Christmas special: the weird and the wonderful

In the process of looking for hot new research topics (or just in the course of my daily working day) I find a fair amount of curious papers. So, as a final entry for the year I thought I'd post a special edition, listing a few of my favourites.

From the department of Advanced Medical Science (literally)¹:

"Obesity significantly increases the difficulty of patient management in the emergency department."

With the objective to "... determine which aspects of ED management are adversely affected by patient obesity, to determine the level of obesity above which management is made more difficult and to make recommendations on how these effects might be mitigated...", this study showed that patient obesity makes it difficult to manage an emergency department. And offered no solutions.


Ever wondered if watching TV or working on your computer late at night affects your sleep? So did a couple of researchers in Brazil who investigated the "Quality of sleep among university students: effects of nighttime computer and television use."²

The internet lost out in this study as it seems to affect sleep a lot more than television. Interestingly, if you manage to use the internet untill 3am, you sleep a bit better. This blogger wonders how much of the "affected sleep" is due to online arguing...



The title of this paper says it all, really: PMS: premenstrual storm? An unusual cause of electrical storm in a young woman with vasospastic angina. ³
Never underestimate how hard it is to be a girl...



Apparently "Hearing loss in stranded odontocete dolphins and whales" ⁴ is a big problem. Researchers speculate that this may have somethig to do with the actual stranding. How do you measure hearing in a dolphin? Well, with great difficulty, but apparently "in all cases, a jawphone consisting of an ITC-1042 piezoceramic transducer embedded in a RTV silicone suction cup was placed on the lower jaw fat pad to deliver sound stimuli." If a response could be detected from the dolphin or whale, then that was marked as the level at which the animal could "hear". There was a strong correlation between stranding and hearing loss in some of the species. (Picture below: a hydrophone)




The brushtail possum is a major pest species of New Zealand. Some researchers are investigating a nanoparticle system containing a chemical sterilitant which could be used orally to control their numbers.⁵ Poor little possums.




Our last two entries are shamelessly of a scatological nature:

A woman with a history of depression presents with abdominal bloating. Her doctor sends her for a colonoscopy. It turns out she's fine, but they do find something odd. A cockroach. ⁶


And finally... Apparently "robotic assisted laparoscopic radical prostatectomy" is a fairly uncomfortable procedure used in prostate cancer. So a few researchers in Seattle wondered whether a suppository containing belladonna (that's deadly nightshade to me and you) and opium would help.⁷ And indeed it did! With no adverse events noted either!





¹ Kam J, Taylor DM. Emerg Med Australas. 2010 Aug;22(4):316-23. Source

² Mesquita G, Reimão R. Arq Neuropsiquiatr. 2010 Oct;68(5):720-5. Source

³ Li J, Zitron E, Katus HA, Becker R. Clin Res Cardiol. 2010 Nov 30. [Epub ahead of print] Source

⁴ Mann D, Hill-Cook M, Manire C, Greenhow D, Montie E, Powell J, Wells R, Bauer G, Cunningham-Smith P, Lingenfelser R, DiGiovanni R Jr, Stone A, Brodsky M, Stevens R, Kieffer G, Hoetjes P. PLoS One. 2010 Nov 3;5(11):e13824. Source

⁵ Kafka AP, McLeod BJ, Rades T, McDowell A. J Control Release. 2010 Oct 31. [Epub ahead of print] Source

⁶ Kumar AR, Perez JA, Miick R, Govil YK Endoscopy. 2010;42 Suppl 2:E209-10. Epub 2010 Sep 15. Source - INCLUDES FULL ARTICLE PLUS PHOTO!

⁷ Lukasewycz S, Holman M, Kozlowski P, Porter CR, Odom E, Bernards C, Neil N, Corman JM. Can J Urol. 2010 Oct;17(5):5377-82. Source

New skins for old wine

Curcumin is the metabolite that's responsible for the yellow colour of the spice, tumeric. It can be used for food colouring (it's E number is E100), to quantify boron ¹, and to treat a number of ailments.

The first research on curcumin looked at its antibacterial properties ², and since then researchers have looked at its antioxidant properties ³, its use as an antirheumatic ⁴, a potential cholesterol-lowering role for it ⁵ and many other medicinal applications.

Recently a group in Canada investigated the effect of tumeric on cancer treatment.⁶ Previous research showed that curcumin also has an anti-cancer effect, but these researchers wanted to know if curcumin given in addition to standard chemotherapy could improve the efficacy of the treatment while keeping side-effects to a minimum. The researchers found that the combined treatment worked at lower doses than monotherapy; that non-cancerous cells remained unaffected; and that cancer cells still responded to the treatment even after the drugs were removed.

Many people scoff at the idea of "natural therapies", but it is important to remember that aspirin was originally made from willow bark. Tumeric might be the next aspirin!


