Month: September 2010

Epstein-Barr virus: Silent companion or causative agent of chronic liver disease

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Petrova M et al. – Chronic EBV–associated hepatitis is suspected in immunocompetent adults with compatible serology, suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T–lymphocytes. EBV is the main cause of post–transplant lymphoproliferative disorders which occur in up to 30% of cases. EBV–driven lymphoproliferative diseases are also recognized in non–immunocompromised patients and liver is involved in up to a third of the cases. Directly implicated in the pathogenesis of different tumors, EBV has a disputable role in hepatocellular carcinoma carcinogenesis. Further research is required in order to establish or reject the role of EBV in human liver cancer.

source:world journal of gastoenterology

Skin diseases associated with hepatitis C virus: Facts and controversies

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Rebora A – Hepatitis C virus (HCV) is a common infectious agent and may induce several systemic disorders like mixed cryoglobulinemia. In the geographic areas where HCV infection is hyperendemic, HCV is the predominant etiologic factor for porphyria cutanea tarda and lichen planus. Vasculitides and autoimmune disorders, such as sicca syndrome, are probably often related to the virus. Interferon–a2b, which is largely used in the treatment of HCV–positive patients, may induce cell–mediated autoimmune side effects. Dermatologists may help to identify those patients timely.

Tranexamic acid for trauma

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We were very interested in the CRASH-2 trial.1 It showed not only the efficacy of tranexamic acid, but also its excellent safety in a large cohort of patients. Although the inclusion criteria for this trial were very relevant to routine clinical practice, hypotension in a trauma patient can be related to other causes (pneumothorax, spinal cord injury, etc) and not necessarily to documented bleeding.2
The CRASH-2 trial included younger patients than in other series and therefore underestimates pre-existing occlusive lesions with their corollary of platelet antiaggregant or anticoagulant treatments that predispose to bleeding.
A high frequency of coagulopathy is established on emergency-room admission and is affected by prehospital management and the magnitude of injury (reflected by the injury severity score [ISS]). ISS is not presented in the results of the CRASH-2 trial. Organisation of the health-care system therefore has a major role.3 The CRASH-2 trial does not take into account prehospital organisation, raising the question of whether these results can be extrapolated to all health-care systems.
Since randomisation did not take into account patients in whom tranexamic acid would have been immediately indicated, this trial excluded the most critically ill patients.
Many European and North American studies on the therapeutic approach to haemorrhage have assessed the effect on mortality of the transfusion ratio of fresh frozen plasma to packed red blood cells.4 The CRASH-2 trial did not address this issue. Although this trial done on an intention-to-treat basis has a substantial statistical power, the absence of analysis of the transfusion ratio could represent a bias and a limitation to the use of tranexamic acid for the most seriously ill patients. Finally, the prevalence of thrombotic complications in the CRASH-2 trial remains relatively low compared with other studies.5
Owing to its power and rigorous methods, this trial nevertheless remains a major trial in the therapeutic approach to haemorrhage in trauma patients, showing that this inexpensive and easy-to-use molecule could be particularly useful in emergency situations without any major adverse effects.
source:Lancet

COX inhibition: Naproxen by proxy

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Naproxen is one of the original non-steroidal anti-inflammatory drugs (NSAIDs) that target the cyclooxygenase (COX) enzymes, yet the molecular basis of its interaction with COX enzymes has not been well established. Through a structure-activity-guided approach, Lawrence Marnett and colleagues uncover interactions that dictate naproxen binding to COX-2 and distinguish it from other NSAIDs that bind the COX enzymes.

There are at least four structural classes of molecules that characterize NSAIDs. Naproxen is a relatively simple molecule, containing three functional groups: an arylpropionic acid (carboxylate), a p-methoxy group and an α–methyl group on a naphthyl scaffold. As a drug, naproxen inhibits both COX-1 and COX-2 with comparable IC50s and exhibits gastrointestinal side effects, but reduced cardiovascular side effects relative to other selective as well as non-selective COX inhibitors.

