Suppression of Heavy Drinking and Alcohol Seeking by a Selective ALDH-2 Inhibitor

Background: Inherited human aldehyde dehydrogenase 2 (ALDH‐2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH‐2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH‐2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH‐2 inhibitor might affect other metabolic factors involved in regulating drinking. Methods: Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co‐crystal structure of ALDH‐2 and daidzin. We tested the efficacy of a highly selective reversible ALDH‐2 inhibitor, CVT‐10216, in models of moderate and high alcohol drinking rats. We studied 2‐bottle choice and deprivation‐induced drinking paradigms in Fawn Hooded (FH) rats, operant self‐administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue‐induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm. Results: CVT‐10216 increases acetaldehyde after alcohol gavage and inhibits 2‐bottle choice alcohol intake in heavy drinking rodents, including deprivation‐induced drinking. Moreover, CVT‐10216 also prevents operant self‐administration and eliminates cue‐induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT‐10216 prevents alcohol‐induced increases in NAc DA without changing basal levels. CVT‐10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses. Conclusion: Our findings suggest that selective reversible ALDH‐2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.     

A request for an abortion

How to manage to abortion request by a hypothetical 30-year old married woman who states the she fears a deformed child because of taking an antibiotic combination, cotrimoxazole, containing trimethoprim is discussed by 3 physicians. The 1st doctor would confirm pregnancy with an exam and a laboratory test, schedule another consultation for counseling, and schedule a pelvic ultrasound if she decides to carry the pregnancy. If she wants an abortion, the physician would counsel her at length about her marriage and the emotional consequences of abortion. The 2nd physician would advise her that fetal abnormality from trimethoprim has not been reported in women. Since this doctor is personally opposed to abortion, she would refer the patient to another doctor to make the arrangements, and counsel her again afterward. The 3rd physician added the advice that 1-2% of all U.K. births are abnormal in some way. He would take steps to establish the precise gestational date, recommend an ultrasound scan at 18 weeks to cover himself legally and suggest that the patient's husband join in the counseling session to help bring out feelings about the marriage and the pregnancy.     

Serologic changes during induction of lupus-like disease by procainamide

Procainamide-induced lupus is a well-recognized syndrome, but the events leading up to clinical symptoms are obscure. In the present study, serologic changes in a 69-year-old man were monitored during his treatment with procainamide and after discontinuation of procainamide because of symptoms of drug-induced lupus. Antihistone antibodies of unique specificity and in vivo complement activation were detected after one year of procainamide therapy during a period prior to development of significant clinical symptoms. Antihistone antibodies and complement activation substantially increased during a full-blown episode of lupus-like symptoms. Progressive return to normal laboratory findings occurred after procainamide was discontinued. The antihistone/complement profile may be useful in the diagnosis of drug-induced lupus and warn of impending clinical deterioration in patients with minimal symptoms.     

高压氧综合治疗糖尿病足的临床疗效观察

糖尿病足(diabetic foot,DF)是常见的糖尿病慢性合并症之一,也是导致糖尿病人截肢致残的主要原因.近年来,糖尿病患病率逐年增高,使糖尿病足的患病率也呈逐年上升的趋势.     

Aortic Valve Rheumatoid Nodules Producing Clinical Aortic Regurgitation and A Review of the Literature

The majority of cardiac involvement in rheumatoid arthritis (RA) is an incidental finding at postmortem, as less than 3% of patients with RA have clinical cardiac signs or symptoms. Most cardiac involvement in RA involves the pericardium and has been known since Charcot first described an RA patient with pericarditis in 1881. Cardiac involvement takes two different forms: non-specific inflammatory changes and specific granuloma formation. Specific rheumatoid nodules in the heart are an infrequent complication of RA. This is the first case report of a surgically excised heart valve with rheumatoid nodules. A 74-year-old RA patient with a high seropositive rheumatoid factor presented with severe aortic regurgitation and underwent a valve replacement. The native aortic valve showed significant stenosis with multiple, classic rheumatoid nodules. Cardiovas Pathol 1999;8: 333–338     

Refractory pouchitis: does it reflect underlying Crohn's disease?

Typical ''pouchitis'' is a well recognised complication of ileal pouches in ulcerative colitis. Infrequently, a refractory pouchitis (RP) presents with certain clinical, endoscopic, and pathological features resembling Crohn''s disease and is often ascribed to misdiagnosis of the initial colitis. To test that hypothesis and to identify risk factors for RP, this study reviewed cases of presumed ulcerative colitis with ileal pouches constructed at The Mount Sinai Hospital between 1973 and 1986. Twenty four cases with RP (16 Kock pouches and eight pelvic pouches) and 21 controls were compared for eight clinical variables. The original colectomy slides from 15 RP and 18 control cases were reviewed blindly, classified into five histological categories (corresponding to definite ulcerative colitis, definite Crohn''s disease, and three indeterminate groups), and scored for 23 histological features. There were no significant clinical differences between RP and control cases except for more frequent extraintestinal manifestations (38% v 5%) and male preponderance (79% v 43%) in RP. There were also no significant differences between the distributions of RP cases and controls among the five histological categories or in the 23 histological features studied. Refractory pouchitis therefore does not seem to reflect underlying Crohn''s disease, but may be linked to immunological mechanisms that are manifested clinically as extraintestinal complications.