¹Roth HJ, Miller B. On the color reaction between boric acid and curcumin. I. Boric acid-curcumin complexes. Arch Pharm (Weinheim)297:617-23 (1964)

²SCHRAUFSTATTER E, BERNT H. Antibacterial action of curcumin and related compounds. Nature. 164(4167):456 (1949)

³ Sharma OP. Antioxidant activity of curcumin and related compounds. Biochem Pharmacol. 25:1811-2 (1976)

⁴Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res. 71:632-4 (1980)

⁵Soudamini KK, Unnikrishnan MC, Soni KB, Kuttan R. Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin. Indian J Physiol Pharmacol. 36:239-43 (1992)

⁶
Chatterjee SJ, Pandey S. Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy. Cancer Biol Ther. 2011 Jan 29;11(2). [Epub ahead of print]

Nanobots!

In Star Trek: The Next Generation episode Evolution (1989), Wesley Crusher creates Nanobots called “nanites” which unexpectedly evolve to the point of sentience.

According to the Futurama Wiki "The Nanobots were a model of Robots created by Professor Hubert J. Farnsworth that inhabited the Robo-Planetoid during August of 3010."

Recently, Prof Joseph Wang and his team at UCSD published a paper on fuel free nanomotors¹. These nanomotors or nanoshuttles are designed to pick up, transport, and deliver drugs to their target more efficiently than current nanotherapy strategies.

Each nanoshuttle has a polypyrrole-cadmium nanowire containing a diode, which allows an electric current to flow in only one direction.² In order to get the nanoshuttles to move, an alternating current electric field is applied to the nanowires - this propels the shuttle by converting electrical energy into movement. The nanoshuttles are propelled a distance equivalent to seven times their body length in one second.


¹ Kagan D et al. Small Oct 27 (2010) E-pub
² Burch H. Nanomotors go fuel-free. Chemical Science 09 February 2010. (Source) This article includes a video.

Nanotherapy for targeted cancer treatment

Many researchers are currently investigating more effective, targeted ways of delivering cancer drugs and therapies to patients.

Two such innovative studies have looked at the use of wheat germ agglutinin and folic acid, respectively, as a conjugate to target tumors.

A team in Singapore have modified the nano-encapsulated drug, paclitaxel, with wheat germ agglutinin (WGA) to target colon cancer cells.¹ These cells express a greater amount of WGA-binding glycoproteins. Nanoparticles modified with WGA showed greater uptake into cancer cells when compared to unmodified particles. The WGA-modified particles also showed an enhanced anti-proliferative activit.

In India, a research team have modified nanoparticles loaded with grape seed extract(active as a neutraceutical), in order to target them to folate receptor over-expressing cancers.² The nanoparticles were conjugated with folic acid in order to target them to these cells. Folate receptor positive cancer cells readily took up the nanoparticles, showing enhanced bioavailability to tumor cells, sparing the normal ones.

Both these reports underline the application of modifications to target cancer therapies - strategies that may greatly improve the side-effects of chemotherapy.

¹ Wang C, Ho PC, Lim LY. Wheat germ agglutinin-conjugated PLGA nanoparticles for enhanced intracellular delivery of paclitaxel to colon cancer cells. Int J Pharm 400:201-10 (2010).

² Narayanan S, Binulal NS, Mony U, Manzoor K, Nair S, Menon D. Folate targeted polymeric 'green' nanotherapy for cancer. Nanotechnology 21:285107 (2010).

Neurorehabilitation - gaming systems

In a marriage of medicine and gaming culture, virtual reality games have been investigated in the rehabilitation of stroke patients.¹

Researchers in Barcelona have investigated novel technology-based neurorehabilitation techniques in the treatment of strokes. A special aspect of this technique was the fact that the game could be adjusted and personalized for each patient.

While a stroke causes massive damage, brain cells can reorganize themselves. Therefore the aim of rehabilitation is to maximize the effect of this plasticity. The Spanish research team developed the Rehabilitation Gaming System (RGS), a virtual reality-based neurorehabilitation program .

The RGS tracks arm and finger movements and maps them onto a virtual environment. The user controls the movement of two virtual limbs that are viewed on a screen. The RGS "game" that the researchers used was called Spheroids (see figure below). In this game the user has to catch and place spheres that move towards them. The idea behind this is that, when the patients use their limbs and observe the virtual limbs move in a way that is controlled by them, conditions are created that stimulate the reorganization of neurons involved in motor functions.


The researchers also tried to make the tasks just challenging enough to remain engaging for the patients. The RGS automatically adjusts the difficulty of the task with respect to the measured performance of a subject in order to keep them encouraged and to maximize effect.

The researchers concluded that the RGS is a promising neurorehabilitation tool that can be used to alleviate the deficits brought on by lesions to the central nervous system as the ones caused by stroke.

