White light-activated antibacterial coating-a new weapon against superbugs ?

I read in an article that infection costs the NHS around £1 billion per year and it is estimated that as many as 5,000 patients die each year in the UK as a direct result of an HCAI.

Cutting rates of healthcare associated infections (HCAIs) such as Methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C.Diff) is a key priority for healthcare professionals. Recently in my earlier blog, I did mention that they were able to culture many bacterii from the cell phones of the health workers !.

Thogh govts., are taking many intiatives with sterlisation of the instrements, the rooms still something has to be done. But this is really something interesting which I read recently and want to share with...

Miss Zoie Aiken and her colleagues presented the work at the Society for General Microbiology meeting in Harrogate on 31 March, 2009. The veneer-like surface, made of titanium dioxide with added nitrogen. When it is activated by white light, similar to those used in hospital wards and operating theatres, it produced a decrease in the number of bacteria surviving on the test surface. Really interesting and the basis for this research is that "Titanium dioxide based coatings can kill bacteria after activation with UV light. The addition of nitrogen to these coatings enables photons available in visible light to be utilised to activate the surface and kill bacteria".

The following are the conclusions :

1. the activity of the coating is assessed against a range of different bacteria such as MRSA and other organisms which are known to cause infections in hospitals. At present researchers claim that the coating is active against Escherichia coli. However, E. coli is more difficult to kill than bacteria from the Staphylococcus group which includes MRSA and the results to date are encouraging.

2. the coating has currently been applied onto glass using a method called APCVD (atmospheric pressure chemical vapour deposition and the researchers want to try out plastic.

Once again congrats and best wishes for further research..

Source : http://www.sgm.ac.uk/

Vaccine for Enterotoxigenic E. coli?

We know that Escherichia coli is a bacterium that normally lives in the intestines of humans and other animals. Most types of E. coli are harmless, but some can cause disease. Disease-causing E. coli are grouped according to the different ways by which they cause illness. Enterotoxigenic Escherichia coli, or ETEC, is the name given to a group of E. coli that produce special toxins which stimulate the lining of the intestines causing them to secrete excessive fluid, thus producing diarrhea. The toxins and the diseases that ETEC causes are not related to ETEC was first recognized as a cause of human diarrheal illness in the 1960s. It have since emerged as a major bacterial cause of diarrhea among travelers and children in the developing world. ETEC is increasingly recognized as an important cause of foodborne illness in developed nations, such as the United States.

ETEC produces two toxins, a heat-stable toxin (known as ST) and a heat-labile toxin (LT). Although different strains of ETEC can secrete either one or both of these toxins, the illness caused by each toxin is similar.

Infection with ETEC can cause profuse watery diarrhea and abdominal cramping. Fever, nausea with or without vomiting, chills, loss of appetite, headache, muscle aches and bloating can also occur but are less common. Illness develops 1-3 days after exposure and usually lasts 3-4 days. Some infections may take a week or longer to resolve. Symptoms rarely last more than 3 weeks. Most patients recover with supportive measures alone and do not require hospitalization or antibiotics.

Antibiotics can shorten the duration of diarrheal illness and discomfort, especially if given early, but they are usually not required. ETEC is frequently resistant to common antibiotics, including trimethoprim-sulfamethoxazole and ampicillin. Because resistance to antibiotics is increasing worldwide, the decision to use an antibiotic should be carefully weighed against the severity of illness and the risk of adverse reactions, such as rash, antibiotic-associated colitis, and vaginal yeast infection. Fluoroquinolones have been shown to be effective therapy.

Now thanx to A. Mahdi Saeed, a professor of epidemiology and infectious disease in MSU's colleges of Veterinary Medicine and Human Medicine has achieved a milestone - he has successfully developed vaccine for this, congrats for his group. Saeed created a biological carrier to attach to the toxin that once introduced into the body induces a strong immune response. This was done by mapping the toxin's biology and structure during the design of the vaccine. After creating the carrier in a lab at MSU, Saeed and his team tested it on mice and found the biological activity of the toxin was enhanced by more than 40 percent, leading to its recognition by the body's immune system. After immunizing a group of 10 rabbits, the vaccine led to the production of the highest neutralizing antibody ever reported for this type of the toxin. Though human clinical trials are yet to be done the group is optimistic about the outcome. The Vaccine, also has some other properties like a laxative (helping the bowel movement for the post surgery anestheia impact) and urinary retention. Hope they will achieve the claims. Once again congratulation for this achievement. More ....

