4

http://www.mayoclinic.org/diseases-conditions/wolff-parkinson-white/basics/causes/con-20043508

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PCSK9 Inhibitors – a solution for familial hypercholesterolaemia and ischaemic heart disease?

PCSK9 stands for Proprotein Convertase Subtilisin Kexin type 9 and it was first discovered in 2003[1] by Dr. Seidah et al. and it is a 692-amino acid glycoprotein.[2] PCSK9 is secreted by the liver into the circulation[3] and it controls the “number of low-density lipoprotein receptors (LDLR) on the cell surface”[4] and therefore ultimately the amount of LDL cholesterol (LDL-C) in the blood. This is because “PCSK9 can increase levels of LDL cholesterol by decreasing the availability of LDL receptors.”4

Normally a “low-density lipoprotein (LDL) binds to the LDL receptor on the hepatocyte surface”4 where they both then “enter the cell via endocytosis”4 and after that the “LDL receptor dissociates from the LDL and returns to the cell surface”4 in order to bind to more LDL-C particles. Then the “LDL-C is degraded within a lysosome into its protein and lipid components.”4 “The receptor repeats the 10-minute cycle hundreds of times during its 20-hour lifespan”4 lowering the LDL-C levels in the blood. However the process is altered ever so slightly if PCSK9 is present. When PCSK9 is present the PCSK9 protein binds to the LDL receptor along with the LDL molecule and this causes the LDL receptor to be unable to dissociate from the LDL and return to the cell surface of the liver cell. Consequently, it is broken down by the lysosome along with the LDL molecule. This lowers the number of LDL receptors on the cell surface and therefore increases the concentration of LDL-C in the blood.4 In other words the presence of PCSK9 prevents the LDL receptor from escaping the lysosome and so it is also broken down resulting “in decreased numbers of LDLR available on the hepatic cell surface to bind LDL particles and remove them from the circulation and therefore to a subsequent increase in circulating LDL-cholesterol plasma levels.”[5]

However there can be mutations in PCSK9 which can either lead to a gain of function or a loss of function. “Loss of function mutations lead to higher levels of the LDL receptor and lower LDL cholesterol levels.”[6] Basically, a loss of function mutation causes less PCSK9 to be produced. Therefore there are more LDL receptors as they aren’t broken down due to them being able to dissociate from the LDL and return to the hepatocyte (liver cell) surface. This causes a low level of LDL cholesterol to be found in the blood which is “associated with reduced risk of coronary heart disease.”[7] Gain of function mutations cause too much PCSK9 to be produced and “gain of function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma.”6 Essentially, a gain of function mutation (which results in hypercholesterolemia[8]) increases the effect of PCSK9 expressed making it much more effective as more LDL receptors are degraded – as they can’t dissociate from the LDL-C and so they are broken down – therefore more cholesterol is left in the blood and not removed from circulation. For example “the most powerful PCSK9 gain-of-function mutation, D374Y, is responsible for LDL cholesterol levels of ~10 mmol/L versus ~3 mmol/L in normal subjects.”[9]                                                          

Hypercholesterolemia “is a condition characterised by very high levels of cholesterol in the blood”[11] and it is “caused by mutations in the LDLR gene.”[12] These “mutations in the LDLR gene cause an inherited form of high cholesterol called familial hypercholesterolemia”12 which is an autosomal dominant genetic condition meaning if a person has familial hypercholesterolemia there is a 50% chance of passing it onto their child.[13] There are three types of familial hypercholesterolemia (FH): heterozygous FH, compound heterozygous FH and homozygous FH. Heterozygous FH is the most common type and “recent studies indicate that heterozygous FH may affect 1 in 200-250 people.”13 Compound heterozygous FH is where “a child inherits two different types of mutations in FH-causing genes from its parents. This usually leads to a more severe form of FH with higher cholesterol levels.”13 Finally homozygous FH, which is rare, is where “a child inherits the same mutation in FH-causing genes from each parent.”13 Homozygous FH causes such high cholesterol levels that “sudden death from heart attack is common in childhood or adolescence.”13 Globally “there are an estimated 14-34 million people living with FH.”13 It is the “most common genetic condition in the world.”13

An average person has a cholesterol level of about 4.5-6 mmol/l whereas people with heterozygous FH have an approximate LDL-C level of 7.5-12 mmol/l and sufferers of homozygous FH are in the range of 15-30 mmol/l.13

High LDL-C concentrations are dangerous because it can lead to heart disease which “kills more people in the UK than any other disease.”[14] Cholesterol, which is a waxy fat-like substance,  is produced in the body by the liver and can lead to the creation of an atheroma (“a fatty deposit that forms within the wall of an artery.”14) An atheroma restricts blood flow by narrowing the lumen of the artery. This then increases the likelihood of a thrombus forming, which is a blood clot, and this prevents blood flowing through the blood vessel. If a thrombus occurs in a coronary artery (an artery which provides the heart muscle with blood and therefore oxygen and glucose) then the heart muscle will be unable to respire and it would lead to the heart muscle dying and the person would have a heart attack – a myocardial infarction.

Thus, in order to reduce the number of people with high cholesterol levels and hence lower the number of deaths due to ischaemic heart disease the amount of PCSK9 needs to be lowered or removed entirely. Inhibiting PCSK9 would be the way to do that and a few drugs have been developed recently that are able to inhibit PCSK9.

“There are thought to be around 20 PCSK9 inhibitors in development but the two frontrunners are Amgen’s Evolocumab (Repatha) and Regeneron/Sanofi’s Alirocumab (Praluent.)”[15] Evolocumab and Alicorumab, like other PCSK9 inhibitors, are monoclonal antibodies[16] and “are administered subcutaneously”[17] and they need to be “self-injected every two weeks.”[18]

Recent studies for the “efficacy and safety of Evolocumab”[19] used 4465 patients to further test Evolocumab. These patients received either a 140mg dosage every two weeks or a 420mg monthly dose of Evolocumab and the “patients were followed for a median of 11.1 months.”19 The results showed that “Evolocumab reduced the level of LDL cholesterol by 61% from a median of 120mg per decilitre to 48mg per decilitre.”19 The FDA (Food and Drug Administration) will have made their decision on whether Evolocumab should be approved by August 27th 2015.[20]

Similarly, Alirocumab has been recently tested and The New England Journal of Medicine states that “2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per decilitre (1.8 mmol per litre) or more and were receiving treatment with statins at the maximum tolerated dose”[21] have been involved in the trial. They also said that the “patients were randomly assigned in a 2:1 ratio to receive Alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks.”21 The results showed that “the difference between the Alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62 percentage points; the treatment effect remained consistent over a period of 78 weeks. The Alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).”21 The verdict for Alirocumab will have been made by the FDA by July 24th 2015.[22]

Overall, both inhibitors approximately lower “LDL cholesterol levels up to 65%.”[23] However, these inhibitors which have been called “one of the biggest developments in a long time in cardiology” by Steve Nissen, the chairman of cardiovascular medicine at Cleveland Clinic[24] would be a very expensive treatment. It is estimated to cost anywhere “from $7,000 to $12,000 per patient annually”[25] and this medication is speculated to “cost the U.S Healthcare system as much as $23 billion a year.”25 On the other hand “analysts predict Evolocumab and Alirocumab could each generate annual sales of over $1 billion by 2020.”[26]

Is the potential to cure ischaemic heart disease, which according to the WHO (World Health Organisation) is the largest cause of death in the world,[27] worth the colossal price tag of these PCSK9 inhibitors when there are current treatments, far cheaper treatments, which work extremely well like statins? Furthermore, the long term effects of these drugs are unknown and so are they really needed?