¹ Cameirão MS, Bermúdez i Badia S, Oller ED, Verschure1 PFMJ. Neurorehabilitation using the virtual reality based Rehabilitation Gaming System: methodology, design, psychometrics, usability and validation. Journal of NeuroEngineering and Rehabilitation 7:48 (2010).
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Stem cell therapy for cardiovascular disease

Stem cell therapy is controversial, mostly for the application of foetal stem cells in a large proportion of research.

A new type of stem cell has been developed by researchers in Japan, called induced pluropotent stem (iPS) cells. These cells derive from somatic (body) cells, and therefore are a lot less morally questionable than foetal cells.

A recent study has investigated the usage of iPS cells in the treatment of ischemia ¹ - the restriction of blood supply to a specific body part that can lead to tissue damage. Hind limb ischemia in mice was treated with iPS cells specifically treated to produce a protein called fetal liver kinase-1 (Flk-1). This protein plays an important role in the formation of blood vessels.

Transplantation of stem cells producing Flk-1 into the damaged limbs of mice accelerated the formation of new blood vessels, showing that this therapy could potentially rescue tissues that have suffered restricted blood flow. This could potentially be applied after events such as heart attacks.

¹ Suzuki et al. Therapeutic angiogenesis by transplantation of induced pluripotent stem cell-derived Flk-1 positive cells. BMC Cell Biology 11:72 (2010)

Rubbish! Chilis don't make you lose weight! ...or do they?!

Research on the effect of chili peppers on metabolic rate, continues.

In a study done at McMaster University in Canada, researchers tested the effect of capsinoids (substances present in chili peppers, and related to the more famous compound capsaicin) on energy expenditure, fat burning, and levels of certain molecules in the blood.¹

Twelve healthy male subjects were observed before and after a 90 minute stationary bike ride. During two separate experiments all subjects took (randomly) either a placebo or a treatment containing 10mg capsinoid, so that each subject had results that represented the effect of capsinoids and the effect of placebo. The subjects were tested with respect to oxygen consumption, respiratory exchange ratio (RER), heart rate, perceived exertion, and blood metabolites. Previous research on other andrenergic agonists (like caffeine) showed that these variables are changed by the treatment both during rest and during exercise. However, in the current study effects were mainly significant during rest. The main findings in this study were that, versus a placebo, 10 mg of capsinoids induced a rise in resting oxygen consumption, a decline in RER, an increase in plasma norepinephrine, and a decline in serum free fatty acids at rest. 10 mg of capsinoids also blunted the small but significant rise in blood lactate observed at the onset of exercise seen in the placebo group (0 mg).

This means that capsinoids raise the resting metabolic rate (shown as an increase in oxygen consumption) without increasing resting heart rate (none were observed in the study). Furthermore, the increase in norepinephrine and decline in RER suggest that the body burns more fat at rest. However, the effect of capsinoids on metabolism didn't carry over into exercise, where both groups showed similar metabolic states.

Capsinoids, therefore, represent a useful treatment for patients who want to lose weight, regardless of their level of physical activity.

¹ Josse et al. Effects of capsinoid ingestion on energy expenditure and lipid oxidation at rest and during exercise. Nutrition & Metabolism 7: 65 (2010).

Aspirin as a treatment for schizophrenia

Based on research that suggested that inflammation plays a role in schizophrenia (see below), further research has been done to investigate whether aspirin could improve existing anti-psychotic treatment.¹

Seventy patients in total took part in the randomized, placebo-controlled trial. One group of patients received their normal anti-psychotic treatment plus placebo, while the other group received their normal anti-psychotic treatment along with 1000mg of aspirin per day. During a 3-month follow up, patients were assessed according to the Positive and Negative Syndrome Scale (PANSS) - a medical scale used for measuring symptom severity of patients with schizophrenia. Researchers also tested the patients' cognitive function and changes in their immune systems.

Patients who took aspirin showed greater improvement in their PANNS scores, and therefore reduced the symptoms of schizophrenia. The reduction was greater in patients who have a more altered immune function. The researchers concluded that inflammation may be a potential new target for antipsychotic drug development.

¹ Laan W et al. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 71: 520-7 (2010).
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Inflammation linked to metabolic syndrome and mental disorders

Recent results provide evidence that link inflammation with an increased risk of metabolic syndrome and schizophrenia.¹ Metabolic syndrome is characterised by central obesity, raised blood pressure, sub-optimal cholesterol and triglyceride profiles, and raised blood glucose.

In the study, white blood cell count (WBC) was determined in 199 patients. Increased WBC strongly predicted the condition of metabolic syndrome. Further significant correlations were found between high WBC and the Brief Psychiatric Rating Scale (BPRS) - a rating scale which is used to measure psychiatric symptoms such as depression, anxiety, hallucinations and unusual behaviour.

The researchers concluded that WBC can be used as a marker to predict an increased risk for metabolic syndrome and more severe psychiatric symptoms in patients with schizophrenia.

