1,4-Benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonists.

A series of 1,4-benzodiazepines, N-1-substituted with an N-isopropyl-N-phenylacetamide moiety, was synthesized and screened for CCK-A agonist activity. In vitro agonist activity on isolated guinea pig gallbladder along with in vivo induction of satiety following intraperitoneal administration in a rat feeding assay was demonstrated.

CT patterns of nodular hepatic and splenic sarcoidosis: a review of the literature.

PURPOSE: The purpose of our study was to investigate the less commonly demonstrated CT patterns nodular hepatosplenic sarcoidosis. METHOD: We studied five women patients, utilizing contrast enhanced incremental or spiral CT. We also performed a literature search of hepatosplenic sarcoid for the years 1966-1995. RESULTS: We found five nodular hepatic and/or splenic patterns of sarcoidosis. CONCLUSION: We conclude that increased awareness and recognition of these patterns of nodular hepatic/splenic sarcoidosis on CT will greatly improve detection and diagnosis of abdominal sarcoidosis.

Treatment of hypotension after hyperbaric tetracaine spinal anesthesia. A randomized, double-blind, cross-over comparison of phenylephrine and epinephrine.

BACKGROUND: Despite many advantages, spinal anesthesia often is followed by undesirable decreases in blood pressure, for which the ideal treatment remains controversial. Because spinal anesthesia-induced sympathectomy and management with a pure alpha-adrenergic agonist can separately lead to bradycardia, the authors hypothesized that epinephrine, a mixed alpha- and beta-adrenergic agonist, would more effectively restore arterial blood pressure and cardiac output after spinal anesthesia than phenylephrine, a pure alpha-adrenergic agonist. METHODS: Using a prospective, double-blind, randomized, cross-over study design, 13 patients received sequential infusions of epinephrine and phenylephrine to manage hypotension after hyperbaric tetracaine (10 mg) spinal anesthesia. Blood pressure, heart rate, and stroke volume (measured by Doppler echocardiography using the transmitral time-velocity integral) were recorded at baseline, 5 min after injection of tetracaine, and before and after management of hypotension with epinephrine and phenylephrine. Cardiac output was calculated by multiplying stroke volume x heart rate. RESULTS: Five min after placement of a hyperbaric tetracaine spinal anesthesia, significant decrease in systolic (from 143 +/- 6 mmHg to 125 +/- 5 mmHg; P < 0.001), diastolic (from 81 +/- 3 to 71 +/- 3; P < 0.001), and mean (from 102 +/- 4 to 89 +/- 3; P < 0.001) arterial pressures occurred. Heart rate (75 +/- 4 beats/min to 76 +/- 4 beat/min; P = 0.9), stroke volume (115 +/- 17 to 113 +/- 13; P = 0.9), and cardiac output (8.0 +/- 1 l/m to 8.0 +/- 1l/m; P = 0.8) did not change significantly after spinal anesthesia. Phenylephrine was effective at restoring systolic blood pressure after spinal anesthesia (120 +/- 6 mmHg to 144 +/- 5 mmHg; P < 0.001) but was associated with a decrease in heart rate from 80 +/- 5 beats/min to 60 +/- 4 beats/min (P < 0.001) and in cardiac output from 8.6 +/- 0.7 l/m to 6.2 +/- 0.7 l/m (P < 0.003). Epinephrine was effective at restoring systolic blood pressure after spinal anesthesia (119 +/- 5 mmHg to 139 +/- 6 mmHg; P < 0.001) and was associated with an increase in stroke volume from 114 +/- 12 ml to 142 +/- 17 (P < 0.001) and cardiac output from 7.8 +/- 0.6 l/m to 10.8 +/- 1.1 l/m (P < 0.001). CONCLUSIONS: Epinephrine management of tetracaine spinal-induced hypotension increases heart rate and cardiac output and restores systolic arterial pressure but does not restore mean and diastolic blood pressure. Phenylephrine management of tetracaine spinal-induced hypotension decreases heart rate and cardiac output while restoring systolic, mean, and diastolic blood pressure.