To probe the interaction between naproxen and the COX enzymes, Marnett and colleagues mutated residues R120 and Y355 of murine COX-2 (mCOX-2), as these residues have been identified to mediate the canonical interaction of the arylcarboxylic acid family of NSAIDs. These mutations suggest that the carboxylate group of naproxen binds in the canonical orientation, coordinated to these two residues. To verify this and to identify other naproxen interactions with mCOX-2, the authors solved the co-crystal structure at 1.7 Å resolution.

This high resolution structure enabled visualization of solvent, ion and detergent molecules not observed in lower resolution structures of the COX enzymes, as well as subtle differences from existing co-crystal structures with COX-2. The naproxen-mCOX-2 complex also revealed a single orientation of naproxen within the COX-2 active site. Beyond the hydrogen-bonding interactions of the naproxen carboxylate group to R120 and Y355 predicted from the mutagenesis data, all other interactions are van der Waals contacts. W387 is an important residue at the top of the mCOX-2 active site. That naproxen was unable to inhibit a W387F mutant, whereas other NSAIDs like diclofenac and indomethacin could inhibit enzymatic activity suggests that an interaction between naproxen and this residue is specific to this NSAID.

Turning to mutagenesis of the naproxen molecule, the authors substituted the α–methyl group with hydrogen, ethyl or dimethyl substituents and found a loss of enzymatic potency with each of them, indicating that an (S)-methyl group at this position is critical. The co-structure shows that this group inserts into a small hydrophobic cleft below V349, which seems to anchor naproxen within the active site and reinforce the canonical binding orientation. A similar structure-activity relationship analysis of the naproxen p-methoxy group suggested the importance of this constituent at the top of the enzyme active site channel. Interestingly, p-ethyl and p-methylthio substitutions at this position still allowed inhibition of mCOX-2, but these compounds could not inhibit ovine COX-1.

Also surprising was that both of these analogs inhibited the W387F COX-2 mutant as effectively as they inhibited the wild-type enzyme.

To follow up on these observations of COX-2 selectivity, the authors solved a second co-structure, this time between the p-methylthio naproxen derivative and mCOX-2. Compared to the naproxen co-structure, there was a shift of the carboxylate tails of the compounds and a new interaction between the naphthyl backbone of the p-methylthio naproxen, while many of the other interactions remain the same in the two co-structures.

These results define the contribution of the COX protein and naproxen atoms to the affinity and suggest that there is little tolerance for mutation in either component. This could tend to complicate any attempts to modify naproxen to eliminate the unwanted gastrointestinal side effects of the drug.

Gene-therapy hope for β-thalassaemia patients

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The genetic disorder β-thalassaemia demands blood transfusions throughout life.Andrey Prokhorov/iStockphoto

Gene therapy for a form of β-thalassaemia, a genetic disorder whose sufferers require frequent blood transfusions because they cannot properly produce red blood cells, seems to have been successful in a patient who, three years after treatment, no longer requires transfusions1. Doubts remain, however, over whether a set of lucky circumstances is behind the success.

Patients with β-thalassaemia carry faulty copies of the genes needed to produce the β-globin chain of haemoglobin, sometimes lacking the genes altogether. This leads to a shortage of red blood cells, the body’s oxygen carriers.

Sufferers must have regular blood transfusions throughout their lives, an inconvenient and debilitating regime that ultimately shortens life expectancy. The only known cure is stem-cell transplantation, but few patients are able to find a suitable donor.

Because of the gruelling nature of this treatment, the development of gene therapies for β-thalassaemia is seen by many as an exciting prospect. The subject of the latest trial was an 18-year-old man with βE/β0-thalassaemia — in this form of the disease, one copy of the β–globin gene produces unstable β-globin and the other copy is non-functional.

Around half of the patients with this form of β-thalassaemia are dependent on transfusions, and the patient concerned had received blood transfusions since the age of three.