¹ Fan X et al. Higher white blood cell counts are associated with an increased risk for metabolic syndrome and more severe psychopathology in non-diabetic patients with schizophrenia. Schizophrenia Research 118: 211-217 (2010).
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An effective treatment for Alzheimer's disease

Alzheimer's disease reduces the number of nerve cells in the brain, causing it to shrink. Nerve cells can't be replaced naturally, and no cure has yet been discovered, therefore this is irreversible. Alzheimer's disease also leads to a decrease in the number of neurotransmitters, particularly acetylcholine, therefore transmission of neural messages is decreased. The disease leads to deterioration of brain function, resulting in memory loss, reduced language skills and behavioural and emotional problems.

Alzheimer's disease can be treated with acetylcholinesterase inhibitors, although they aren't very effective and most people get little benefit from them.¹ A couple of years ago the first steps were made to investigate the usage of a new drug in the treatment of Alzheimer's disease. Etanercept is an inhibitor that regulates the transmission of signals between neurons in the brain. It regulates the function of a protein called TNF-alpha that is usually involved in inflammation.² A number of investigations have related excess TNF-alpha to the progression of Alzheimer's disease, as it seems to also act as a neural transmitter in the human body.²

Etanercept has previously been used in the effective relief of pain, through perispinal administration (injection around the spine, but not into the spinal column).² This indicated that etanercept crosses the blood-brain membrane barrier, and suggested that the veins around the spine can be used to transport drugs to the spine and the brain.

In a case study, two patients were treated with perispinal etanercept.² The first patient had impairments in attention, linguistic processing, and memory. After treatment with a non-effective drug, he had become effectively mute before his treatment regime was changed to include perispinal etanercept. The patient's speech, as well as his movement, increased significantly after treatment, with the greatest improvement seen in the week after treatment.

The second patient was an 80 year-old who had a history of increasing word-finding difficulty, and worsening memory and handwriting. Even just 8 minutes after treatment with etanercept, the patient showed improvement, being able to recite the days of the week backwards, something he was incapable of doing before treatment. His conversational ability, attention span, and forgetfulness all improved in the weeks post-treatment, with the greatest effect being seen in the first week.

Since the greatest effect was observed one week after etanercept treatment, weekly treatments might be the most effective. Although this study has limitations, it adds to the range of treatments available to treat Alzheimer's disease.


¹ http://hcd2.bupa.co.uk/fact_sheets/html/alzheimers_disease.html
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² Tolbinick E and Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease. BMC Neurology 8:27 (2008)

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Singing therapy for COPD

Chronic obstructive pulmonary disease(COPD) is a term used for a number of lung conditions that all affect ease of breathing, such as bronchitis and emphysema. COPD is a long-term disease that damages the airways, making them increasingly narrow, and thereby further obstructing airflow. Symptoms can be mild, including cough, phlegm, and shortness of breath during the winter or after a cold, to severe, with constant shortness of breath severely affecting daily activities. COPD cannot be cured, but it can be treated.

Patients with COPD often try to compensate for obstructed airways by changing the way they breathe. This may lead to stress on the respiratory muscles, while short, rapid breaths may cause an increased sense of panic, and exacerbate feelings of breathlessness.

A recent randomised controlled trial¹ looked at the effect of a 6-week singing course on the breathing patterns of patients with COPD. Patients who took part in the singing course showed significant improvements in their perceived quality of life as well as anxiety levels when compared to patients who didn't sing. When interviewed, 8 of the patients who took part in singing felt that it had a positive effect on their well-being, community support, achievement, and physical sensation.

In a larger study where a number of open singing workshops were offered, almost all of the 150 patients experienced the workshop as very enjoyable, and thought it had taught them how to breathe in a different way. The vast majority felt a marked physical difference after the workshop.

Therefore singing classes can improve the lives of patients with COPD, with a number of positive effects and no negative effects.

¹ Lord VM et al. Singing teaching as a therapy for chronic respiratory disease - a randomised controlled trial and qualitative evaluation. BMC Pulmonary Medicine 10:41 (2010)
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If you develop it, they will use it

Research from the department of "why didn't we think of that?": in research sponsored by Reckitt Benckiser Healthcare International Ltd, the treatment of pain with a tablet containing both paracetamol and ibuprofen was investigated.¹ These pain killers (analgesics) work in different ways, and therefore can be used together safely without causing overdose. Paracetamol, in contrast to ibuprofen, can accumulate in the liver when overdose occurs, and cause massive damage.

Volunteers were given either a combination paracetamol-ibuprofen tablet, or the two analgesics seperately. The combination pill showed a more rapid absorption of paracetamol, compared to paracetamol taken on its own. The mean blood concentrations of both paracetamol and ibuprofen were higher, earlier, than when the drugs were taken individually.

When the combined paracetamol-ibuprofen tablet was taken after a meal, absorption of ibuprofen was delayed by 25 minutes, and that of paracetamol was delayed by 55 minutes. The maximal blood concentration of both was also decreased when the tablet was taken after a meal. The study also determined that the combination tablet causes therapeutic dose levels of ibuprofen and paracetamol for approximately 12 hours when given three times per day. Therefore a combination paracetamol-ibuprofen treatment could provide enhanced pain relief for more severe pain.