First of all “even when treated with potent statins, many patients fail to achieve LDL-cholesterol targets and therefore their risk of accelerated atherosclerosis and cardiovascular death remains high.”[28] When 9950 coronary artery disease patients were looked at “only 37% on a statin alone achieved an LDL-cholesterol of <70 mg/dL, and most were on moderate-to-high-potency statins”[29] with <70 mg/dL being the “recommended LDL-cholesterol goal.”29 Furthermore, some patients are unable to take the required high doses of statins necessary to lower their LDL-C levels as a result of side effects[30] most notably muscular symptoms such as myalgia (muscle pain.)[31] Additionally, not only are PCSK9 inhibitors being looked into for reducing the risk of coronary heart disease but “very recent data revealed that the absence of PCSK9 can be protective against melanoma invasion in mouse liver, and that this is due to lower circulating LDL-C.”9 This “opens the door to novel applications of PCSK9 inhibitors/silencers in cancer/metastasis.”9

In conclusion, PCSK9 inhibitors seem to be a very effective treatment for individuals with a high risk of heart disease due to exceedingly high cholesterol levels. They are able to lower the LDL-C concentrations of individuals who aren’t able to reach their safe and recommended levels using statins and they will save countless lives by preventing death from ischaemic heart disease and hypercholesterolemia. Therefore, I believe that PCSK9 inhibitors such as Evolocumab and Alirocumab are effective solutions to familial hypercholesterolemia and ischaemic heart disease.

 

References:

[1] Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia, Nature Genetics 34, 154-156, (2003).

[2] http://www.hindawi.com/journals/scientifica/2012/927352/

[3] http://www.eas-society.org/the-pcsk9-decade-what-will-the-future-hold.aspx

[4] http://cholesterolmatters.com/en/what-is-pcsk9.html

[5] http://www.ncbi.nlm.nih.gov/pubmed/25470376

[6] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386899/

[7] http://www.ncbi.nlm.nih.gov/pubmed/16554528

[8] http:[email protected][email protected][email protected]/documents/downloadable/ucm_438651.pdf

[9] http://www.ncbi.nlm.nih.gov/pubmed/23317404

[10] http://cholesterolmatters.com/en/pcsk9-mutation.html

[11] http://ghr.nlm.nih.gov/condition/hypercholesterolemia

[12] http://ghr.nlm.nih.gov/gene/LDLR

[13] http://www.pcsk9forum.org/about-pcsk9/who-could-benefit-from-pcsk9-inhibitors/

[14] Glenn Toole, Susan Toole, AQA Biology AS. (Nelson Thornes, Cheltenham, 2008), p.94

[15] http://www.pharmaceutical-journal.com/news-and-analysis/features/pcsk9-inhibitors-the-next-cholesterol-lowering-blockbusters/20068181.article

[16]http://www.health.harvard.edu/blog/pcsk9-inhibitors-a-major-advance-in-cholesterol-lowering-drug-therapy-201503157801

[17] http://consultqd.clevelandclinic.org/2014/05/pcsk9-inhibitors-show-promise-where-statins-fall-short/

[18] www.vox.com/2015/6/11/8762211/new-cholesterol-drugs

[19] http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500858

[20] http://www.drugs.com/slideshow/pcsk9-inhibitors-a-new-option-in-cholesterol-treatment-1166#slide-7

[21] http://www.nejm.org/doi/full/10.1056/NEJMoa1501031

[22] http://www.drugs.com/slideshow/pcsk9-inhibitors-a-new-option-in-cholesterol-treatment-1166#slide-8

[23]  http://time.com/3915461/cholesterol-drug-heart-disease/

[24]http://www.washingtonpost.com/news/to-your-health/wp/2015/06/08/could-these-new-cholesterol-drugs-save-many-americans-from-heart-attacks/

[25] http://blogs.wsj.com/pharmalot/2015/06/09/how-much-those-new-cholesterol-drugs-could-cost-23-billion-a-year/

[26] http://www.drugs.com/slideshow/pcsk9-inhibitors-a-new-option-in-cholesterol-treatment-1166#slide-11

[27] http://www.who.int/mediacentre/factsheets/fs310/en/

[28] www.pcsk9forum.org/about-pcsk9/what-are-pcsk9-inhibitors/

[29] http://www.hindawi.com/journals/cholesterol/2012/861924/

[30] http://www.pcsk9forum.org/about-pcsk9/why-are-new-treatments-needed/

[31] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138147/

 

 

 

 

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Hypoplastic Left Heart Syndrome

What is Hypoplastic left heart syndrome?

Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect which occurs in approximately 1 in 5000 babies. The term ‘hypoplastic’ refers to the underdevelopment of a tissue or an organ. Therefore HLHS involves the underdevelopment, or sometimes absence, of left-sided heart structures. For example, the left ventricle, left atrium, bicuspid valve or the aorta could potentially be really small.

This ultimately results in the left side of the heart not functioning properly. Furthermore, an atrial septal defect (a hole between the atria – the top two chambers of the heart) is normally present.

Oxygenated blood is normally pumped to the body via the contraction of the left ventricle. However, in HLHS the left ventricle may be so underdeveloped that it is incapable of pumping blood around the body.

Cause:

The cause for HLHS is unknown, however, it is mostly down to genetic factors caused by mutations to genes in chromosomes. Environmental factors such as: what medication was taken by the mother, or what she ate or drank and what she came into contact with whilst pregnant may also play a significant part in the development of this condition.

Signs and Symptoms:

  • Cyanosis (blue skin colour)
  • Difficulty breathing and/or fast breathing
  • Heart Murmur
  • Tiredness
  • Poor feeding
  • Cold hands and feet
  • Pounding heart
  • Weak pulse

Diagnosis:

HLHS is commonly diagnosed before birth during an ultrasound. If the doctor believes that there is an issue associated with the heart then a foetal echocardiogram (an ultrasound of the heart) would be requested and this would lead to the discovery of HLHS.

However, it may not be diagnosed before birth and upon seeing the noticeable symptoms or upon hearing a heart murmur an echocardiogram would be carried out and this would show that it’s Hypoplastic Left Heart Syndrome (due to the small or non-existent left sided features.)

Treatment:

To treat HLHS the new-born would immediately need prostaglandin. This medication prevents the ductus arteriosus from closing. This is very important as the ductus arteriosus connects the pulmonary artery to the aorta which allows oxygenated blood to be sent to the rest of the body. If it closed in an infant with HLHS then it would die due to the body being unable to receive oxygenated blood as the only route to the aorta and thus the body is the ductus arteriosus, unless an atrial septal defect was present.

