Brain banking in the United States and Europe: Importance, challenges, and future trends.

In recent years, brain banks have become valuable resources for examining the molecular underpinnings of various neurological and psychological disorders including Alzheimer disease and Parkinson disease. However, the availability of brain tissue has significantly declined. Proper collection, preparation, and preservation of postmortem autopsy tissue are essential for optimal downstream brain tissue distribution and experimentation.

Two-stage reflective self-seeding scheme for high-repetition-rate X-ray free-electron lasers.

X-ray free-electron lasers (XFELs) open a new era of X-ray based research by generating extremely intense X-ray flashes. To further improve the spectrum brightness, a self-seeding FEL scheme has been developed and demonstrated experimentally. As the next step, new-generation FELs with high repetition rates are being designed, built and commissioned around the world.

Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients.

Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2.

2,3-Disubstituted acrylamides as potent glucokinase activators.

The phenylacetamide 1 represents the archtypical glucokinase activator (GKA) in which only the R-isomer is active. In order to probe whether the chiral center could be replaced, we prepared a series of olefins 2 and show in the present work that these compounds represent a new class of GKAs. Surprisingly, the SAR of the new series paralleled that of the saturated derivatives with the exception that there was greater tolerance for larger alkyl and cycloalkyl groups at R(2) region in comparison to the phenylacetamides.

Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675).

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described.

Spinal anaesthesia with a micro-catheter in high-risk patients undergoing colorectal cancer and other major abdominal surgery.

Extended spinal anaesthesia using a spinal micro-catheter was used as a primary method of anaesthesia for elective colorectal cancer surgery in 68 high risk patients over a 14-year period in our institution. The technique was also useful in eight elective and 13 emergency abdominal surgeries. All patients suffered from severe chronic obstructive airway disease requiring multiple inhalers and drugs (ASA III).

Quality of clinical documentation and anticoagulation control in patients with chronic nonvalvular atrial fibrillation in routine medical care.

Objective: Anticoagulation quality and record documentation were retrospectively assessed in patients with chronic nonvalvular atrial fibrillation (CNVAF) managed in a routine care setting.

Methods: Medical record data extraction from physician practices in 4 regions of the United States.

Results: Of 686 patients, 59% had an electrocardiogram confirming CNVAF, 84% listed at least 1 stroke risk factor, and 60% indicated the goal target international normalized ratio (INR).

Variance of surgeons versus pathologists in staging of colorectal cancer.

Aim: Accurate staging of colorectal cancer depends on adequate retrieval and reporting of lymph nodes in the specimen. The presence of positive lymph nodes is an indication for adjuvant therapy. Both surgeons and pathologists influence the number of lymph nodes that are retrieved and reported in specimens.

Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.

Postural orthostatic tachycardia syndrome encompasses a group of disorders characterized by orthostatic intolerance. We describe the anaesthetic management of analgesia for labour and of Caesarean section in a parturient suffering from this disorder. Worsening of her symptoms during pregnancy was managed with an increase in the dose of beta-blockers taken by the patient.

Cost-effectiveness of differing perioperative beta-blockade strategies in vascular surgery patients.

Objectives: To determine the incremental value of different strategies of both oral and intravenous beta-blockade during the perioperative period in high-risk vascular patients in reducing costs and improving outcomes.

Design: Decision analytic model incorporating costs from provider's perspective

Interventions: Five perioperative strategies in patients undergoing abdominal aortic aneurysm surgery: (1). no routine beta-blockade, (2).

Evaluation of flexible sigmoidoscopy as an investigation for "left sided" colorectal symptoms.

Background: Colonoscopy is the best way of imaging the colon with concurrent biopsy and treatment. However it is expensive, requires full bowel preparation, and carries a risk of complications. Flexible sigmoidoscopy is an alternative way to investigate symptoms that raise the suspicion of a lesion of the rectum or left colon.

Evaluating a spoken dialogue system for recording clinical observations during an endoscopic examination.

Paper, keyboard or mouse-driven systems may not be suitable for data capture because of the hands-busy constraint imposed by an endoscopic examination. A Spoken Dialogue System (SDS) has a number of advantages when compared to keyboard and mouse-driven input modalities, particularly with respect to hands free and eyes-free control of a system. However, any emerging technology will never deliver improved organizational effectiveness if it is not accepted and used.

Allosteric activators of glucokinase: potential role in diabetes therapy.

Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types.

Altering substrate specificity of phosphatidylcholine-preferring phospholipase C of Bacillus cereus by random mutagenesis of the headgroup binding site.