Or, of course, you could just buy the two seperately, and take them together.




¹Tanner T, Aspley S, Munn A, Thomas T. The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol. BMC Clinical Pharmacology 10:10 (2010).
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The effect of drug use on pain tolerance

Research has shown that former opiate addicts that have been treated with methadone, and thereafter systematically taken off the methadone treatment, show decreases in brain function and abnormal pain thresholds.¹

A recent study tested the mental acuity of former opiate-dependent subjects before and after being exposed to a treatment that caused pain. The subjects were treated with a heat stimulus at their pain threshold. Their mental acuity was tested with a Stroop test. In this test you are instructed to name the colour that a word has been written in, when the word itself describes a colour (see image right).

Control subjects performed better than former opiate-dependent subjects in the Stroop test, when no pain was experienced. (Controls were never opiate-dependent and weren't exposed to methadone treatment either. ) In general, females performed better than males under these conditions. However, under painful conditions, male former opiate-dependent individuals showed a greater improvement in Stroop test scores than male control subjects or females of either group.

Therefore previous opiate dependence affects brain function, with males seemingly being more affected than females. However, response to pain is also altered, with males who were previously opiate dependent showing greater improvements in Stroop scores than females and control subjects.

¹Aniskin DB, MD; Fink E, MD; Prosser J, MD; Cohen LJ, PhD; Boda N, MD; Steinfeld M, MS; Galynker II, MD, PhD. The Effect of Pain on Stroop Performance in Patients With Opiate Dependence in Sustained Remission. Journal of Addiction Medicine doi: 10.1097/ADM.0b013e3181d77c07
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Swine flu treatment

In 2009 the Influenza A (H1N1) virus caused a global flu pandemic. It was commonly known as "swine flu" due to the presence of genetic elements from swine influenza. Recently a second occurrence of swine flu in India has claimed 13 lives, and continues to be a threat. ¹

Research underaken at Louisiana State University points to the usage of plasma exchange to treat patients with swine flu.² In these patients the disease reached severe proportions, being associated with inflammation of the lungs, shortness of breath, low blood-oxygen levels, and compromised circulation.

All the patients received three exchanges of blood plasma on consecutive days, showed no side effects, and survived despite the fact that the disease was expected to be fatal.

A critical key to the efficacy of this treatment was the already existent infrastructure that facilitated rapid response. This treatment provides an alternative when other treatments have been unsuccessful in addressing serious complications of swine flu.


¹ H1N1 vaccination drive for medical, para-medical staff launched. The Times of India: Aug 8, 2010.
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²Patel P et al. Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza-An associated respiratory failure and hemodynamic shock. Pediatric Critical Care Medicine doi: 10.1097/PCC.0b013e3181e2a569 (2010)
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Prosthetic limbs

Recent TV coverage of the use of prostheses in animals^{1, 2} have brought to the attention the novel invention of the Intraosseus Transcutaneous Amputation Prosthesis (ITAP).³

Traditional prostheses are attached to limb stumps by straps or other attachment methods. Therefore the stump, covered in soft tissue and skin, presses on the prosthesis. This can lead to a number of complications, such as pressure sores. These prosthetics can also be quite inefficient if the muscles that move the prosthesis are active far away from the prosthesis.

The ITAP was developed by researchers at University College London to address these issues. The ITAP prevents trauma to soft tissues by redistributing stress to the bone. However, the ITAP creates a breach in the skin's protective barrier to infection - therefore a method was required to prevent infection from occurring around the entry point of the prosthesis. The ITAP was therefore modelled on deer antlers, as antlers represent bone that grows out of a skin base, without infection occurring (Fig. 1).






The research group developed a pin that could be inserted into bone, and which had an external peg to which a prosthetic limb could be attached (Fig. 2). The surface of the pin is shaped with grooves to prevent rotation in the bone (Fig.2: 1), and also treated with a substance such as hydroxy apatite (a form of calcium phosphate), to encourage integration into the bone. The middle section of the pin consists of a flange (Fig.2: 4) that which forms a link between the bone and the epithelial surface of the soft tissue surrounding it. This flange has a porous coating (Fig.2: 6) to encourage soft tissue growth. This can further be promoted by treating the surfaces with adhesion-promoting proteins, such as fibronectin or laminin. The implant attaches directly to the skin at this point - something that has never been done before. A successful seal between the implant and the skin prevents infections. The exterior peg (Fig.2: 5) is treated with a diamond-like carbon layer that prevents the adhesion of micro-organisms, further reducing the risk of infection.