Sonographic evaluation of acute intrascrotal pathology.

High-resolution, real-time sonography is commonly used for the evaluation of acute scrotal pathology. Pulsed and color Doppler techniques enhance diagnostic accuracy [1, 2]. However, extensive distortion of intrascrotal anatomy can occur with advanced inflammation, infarction, or trauma, leading to decreased specificity of the sonographic examination.

Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger".

Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.

Anesthetic management of a massively morbidly obese patient.

BACKGROUND AND OBJECTIVES: A 408-kg patient presented for surgical resection of a lower extremity mass. METHODS: A specially designed bed and well-planned transport were used to deliver the patient to the operating room suite. The anesthetic technique included a continuous subarachnoid catheter with tetracaine and epinephrine. Intraoperative monitoring consisted of electrocardiography, pulse oximetry, intraarterial blood pressure, and mental status examinations. Massive intraoperative hemorrhage was treated with rapid volume infusions and vasopressors. RESULTS: Resection of a lower extremity mass was accomplished and the patient was eventually discharged from the hospital. CONCLUSIONS: The case report emphasizes that prior planning of all aspects of patient care is important in massively morbidly obese patients and that regional anesthesia is a valuable option in these patients.

The job outlook in brief 1990-2005.

Every 2 years, the Bureau of Labor Statistics publishes a summary of the expected change in employment for about 250 occupations. Here are the most recent projections, along with the available information on the expected competition for jobs.

Experimental short-bowel syndrome: effect of an elemental diet supplemented with short-chain triglycerides.

To determine whether short-chain triglycerides (SCTs, 1:1 triacetin:tributyrin, wt:wt) enhance intestinal adaptation in short-bowel syndrome (SBS), male Sprague-Dawley rats underwent 60% distal small-bowel resection with cecectomy and received either a chemically defined diet (CD) or a CD containing 40% of nonprotein energy as either medium-chain triglycerides (MCTs) or SCTs. After 12 d the SCT group had significantly increased jejunal mucosal weight compared with the MCT and CD groups and had significantly increased segment weight and mucosal protein compared with the CD group. In the colon the SCT group had significantly increased segment and mucosal weights and mucosal protein and DNA compared with both the MCT and CD groups. Body-weight change and measurements of serum ketones, albumin, glucose, and triglycerides revealed no significant differences among groups. SCTs improved jejunal and colonic adaptive growth and maintained comparable nutritional status in SBS when compared with CD alone or CD with MCTs.

Arthroscopy update #8. Auxiliary portal for assessing patellofemoral alignment.

An auxiliary arthroscopic portal may be used to improve visualization and evaluation of the patellofemoral joint. A reusable transquadriceps tendon portal, which assesses patellar alignment within a 0 degree to 90 degrees range of motion, is described.

Stimulation of intestinal mucosal growth with intracolonic infusion of short-chain fatty acids.

Dietary fiber, which stimulates intestinal mucosal growth, is fermented by anaerobic bacteria in the rat hindgut to the short-chain fatty acids (SCFA) acetate, propionate, and butyrate. Butyrate is the preferred oxidative fuel of the colonocyte in vitro, and the provision of preferred intestinal fuels has been shown to stimulate mucosal proliferation in vivo. This study determined whether chronic colonic infusion of butyrate or a combination of SCFA would stimulate intestinal mucosal growth in an animal deprived of its normal source of SCFA, fiber fermentation in the cecum. Adult male Sprague-Dawley rats were fed a fat- and fiber-free elemental liquid diet and underwent cecectomy, ileocolic anastomosis, and insertion of a proximal colonic infusion catheter. Rats were then assigned to receive either a continuous infusion of butyrate (20 mM, 40 mM, or 150 mM), SCFA (70 mM acetate + 35 mM propionate + 20 mM butyrate), or saline, or to receive no infusion. A seventh group underwent proximal colonic transection and reanastomosis. After 7 days, jejunal, ileal, and proximal colonic segments were analyzed for mucosal weight, protein, RNA, and DNA. In the colon, the 40-mM butyrate infusion resulted in significant elevations in all mucosal parameters relative to all three control groups, saline infusion, no infusion, and transection. Both the 20-mM butyrate and the SCFA groups showed increased colonic mucosal DNA compared to controls. In the jejunum and ileum, mucosal DNA content was significantly greater in the SCFA group than in the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrasound surveillance of the cervix during pregnancy in diethylstilbestrol-exposed offspring.