Surgery would be essential in order for the survival of the child. In fact, three surgeries would be needed:

  1. Norwood Procedure – This open heart operation is carried out straight after the diagnosis of HLHS and this is usually around the first few days of the child’s life. It involves stopping the heart and allowing a machine, called a heart-lung machine, to perform the role of the heart. The surgeon enlarges the aorta – using a patch – and disconnects the pulmonary artery from the right ventricle and connects the aorta to the right ventricle instead. This now allows the right ventricle to pump blood around the body instead of the hypoplastic left ventricle. To allow deoxygenated blood to reach the lungs a shunt (made of Gore-Tex) is created joining the new aorta to the pulmonary artery. Essentially, the right ventricle now performs the job of both ventricles as it pumps blood to both the body and lungs. Therefore, the heart is now relying on a single ventricle. This surgery is extremely challenging and very long. It can take approximately six hours to complete. The survival rate is about 80% and the child can normally go home after 3-4 weeks. However, in some cases (e.g in very small babies) the Norwood Procedure isn’t suitable and instead the Hybrid procedure is preferred. This consists of keeping the ductus arteriosus open using a stent and making the atrial septal defect larger (which would allow blood to enter the aorta and to be sent to the body) and finally placing small bands on the pulmonary arteries which reduces the amount of blood flowing in them and thus protecting the lungs. This operation is usually 1-2 hours long and doesn’t require a heart-lung bypass machine. Cyanosis would still occur after either of these surgeries due to the mixing of oxygenated and deoxygenated blood still taking place.
  2. Bi-directional Cavo-Pulmonary Shunt Procedure – This second operation is undertaken when the child is between three to twelve months of age. The aim of this operation is to reduce the workload of the right ventricle. This is done by connecting the superior vena cava directly to the pulmonary artery. This improves the quality of life for the patient as the heart doesn’t have to work as hard as deoxygenated blood returning from the upper part of the body goes straight to the lungs via the pulmonary artery. This also is better for the lungs as they now receive blood at lower venous pressures rather than much higher arterial pressures. The shunt added in the Norwood Procedure is then removed. The child will still have a blue appearance even though deoxygenated blood from the upper part of the body no longer mixes with oxygenated blood in the right ventricle. This is due to the mixing of deoxygenated blood from the lower part of the body and the oxygenated blood in the right ventricle.
  3. The Fontan Procedure – This is the final stage and it takes place when the infant is between 18 months and four years of age. The purpose is to finally stop the mixing of deoxygenated and oxygenated blood which leads to partially oxygenated blood and therefore cyanosis. This is achieved by connecting the inferior vena cava, which brings deoxygenated blood from the lower part of the body, to the pulmonary artery. The right ventricle no longer has to pump blood to both the lungs and the rest of the body. It only has to send it to the body which was meant to have been done by the left ventricle.

Future of the child:

Even with all of these surgeries the child will still not be cured of HLHS and a heart transplant may be necessary. However, infant hearts are rarely obtainable and so one may not be available for the child. If they are able to receive a donated infant heart then they will have to take anti-rejection medication for the rest of their lives and this will severely weaken their immune system.

Even if the surgeries go well complications may develop which include:

  • Fluid in the lungs (pleural effusion)
  • Heart failure
  • A fast and irregular heart rhythm (arrhythmia)
  • Stroke
  • Problems of the development of the brain and nervous system
  • Easily becoming tired and breathless during exercise
  • Endocarditis
  • Death

Every patient would also need to regularly visit a cardiologist who would look out for any  of these complications.

Bibliography:

http://www.cdc.gov/ncbddd/heartdefects/hlhs.html

http://www.gosh.nhs.uk/medical-information/search-medical-conditions/hypoplastic-left-heart-syndrome

https://www.bhf.org.uk/~/media/files/publications/children-and-young-people/c9understanding-your-childs-heart-hypoplastic-left-heart0210.pdf

https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome

http://www.mayoclinic.org/diseases-conditions/hypoplastic-left-heart-syndrome/basics/definition/con-20031294

http://www.childrenshospital.org/conditions-and-treatments/conditions/hypoplastic-left-heart-syndrome-hlhs

http://www.cincinnatichildrens.org/health/h/hlhs/

https://www.nlm.nih.gov/medlineplus/ency/article/001106.htm

http://www.lhm.org.uk/info/hypoplastic-left-heart-syndrome-44.aspx

 

 

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Hypoplastic Left Heart Syndrome

What is Hypoplastic left heart syndrome?

Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect which occurs in approximately 1 in 5000 babies. The term ‘hypoplastic’ refers to the underdevelopment of a tissue or an organ. Therefore HLHS involves the underdevelopment, or sometimes absence, of left-sided heart structures. For example, the left ventricle, left atrium, bicuspid valve or the aorta could potentially be really small.

This ultimately results in the left side of the heart not functioning properly. Furthermore, an atrial septal defect (a hole between the atria – the top two chambers of the heart) is normally present.

Oxygenated blood is normally pumped to the body via the contraction of the left ventricle. However, in HLHS the left ventricle may be so underdeveloped that it is incapable of pumping blood around the body.

Cause:

The cause for HLHS is unknown, however, it is mostly down to genetic factors caused by mutations to genes in chromosomes. Environmental factors such as: what medication was taken by the mother, or what she ate or drank and what she came into contact with whilst pregnant may also play a significant part in the development of this condition.

Signs and Symptoms:

  • Cyanosis (blue skin colour)
  • Difficulty breathing and/or fast breathing
  • Heart Murmur
  • Tiredness
  • Poor feeding
  • Cold hands and feet
  • Pounding heart
  • Weak pulse

Diagnosis:

HLHS is commonly diagnosed before birth during an ultrasound. If the doctor believes that there is an issue associated with the heart then a foetal echocardiogram (an ultrasound of the heart) would be requested and this would lead to the discovery of HLHS.

However, it may not be diagnosed before birth and upon seeing the noticeable symptoms or upon hearing a heart murmur an echocardiogram would be carried out and this would show that it’s Hypoplastic Left Heart Syndrome (due to the small or non-existent left sided features.)

Treatment:

To treat HLHS the new-born would immediately need prostaglandin. This medication prevents the ductus arteriosus from closing. This is very important as the ductus arteriosus connects the pulmonary artery to the aorta which allows oxygenated blood to be sent to the rest of the body. If it closed in an infant with HLHS then it would die due to the body being unable to receive oxygenated blood as the only route to the aorta and thus the body is the ductus arteriosus, unless an atrial septal defect was present.

Surgery would be essential in order for the survival of the child. In fact, three surgeries would be needed:

  1. Norwood Procedure – This open heart operation is carried out straight after the diagnosis of HLHS and this is usually around the first few days of the child’s life. It involves stopping the heart and allowing a machine, called a heart-lung machine, to perform the role of the heart. The surgeon enlarges the aorta – using a patch – and disconnects the pulmonary artery from the right ventricle and connects the aorta to the right ventricle instead. This now allows the right ventricle to pump blood around the body instead of the hypoplastic left ventricle. To allow deoxygenated blood to reach the lungs a shunt (made of Gore-Tex) is created joining the new aorta to the pulmonary artery. Essentially, the right ventricle now performs the job of both ventricles as it pumps blood to both the body and lungs. Therefore, the heart is now relying on a single ventricle. This surgery is extremely challenging and very long. It can take approximately six hours to complete. The survival rate is about 80% and the child can normally go home after 3-4 weeks. However, in some cases (e.g in very small babies) the Norwood Procedure isn’t suitable and instead the Hybrid procedure is preferred. This consists of keeping the ductus arteriosus open using a stent and making the atrial septal defect larger (which would allow blood to enter the aorta and to be sent to the body) and finally placing small bands on the pulmonary arteries which reduces the amount of blood flowing in them and thus protecting the lungs. This operation is usually 1-2 hours long and doesn’t require a heart-lung bypass machine. Cyanosis would still occur after either of these surgeries due to the mixing of oxygenated and deoxygenated blood still taking place.
  2. Bi-directional Cavo-Pulmonary Shunt Procedure – This second operation is undertaken when the child is between three to twelve months of age. The aim of this operation is to reduce the workload of the right ventricle. This is done by connecting the superior vena cava directly to the pulmonary artery. This improves the quality of life for the patient as the heart doesn’t have to work as hard as deoxygenated blood returning from the upper part of the body goes straight to the lungs via the pulmonary artery. This also is better for the lungs as they now receive blood at lower venous pressures rather than much higher arterial pressures. The shunt added in the Norwood Procedure is then removed. The child will still have a blue appearance even though deoxygenated blood from the upper part of the body no longer mixes with oxygenated blood in the right ventricle. This is due to the mixing of deoxygenated blood from the lower part of the body and the oxygenated blood in the right ventricle.
  3. The Fontan Procedure – This is the final stage and it takes place when the infant is between 18 months and four years of age. The purpose is to finally stop the mixing of deoxygenated and oxygenated blood which leads to partially oxygenated blood and therefore cyanosis. This is achieved by connecting the inferior vena cava, which brings deoxygenated blood from the lower part of the body, to the pulmonary artery. The right ventricle no longer has to pump blood to both the lungs and the rest of the body. It only has to send it to the body which was meant to have been done by the left ventricle.