Oral Etoricoxib as post surgery drug?

Developed as an alternative to conventional non-steroidal anti-inflammatory drugs (NSAIDs), which can cause intestinal bleeding, "coxibs" are licensed for chronic and acute pain.

Single dose oral etoricoxib produces high levels of good quality pain relief after surgery, says lead researcher Andrew Moore, of the Pain Research and Nuffield Department of Anaesthetics at the University of Oxford.Moore adds that the long lasting action of etoricoxib makes it qualitatively different from other coxibs and ibuprofen. A longer time before remedication is likely to benefit patients by providing long-lasting pain relief. More...

Simponi the first biologic therapy to be approved for rheumatologic diseases !

We did know about the three 3 TNF inhinitors (namely-Infliximab, Etanercept and Adalimumab), the last still to be approved by US.

Like Infliximab and Etanercept, Adalimumab binds to TNFα preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein. TNFα inactivation has proven to be important in down regulating the inflammatory reactions associated with autoimmune diseases. As of 2008 adalimumab has been approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis.

Humira (brand name is an abbreviation of "Human Monoclonal Antibody in Rheumatoid Arthritis") is marketed in both preloaded 0.8 ml syringes and also in preloaded pen devices (called Humira Pen), both injected subcutaneously, typically by the patient at home. It cannot be administered orally, because the digestive system would destroy the drug. But its now the turn of Golimumab, a new fully human monoclonal antibody. Being a fully human MAb directed against TNF, Golimumab resembles Adalimumab (Humira, Abbott), which was the first such product to reach the market. Now the Canadian government has approved Golimumab along with ‘methotrexate’ for the treatment of three forms of Rheumatiod arthritis (Rheumatoid Arthritis, Ankylosing Spondylitis & Psoriatic Arthritis) and more over making this treatment the first biologic therapy to be approved.

With this approval in Canada, Simponi (Golimumb), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms in adult patients with moderately to severely active RA; reducing signs and symptoms in adult patients with moderately to severely active PsA, alone or in combination with MTX; and reducing signs and symptoms in adult patients with active AS who have had an inadequate response to conventional therapies. More...

A New approach for the TB drug discovery ?

We are aware that the development of new drugs to combat tuberculosis (TB) has become urgent, as strains of TB resistant to all major anti-TB drugs have emerged worldwide. The World Health Organization estimates that one third of the world's population is asymptomatically infected with TB and that ten percent will eventually develop the disease. More over people with HIV are more prone to TB and hence the need is urgent. As it has happened in other fields of drug discoveries, its something really interesting now it’s the turn of TB drugs, thanx to Barbara Gerratana, Asst., Prof.,. of Chemistry and Biochemistry, university's College of Chemical and Life Sciences, Maryland for their achievement. The significance of the research lies in the fact that “ the NAD+ synthetase enzyme is essential for the survival of the tuberculosis bacteria and hence it can be considered as a drug target.”. So even the structure based inhibitors specific for M. tuberculosis NAD+ synthetase, can be tried and tested for the tuberculosis activity.

Even the experts are really happy over the outcome of the research and following are the lines of appreciation from Clifton E. Barry, Chief of the Tuberculosis Research Section of the Intramural Research Division of the National Institute of Allergy and Infectious Diseases “NadE [NAD+ synthetase] represents one of a small handful of TB drug targets that has iron-clad validation, the lack of a crystal structure was the only serious impediment to drug development and this study represents a hugely important step forward. Inhibiting NadE even kills non-replicating cells, so this discovery may well benefit the one-third of the human population that carries latent bacteria.".

Most interesting part of the research is the fact that “there are only two pathways involved in producing NAD+ in the tuberculosis bacterium and both depend on the activity of NAD+ synthetase to obtain NAD+ (unlike in human beings, where in several different complex pathways..). One can target these two pathways and get good drugs, those are essential and there by one can overcome the drawbacks of the present drugs (current treatment of tuberculosis targets the active tuberculosis bacterium and has little effect on the non-replicating bacterium). Once again congrats for the research group……

Fluorescent anesthetic compound – a new avenues for drug discovery?