The ITAP was first used in a clinical trial in 2005 in a woman who had lost a thumb due to a bite from a horse.⁴ ITAP products have been used for the prosthetic replacement of 12 fingers and thumbs, 1 arm, 2 legs, and 5 craniofacial bones in humans, and for the replacement of thoracic and pelvic limbs in a number of cats and dogs (see a photo⁵ of Coal, an American Bulldog who received an ITAP at Fitzpatrick Referrals).











¹ http://www.bbc.co.uk/programmes/b00syxlx
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² http://www.fitzpatrickreferrals.co.uk/
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³ Blun G et al. Transcutaneous prosthesis. US patent 7014661
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⁴ http://www.ukti.gov.uk/investintheuk/sectoropportunities/lifesciences/localisation/110831.html (2010)
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⁵ Fitzpatrick N. Intraosseous Transcutaneous Amputation Prosthesis. The SPVS Review pp43-52 (2009)
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Obesity - disease or lack of willpower?

Debate rages over whether obesity is caused by lifestyle or is actually a disease.

A lot of research has pinpointed genetic factors that are associated with obesity and even some behaviours. Certain changes in DNA are strongly correlated with the incidence of obesity, such as the deletion of DNA from chromosome 16¹ and specific changes in single nucleotides in 13 different genes in the human genome.² A research group in Spain has found a strong association between single nucleotide polymorphisms (SNPs) in a gene related to the circadian clock³, and cessation of a weight-reduction program. These SNPs were also associated with extreme snacking, eating when bored, skipping breakfast, and abdominal obesity.

The value of this research lies in the potential to tailor weight-loss programs to the individual. At the Nutrition, Physical Activity, and Metabolism 2010 conference held in March in San Francisco, data was presented showing that people responded better to diets when these diets were assigned based on their genotype, instead of randomly.⁴

Subjects were put on either the Atkins, Ornish, Traditional, or Zone diets, and the presence of specific forms of three different genes were determined. There was a strong and significant correlation between certain genotypes, a specific weightloss regime, and amount of weight lost. The proportion of people who responded well to low-carb diets compared to those who responded well to low-fat diets was approximately 50-50.

So your genes might tell you whether you're predisposed to gaining weight. It can also help you to choose strategies to manage weight loss. Increasing knowledge of the links between genes and disease allow for the development of more sophisticated drugs and treatments.

¹Walters R.G. et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463, 671-675 (2010).
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²Cheung C.Y.Y. et al. Obesity Susceptibility Genetic Variants Identified from Recent Genome-Wide Association Studies: Implications in a Chinese Population. The Journal of Clinical Endocrinology & Metabolism 95: 1395-1403 (2010).
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³Garaulet M. et al. PERIOD2 Variants Are Associated with Abdominal Obesity, Psycho-Behavioral Factors, and Attrition in the Dietary Treatment of Obesity. Journal of the American Dietetic Association 110: 917-921 (2010).
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⁴O'Riordan M. Dieting by DNA? Popular diets work best by genotype, research shows. Heartwire (2010)
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Antibody therapy

Ron Levy, professor of Medicine at Stanford University, is the man who took the first steps in the development of antibodies as a therapy.¹ In 1976 Dr. Levy discovered that antibodies can be made in the lab that will identify and bind to cancerous cells, triggering an immune response that destroys the cancerous cells. His initial work focused on creating tailor-made antibodies for use in individual patients, but as this would be unfeasible at an industrial level, the treatment was developed into a large-scale drug. This drug didn't target only cancer cells, but targeted all B-cells of the immune system. The results were surprising, as people did very well despite having their bodies depleted of B-cells - cells that form a significant part of the immune system. This drug is marketed under the name "Rituximab" or "Rituxan".

Rituximab works by identifying a specific protein on the outside of B-cells, called CD20.² When Rituximab binds to CD20, the body's immune system is triggered, leading to the destruction of that B-cell. Since Rituximab doesn't distinguish between cancerous and non-cancerous B-cells, all B-cells in the body are targeted. This therapy has a number of serious potential side-effects, but is attractive to use since it doesn't cause the nausea and malaise caused by other treatments like chemotherapy. It can also be used repeatedly if relapse occurs, with improved response at each consecutive treatment.

Rituximab has been used successfully in the treatment of lupus³, rheumatoid arthritis⁴, and in transplants to prevent rejection of transplanted tissue.⁵

Since the development of Rituximab, a large amount of research has been done on the usage of antibodies to treat various cancers and diseases. As can be seen from the illustration below, antibody therapies have been developed to treat blood-related cancers (hematologic malignancies) and solid tumors, targeting a number of surface proteins on B-cells. There is an excellent review on the topic of antibody therapies, their development and application, as well as their potential use in the targeting of influenza virus here.<sup>6