Future of the child:

Even with all of these surgeries the child will still not be cured of HLHS and a heart transplant may be necessary. However, infant hearts are rarely obtainable and so one may not be available for the child. If they are able to receive a donated infant heart then they will have to take anti-rejection medication for the rest of their lives and this will severely weaken their immune system.

Even if the surgeries go well complications may develop which include:

  • Fluid in the lungs (pleural effusion)
  • Heart failure
  • A fast and irregular heart rhythm (arrhythmia)
  • Stroke
  • Problems of the development of the brain and nervous system
  • Easily becoming tired and breathless during exercise
  • Endocarditis
  • Death

Every patient would also need to regularly visit a cardiologist who would look out for any  of these complications.

Bibliography:

http://www.cdc.gov/ncbddd/heartdefects/hlhs.html

http://www.gosh.nhs.uk/medical-information/search-medical-conditions/hypoplastic-left-heart-syndrome

https://www.bhf.org.uk/~/media/files/publications/children-and-young-people/c9understanding-your-childs-heart-hypoplastic-left-heart0210.pdf

https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome

http://www.mayoclinic.org/diseases-conditions/hypoplastic-left-heart-syndrome/basics/definition/con-20031294

http://www.childrenshospital.org/conditions-and-treatments/conditions/hypoplastic-left-heart-syndrome-hlhs

http://www.cincinnatichildrens.org/health/h/hlhs/

https://www.nlm.nih.gov/medlineplus/ency/article/001106.htm

http://www.lhm.org.uk/info/hypoplastic-left-heart-syndrome-44.aspx

 

 

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Tetralogy of Fallot

Tetralogy of Fallot

What is Tetralogy of Fallot?

Tetralogy of Fallot is a congenital heart defect (one which is present at birth.) In fact, it is one of the most common congenital heart defects. It affects approximately 5 in 10,000 live births. Fallot was the name of the doctor who discovered this condition and the word tetralogy relates to the four main features associated with this heart condition.

The Four Defects:

The main four abnormalities in TOF are:

  1. Pulmonary Stenosis
  2. Ventricular Septal Defect
  3. Overriding Aorta
  4. Right Ventricle Hypertrophy

Pulmonary Stenosis:

Pulmonary Stenosis is where there is an obstruction to the flow of blood from the right ventricle into the pulmonary artery caused by one or more points of narrowing. It can also be caused by the pulmonary valve being too narrow or being unable to open fully. Therefore, the blood flowing out of the right ventricle is reduced.

Ventricular Septal Defect:

A ventricular septal defect is where there is a hole between the right and left ventricles. This leads to the mixing of oxygenated blood from the left ventricle and deoxygenated blood from the right ventricle. Consequently, blood is only somewhat oxygenated and therefore not enough oxygen reaches the child’s respiring tissues.

Overriding Aorta:

This is where the aorta is enlarged and positioned above the ventricular septal defect rather than attached to the left ventricle. Thus, oxygen-poor blood from the right ventricle is able to enter the systemic circulation (circulation of blood from the heart to the body and back) more easily.

Right Ventricle Hypertrophy:

Right Ventricle Hypertrophy means that the walls of the right ventricle have become thicker. This is due to the pulmonary artery narrowing and so the muscle thickens (hypertrophies) in order to develop sufficient pressure to pump blood through the narrower artery.

 Symptoms:

The above four malformations result in a few symptoms listed below.

  • Cyanosis – bluish colour of the skin, lips and nails caused by low levels of oxygen.
  • A Heart Murmur
  • High breathing rate
  • Poor feeding and difficulty gaining weight
  • Clubbing of the fingers

Diagnosis:

Cyanosis is one indication of a heart problem. Once a new-born is seen to be cyanotic they are supplied with extra oxygen and if there is an improvement in oxygen levels then the medical staff would know that something is wrong with the lungs. However, if the oxygen levels don’t improve then the problem is cardiac.

After establishing that it’s cardiovascular the heart would then be listened to. A heart murmur would be found and so an echocardiogram would be carried out. This would reveal the four defects associated with tetralogy of Fallot and subsequently a diagnosis would be reached.

Treatment and Complications:

Tetralogy of Fallot is treated by open heart surgery and has a 98% survival rate. Some cases require surgery soon after birth whereas some require surgery 3-6 months after birth, depending on the severity of the condition. The heart is stopped and opened and a heart bypass machine performs the role of the heart for the duration of the operation. The ventricular septal defect would be closed using a patch and therefore blood will be prevented from shunting. The pulmonary valve would be widened or replaced and the pulmonary artery would be widened by removing (resecting) obstructive muscle tissue.

The main complications of this treatment are:

  • Tachycardia – a fast heart rate
  • Narrowing of the Pulmonary Artery once again
  • Narrowing of the Pulmonary Valve
  • Leaking of the Pulmonary Valve
  • Infective Endocarditis – an infection of the inner layer of the heart (endocardium).

 Outlook:

The outlook of most patients is very good. They start to gain weight shortly after surgery and can lead normal active lives. On the other hand, they will be left with a scar down the middle of their chests and it would be necessary for them to regularly attend check-ups with a cardiologist.

 

Bibliography:

http://www.gosh.nhs.uk/medical-information/search-medical-conditions/tetralogy-fallot

https://www.bhf.org.uk/~/media/files/publications/children-and-young-people/c5understanding-your-childs-heart-tetralogy-of-fallot1208.pdf

http://www.chfed.org.uk/how-we-help/information-service/heart-conditions/tetralogy-of-fallot-fallots-tetralogy/

https://www.nhlbi.nih.gov/health/health-topics/topics/tof

http://www.nhs.uk/Conditions/Congenital-heart-disease/Pages/Treatment.aspx

http://www.cincinnatichildrens.org/patients/child/encyclopedia/defects/tof/

https://www.nhlbi.nih.gov/health/health-topics/topics/tof/treatment

 

 

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Total Anomalous Pulmonary Venous Drainage

Total Anomalous Pulmonary Venous Drainage – T.A.P.V.D

 

What is T.A.P.V.D?

T.A.P.V.D stands for Total Anomalous Pulmonary Venous Drainage. It is an incredibly rare congenital heart defect (approximately 1 in 20,000 babies are born with it.)

T.A.P.V.D is where the pulmonary veins, which bring oxygenated blood from the lungs and back to the heart, don’t connect to the left atrium as they should. Instead the pulmonary veins connect to various other veins which lead to the right atrium. This is a serious problem as the right atrium ultimately sends blood to the lungs via the pulmonary artery to become oxygenated and because the pulmonary veins, carrying oxygenated blood, are connected to the right atrium oxygenated blood is constantly being sent to the lungs. Thus oxygenated blood won’t ever reach respiring tissues!