We did know about the fluorescent biomarkers in drug discovery, especially to establish the mode of action of drugs. But this is something really interesting by using the fluorescing compound 1-aminoanthracene, (1-AMA), the team developed a high-throughput assay to test for the anesthetic activity.

This research is of great importance because of the fact that one can search for new anesthetic drugs and also new molecular targets with help of high resolution images of the compounds in action. As the compound is fluorescent, researchers will be able to image the compound in vivo (to study its physiological effects). Also one can assess the mode of action and know the concentrations (dose required) of anesthetic administration. Hope this will go a long way in the history of drug discovery, as one can improve the efficacy with reduced side effects.

Researchers confirmed the compound 1-AMA, as anesthetic after testing it successfully in tadpoles. By using transparent, albino tadpoles in the study, researchers were able to follow the fluorophore tag and image it in the brain of the immobilized, living animal.

The following is the explanation of the research group :

Researchers noticed a resemblance in the crystal structure of the apoferritin protein to that of the transmembrane region of the superfamily of ligand-gated channels that includes the GABA receptor. Anesthetics are known to positively modulate GABA signaling.

Because 1-AMA competes with other anesthetics to bind to apoferritin, researchers surmised that the protein likely binds to the same region of apoferritin as traditional anesthetics and thus shares their mechanism of action. Fluorescence of 1-AMA is enhanced when bound to apoferritin. Thus, displacement of 1-AMA by other anesthetics attenuates the fluorescence signal and allows determination of anesthetic affinity, that is, the drugs that bind tightly to the ferritin anesthetic site. In this way, 1-AMA fluorescence could be used to discover new anesthetics. This provides a unique fluorescence assay for compound screening and anesthetic discovery.

Using confocal microscopy to image the distribution of the protein, the team found that 1-AMA localizes largely in the brain and olfactory regions, unlike some general anesthetics which spread widely throughout the body. Ideally, clinical anesthetics would have a very focused target area in order to minimize systemic toxicity.

Though further studies are essential it’s a good beginning congrats Ivan J. Dmochowski and his group for this achievement.

As we know that, anesthetics bind weakly to their chemical targets and there by leading to some unintended side effects and hence searching for new targets in the central nervous system is difficult. But now with this technique, one can search for other compounds. Like what they have achieved.

Broccoli sprouts may help prevent stomach cancer !

Pict., of Broccoli (Structures of DIM & Sulforaphane respectively)

We knew that Broccoli has anticancer activity due to the presence Diindolylmethane, DIM (Str-1). DIM is a natural compound formed during the autolytic breakdown of glucobrassicin present in food plants of the Brassica genus, including broccoli, cabbage, Brussels sprouts, cauliflower and kale. The autolytic breakdown of glucobrassicin requires the catalytic reaction of the enzyme myrosinase which is endogenous to these plants and released upon rupture of the cell wall

(the same compound, has been tested for viral nfections,bacterial infections and immune deficiency diseases also). And boiling the Broccoli, will lead to the loss of this compound has been also established

Now more interestingly, Dr. Jed Fahey has come out with something different and this time they have mentioned about a phytochemical from broccoli, i.e., sulforaphane. Though the cancer protective effects of sulforaphane is known two decades ago, but this is the first study to show an effect of broccoli in humans on the bacterial infection that leads to stomach cancer. In this study, researchers enrolled 48 Helicobacter-infected Japanese men and women and randomly assigned them to eat 70 grams of fresh broccoli sprouts daily for eight weeks or an equivalent amount of alfalfa sprouts.

Researchers assessed the severity of H. pylori infection at enrollment, and again at four and eight weeks using standard breath, serum and stool tests. H. pylori levels were significantly lower at eight weeks on all three measures among those patients who had eaten broccoli sprouts, while they remained the same for patients who had eaten alfalfa sprouts.

A reduction in H. pylori is expected to lead to a reduction in stomach cancer due to their well-established cause-and-effect link. Stomach cancer has a grim prognosis and is the second most common and the second deadliest cancer worldwide. Congrats Dr. Jed Fahey and group...