1</sup> http://stanmed.stanford.edu/2004fall/levy.html
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²Pescovitz M.D. Rituximab, an Anti-CD20 Monoclonal Antibody: History and Mechanism of Action. American Journal of Transplantation 6:859-866 (2006).
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³ Eisenberg R. SLE - Rituximab in lupus. Arthritis Res Ther. 5: 157–159 (2003).
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⁴ http://www.rituxan.com/ra/patient/index.xhtml
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⁵ Salama A. and Pusey C.D. Drug Insight: rituximab in renal disease and transplantation. Nature Clinical Practice Nephrology 2: 221-230 (2006).
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⁶ Guzmán F. Overview on monoclonal antibody therapy: PPT, images and videos. Pharmacology Corner http://pharmacologycorner.com/overview-on-monoclonal-antibody-therapy-ppt-images-and-videos/
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Bone Marrow Mononuclear Cell Therapy

"Bone Marrow Mononuclear Cell Therapy" is a form of stem cell therapy. There has been a lot of research on the use of stem cell therapy to treat heart attacks, emphysema, as well as stroke. This entry focuses on stroke treatment.

A novel approach to treating stroke has been invstigated by a research group in Germany.¹ The investigators took bone marrow cells from human volunteers, isolated mononuclear cells from it, and used these to treat stroke in rats.

The bone marrow cells were transplanted directly into the carotid artery three days after stroke was induced in the rats. Rat behaviour was tested before stroke, as well as 2, 5, 14, 23 and 30 days after stroke.

Unfortunately, treatment didn't improve recovery compared to non-treated rats. This study was based on previous research focusing on the treatment of heart attack with mononuclear bone marrow cells, and suggests that one therapy can't directly be translated to another disease. However, the fact that researchers waited three days before treating the stroke might also be significant. It is essential that stroke patients are treated as soon as possible after stroking - for strokes caused by blood clots the treatment window is 3 hours after stroke.²

Previous research into treating stroke with bone marrow cells focused on the use of stromal bone marrow cells³ and not mononuclear cells. Mononuclear cells come mostly from red bone marrow, which gives rise to cells associated with the immune system such as monocytes and lymphocytes. In contrast, stromal stem cells come from the stroma which contains a number of cells that create the correct environment for the production of mononuclear cells in the red bone marrow. The bone marrow stroma contains cells like fibroblasts and macrophages, as well as other factors like colony stimulating factor, which all support the differentiation of blood-related cells in the red bone marrow. Therefore the type of cell used to treat stroke might also be of significance.

Even though mononuclear cells did not effectively treat stroke in this study, mononuclear cells have been used with success in the treatment of heart attack ^{4, 5} and emphysema. ⁶

¹ Minnerup et al. Intracarotid administration of human bone marrow mononuclear cells in rat photothrombotic ischemia. Exp Transl Stroke Med. 2: 3. (2010) (doi:10.1186/2040-7378-2-3)

² http://www.ninds.nih.gov/news_and_events/news_articles/stroke_pooled_analysis_030404.htm

³ Andrews et al. Human adult bone marrow-derived somatic cell therapy results in functional recovery and axonal plasticity following stroke in the rat. Experimental Neurology 211: 588-592 (2008).
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⁴ Lunde K et al. Intracoronary Injection of Mononuclear Bone Marrow Cells in Acute Myocardial Infarction. New England Journal of Medicine 355: 1199-1209 (2006).
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⁵Leblond, A-L et al. Bone marrow mononuclear stem cells: potential in the treatment of myocardial infarction. Stem Cells and Cloning: Advances and Applications 2: 11–19 (2009).
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⁶ Cruz F et al. Bone Marrow-derived Mononuclear Cell Therapy Improved Lung Mechanics And Histology In A Murine Model Of Emphysema. Am. J. Respir. Crit. Care Med. 181: A1013 (2010).
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Vaccines - Alzheimer's Disease

There are a number of promising vaccines currently being developed for the treatment of Alzheimer's disease.

Alzheimer's disease is associated with the build up of beta-amyloid plaques that cause the degradation of nerve cells. Most treatments are aimed at preventing the formation of plaques, or breaking up plaques that already exist.

AFFiRiS AG is an Austrian company that has recently entered its Alzhemier's vaccine, AD02, into phase II trials.¹ This means that the vaccine will be used on a large group of human volunteers, as previous small-scale trials have shown positive results. AD02 works by identifying and attacking Alzheimer-related beta-amyloid plaques, and breaking them up.

A group in India has developed an alternative vaccine which they claim is safer than current vaccines,² as it is based on a synthetic form of beta-amyloid, while antibodies can still identify it, and prevent the build up of plaques.

A large collaborative research group in Ohio, USA, has studied the usage of a specific peptide both before the onset of Alzheimer's disease, and after.³ The peptide is similar to a specific part of the plaque-forming beta-amyloid, and therefore induces the immune system to make antibodies specific to these proteins. The group suggests that this peptide provides a much safer alternative to current vaccination strategies.