That is why an atrial septal defect or a foramen ovale is required for survival of Total Anomalous Pulmonary Venous Drainage. An atrial septal defect is a hole between the two atria and allows oxygenated blood to mix with deoxygenated blood forming partially oxygenated blood. This then allows the new-born’s respiring tissues to receive some oxygen and hence remain alive. A foramen ovale also allows blood to move from the Right Atrium to the Left Atrium.

Variations of T.A.P.V.D

There are four types of T.A.P.V.D – which one you have depends on where the pulmonary veins are connected to.

  • Supracardiac T.A.P.V.D is where the pulmonary veins are connected to the Superior Vena Cava.
  • Infracardiac T.A.P.V.D (also known as Infradiaphragmatic T.A.P.V.D) is where the pulmonary veins join to the Inferior Vena Cava.
  • Cardiac T.A.P.V.D is where the pulmonary veins lead blood to the right atrium through the coronary sinus.
  • Mixed T.A.P.V.D is where the pulmonary veins are connected to various sites and so it is a mix between any or all of the previously mentioned forms of T.A.P.V.D

In Summary all of the types of T.A.P.V.D end up sending blood to the Right Atrium instead of the Left Atrium.

There is also a similar condition called P.A.P.V.D. The difference being that P.A.P.V.D stands for Partially Anomalous Pulmonary Venous Drainage and it is where some of the pulmonary veins connect normally to the Left Atrium and the others are positioned incorrectly leading to the Right Atrium. Furthermore, T.A.P.V.D is life threatening and is usually diagnosed within the first few days of the baby’s life whereas P.A.P.V.D can be diagnosed at any time in one’s life, even at old age, due to it being less severe.

Detection

T.A.P.V.D is usually detected a couple of days after birth because it is rather difficult to do so during pregnancy. This is because the doctor first needs to suspect a heart problem from the prenatal scans and then if the doctor suspects a problem then further tests may be carried out such as a foetal echocardiogram. However, these tests may not necessarily lead to the discovery of the serious congenital heart defect. This is because for T.A.P.V.D to be confirmed the pulmonary veins need to be seen incorrectly positioned and leading to the Right Atrium. However, not much blood goes to the lungs of a foetus therefore the doctor won’t be able to see the pulmonary veins properly because they wouldn’t show up clearly and so T.A.P.V.D wouldn’t be detected because the doctor can’t tell if the veins are connected to the correct area. Consequently, it is uncommon for T.A.P.V.D to be detected during pregnancy and it is much more likely that it would be detected soon after birth due to the various symptoms.

Symptoms

The signs and symptoms after birth are seen quite quickly and these include:

  • Cyanosis – a blue skin colouration because of the lack of oxygen.
  • Breathing difficulties
  • Tachypnea
  • Abnormal Heart Sounds
  • Heart Murmur
  • Poor feeding / weight gain / growth

Diagnosis

At this point it is unknown what condition the baby has therefore a number of tests would be carried out such as:

  •  An electrocardiogram ( which measures the electrical activity of the heart)
  • Chest x-rays
  • Echocardiogram (ultrasound of the heart)
  • MRI of the heart
  • Cardiac catheterisation

These tests ultimately lead to the diagnosis of T.A.P.V.D because they would inform the doctors that the pulmonary veins are connected to the wrong chamber of the heart. It would also allow them to see if there are any other abnormalities.

Treatment

The treatment is open heart surgery as soon as possible. First of all the chest has to be opened up using a saw allowing the heart to be seen. Once open the surgeon would connect the pulmonary veins to the correct place and the atrial septal defect would be closed. After that the sternum needs to be put back together and the skin would need stitching up; leaving a large scar from the top of the chest to the bottom of the sternum. The surgery is carried out under general anaesthetic and the survival rate is approximately 90%.

Complications

There are a number of complications that can arise due to the surgery including:

  • Arrhythmia – an irregular heartbeat that can be too fast or too slow.
  • Sepsis
  • Chylothorax
  • Breathing difficulties
  • Heart failure
  • Lung infections
  • Hypertension
  • Organ failure
  • Formation of an obstruction at the new connection

After the operation the patients are placed in post-operative intensive care and they usually require a ventilator.

Outlook

The outlook of a patient after successful operation and correction of T.A.P.V.D is very good. They are able to lead normal lives unless of course they developed complications.

They will however need to regularly visit a cardiologist who would keep an eye open to make sure no complications or other problems crop up e.g. the formation of an obstruction at the new connection or heartbeat abnormalities.

 

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What is Type 1 Diabetes?

Although diabetes mellitus, or, more commonly, just ‘diabetes’, is a condition (or, technically, a group of conditions) affecting over 382 million people worldwide, it is a condition which many people don’t know much about. In this article, I will explore type 1 diabetes mellitus (T1DM) as well as a potential stem cell treatment for it.

So what exactly is T1DM? Put simply, it is a metabolic disorder leading to chronic hyperglycaemia (high blood glucose levels for prolonged periods). Unlike type 2 diabetes, it results from the autoimmune destruction of the beta cells of the islets of the Langerhans in the pancreas. Beta cells are the cells which produce insulin (the hormone which regulates the uptake of glucose into cells) – this means that people with T1DM are insulin-deficient. It doesn’t take a genius to work out that without insulin, glucose uptake into cells is going to be affected.

T1DM usually develops in children, although the exact cause isn’t known. The most common symptoms of diabetes are polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). There is no cure – however, if left untreated, T1DM can lead to some serious chronic complications.

The main 3 chronic complications arise from microangiopathy (damage to small blood vessels) due to high blood glucose concentrations. Diabetic retinopathy, which is damage to the retina, can cause macular edema (swelling of the macula) and, ultimately, blindness. This is actually the leading cause of blindness in non-elderly adults. Damage to the kidney, known as diabetic nephropathy, can lead to chronic renal failure, eventually requiring dialysis. Finally, diabetic neuropathy, the most common complication, is damage to nerves in the body, affecting movement, touch, and the autonomic nervous system (the nerves serving vital organs such as the heart, lungs and gastrointestinal system to name a few). This is just a selection of complications; if you have diabetes, the risk of cardiovascular disease is doubled.

To minimise the risk of such complications, people with T1DM undergo a strict treatment regime to manage their condition. First and foremost, at-least-daily insulin injections are used with the goal of lowering the blood glucose level to the normal level, avoiding the aforementioned complications. Additionally, it is frequently recommended that patients suffering from diabetes lead a healthy lifestyle (ie maintaining a healthy weight and exercising frequently).

Although this treatment is usually successful, research is being undertaken into the use of human embryonic stem cells (hESCs) to treat T1DM. Previous attempts didn’t lead to much – researchers used human pluripotent stem cells (hPSCs) to produce beta cells. In spite of that, they lacked the characteristics of bona fide beta cells (normal beta cells found in non-diabetics). However, researchers at Harvard University have had a breakthrough – they have managed to develop a technique to generate large quantities of glucose-responsive beta cells from hPSCs in vitro. These  are very similar to mature beta cells – they have the flux Ca2+ response (the mechanism used to secrete insulin), and they can package insulin into granules for secretion, just like in humans. When exposed to glucose in vitro, they secreted insulin in quantities comparable to adult beta cells. Additionally, when tested in mice, human insulin was secreted into the serum, improving the hyperglycaemia in the mice. Currently, 40 patients are undergoing a clinical trial to test this potential treatment – hopefully it will be successful!