Niacin as one of the best and cheapest ways to manage cholesterol !

Niacin (nicotinic acid or vitamin B3), has long been regarded as one of the most effective weapons in managing cholesterol. It can lower levels of triglycerides, fatty acids and to a lesser extent, the "bad" kind of cholesterol (LDL) while at the same time powerfully increasing the "good" kind (HDL). But because of its side effect (it causes embarrassing, uncontrollable intense flushing, a rush of blood to the face and other skin surfaces accompanied by a prickling sensation) its not being used. Now thanks to the researchers lead by Dr. Robert Walters, who have come up with a novel explanation (allergy). The following is the explanation of the researchers :

Niacin stimulates production of a vasodilator that dramatically increases blood flow to the face, causing the flush and the hot, prickly sensation - and beta-arrestin1 is the culprit that enables that to happen. However, beta-arrestin1 plays no role whatsoever in niacin's ability to lower cholesterol and fatty acids.

The finding reinforces some of Lefkowitz's (who has jointly worked with this group) recent research (that demonstrated that beta-arrestins which oftenly work in tandem with G proteins) can sometimes work independently of them and there by initiating their own signals.

The discovery opens the door to the possibility of developing a "biased ligand," a drug that would trigger GP109A, but not the beta-arrestins. Though further studies are essential in this regard, its a good beginning, as the research has achieved the first target i.e., to keep all the lipid-modifying benefits of niacin, but isolate its downside. Congrats Dr. Robert Walters et. al.,

Visualization of single ribonucleic acid in living cell achieved?

Yes says a research group lead by Philip Santangelo, an Asst., Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. This finding is of importance because of the fact that, this tool will help scientists learn more about how RNA operates within living cells. And more over the researchers have overcome some of the drawbacks of the earlier method like “the need for synthetic RNA or a large number of fluorescent molecules”.

In the study, the probes - produced by attaching a few small fluorescent molecules called fluorophores to a modified nucleic acid sequence and combining the sequences with a protein - exhibited single-molecule sensitivity and allowed the researchers to target and follow native RNA and non-engineered viral RNA in living cells.

The significance of the research lies in the fact that the probes recognize RNA sequences and bind to them using the same base pairing most of us are familiar in regards to DNA, For their experiments, the team used a bacterial toxin to transport the probes into living cells - a delivery technique that when combined with the high affinity of the probes for their targets, required significantly fewer probes than existing techniques. The toxin created several tiny holes in the cell membrane that allowed the probes to enter the cell's cytoplasm and later testing the sensitivity by the conventional fluorescence microscopy to image individual probes inside a cell. More interestingly, they were able to overcome the draw back of earlier method like “accumulation of probes inside a cell”.

With single-molecule sensitivity accomplished, the researchers investigated whether they could visualize individual RNA molecules using the probes. To do this, they simultaneously delivered probes designed to target a human messenger RNA (mRNA) sequence region and a probe designed with no target in the human genome. They were able to image unbound probes of both types as well as individual RNA molecules that had attached to the former probes.

With this the researchers also were, able to observe a process called dynamic RNA-protein co-localization (joining of RNA molecules and RNA binding proteins in a single cell). Congratulations for the group and wish them further success in their endeavor…More..

New hope for patients suffering from Parkinson’s Disease ?

A novel method for the treatment of patients suffering from parkinson's disease (and probably will be the first of its kind in the history of the treatment of Parkinson's disease- if established) has been achieved by Dr. Miguel Nicolelis, Deane Professor of Neuroscience at Duke. The research is of great importance becoz., of the fact that the researchers have developed a prosthetic device that applies electrical stimulation to the dorsal column in the spinal cord (which is a main sensory pathway carrying tactile information from the body to the brain). The device was attached to the surface of the spinal cord in mice and rats with depleted levels of the chemical dopamine - mimicking the biologic characteristics of someone with Parkinson's disease along with the impaired motor skills seen in advanced stages of the disease. When the device was turned on, the dopamine-depleted animals' slow, stiff movements were replaced with the active behaviors of healthy mice and rats. Improved movement was typically observed within 3.35 seconds after stimulation.