The usage of DNA in a vaccine that might prevent and treat Alzheimer's disease has also been investigated.⁴ Researchers at the University of Texas studied the effect of vaccinating mice with DNA. The DNA causes the production of beta-amyloid in the mouse which triggers the mouse's immune response against the Alzheimer-causing forms of beta-amyloid. Therefore these mice would have better defence against the onset of Alzheimer's disease, since their immune systems will have been primed against it.

And finally, a totally different approach has been taken by the group of Tsuneya Ikezu at the University of Nebraska. Instead of using beta-amyloid in a vaccine, they've studied the usage of a signalling molecule that plays an important role in controlling inflammation.⁵ This molecule, interleukin 4, plays an important role in immune response. In mice models it was shown that increased levels of interleukin 4 was associated with a decrease in beta-amyloid plaque formation and an increase in nerve cell growth. It also improved spatial learning, showing that it supports brain function.


¹ Press release from AFFiRiS AG
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² Subramanian S et al. Design and development of non-fibrillar amyloid β as a potential Alzheimer vaccine. Biochemical and Biophysical Research Communications 394: 393-397 (2010).
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³ Wang CM et al. Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer's disease. Neurobiology of Disease 39: 409-422 (2010).
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⁴ Qu BX et al. Analysis of three plasmid systems for use in DNA Aβ42 immunization as therapy for Alzheimer's disease. Vaccine 28: 5280-5287 (2010).
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⁵ Kiyota T et al. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. doi: 10.1096/fj.10-155317 (2010).
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Vaccines - HIV

There are two disease on which a lot of vaccine research is being done - HIV and Alzheimer's disease. This entry will look at the former.

HIV/AIDS

A US-based group from the Baylor Research Institute has patented a vaccine¹ that uses a human antibody to which a small piece of viral protein is attached. In particular, they've produced two variants of this vaccine using two different viral proteins. The combination of antibody and antigen will stimulate the body to produce antibodies aimed at the HI virus.

Another group has done research on the usage of a lentiviral vector as an HIV vaccine.² The lentiviral vector is transferred into cells in the body and produces non-harmful proteins from the HI virus. The human body recognises these proteins as foreign and produces antibodies against the virus.

At the 16th International Symposium on HIV and Emerging Infectious Diseases in France the development of a therapeutic AIDS vaccine was presented.³ This vaccine, V-1 Immunitor, is an oral pill prepared from HI viral proteins (antigens) that have been heat-inactivated. HIV-positive patients who took these oral preparations showed an increase in white blood cells, decreased viral load, increased body weight, and extended survival. These results, obtained in Russia, reflected previous results obtained in Thailand.


¹ (WO/2010/009346) HIV VACCINE BASED ON TARGETING MAXIMIZED GAG AND NEF TO DENDRITIC CELLS
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² Lemiale F et al. An HIV-based lentiviral vector as HIV vaccine candidate: Immunogenic characterization. Vaccine 28: 1952-1961 (2010)
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³ Bourinbaiar A et al. Pilot trial of oral therapeutic HIV vaccine, V-1 Immunitor, on HIV and HIV/HCV patients in Russia. Retrovirology 7 (Suppl 1): 30. (2010)
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Stroke treatment

Granulocyte colony stimulating factor (G-CSF) is a molecule that carries a signal to the bone marrow, causing it to produce granulocytes and neutrophils (types of white blood cell), as well as stem cells.

Researchers have recently found that G-CSF can cause the growth of neurons (nerve cells - such as those in the brain) in young animals. A lot of scientists disagree whether neurons can grow in adult animals (or humans), and believe that damaged brain cells or other neurons cannot be replaced. However, a study¹ has shown that treatment with G-CSF after a stroke improved recovery in aged rats. Treated rats survived better and showed greater improvement in mobility and memory. The scientists observed an increase in a number of neurons, which shows that neurons can be "born" even in adult animals.

This research points the way towards more effective treatment of stroke victims, and could mean an improved prognosis for many stroke patients in the future.

¹ Popa-Wagner A et al. Effects of Granulocyte-Colony Stimulating Factor After Stroke in Aged Rats. Stroke 41:1027 (2010).
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Spinal cord injury

A study funded by the Korean Government has found that neural stem cells can be genetically modified to transfer therapeutic genes to a damaged spinal cord. ¹

The scientists introduced a gene that makes ventricular endothelial growth factor (VEGF) to some neural stem cells in the lab.

The neural stem cells that expressed VEGF were injected into the damaged spinal cords of rats, and showed that it could cause growth of a number of nerve cells, increase the density of blood vessels in the area, enhance tissue sparing, and improve the recovery of mobility in injured rats.

VEGF has been studied to treat heart-related disease for quite some time now, but this study identifies a new way of applying it. It points the way to potential treatment for people with spinal cord injuries.

¹Kim HM et al. Ex Vivo VEGF Delivery by Neural Stem Cells Enhances Proliferation of Glial Progenitors, Angiogenesis, and Tissue Sparing after Spinal Cord Injury. PLoS ONE 4(3): e4987. doi:10.1371/journal.pone.0004987.
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