Conserved features of intermediates in amyloid assembly determine their benign or toxic states

Some amyloid-forming polypeptides are associated with devastating human diseases and others provide important biological functions. For both, oligomeric intermediates appear during amyloid assembly. Currently we have few tools for characterizing these conformationally labile intermediates and discerning what governs their benign versus toxic states. Here, we examine intermediates in the assembly of a normal, functional amyloid, the prion-determining region of yeast Sup35 (NM). During assembly, NM formed a variety of oligomers with different sizes and conformation-specific antibody reactivities. Earlier oligomers were less compact and reacted with the conformational antibody A11. More mature oligomers were more compact and reacted with conformational antibody OC. We found we could arrest NM in either of these two distinct oligomeric states with small molecules or crosslinking. The A11-reactive oligomers were more hydrophobic (as measured by Nile Red binding) and were highly toxic to neuronal cells, while OC-reactive oligomers were less hydrophobic and were not toxic. The A11 and OC antibodies were originally raised against oligomers of Aβ, an amyloidogenic peptide implicated in Alzheimer's disease (AD) that is completely unrelated to NM in sequence. Thus, this natural yeast prion samples two conformational states similar to those sampled by Aβ, and when assembly stalls at one of these two states, but not the other, it becomes extremely toxic. Our results have implications for selective pressures operating on the evolution of amyloid folds across a billion years of evolution. Understanding the features that govern such conformational transitions will shed light on human disease and evolution alike.     

Long-term medical management of gastro-esophageal reflux disease: how long and when to consider surgery?

Gastro-esophageal reflux disease is a chronic, long standing disease. Spontaneous remission of GERD is rare and conservative management including life style modification measures is unlikely to relieve symptoms. Majority of patients with reflux disease require long-term acid suppressants. Proton pump inhibitors are the choice of drugs in management of these patients. The end point of treatment is not clear. Duration of treatment is individual based. The symptoms may be intermittent or on most days of the week. The treatment is therefore either a short course which may be for 8 to 12 weeks or 6 months, or continuous, intermittent or 'on-demand' basis. The maintenance therapy is with the lowest proton pump inhibitor (PPI) dose necessary for adequate symptom relief. Whether long-term PPI actually alters the natural history of reflux disease other than to reduce the incidence of peptic stricture is not known. Reported adverse effects due to PPI include Clostridium difficile colitis and bacterial gastroenteritis, osteoporosis, and vitamin B12 deficiency. Anti-reflux surgery is indicated for youngsters, those not willing for long-term PPI i.e. for years, large volume refluxers, especially the supine refluxers and bile refluxers.     

Mechanisms of axonal dysfunction in diabetic and uraemic neuropathies

The global burden imposed by metabolic diseases and associated complications continue to escalate. Neurological complications, most commonly peripheral neuropathy, represent a significant cause of morbidity and disability in patients with diabetes and chronic kidney disease. Furthermore, health care costs are substantially increased by the presence of complications making investigation into treatment a matter of high priority. Over the last decade nerve excitability techniques have entered the clinical realm and enabled in vivo assessment of biophysical properties and function of peripheral nerves in health and disease. Studies of excitability in diabetic neuropathy have demonstrated alteration in biophysical properties, including changes in Na⁺ conductances and Na⁺/K⁺ pump function, which may contribute to the development of neuropathic symptoms. Interventional studies have demonstrated that these changes are responsive to pharmacological agents. Excitability studies in patients with chronic kidney disease have demonstrated prominent changes that may contribute to the development of uraemic neuropathy. In particular, these studies have demonstrated strong correlation between hyperkalaemia and the development of nerve dysfunction. These studies have provided a basis for future work assessing the benefits of potassium restriction as a therapeutic strategy in this condition.     

Evaluation of the efficacy of tranexamic acid on blood loss in orthognathic surgery. A prospective, randomized clinical study

The purpose of this prospective, randomized, double blind study was to assess the effect of tranexamic acid on blood loss, quality of surgical field and duration of surgery in adolescent orthognathic surgery patients. 50 consecutive patients, scheduled for orthognathic surgery were included. The study group (n=25) received tranexamic acid 10mg/kg as a bolus preoperatively followed by 1mg/kg as a maintenance dose intra operatively; the control group (n=25) received placebo (normal saline). All patients received moderate hypotensive anaesthesia with nitroglycerin and had surgery according to a standard protocol. Intra operative blood loss, duration of surgery, quality of surgical field, blood transfusion and complications, if any, were recorded. The mean total blood loss was 166.1±65.49ml in the study group and 256.4±77.80ml in the control group. The results showed statistically significant reduction in blood loss (p<0.001) and improved quality of surgical field (p<0.001) in the study group. There was no significant difference in duration of surgery and transfusion requirements between the two groups. In conclusion, preoperative and intra operative administration of the antifibrinolytic agent, tranexamic acid, is effective in controlling blood loss and improving the quality of the surgical field.