More interesting about this research is the fact, when the device was used without additional medication, Parkinsonian animals were 26 times more active. When stimulation was coupled with medication, only two L-DOPA doses were needed to produce movement compared to five doses when the medication was used by itself. When I talked to a Physiotherapist, he was also unaware of the basis behind this invention. But the explaination given by the authors is something interesting and justifies it i.e., the rhythmic brain activity in the animals with Parkinson's disease resembled the mild, continuous, low-frequency seizures that are seen in those with epilepsy. One effective therapy for treating epilepsy involves stimulating the peripheral nerves, which facilitate communication between the spinal cord and the body. Researchers took that concept and developed a modified approach for a Parkinson's disease model. The low frequency seizures, or oscillations, seen in the animal model of Parkinson's disease have been observed in humans with the condition. Stimulating the dorsal column of the spinal cord reduces these oscillations, which researchers believe creates the ability to produce motor function. Congrats Dr. Nicole, and hope with more studies this method becomes a ray of hope for those sufferers..

New TB vaccine ?

         On March 11, I did mention about the improvement for the existing BCG vaccine for tuberculosis. But this is something really interesting a new vaccine (AdAg85A vaccine) for TB, has been developed using a genetically modified adenovirus by a group of researchers lead by Prof. Zhou Xing of McMaster University. 
 

     As we are aware TB ranks second only to HIV among infectious killers worldwide, claiming nearly two million lives annually. The disease is evolving faster than therapies with the emergence in recent years of strains that are resistant to every last one of the antibiotic defences. This reserach is of great importance because of the fact that  new TB vaccine using a genetically modified adenovirus - a virus responsible for the common cold. After removing a small portion of the gene, they inserted part of the TB gene responsible for immunity. It is natural ways of making the body use its own immune machinery.

 

   And going by the claims that (based on all pre-clinical studies carried out on animals, including mice, guinea pigs -who are very prone to TB  and cattle), this vaccine appears to be a very promising candidate vaccine.

  Once they will be able to conlcude (may be after mid April/May), about the safety of the vaccine, this research will go a long way in the history of TB research... Congrats Prof. Xing and group.  More..

Successful clinical results for plant-produced insulin....

          On Jan 25th, 2009  I did write a blog on "Insulin from Plants ?".  It has come true now and SemBioSys Genetics  has come up with clinical results for the plant-produced insulin, congrats once again.  The results are of great importance because of the fact that SBS-1000 (produced by SemBioSys, from plant) was bioequivalent to Eli Lilly's Humulin R, a widely-used human insulin in North America, meeting all four of the endpoints outlined below and also SBS-1000 in humans showed pharmacokinetics and pharmacodynamics indistinguishable from Eli Lilly's Humulin R, as SemBioSys had previously shown in animals.

        Though  final analyses regarding safety data are not yet available, the adverse events observed were typical for a study involving recombinant human insulins (Humulin R and Humulin S) . The most common events were insulin injection site reactions, pain at the site of glucose infusion, headache and dizziness, with all similar rates of occurrence for both Humulins and SBS-1000. There were no serious adverse events and there were no events indicative of a systemic allergic response to any of the insulins.  Best of luck for ur further efforts. More....  

Improved synthetic biology for Artemisinin....

We know that Artemision, is a drug to treat multi-drug resistant strains of falciparum malaria. And also fermenting artemisinin via engineered microbes, such as yeast, can be done at far lower costs than extracting the drug from Artemsisia annua , the sweet wormwood tree, making microbial-based artemisinin a much cheaper but equally effective treatment. However the cost of extracting artemisinin from wormwood trees, which only produce the drug under a narrow set of agricultural and climatological conditions or manufacturing it entirely through chemical synthesis is too high. This encouraged Dr. Keasling and his group to undertake this research and are succesful in achieving an improved method, where in the cost will drastically down. And this research is also of great important by the fact that, the same method can be elaborated to make biofuels.

In 2003, they reported their first success. By transplanting genes from yeast and from the sweet wormwood tree into E. coli bacteria and then bypassing the E. coli's metabolic pathway and engineering a new one based on the mevalonate pathway in yeast, they were able to induce the bacteria to produce amorphadiene, a chemical precursor to artemisinin. Even though the yields were low, they achieved one more significance by res using the re-synthesis and other techniques to improve the yield of amorphadiene in E. coli by a million fold. As the conversion of artemisinic acid to artemisinin in high yields are already known, this finding is of great importance.

