Udp-glucuronosyltransferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes.

The predominant metabolic pathway of gemcabene in humans is glucuronidation. The principal human UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of gemcabene were determined in this study. Glucuronidation of gemcabene was catalyzed by recombinant UGT1A3, recombinant UGT2B7, and recombinant UGT2B17, as well as by human liver microsomes (HLM). Gemcabene glucuronidation in recombinant UGTs and HLM followed non-Michaelis-Menten kinetics consistent with homotropic activation, but pharmacokinetics in humans were linear over the dose range tested (total plasma C(max), 0.06-0.88 mM). Gemcabene showed similar affinity (S(50)) for recombinant UGTs (0.92-1.45 mM) and HLM (1.37 mM). S-Flurbiprofen was identified as a more selective inhibitor of recombinant UGT2B7-catalyzed gemcabene glucuronidation (>23-fold lower IC(50)) when compared with recombinant UGT1A3- or recombinant UGT2B17-catalyzed gemcabene glucuronidation. The IC(50) for S-flurbiprofen inhibition of gemcabene glucuronidation was similar in HLM (60.6 microM) compared with recombinant UGT2B7 (27.4 microM), consistent with a major role for UGT2B7 in gemcabene glucuronidation in HLM. In addition, 5,6,7,3',4',5'-hexamethoxyflavone inhibited recombinant UGT1A3 and recombinant UGT2B17-catalyzed gemcabene glucuronidation (with 4-fold greater potency for recombinant UGT1A3) but did not inhibit gemcabene glucuronidation in HLM, suggesting that UGT1A3 and UGT2B17 do not contribute significantly to gemcabene glucuronidation. Reaction rates for gemcabene glucuronidation from a human liver bank correlated well (r(2)=0.722, P<0.0001; n=24) with rates of glucuronidation of the UGT2B7 probe substrate 3'-azido-3'-deoxythymidine. In conclusion, using the three independent experimental approaches typically used for cytochrome P450 reaction phenotyping, UGT2B7 is the major enzyme contributing to gemcabene glucuronidation in human liver microsomes.     

Institutional and individual learning curves for focused abdominal ultrasound for trauma: cumulative sum analysis

OBJECTIVE: To evaluate both institutional and individual learning curves with focused abdominal ultrasound for trauma (FAST) by analyzing the incidence of diagnostic inaccuracies as a function of examiner experience for a group of trauma surgeons performing the study in the setting of an urban level I trauma center. SUMMARY BACKGROUND DATA: Trauma surgeons are routinely using FAST to evaluate patients with blunt trauma for hemoperitoneum. The volume of experience required for practicing trauma surgeons to be able to perform this examination with a reproducible level of accuracy has not been fully defined. METHODS: The authors reviewed prospectively gathered data for all patients undergoing FAST for blunt trauma during a 30-month period. All FAST interpretations were validated by at least one of four methods: computed tomography, diagnostic peritoneal lavage, celiotomy, or serial clinical evaluations. Cumulative sum (CUSUM) analysis was used to describe the learning curves for each individual surgeon at target accuracy rates of 85%, 90%, and 95% and for the institution as a whole at target examination accuracy rates of 85%, 90%, 95%, and 98%. RESULTS: Five trauma surgeons performed 546 FAST examinations during the study period. CUSUM analysis of the aggregate experience revealed that the examiners as a group exceeded 90% accuracy at the outset of clinical examination. The level of accuracy did not improve with either increased frequency of performance or total examination experience. The accuracy rates observed for each trauma surgeon ranged from 87% to 98%. The surgeon with the highest accuracy rate performed the fewest examinations. No practitioner demonstrated improved accuracy with increased experience. CONCLUSIONS: Trauma surgeons who are newly trained in the use of FAST can achieve an overall accuracy rate of at least 90% from the outset of clinical experience with this modality. Interexaminer variations in accuracy rates, which are observed above this level of performance, are probably related more to issues surrounding patient selection and inherent limitations of the examination in certain populations than to practitioner errors in the performance or interpretation of the study.     

Restorative proctocolectomy with J-pouch ileoanal anastomosis

Restorative proctocolectomy with ileoanal anastomosis, complemented by a pouch formed with the last foot of terminal ileum, is the procedure of choice for patients in need of surgical treatment for ulcerative colitis and familial polyposis. The procedure has undergone many technical modifications that have ensured a very high degree of continence and an acceptable number of daily bowel movements. Herein we describe the operative technique we use in the majority of our patients, a restorative proctocolectomy with hand-sewn J-pouch ileoanal anastomosis with protecting ileostomy. We also comment on the immediate postoperative care and on the long-term functional results.     