As ever with embryonic stem cells, there are certain ethical issues which need to be considered. Previously, unused embryos from IVF were donated for research. However, embryos are now being produced for research purposes – these can’t be implanted into the womb anyway. Some organisations, such as the Catholic Church, see the use of embryos as murder since life starts at conception. However, such ethical issues need to be balanced against the benefits of the research and the treatment – in this case, millions of people around will have something to gain from this research. There may also be alternatives, for example, induced pluripotent stem cells (pluripotent stem cell derived from adult somatic cells), however this phenomenon deserves it’s own article!

Diabetes affects many people around the world and has the potential to cause serious complications. However, with the right research, hopefully a new, long-term treatment for diabetes can be developed.

The Death Virus: An Overview
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The Death Virus: An Overview

The Ebola virus, or ‘Death Virus’ is a major concern due to the recent outbreak across West Africa, in countries such as Sierra Leone, Guinea and Liberia. The disease is now at an international scale, with precautions even being taken to prepare in the UK. So, what is Ebola and how is it so deadly?

The Ebola virus has been found in five different strains, four of which have been known to affect humans. If you were to look at an electron micrograph of members of the ‘Ebolavirus’ genus, you would see their characteristic thread-like structure. The virus can be transmitted to humans from the carcasses of primates such as gorillas and chimpanzees, usually to one individual. The virus is then spread to other persons through contact of bodily fluids.

The spread of Ebola that has led to an epidemic has occurred in poor hospital conditions, where safety precautions have not been properly carried out, or are simply unknown. A person is said to be infected with the virus for as long as it remains in their blood. The incubation period ranges from 2-21 days over which symptoms appear suddenly and can vary between cases. Many symptoms are mistaken for malaria and can include high fever, headache, joint pain, and both internal and external bleeding. In the later stages the symptoms worsen and can include haemorrhaging, purpura and petechia. Interior bleeding is said to be caused by the reaction between the virus and platelets. These platelets then cut cell-sized holes into the capillary walls. By the second week of infection, the fever will either lessen, or the patient will experience multi-organ failure. The cause of death is usually hypovolemic shock or multi-organ failure.

As Ebola is a virus, it does not replicate through cell division, rather it uses a host cell to multiply and assemble itself in the cell. For a virus to invade a host cell, there must be some sort of molecule on the surface of the host cell to be used as recognition for the virus. Such a molecule is called a receptor. The cell must possess that particular receptor for the virus to enter, otherwise the virus cannot invade. This comes to show that it is important for scientists to find out which receptor it is that the virus uses, as it can be used to help to develop a vaccine or other cure to prevent the virus from invading.

The development of a cure is desperately needed as mortality rates for the disease are very high. There is no specific licensed vaccine or other standard treatment. Since patients are usually dehydrated, doctors mainly work to replace electrolyte imbalance and maintain blood levels. At present, the development of effective and rapid-working vaccines is ongoing.

Glossary:

Carcass- The dead body of an animal

Electrolyte- The ionised parts of a living cell, blood, or other organic matter

Haemorrhage- An escape of blood from a ruptured blood vessel

Hypovolemic shock- An emergency condition in which severe blood and fluid loss make the heart unable to pump enough blood to the body

Incubation period- The period between exposure to an infection and the appearance of the first symptoms

Mortality rates- The number of deaths in a given area or period, or from a particular cause

Petechia- A small red or purple spot caused by bleeding to the skin

Platelets- A cell fragment found in large numbers in the blood which is involved in blood clotting

Purpura- A rash of purple sports on the skin caused by internal bleeding from small blood vessels

External links:

http://www.news-medical.net/health/What-is-Ebola.aspx

https://www.bcm.edu/departments/molecular-virology-and-microbiology/ebola

Lily
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Is Altitude Training the best way to legally improve sporting performance?

Please follow the link below to view my Biology AS Coursework looking at the effectiveness of Altitude training on Elite Performers. Also explores the effectiveness of Performance Enhancing Energy Drinks and Ice Baths as a recovery method.

Is altitude training the best way to legally improve sporting performance?

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What are the current treatments of schizophrenia?

What are the current treatments of schizophrenia?

Abstract

I discuss the available treatments for schizophrenia. I comment upon the socio-economic issues arising from living with schizophrenia and the aforementioned treatments. I examine a case study in management of schizophrenia in the NHS. Furthermore, I evaluate two alternative methods to control schizophrenia – one holistic and the other supplementary to a more rigorous regimen. I discuss the impact of schizophrenia on other individuals; especially close family members, as well as wider society. Moreover, the article scrutinizes different antipsychotic drugs and their chemical composition. Finally, I comment upon the validity of two different sources I have used in the creation of this article.

Introduction

Schizophrenia is a mental condition. It is characterised by positive and negative symptoms, where positive symptoms are where there is a shift in disposition, such as hallucinations and delusions, or negative symptoms, where there is dampened emotional and social function, which can manifest itself as ennui or lack of emotion 1. The condition usually manifests itself in adolescence, where it is frequently misdiagnosed as angst or hormonal imbalance. Schizophrenia, like other mental disorders, is expressed in episodes, whereby the intensity of the symptoms increases with the onset of an episode and a regression to the mean when there is no episode; this is the most common form of schizophrenia, and is known as acute schizophrenia 2. The causes of schizophrenia are currently not known, but the key risk factors identified are genetics; brain development; disparity of dopamine and serotonin and birth complications 11. The condition, however can remain dormant until triggers, such as substance abuse and stress 11, can lead to development of schizophrenia.
Hallucinations, a positive symptom, are sensations that an individual experiences which are not the result of external stimulation. These hallucinations can involve perception of any of the senses, but it is reported that hearing is the most common at 50% of cases 35.
Delusions, a positive symptom, are misapprehensions of situations or incorrect assertions ₄. These come often as a result of trying to explain recurring hallucinations. These beliefs are immovable and the subject demonstrates absolute faith in the validity of their explanation 5.

A negative symptom of schizophrenia is blunted affect, whereby the subject shows little or no emotion, especially when there is a call for emotional response e.g. social interaction. This lack of emotion can manifest itself as physical and verbal 6.     Another negative symptom is anhedonia, or an inability to feel pleasure from typical acts e.g. hobbies, sports and relationships. Subjects often cite feeling “emotionally empty” 7. Of all symptoms of schizophrenia, negative symptoms and, more specifically, symptoms that degrade quality of life, are quoted as being most debilitating to subjects 8.

Public perceptions of schizophrenia range from personal experience of looking after family members with the condition, to ignorance of the condition. It is reported by “Only 25 per cent agreed with the statement that “most women who were once patients in a mental hospital can be trusted as babysitters””9. Furthermore, it is suggested that only “34%” of participants in another study acknowledged schizophrenia as a mental condition 8.

Schizophrenia is becoming a major issue in the world. The World Health Organisation states that, globally, “24 million people” suffer from schizophrenia and “90% of people with untreated schizophrenia are in developing countries” 12. From 2001 to 2009, abuse of hallucinogens has increased from 8.2% to 9.3% of 16-59 year olds in England and Wales 13.