Philippe Leboulch of Harvard Medical School, part of the team that carried out the study, described the treatment as “life-changing”. “Before this treatment, the patient had to be transfused every month. Now he has a full-time job as a cook,” he says.

Unrepeatable?

However, Michael Antoniou of King’s College London, suggests that this case was “an extremely fortuitous event”, and that the positive outcome seen is unlikely to be repeatable in other patients.

The procedure was carried out as follows. In 2007, an international team led by Marina Cavazzana-Calvo of University Paris-Descartes extracted haematopoietic stem cells (HSCs) from the patient’s bone marrow. These cells give rise to all blood cell types, including the haemoglobin-containing red cells. The researchers cultured these cells, and mixed them with vectors based on the lentiviruses — a retrovirus subgroup with a long incubation period — into which a functional copy of the β-globin gene had been introduced. These vectors were shown in preclinical trials to be safer than those derived from the retroviruses — which are also replicated in a host cell — that have been used in previous gene-therapy procedures.

Chemotherapy was used to eliminate as many of the patient’s faulty HSCs as possible, to prevent dilution of the genetically corrected cells, which were then transplanted. Levels of healthy red blood cells and normal β-globin in the subject’s body gradually rose until, around a year after the treatment, he no longer required transfusions. After 33 months he remains mildly anaemic, but the fact that he remains transfusion-free has been hailed as a success.

However, that achievement is tempered by a cautionary note. The researchers have detected overexpression of a protein called HMGA2, which has been linked to cancers, in a high proportion of the genetically modified cells.

Overexpression occurred because the lentivirus vector can randomly integrate into chromosomes. By chance, one transplanted haematopoietic cell clone contains a vector insertion in the HMGA2 gene. A year after the transplant, the researchers noticed that the proportion of genetically modified cells that originated from this particular cell clone was rising until it reached a plateau at around 50%.

The reasons for the over-representation of that particular clone remain unclear, but that could be down to the fact that the patient’s haematopoietic system was reconstituted from just a few modified HSCs. Luigi Naldini, a gene-therapy researcher at San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, says that successfully grafting a larger initial population of modified HSCs could potentially prevent the problem from developing.

source: nature

Multiple sclerosis: Putting a dampener on inflammation

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Multiple sclerosis is a chronic, demyelinating disease of the central nervous system that is thought to have an inflammatory aetiology. High levels of glutamate are found in the brains of patients with multiple sclerosis, but the link between this excitatory neurotransmitter and the immunopathology is not clear. Now, Fallarino et al. suggest a role for metabotropic glutamate receptor 4 (mGluR4) signalling in dampening the immune response during neuroinflammation, highlighting a pathway that could be exploited therapeutically.

DigitalVision

Previous work in a rodent model of multiple sclerosis — experimental autoimmune encephalomyelitis (EAE) — had shown that activation of specific mGluRs, including mGluR4, could help to mediate recovery from disease. The authors therefore assessed the clinical symptoms of mice with EAE that lacked the gene encoding mGluR4 (Grm4−/− mice) and discovered that they had more severe symptoms and an earlier onset of disease than wild-type mice.

mRNA profiling of CD4+ T cells, key effector immune cells, from the brain and lymph nodes of Grm4−/− mice indicated that differentiation of these cells into pro-inflammatory T helper 17 (TH17) cells was favoured over differentiation into regulatory T (TReg) cells, which was in contrast to wild-type mice. Furthermore, EAE-induced inflammation was greater in the knockout mice, with higher levels of pro-inflammatory cytokines and lower levels of inflammation-suppressing cytokines than in wild-type mice with EAE.

Reverse transcription PCR on various cell types from wild-type mice showed that mGluR4 expression was highest in CD4+ T cells and dendritic cells — immune cells that can promote T cell differentiation into a regulatory or an inflammatory phenotype depending on signals from the local environment. Cultures of activated T cells from Grm4−/− mice had the same cytokine profile and rate of proliferation as those from wild-type mice. By contrast, activated dendritic cells from Grm4−/− mice, but not wild-type mice, had a pro-inflammatory cytokine profile. In particular, these cells secreted high levels of interleukin-6 (IL-6) and low levels of IL-27, a profile that is known to promote the differentiation of naive T cells into TH17 rather than TReg cells. Therefore, the effect of mGluR4 signalling on the T cell phenotype seems to be mediated through dendritic cells.