The case for intraocular delivery of PPAR agonists in the treatment of diabetic retinopathy

ABSTRACT: BACKGROUND: Systemic therapeutics targeting the peroxisome proliferator-activated receptors have been found to be beneficial in the treatment of diabetic retinopathy. In this paper, we provide a rationale for the use of these therapeutics as intraocular agents. In addition, we introduce the peroxisome proliferator-activated receptors and describe their functions in response to the drugs. DISCUSSION: Based on the evidence of large-scale clinical studies investigating the systemic administration of fenofibrate, this ligand for peroxisome proliferator-activated receptor-alpha is potentially a good candidate for intraocular delivery. Here, we describe the mechanisms by which it might be acting to improve diabetic retinopathy, its relative safety and we speculate on how it could be developed for intraocular delivery. SUMMARY: In this paper, we provide a rationale for the further investigation of peroxisome proliferator-activated receptor-alpha agonists as intraocular agents for the treatment of diabetic retinopathy.     

Three Meals a Day is Passé at Progressive Hospital

Modern medical simulation technology (MST) debuted in 1960 with the development of Resusci Annie (Laerdal 2007), which assisted students in the acquisition of proper ventilation and compression techniques used during basic life support. Following a steady stream of subsequent technological advances and innovations, MST manufacturers are now able to offer training aids capable of facilitating innovative learning in such diverse areas as human patient simulators, simulated clinical environments, virtual procedure stations, virtual medical environments, electronic tutors, and performance recording. The authors list a number of the most popular MSTs presently available while citing evaluative efforts undertaken to date regarding the efficacy of MST to the medical profession. They conclude by proposing a variety of simulation innovations of prospective interest to both medical and technology personnel while offering healthcare administrators a series of recommended considerations when planning to integrate MST into existing medical systems.     

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall–Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.     

Ruptured papillary muscle, a complication of myocardial infarction: clinical presentation, diagnosis, and treatment

Ruptured papillary muscle due to myocardial infarction was encountered in 14 patients during the period 1975-1983. Five of the 14 patients had a history of angina pectoris and two had a history of prior myocardial infarction. Eleven patients with myocardial infarction developed additional pain due to myocardial ischemia and/or a murmur of mitral regurgitation and pulmonary edema within a week, 3 others had a prolonged course with intermittent pain due to myocardial ischemia and breathlessness for longer periods and then deteriorated. Thirteen of our 14 patients developed a murmur and all but one had pulmonary edema on the chest x-ray. Five patients had infarction patterns on the electrocardiogram, the remainder of the patients had only ST- and T-wave changes. Echocardiograms showed fine flutter and notching of the anterior mitral leaflets and vigorous contractions of the left ventricle. Only one patient was demonstrated to have a papillary muscle tip prolapsing into the left atrium on two-dimensional echocardiography. Twelve patients underwent surgery and 8 survived. Seven patients had single-vessel coronary disease, 4 involving the circumflex system and 3 involving the right coronary system. Four of the 7 patients with single-vessel coronary disease survived surgery. Five patients went to surgery with the intra-aortic balloon pump in place and only 3 survived. Three others had the pump inserted intraoperatively and 2 of these survived. Six of 9 patients who had mitral valve replacement and coronary bypass survived. Ejection fraction ranged from 40 to 79%. Surgical survival did seem to be related to the extent of papillary muscle rupture, with the best results occurring in the group with a small portion of the tip ruptured. Seven patients had a stormy clinical course and required surgery within 10 days of rupture. Four of these 7 survived. It seems reasonable to believe that these patients who often have small infarction and limited coronary disease have good potential for survival. Our approach has been to move toward surgery once the diagnosis is made to avoid the sudden deterioration that frequently occurs. The surgical mortality in this group remains in the 30 to 40% range.     

Helicobacter pylori and risk of gastroenteritis

BACKGROUND: Helicobacter pylori infection is thought to modify susceptibility to gastroenteritis. METHODS: Members of northern California households with an index case of gastroenteritis were interviewed regarding recent episodes and tested for H. pylori. Conditional logistic regression was used to evaluate the risk of secondary gastroenteritis within households matched for members with secondary gastroenteritis (cases) and those without symptoms (control subjects). Case and control subjects were also tested for hepatitis A virus (HAV). RESULTS: Of 801 households, 205 (26%) had at least 1 member with secondary gastroenteritis, of which 116 (56%) also included at least 1 member without symptoms (158 case and 285 control subjects). Compared with uninfected members and adjusting for age, those with antibodies to only 1 infection were at a decreased risk of secondary gastroenteritis (odds ratio [OR] for H. pylori infection, 0.25 [95% confidence interval [CI], 0.08-0.82]; OR for HAV, 0.45 [95% CI, 0.23-0.87]). Having antibodies to both H. pylori and HAV did not add to this negative effect (adjusted OR, 0.39 [95% CI, 0.18-0.84]). CONCLUSIONS: H. pylori did not increase the risk of gastroenteritis in these households. A strong negative association between H. pylori infection and gastroenteritis is likely explained by prior exposure and immunity to other enteric pathogens.