Twenty-three diethylstilbestrol (DES)-exposed patients were evaluated through 27 pregnancies to determine their eligibility for admission to a prospective protocol that combined serial ultrasound surveillance of the lower uterine segment-cervical complex with periodic pelvic examinations to diagnose cervical incompetency. Of these, 21 pregnant women, including seven vaginectomy patients, were matched to 84 low-risk controls to determine the following: 1) the effect of DES exposure on reproductive performance, 2) the efficacy of ultrasound selection of cerclage candidates, and 3) the influence of previous partial vaginectomy on reproductive outcome. Five DES-exposed patients were diagnosed as having cervical incompetency and had cerclages placed. There were no missed diagnoses of cervical incompetency. The DES-exposed patients delivered statistically earlier in gestation than did controls (268 +/- 13 versus 276 +/- 10 days). It was not evident that this difference was important clinically, as there were no neonatal deaths, very low birth weight infants, second-trimester losses, or deliveries before 252 days (36 weeks) among the study patients. Previous vaginectomy did not affect the frequency of the diagnosis of cervical failure or the neonatal outcome. After ultrasound surveillance and treatment for incompetent cervix, a majority of our patients delivered at term without cerclage placement. Therefore, routine cerclage placement is not recommended. Knowledge of the ultrasound criteria for diagnosing cervical incompetency is required.

Fast atom bombardment mass spectrometric investigation of in vitro degradation within the disulfide-linked core of atrial natriuretic factor.

The use of high-performance liquid chromatography and fast atom bombardment mass spectrometry are shown to be an efficient combination for investigating protease-mediated digestion of synthetic analogs of the peptide hormone ANF (atrial natriuretic factor). As examples of the reported methodology, rANF5-23-NH2 and rANF7-23-NH2 were digested with the endopeptidase thermolysin. These truncated analogs were selected to investigate metabolism within the disulfide-linked core of ANF, particularly at the Cys7-Phe8 bond. While this position was the site of initial hydrolysis for rANF5-23-NH2 (t1/2 = 0.5 min), the Cys7-Phe8 bond remained intact for all observed degradation products of rANF7-23-NH2 (t1/2 = 16 min). These findings suggest that improved stability towards endopeptidase-mediated core hydrolysis may be conferred to analogs of ANF by removal of the first six residues from the N-terminus.

Receptor binding affinity and thermolysin degradation of truncated and retro-inverso-isomeric ANF analogs.

The peptides H-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-NH2 (rANF8-15-NH2), Ac-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-NH2 (Ac-rANF8-15-NH2), and their corresponding retro-inverso-isomeric peptides H-D-Ile-D-Arg-D-Asp-D-Ile-D-Arg-Gly-Gly-D-Phe-NH2 (D-rANF15-8-NH2), Ac-D-Ile-D-Arg-D-Asp-D-Ile-D-Arg-Gly-Gly-D-Phe-NH2 (Ac-D-rANF15-8-NH2), were evaluated for their ability to compete for the binding of 125I-rANF5-28 to cultured spontaneously hypertensive rat (SHR) aortic smooth muscle cell membranes. Their stability toward hydrolysis by the neutral endopeptidase thermolysin was also studied. The octapeptides rANF8-15-NH2 and Ac-rANF8-15-NH2 bound with IC50's of 367 pM and 1900 pM, respectively, but were rapidly hydrolyzed by thermolysin. Retro-inverso-isomers were prepared to provide molecules with an improved enzymatic stability. The retro-inverso-isomers were completely stable to thermolysin but were virtually inactive in the binding assay (IC50 greater than 1 microM).