The intracellular signalling pathway that links dendritic cell activation with the production of TH17-type cytokines involves increased cyclic AMP formation. Administration of a positive allosteric modulator of mGluR4 known as PHCCC attenuated this cAMP increase in activated wild-type dendritic cells. In vivo, administration of PHCCC to mice with EAE attenuated disease in a statistically significant, dose-dependent manner and was associated with an increase in TReg cells in the lymph nodes. Thus, allosteric modulators of mGluR4, which are currently under investigation for Parkinson’s disease, might provide an opportunity to harness what seems to be a protective effect of glutamate in patients with multiple sclerosis.

source: Natrure

orphan drug

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To determine whether a general societal preference for prioritising treatment of rare diseases over common ones exists and could provide a justification for accepting higher cost effectiveness thresholds for orphan drugs.

Design Cross sectional survey using a web based questionnaire.

Setting Norway.

Participants Random sample of 1547 Norwegians aged 40-67.

Main outcome measure Choice between funding treatment for a rare disease versus a common disease and how funds should be allocated if it were not possible to treat all patients, for each of two scenarios: identical treatment costs per patient and higher costs for the rare disease. Respondents rated five statements concerning attitudes to equity on a five point Likert scale (5=completely agree).

Results For the equal cost scenario, 11.2% (9.6% to 12.8%) of respondents favoured treating the rare disease, 24.9% (21.7% to 26.0%) the common disease, and 64.9% (62.6% to 67.3%) were indifferent. When the rare disease was four times more costly to treat, the results were, respectively, 7.4% (6.1% to 8.7%), 45.3% (42.8% to 47.8%), and 47.3% (44.8% to 49.8%). Rankings for attitude on a Likert scale indicated strong support for the statements “rare disease patients should have the right to treatment even if more expensive” (mean score 4.5, SD 0.86) and “resources should be used to provide the greatest possible health benefits” (3.9, 1.23).

Conclusions Despite strong general support for statements expressing a desire for equal treatment rights for patients with rare diseases, there was little evidence that a societal preference for rarity exists if treatment of patients with rare diseases is at the expense of treatment of those with common diseases.

source:BM J

SYK in RA

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Two recent reports by Weinblatt and colleagues suggest that R788, an orally administered inhibitor of the tyrosine kinase Syk, is effective in patients who have active rheumatoid arthritis despite treatment with methotrexate.3,4 On the heels of an earlier, short-term, dose-escalation trial,3 in this issue of the Journal, Weinblatt et al. report the results from a phase 2, double-blind, placebo-controlled trial involving a total of 457 patients.4 At 6 months, patients who received either 100 mg of R788 twice daily or 150 mg once daily, as compared with patients receiving placebo, had significant clinical improvement, as measured by American College of Rheumatology (ACR) 20 and ACR 50 response rates (which indicate at least a 20% and 50% reduction, respectively, in the number of both tender and swollen joints and improvement in at least three of five other criteria), as well as by individual measures of disease. The remission rate (as defined by a score of <2.6 in the Disease Activity Score for 28-joint counts [DAS28], in which scores range from 0 to 9.31, with higher scores indicating more disease activity) was greater by a factor of 3 to 4 in both R788 groups as compared with the placebo group at 6 months. Clinical effects were observed within the first week of treatment, and the percentage of patients in whom an ACR 20 response was achieved continued to increase over time. Patients who had previously had no response to biologic therapy also showed significant improvement (as assessed with the use of ACR 20 criteria) with R788 as compared with placebo, albeit at a rate lower than that in the overall patient population. Adverse effects included diarrhea, which was dose-related and reversible, and increased blood pressure, which occurred predominantly in patients who had a history of hypertension and which was managed by adjustment of blood-pressure medications. These findings show the clinical efficacy of R788 in patients with rheumatoid arthritis who have had a suboptimal response to methotrexate. Whether R788, alone or in combination with methotrexate, will slow or prevent the development of erosions will be of great interest.