Case Study: Care Programme Approach (CPA) – The current solution used by the National Health Service, United Kingdom 

A current treatment is to implement a Care Programme Approach (CPA). This is a plan based on four steps 14:

  1. Assessment – The holistic requirements of the subject are mapped.
  2. Care Plan – Based upon the findings of the assessment, you are assigned a plan to address your condition.
  3. Appointment of a care co-ordinator – You are allocated a keyworker, who is a social worker or nurse, who will oversee your care plan.
  4. Review – Throughout recovery, your progress will be reviewed and the care plan will be adjusted to optimise recovery.

This is a holistic approach to treating schizophrenia, as it affects the mental, physical, emotional and social wellbeing of the subject. Thus, each step in the process addresses each facet of schizophrenia and the subject. As schizophrenia is highly specialised in effect of symptoms on each subject, the CPA is personalised to each subject who presents with schizophrenia to the NHS.

In terms of treating the initial mental side of schizophrenia, antipsychotic drugs are most effective. Antipsychotic drugs manage psychosis (aberrations of the mind) by reducing the severity of the symptoms, such as hallucinations and delusions 15.

There are two types of antipsychotic drugs based upon when they were discovered: typical (also known as first-generation) antipsychotic drugs which were developed in the 1950s 16, and atypical (also known as second-generation) antipsychotic drugs which came later in the 1970s 17. Both types of drugs stop the flow of dopamine in the brain. Atypical drugs also target serotonin receptors in the brain 18.

Typical antipsychotic drugs can be sorted into five categories:

  1. Butyrophenones e.g. Moperone. These compounds have phenyl-1-butanone 19.
  2. Diphenylbutylpiperidine e.g. Pimozide. These compounds inhibit contractions of rat vas deferens that are dependent on concentrations of potassium and calcium at “40-350nM” 20.
  3. Phenothiazines e.g. Pipotiazine. These compounds inhibit dopamine-based communication in the brain by inhibiting receptors 22.
  4. Thioxanthenes e.g. Tiotixene. These compounds work by dampening the D2 receptors in the brain, thereby stopping psychosis from taking hold of the brain 23.
  5. Others e.g. Loxapine. These compounds work in a similar manner to Thioxanthenes, except Loxapine has chlorine, nitrogen and oxygen instead 24.
  6. There are various risks associated with dosages of first-generation antipsychotics. The most common are cramps, dry mouth and weight gain 25. More serious adverse side effects are Tardive dyskinesia, which causes slow but constant involuntary muscle movement 26 and Neuroleptic malignant syndrome, which causes delirium and muscle rigidity, and can be fatal 27.

Atypical antipsychotics cannot be categorised, but the most common are:

  1. Clozapine (Clozaril) – This is widely regarded as the most effective atypical antipsychotic 28. It is given as a last resort, when other drugs have not been successful 29. It works by inhibiting the D1, D2 and D3 receptors 30. However, it has a high binding profile with the 5-HTSA receptor, which is used in serotonin transmission 30, so dosages to the subject are low (between 10-50 mg) 31.
  2. Risperdal – This is also a widely popular drug to use. It is generally used in acute schizophrenia 32. Compared to Clozapine, it has a more benign binding profile, but still having a high binding profile with the 5-HTSA receptor 30. It is not as efficacious as Clozapine 33.
  3. Seroquel (quetiapine) – This is a relatively new drug 34. It has fewer side-effects of a lower severity than the other atypical antipsychotics, with drowsiness being the most common 34. It inhibits dopamine and serotonin levels in the brain 35. It is used only on subjects over the age of 13 36. It has the same binding profile as Risperdal 30.

To treat the social effects of schizophrenia, the CPA calls for the instating a community mental health team (CMHT) to each subject. This team is made up of professionals from a wide background of care fields. They would include social workers, pharmacists, counsellors and psychiatrists 14. The subject will meet with the various members of the CMHT and discuss how they are progressing on with their life and address any misgivings towards their condition. In the most acute of cases, a crisis resolution team (CRT) will take over treatment of the subject at their home and plan to reduce the risk of another crisis occurring. If necessary, detention of the subject in a psychiatric ward will be prescribed.

Implications

Ethical: Compulsory Detention

Sometimes, it is required for the good health of the patient that they are hospitalised in a psychiatric ward. This is done in the interests of the patient. Schizophrenia, especially in the paranoid sub-type, can be very destructive to the subject and their surroundings. This can cause harm to themselves and others, evidenced by recent high-profile murders of people, where the murderer suffered from paranoid schizophrenia 37, and fictional books where the pivotal characters are sufferers of schizophrenia or carers of sufferers 38. Furthermore, the adequate medical needs may only be supplied by a psychiatric ward, so, to maintain an acceptable quality of life, the subject may need to reside in a hospital.

One can also make the case for the Hippocratic right of the patient to self-control over how they proceed in their treatment. Under normal circumstances, when the patient is mentally competent, the doctors would make the most medically sensible decision and present it to the patient. This model, however, does not work when the patient, as with more severe forms of schizophrenia, is not mentally competent to understand fully the treatment option being proposed to them. In conventional wisdom, the decision of the progression of treatment therefore lies with the doctors and wider CPA team. It is difficult to ascertain the true intentions of the patient under these conditions, so the decision is made in full awareness of what is best for the patient. Furthermore, the family of the subject may be brought in to give a more personal account of what the subject may want for themselves. This alternate mode, however, is never an equal substitute for the intentions of the patient themselves, so care and attention must be used in judging when the patient is no longer competent to independently make decisions about their treatment.

It can be argued, however that, especially in the case of compulsory detention, this is being done against the wishes of the subject; whom may wish to live with their family or in their local community. Moreover there is pressure upon the NHS in terms of the low numbers of beds, especially when in the flu season, so, if possible, all subjects should be treated in the community rather than in a highly subscribed hospital 39. Additionally, the subject may also pose a risk to other patients on the ward. This can be damaging to the hospital.

In conclusion, I think we should restrain subjects whose schizophrenia is particularly acute, so they pose less of a danger to themselves and others in the community.

Social: Schizophrenics in the community

Schizophrenics in the community can physically dispel common myths about schizophrenia. Just by observing a schizophrenic in their daily life, many can draw parallels with their own lives. It is also good for the subject, who experiences social interaction and becomes less daunted by it. Moreover, the subject is with his family and friends in the community so will be less burdened by having to live a normal life.

On the other hand, the subject may, from negative symptoms, prefer to be in solitude. This does not improve the subject’s social interaction. Also, the community may shun the subject due to perceived difficulties with dealing with the subject, thus depressing the subject further. Likewise, the subject may pose a real threat to the community, particularly if they possess paranoid schizophrenia, so it may be in the greater utilitarian interest of the community to keep away from the subject.

In conclusion, I think that, if the ability is there and it is safe, the subject should be integrated into the community. This will improve the subject’s ability to cope with social interaction, which aids their recovery.

Implications to other humans

Benefits

Others will have their myths about schizophrenia dispelled. This will mean that the image of schizophrenia will improve from the viewpoint that many have, of dangerous individuals who eschew society and are recluses. Also, through helping people with schizophrenia, people gain a broader view of life for different people. Mental health charities like SMART offer people the opportunity to volunteer and help schizophrenics, which contribute to a better quality of life for both the volunteer and subject.

Due to our current understanding of the symptoms of schizophrenia, the medical establishment has progressed to level where treatment of schizophrenia is successful in the majority of cases. Throughout treatment, the social skills of the subject will gradually improve. This allows them to start living a more normal and socially healthy life. If the subject had a job, they will eventually be able to return to it. This benefits the local economy. The improvement in the social activity of the subject also benefits his family relations. The subject will be able to normalise their relations with the family, which in turn leads to a more stable life. This is better for the family of the subject as they can begin to repair the inevitable damage that a schizophrenic family member would have had on family relations. This leads to a more harmonious relationship and a more fulfilling relationship for the rest of the family with the subject. Moreover, with the friends of the subject, the development of the social skills of the subject will improve relations with the subject. This will also help improve the relations of the subject and the friends. The friends will have a more gratifying time in the company of the subject and will boost their general happiness.

