The case for allele‐specific recognition by the TCR

There is a sharp difference in how one views TCR structure–function–behaviour dependent on whether its recognition of major histocompatibility complex‐encoded restriction elements (R) is germline selected or somatically generated. The generally accepted or Standard model is built on the assumption that recognition of R is by the V regions of the αβ TCR, which is not driven by allele specificity, whereas the competing model posits that recognition of R is allele‐specific. The establishing of allele‐specific recognition of R by the TCR would rule out the Standard model and clear the road to a consideration of a competing construct, the Tritope model. Here, the case for allele‐specific recognition (germline selected) is detailed making it obvious that the Standard model is untenable.     

Patients with Gastric Antral Vascular Ectasia (GAVE) Are at a Higher Risk of Gastrointestinal Bleeding in the Absence of Cirrhosis

Background and Aims: Gastric antral vascular ectasia (GAVE) is commonly found in patients with cirrhosis, but it is also associated with other diseases in the absence of cirrhosis. Whether GAVE confers a different severity of gastrointestinal (GI) bleeding between patients with and without cirrhosis remains unknown. We aim to examine whether there is a difference in clinically significant GI bleeding due to GAVE in patients with or without cirrhosis. Methods: This is a retrospective case-control study of patients who were diagnosed with GAVE between January 2000 and June 2014. Patients were categorized into cirrhosis and noncirrhosis groups, and those with an additional GI bleeding source were excluded. Univariate comparisons and multivariable models were constructed using logistic regression. Results: In total, 110 patients diagnosed with GAVE on esophagogastroduodenoscopy (EGD) were included in our analysis; 84 patients had cirrhosis (76.4%) and 26 (23.6%) did not. Active GI bleeding was more prevalent in patients without cirrhosis (63.4% vs. 32.1%, p=0.003) despite similar indications for EGD, and endoscopic treatment with argon plasma coagulation (APC) was required more often in this group, approaching statistical significance (27% vs. 10.7%, p=0.056). There was no difference in bleeding severity, as evidenced by similar re-bleeding rates, surgery, or death attributed to uncontrolled bleeding. The strongest independent risk factor for GI bleeding was the absence of cirrhosis (odds ratio (OR): 5.151 (95% confidence interval (CI): 1.08-24.48, p=0.039). Conclusions: Patients with GAVE in the absence of cirrhosis are at higher risk for active GI bleeding and require more frequent endoscopic treatment than similar patients with cirrhosis. It may be worthwhile to treat GAVE in this population even in the absence of active bleeding.     

Efficacy and safety in clinical trials in cardiovascular disease.

Mortality and morbid events are insensitive guides to the efficacy and safety of interventions in chronic cardiovascular disease (CVD). To enhance the ability to find new and effective long-term treatments, especially for the early stages of CVD, a revised strategy for clinical trials should emphasize efficacy on disease progression while monitoring symptoms and quality of life as guides to clinical benefit. Mortality, which is uncommon except in acute or advanced disease, provides at best a crude guide to net efficacy and safety. It must be monitored to support demonstrated efficacy on disease progression without adverse safety effects. This revised approach, made possible by our enhanced ability to monitor the progression of disease, should make it possible to study earlier disease and to improve cardiovascular health while reducing health care costs.     

Early gastric cancer. 21-year experience.

From 1963 through 1983, 327 patients underwent resection for gastric adenocarcinoma at Charity Hospital in New Orleans. Fifteen lesions (4.6%) were early gastric carcinoma (limited to the mucosa or submucosa regardless of nodal metastases). These lesions were in eight men and seven women (14 blacks and 1 white), with a mean age of 65.3 years (range: 52-80 years). Upper gastrointestinal series were obtained in 13 (6 suspicious, 2 inconclusive, and 5 normal). By comparison, endoscopy on 11 patients provided a tissue diagnosis in ten patients (90.9%). Surgical procedures ranged from total gastrectomy to a local excision, and every specimen was free of lymph node metastases. Macroscopically, there were six Type I, four Type IIb, and Type IIc, three Type III, and one with two separate lesions (IIa and IIb); microscopically, ten were intramucosal and five had submucosal invasion. Five-year survival calculated by the actuarial method was 64.2% (observed) and 100% (adjusted). This compares with 18.8% (observed) for all 327 patients. Six of the patients with early gastric cancer are alive (range: 16-219 months). The nine patients who died had no evidence of recurrent disease at the time of death. Surgical resection of early gastric carcinoma in the United States offers an excellent prognosis similar to the Japanese experience. Increased detection of gastric carcinoma in its curable stages may be achieved through early endoscopic investigation of symptomatic patients.