The role of Syk in the initiation or pathogenesis of rheumatoid arthritis is not well understood. However, Syk is present in the fibroblast-like synoviocytes of patients with rheumatoid arthritis, and phospho-Syk (a potential indicator of active Syk) is seen in significantly greater amounts in the synovial tissues of patients with rheumatoid arthritis than in those of patients with osteoarthritis.5 The possible importance of Syk in rheumatoid arthritis may be linked to its role as a signaling component of Fc receptors, which bind to immunoglobulins, including autoantibodies. Fc receptors are expressed on most immune cells and activate these cells when they are occupied by immune complexes formed by the binding of autoantibodies to their antigen. The activation of these cells promotes various cellular responses including cytokine production, which is a key mechanism by which immune complexes initiate inflammation in the joints. However, it should be noted that the function of Syk is not limited to Fc receptors or to immune cells, since multiple receptors and many cell types (such as B cells, NK cells, and osteoclasts) use Syk.6,7 Therefore the contribution of Syk to the development or severity of arthritis is unlikely to be limited to Fc receptors.

Since the time that the Food and Drug Administration approved imatinib (Gleevec) as the first tyrosine kinase inhibitor (targeting BCR-ABL kinase) used for the treatment of a disease (chronic myelogenous leukemia), an ever-expanding inventory of tyrosine kinase inhibitors has become available for the treatment of multiple types of cancers.8 To date, this is the arena in which tyrosine kinase inhibitors have had their greatest impact; they are routinely used for the treatment of breast cancer, glioblastomas, and pancreatic cancer, among other cancers. An important lesson to be learned from the use of inhibitors like imatinib is that although they are rationally designed for high selectivity to their target, they also show high activity against other tyrosine kinases that have structural similarities to the original target. In the case of imatinib, its ability to inhibit the receptor tyrosine kinase Kit in addition to BCR-ABL kinase has made it useful in treating gastrointestinal stromal tumors that develop from a mutation of the c-kit gene that results in a highly active form of Kit. R788 is known to be a relatively potent inhibitor of the receptor tyrosine kinase Ret,9 a receptor for the glial cell line–derived neurotrophic factor family of extracellular signaling ligands. Ret is involved in development and organogenesis and is expressed in macrophages, which are key contributors to inflammation in rheumatoid arthritis. Thus, the beneficial effects of R788 in patients with rheumatoid arthritis may not be due entirely to its ability to inhibit Syk. Another issue that must be considered is that, unlike many other tyrosine kinases, Syk has tumor-suppressing properties. Increased expression of Syk in neoplastic cells from breast-cancer tumors suppresses tumor growth.10 Moreover, reduced expression of Syk has been found in patients with breast cancer. This suggests that the long-term use of Syk inhibitors should be closely monitored and that its use might be inappropriate for people with a family history of breast cancer.

Clinical trials of Syk inhibitors, together with the trials of Jak3 kinase inhibitors,11 have shown that these inhibitors have considerable promise as new drugs in the treatment of rheumatoid arthritis. They also usher in a new era that extends the therapeutic use of tyrosine kinase inhibitors beyond the treatment of cancers.

Traumatic Brain Injury:Football, Warfare, and Long-Term Effects

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n late July, the National Football League introduced a new poster to be hung in league locker rooms, warning players of possible long-term health effects of concussions. Public awareness of the pathological consequences of traumatic brain injury has been elevated not only by the recognition of the potential clinical significance of repetitive head injuries in such high-contact sports as American football and boxing, but also by the prevalence of vehicular crashes and efforts to improve passenger safety features, and by modern warfare, especially blast injuries. Each year, more than 1.5 million Americans sustain mild traumatic brain injuries with no loss of consciousness and no need for hospitalization; an equal number sustain injuries sufficient to impair consciousness but insufficiently severe to necessitate long-term institutionalization.