Risks

There have been cases of paranoid schizophrenics murdering people. These cases are very high-profile and so people are exposed to them, whenever they happen. This inflates the risk factor of it happening with any schizophrenic, when the statistics point otherwise. Only “5 to 10%” of schizophrenics engage in any violence 40. Most of this violence is directed towards themselves, and the suicide rate amongst schizophrenics is 4% 41. Mental health is a stigmatised and even taboo topic. Those with mental health issues are often shunned by other people, as they hold biased predispositions of mental people as uncontrollable, violent and emotionless. This attitude stems from media publication of extreme stories about paranoid schizophrenia 59. This also occurs as people generally have very little exposure to people with schizophrenia, the majority of whom are people who can lead normal social lives.

Antipsychotic drugs have side effects. These include parkinsonism and akathisia 57.  These side effects impact upon the social life of the subject with his immediate family and friends, as well as wider society, as the subject will have less social control over themselves. People will be less comfortable being around them and this results more distress for the family and friends, as they feel as though the subject is slipping away. This feeling is compounded if more severe side effects, such as pancreatitis ₅₈ or myocardial infarction 57, are felt as the subject will be hospitalised and will cause more distress to the subject, as they are very ill.

The placebo effect in schizophrenia is more pronounced than in other conditions 60, 61. This is most noticable when second generation antipsychotic drugs are used. Thus, there is a risk of overprescription of the medication, which could lead to severe side effects. This can increase the burden placed on the people around the subject as they witness the side effects in action.

Alternative Solutions

Soteria

Soteria is a service which focuses on the providing a calm environment for the subject. It is a civic service, which, instead of using conventional medicine, gives them a space to exercise their freedom 42. Loren Mosher M.D, the founder of Soteria, started it because he became aware of large proportions of patients required “love and food and understanding, not drugs” 45. Thus, he began an experiment whereby he gave patients autonomy over their care, and compared his results against conventional antipsychotic drugs. The results showed that, for early-stage acute schizophrenia, Soteria was a better treatment than antipsychotic drugs 46.

Soteria relies upon techniques pioneered in Eastern medicine of harmony between man and nature. It uses methods such as yoga and acupuncture to relax the individual. This is done to reduce the severity of the symptoms, such as delusions and hallucinations. This is also achieved through a calm and relaxing environment. The buildings are minimalist, with white walls and little colour to reduce the stimulation of the mind. Other techniques, such as music and art therapy, are used in conjunction with the Eastern methods to relax the mind as much as possible. This is done for up to 3 weeks.

Soteria is utilised by mainstream patients as either an early intervention to prevent more acute episodes of psychosis and mental distress later in the intervention, or as a crisis resolution method for people who are not responding adequately to mainstream antipsychotic treatment. It follows the support recovery model of empowerment of the subject. Soteria is usually used by younger patients (<30 years old). Psychosis, instead than being seen as a biomedical issue, is seen rather as an acute personal crisis of the individual and thus Soteria aims to resolve these using treatments less dependent on medication, as this can distress the subject.

Supplements

It has been noted that people with mental disorders have sharp deficiencies in some vitamins, for example Vitamin D. Also, glycine, an amino acid, has been found to be in short supply in people with mental disorders. Fish oil has been touted as an effective supplement, but this is based solely upon anecdotal evidence, with no studies carried out into the efficacy of it in respect to treating schizophrenia 68.

Glycine improves the efficiency of NMDA receptors in the brain, along with glutamate. It is though that if the glutamate in the brain were to be a better neurotransmitter, it would alleviate some of the symptoms of schizophrenia 47.Glycine is an amino acid which has been researched to alleviate the negative symptoms of schizophrenia.

Another supplement that has been used is DHEA. DHEA stands for Dehydroepiandrosterone is hormone which is secreted naturally by the brain and adrenal glands. It is used to reduce the severity of depression and other negative symptoms 66.  The use of DHEA, however, has been cautioned by many health organisations 66, 67 as DHEA can interact very readily with other chemicals in the brain, such as anastrozole and insulin 67. If used, it is recommended to use 7-keto-DHEA, a by-product of DHEA which is not converted to steroid hormones such as oestrogen 67. It is also recommended to take DHEA under a rigourously planned regimen from your doctor.

Lithium is also used as a supplement. It is primarily used a mood stabilising drug. Lithium in the brain stimulates the production of serotonin. It is especially favoured as, when ingested, spreads widely throughout the nervous system, thus providing a more holistic effect than just on the brain. It is generally accepted that lithium is best used to treat mania, though it is also useful in depression 69. It has also been noticed that lithium decreases the suicide risk of schizophrenics 70. Lithium is generally used as early as possible in schizophrenia, as it is most effective when the symptoms are less severe. Lithium interacts with many other chemicals and medication such as antidepressants and dextromethorphan 69, so should be consumed carefully under guidance.

Inositol is a compound that is found in eukaryotic cells or can be synthesised in the laboratory. It is used to treat negative symptoms of schizophrenia, such as depression. It is believed to work by balancing chemical compositions in the brain to optimum levels 71. This reduces the severity of negative symptoms. Inositol is taken within 4 week cycles, as this is when it produces optimum results 71.

Evaluation of sources

Source 2

  • http://www.nhs.uk/Conditions/Schizophrenia/Pages/Symptoms.aspx
  • Last updated 17/09/12

I believe that the NHS website is a very reliable source. Being the national provider of health in the UK, the NHS aims to educate the public on matters of health. Thus, to do so, it requires professionals in the medical field to check information posted on the website are accurate. The NHS is a reputable source of information on medical matters. Also, the page was updated in 2012, which is only one-and-a-half years ago. Medical knowledge is unlikely to have expanded widely in that timeframe, so the information is accurate. The target audience of the website is the general population, so thus the content must reflect this; namely the simplicity of the language and ease of use. The information conveyed is simple. This is done so that people with limited understanding of medical concepts can grasp the premise of the idea. As the NHS is the outlet for medical information for the national population, it must remain up-to-date with the most recent advances in treatment and illness. As progress in different parts of medicine, such as healthy living and chronic diseases, moves at a rapid pace, the information on the NHS website must be updated as such. The editorial policy of the NHS Choices website 72 states that edits made to the text are made by “doctors” and “National charities with a recognised expertise and specialist interest”. Thus, we can be sure that the information posted on the website is reliable as it from trusted academic sources.

Source 25

  • Tyrer, Peter; Kendall, Tim (2009). “The spurious advance of antipsychotic drug therapy”. The Lancet 373 (9657): 4–5. doi:10.1016/S0140-6736(08)61765-1. PMID 19058841.
  • Publisher: Lancet
  • Published: 05 December 2008

I believe that this paper is an accurate source of information. It was published in the Lancet, a reputable peer-reviewed magazine of topics in science. Professor Peter Tyrer is a Professor of Community Psychiatry at Imperial College London, whilst Professor Tim Kendall is a Professor of English at the University of Exeter. Both looked at the community and medical side of antipsychotic medicine and both are experts in their field, with Professor Tyrer the Founder President of the British & Irish Group for the Study of Personality Disorders.

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