PLC(Bc) is a 28.5 kDa monomeric enzyme that catalyzes the hydrolysis of the phosphodiester bond of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine to provide a diacylglycerol and the corresponding phosphorylated headgroup. Because single replacements of Glu4, Tyr56, and Phe66 in the headgroup binding pocket led to changes in substrate specificity [Martin et al.

Pet dogs as sentinels for environmental contamination.

The presence of environmental contaminants in air, water and food may pose significant health risks to the exposed human population. However, problems associated with assessing chronic exposure to low doses of environmental chemicals, multiple exposure routes, diseases with long latency periods, and non-specific health outcomes make it difficult to conduct the appropriate human epidemiologic studies. It may be useful to complement human epidemiology with animal studies.

Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin.

The nucleoside analogue, pentostatin, has demonstrated high complete response rates and long relapse-free survival times in patients with hairy cell leukemia, a disease that historically had been unresponsive to treatment. Long-term data on duration of overall survival and relapse-free survival and incidence of subsequent malignancies with this agent are lacking. Patients completing the treatment phase of a randomized, intergroup study who received pentostatin as an initial treatment or who crossed over after failure of interferon alpha were followed for survival, relapse, and diagnosis of subsequent malignancies.

Long-term outcome following treatment of hairy cell leukemia with pentostatin (Nipent): a National Cancer Institute of Canada study.

We have previously demonstrated that pentostatin (Nipent; SuperGen, San Ramon, CA) is highly effective in the treatment of hairy cell leukemia and report here the long-term outcome of this study. Pentostatin was administered intravenously in cycles of 4 mg/m2 weekly x 3 repeated every 8 weeks. Patients who achieved a complete remission (CR) received two further cycles for consolidation.

Ethanol is a potent inhibitor of canine cerebrospinal fluid production: an acute and reversible effect.

Neuropathological studies have shown increased cerebral spaces in alcoholics, yet, the effect of ethanol on cerebrospinal fluid (CSF) production is not known. We investigated the effects of ethanol on CSF production measured by ventriculocisternal perfusion (VCP) technique, in two groups (n=10 in each) of anesthetized, paralyzed and mechanically ventilated dogs. In group I, which served as control, VCP was performed with normal mock CSF.

Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations.

Background: Heart failure is a highly prevalent disorder that continues to be associated with repeated hospitalizations, high morbidity, and high mortality. Sleep-related breathing disorders with repetitive episodes of asphyxia may adversely affect heart function. The main aims of this study were to determine the prevalence, consequences, and differences in various sleep-related breathing disorders in ambulatory male patients with stable heart failure.

Association of low PaCO2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure.

Background: Central sleep apnea frequently occurs in patients with heart failure. Because it is not practical to perform sleep studies on all patients, readily available laboratory tests that predict sleep apnea would be clinically useful. Arterial PCO2 has a profound influence on breathing during sleep: When it decreases below a certain threshold, apnea occurs.

Different effects of omeprazole and Sch 28080 on canine cerebrospinal fluid production.

We investigated the effects of omeprazole and Sch 28080, a more specific and a more potent inhibitor of K+,H+-ATPase than omeprazole, in canine cerebrospinal fluid (CSF) production. CSF production was measured by ventriculocisternal perfusion (VCP) technique in three groups (n = 10 in each group) of anesthetized, paralyzed and mechanically ventilated dogs. Group I served as control, Sch 28080 (10(-4) mol/l of synthetic CSF) was added to VCP in group II, and omeprazole (10(-5) mol/l of synthetic CSF) was added to VCP in group III, after baseline control CSF production had been determined at 15, 30, 45, and 60 min.

Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study.

Purpose: Therapy of hairy cell leukemia has markedly improved. Interferon alfa-2a and pentostatin are active agents. The National Cancer Institute organized an intergroup trial to compare these agents prospectively in untreated patients.

Thrombocytopenia associated with neoplasia in dogs.

Ten percent (214/2,059) of all dogs with cancer at North Carolina State University Veterinary Teaching Hospital had thrombocytopenia. The thrombocytopenia was associated with infectious/inflammatory etiologies in 4%, miscellaneous disorders (therapy, bone marrow failure, disseminated intravascular coagulation) in 35%, and neoplasia without identifiable secondary factors in 61% of cancer-bearing dogs. Classifying these dogs by tumor groups revealed the following proportionate ratios: lymphoid, 29%; carcinoma, 28%; sarcoma, 20%; hemic neoplasia, 7%; multiple, 5%; unclassified, 3%; benign, 3%; brain, 3%; and endocrine, 3%.