The skull provides the brain with a protective thick, bony encasement, yet its irregular interior presents opportunities for damage to the fragile tissues it has evolved to protect. Direct mechanical trauma injures cortical tissue; traumatic hematomas damage subcortical structures and precipitate vasospasm and ischemia; and sudden movement of the skull on its vertebral axis produces rotational, acceleration, or deceleration injury, damaging the long axons interconnecting brain regions. Research regarding traumatic brain injury has long been challenged by the range of these lesions and clinical manifestations, several of which are frequently present concurrently.

Many complications of traumatic brain injury are evident immediately or soon after injury. Acute post-traumatic sensory, motor, and neurocognitive syndromes are presumed to occur as a result of contusions and axonal disruption. Seemingly mild closed-head injuries (i.e., those without skull fracture) may lead to diverse and sometimes disabling symptoms, such as chronic headaches, dizziness and vertigo, difficulty concentrating, word-finding problems, depression, irritability, and impulsiveness. The duration of such symptoms varies but can be months. Post-traumatic stress disorder frequently accompanies traumatic brain injury, though the relationship is poorly understood.

Causal relationships between traumatic brain injury and delayed sequelae have been less studied because of the variable latency period before overt neurologic dysfunction. Severe single-incident injuries, with or without skull fracture, may lead to permanent brain damage, with incomplete recovery and residual sensory, motor, and cognitive deficits. If consciousness is lost for more than 30 minutes, the risk of Alzheimer’s disease is increased, even if there is substantial recovery from the initial trauma.

Our incomplete understanding of the pathogenesis of traumatic brain injury doesn’t permit the construction of a rigorous temporal sequence of events. The most frequently proposed cellular mechanism is diffuse axonal injury (see figureSpectrum of Pathologic Features and Outcomes of Traumatic Brain Injury (TBI).), which is associated with alterations in many physiological processes. Altered proteostasis is among the most obvious, because proteopathy is often evident at the histopathological level. Here, the pathways of idiopathic and post-traumatic neurodegeneration apparently overlap, since identical protein aggregates accumulate in both conditions. As early as 2 hours after severe brain injury, increased levels of soluble amyloid-β (Aβ) peptide and deposition of amyloid plaques are evident in the brains of 30% of survivors, regardless of their age.2 Acute, single-incident traumatic brain injury is also found in the history of 20 to 30% of patients with Alzheimer’s disease or parkinsonism but in only 8 to 10% of control subjects. Presumably, as-yet-undetermined genetic, environmental, and physical factors distinguish people who are destined to have delayed post-traumatic parkinsonism from those destined to have a delayed dementia identical to Alzheimer’s disease.

Neurocognitive effects of repetitive mild head injury were initially recognized in boxers, with a syndrome that was distinct from the clinical and pathological sequelae of single-incident severe traumatic brain injury. The clinical syndrome of dementia pugilistica (punch-drunk syndrome) is associated with prominent tauopathy, with typical neurofibrillary tangles and neuropil threads, distributed in patches throughout the neocortex. In contrast to the diffuse Aβ amyloidosis that occurs after single-incident traumatic brain injury and in the absence of neurofibrillary tangles, the brain that is affected by dementia pugilistica shows no Aβ deposition; although tauopathy is prominent, the mesiotemporal region, where such tangles first appear in Alzheimer’s disease, is typically spared. The traumatic tearing of neuronal connections (axonal shearing) disconnects or impairs cortical circuitry, thalamic circuitry, or both, contributing to cognitive impairment and dementia. Studies in the 1980s showed that among retired boxers, the numbers of rounds boxed, not win–loss records, were the best predictors of cognitive impairment. However, among boxers who had been knocked out approximately the same number of times, those who carried the APOE ε4 allele were more likely to develop dementia pugilistica than those who did not.1 Parkinsonism can also be associated with dementia pugilistica, in which case the term pugilistic parkinsonism is often used. A preponderance of neurofibrillary tangles and the absence of Lewy bodies distinguish pugilistic parkinsonism from idiopathic Parkinson’s disease; nigral neurons are lost in both conditions.