The most significant part of their reserach is creating a new metabolic pathway in the yeast, similar to the one created in E. coli, then introduced bacterial and wormwood genes into the yeast's DNA that interacted with the yeast's own genes to produce amorphadiene. Finally, they cloned the gene from the wormwood tree that produces the enzyme P450, which the plant uses to convert amorphadiene to artemisinic acid, and expressed it in the amorphadiene-producing yeast strain. And the group wants to use the same technology to make biofuels.... Congrats Dr.Jay D. Keasling...

Improved efficacy of tuberculosis vaccine ?

We know that BCG (Bacille Calmette-Guérin) is a live but weakened form of a bacterium, M. bovis, which causes tuberculosis in cattle. It is sufficiently related to the human pathogen to stimulate production of specialized immune cells that fight off TB infection when it is injected into a person as a vaccine. The bacilli have retained enough strong antigenicity to become a somewhat effective vaccine for the prevention of human tuberculosis. At best, the BCG vaccine is 80% effective in preventing tuberculosis for a duration of 15 years, however, its protective effect appears to vary according to geography.

Many attempts have been made to improve the vaccine by incorporating antigens (molecular components of the bacteria) to induce a stronger immune response. However, tuberculosis and BCG have evasive mechanisms that prevent the development of stronger immune responses. We read oftenly in news paper, about the drug resistant strains and use of combined drugs. Now thanx to the two research groups from UT Health Science Center at Houston. The importance of this research is in the fact that the two groups investigated mechanisms by which BCG evades immune stimulating mechanisms and devised two means to neutralize them.

1. scientists used genetically-modified organisms and
2. a drug used for organ transplantation (Rapamycin, see the structure)to block BCG's evasive mechanisms, causing it to induce stronger immune responses.

This dual approach to the BCG vaccine was associated with a tenfold increase in the number of TB organisms killed and a threefold increase in the duration of protection in tests with an NIH-approved mouse model, Dr. Jagannath said.

The research is of great importance because of the fact that "it has countered the ability of TB organisms to subvert immunization", (Tuberculosis hides in cells so the antigens are not recognized by the immune system. The BCG vaccine also does the same thing). The role of the drug is of great importance, i.e., it modulates the movement of particles in cells, would cause BCG antigens to enter pathways leading to improved immunization. I would say one more significant contribution(or else one more serendipity !) of the drug apart from bieng used in 1. treatment of cancer and inflammation 2. in significantly reducing the frequency of acute kidney transplant rejection.

Though further research to substantiate the claim is essential. Its a good beginning in this direction for the improved efficay of the vaccine.. Congrats Dr. Jagannath and group.. More...

Mode of action of curcumin establlished ?

In India, turmeric (Haldi-in Hindi, Arishin-in Kannada) has been used in food preparation. Curcumin (see the structure left side, is the principal curcuminoid). We used to read about its many properties like antitumour, antioxidant, antimyloid, antiarthritic and many others. Though scientific explanations were not established, still then our forefathers used turmeric for many centuries. Even it has been used in home remedies for cold, cough and as an antiseptic etc. But so for a little was known about the mode of action or how actually it works inside the body. Thanks to Dr.Rammoorthy, a professor of chemistry and biophysics at University of Michigan, has come up with explanation for this.

The authors claims that "curcumin acts as a disciplinarian, inserting itself into cell membranes and making them more orderly, a move that improves cells' resistance to infection and malignancy. More interesting is the technique they use is solid-state NMR spectroscopy(two-dimensional solid-state NMR technique). This technique which is unique helps to reveal atom-level details of these important molecules and the membranous milieu in which they operate.

In a related line of research, Ramamoorthy's team is using the same methods to investigate the effects of curcumin on the formation of amyloids---clumps of fibrous protein believed to be involved in type 2 diabetes, Alzheimer's disease, Parkinson's disease, and many other maladies. Congrats, Dr.Rammoorthy, for this achievement. If proven further details, hope something intersting and useful info for mankind. More..