Examination of the brains of several professional football players and wrestlers has revealed the pathological underpinnings for the cognitive and neuropsychiatric decline seen in these men in later life. Although cognitive decline in longtime professional football players has been noted for years, the first autopsy report from such a player appeared in the literature only recently.3 The pathological findings in this and subsequent cases were identical to those of dementia pugilistica. In all cases, cognitive decline began years after retirement from the game. The term chronic traumatic encephalopathy was introduced as a clinicopathological construct for the neurodegeneration associated with football and wrestling, to distinguish the sequelae of these sports from the late effects of boxing. Whereas in dementia pugilistica the numbers of rounds boxed or knockouts can be roughly correlated with neuropathology, football players’ concussion histories have been poorly maintained, and no dose–response relationship for traumatic brain injury has been established in football or wrestling. One contributing factor is that in football and wrestling cultures, injuries tend to be downplayed in order to keep players in the game, whereas in boxing, knockouts are recorded as part of scoring.

Traumatic brain injury leads to the accumulation of several neurodegeneration-related proteins, including synuclein, ubiquitin, progranulin, TAR DNA-binding protein 43, amyloid precursor protein, and its metabolite, Aβ. New research will target the roles that these abnormal protein structures play in determining the severity of injury and the ultimate outcome. Aβ-lowering medications, which are under study for Alzheimer’s disease, improve outcomes after traumatic brain injury in rodent models,4,5 suggesting a pathway toward potential therapeutic interventions. In future studies, the presence and fate of amyloid pathology in severe traumatic brain injury can be monitored in vivo with amyloid-binding ligands (as seen on positron-emission tomography) and by quantifying levels of Aβ, tau, and phospho-tau in cerebrospinal fluid. Ligands for visualizing other pathological proteins during life are also in development.

One goal of research on traumatic brain injury and chronic traumatic encephalopathy is to understand why acute traumatic brain injury involves Aβ accumulation, yet the neuropathology of chronic traumatic encephalopathy is tauopathy, largely in the absence of obvious amyloid plaques. Laboratory modeling of traumatic brain injury should facilitate the elucidation of the underlying cellular and molecular changes. Better modeling is required, since the configurations of the brain, skull, and spine in species that are used to study traumatic brain injury in the laboratory (rodents and swine) are imperfect models for human disease. Nevertheless, genetically modified rodent models hold promise for delineating pathogenesis in post-traumatic neurodegeneration, as they have done in idiopathic diseases.

Data from helmet concussion monitors that are used on soldiers and football players can aid in predicting the character and location of lesions from an impact of a given force at given coordinates while improving the accuracy of diaries of people at risk for traumatic brain injury. Accurate diaries, in turn, should help in determining more accurately the number and severity of head injuries, allowing estimation of athletes’ cumulative risk. Individual differences in trauma tolerance and genetic influences must also be elucidated. These data can inform prospective studies of the cognitive, neuropsychiatric, and motor performance of soldiers, athletes, and other exposed populations, as well as informing the design of behavioral and pharmacologic interventions for prophylaxis or therapy. A challenge will be translating our improved understanding of the pathogenesis of traumatic brain injury into rational, evidence-based changes in public and sports policy that will minimize exposure to such injuries and their chronic neurodegenerative sequelae.

source:NEJM

Concurrent Liposomal Cisplatin (Lipoplatin), 5-Fluorouracil and Radiotherapy for the Treatment of Locally Advanced Gastric Cancer: A Phase I/II Study

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Koukourakis MI et al. – Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. The authors investigated the feasibility of the combination of 5–fluorouracil/lecovorin–based radio–chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin). Lipoplatin radio–chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio–chemotherapy setting for the treatment of gastric cancer.

source:IJROBP