RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist

The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described.     

An analysis of program and family costs of case managed care for technology-dependent infants with bronchopulmonary dysplasia

Influenza caused low levels of mortality and morbidity in England and Wales in the 1997/98 season. Influenza viruses of the H3N2 and H1N1 subtypes were isolated in small numbers from community and hospital patients in November and December. Their numbers subsequently increased to peak in February, H1N1 a week or two before H3N2. Most of the H1N1 isolates were similar to the A/Bayern/7/95-like virus, included in the vaccine recommended for 1997-98, whereas most H3N2 isolates were A/Sydney/5/97-like, a virus not covered by the season's vaccine but recommended for 1998/99. Consultation rates in general practice for influenza-like illnesses remained low until early February, when a small increase coincided with the increase in laboratory confirmed influenza. Fewer deaths directly attributed to influenza were registered during the surveillance period than in recent years. Localised outbreaks occurred in schools and nursing homes towards the end of the winter.     

The effect of hepatocyte enlargement on the hemodynamic characteristics of the isolated perfused rat liver preparation

The influence of hepatocyte enlargement on intrahepatic hemodynamics was assessed in the isolated perfused rat liver preparation (IPRL) using two experimental models: hypotonic liver cell swelling and phenobarbitone-induced hepatocyte hypertrophy. The analysis of pressure-flow data obtained from the portal vascular bed over a flow range of 0 to 70 mL/min in the presence of a maximally-effective concentration of the vasodilator agent papaverine hydrochloride (6 x 10(-4) mol/L) enabled the calculation of P0, an estimate of the pressure required to passively distend the intrahepatic vasculature, and Gmax, the maximal portal vascular conductance. By comparison with an isotonic perfusion medium (Krebs-Henseleit buffer [KH] containing 2.5% bovine serum albumin [BSA]), perfusion with a hypotonic medium induced a significant increase in mean hepatocyte cross-sectional area (H(A)) (590 +/- 21 vs. 324 +/- 23 microm(-2), p < .05), a fall in Gmax (0.39 +/- 0.08 vs. 2.02 +/- 0.18 mL/min/g/mm hg, P < .001), and an increase in P0 (2.96 +/- 0.38 vs. 1.58 +/- 0.07 mm hg, P < .001). Phenobarbitone administered in drinking water (0.5 g/L) over a period of 60 days also induced a significant degree of hepatocyte enlargement (HA, 510 +/- 29 microm2, P < .05). On day 7, portal pressure measured in vivo in this group was significantly elevated compared with untreated controls (10.5 +/- 0.3 vs. 8.4 +/- 0.2 mm hg, P < .001), while in the IPRL Gmax was reduced (0.48 +/- 0.01 mL/min/g/mm hg, P < .001), and P0 was increased (2.23 +/- 0.17 mm hg, P < .05). However, with continued phenobarbitone treatment portal pressure, Gmax and P0 returned toward control values. The results confirm that hepatocyte enlargement is associated with a significant disturbance of intrahepatic hemodynamics but also that some adaptation occurs if hepatocyte enlargement is sustained over a prolonged period of time.     

Schizophrenia and genetics: a review and critique for the psychiatric nurse

OBJECTIVES: To study the role of the LDL receptor in the clearance of chylomicron remnants in humans. DESIGN: Chylomicron remnant clearance was studied in five untreated subjects with heterozygous familial hypercholesterolaemia (FH) and nine normolipidaemic controls, by oral retinyl palmitate-fat loading tests. Fasting plasma triglycerides (TG), which are important determinators of chylomicron and remnant clearance, were not significantly different between FH (1.76+/-0.32 mmol L(-1), mean+/-SEM) and controls (1.26+/-0.18 mmol L(-1). Chylomicrons (Sf > 1000) and their remnants (Sf < 1000) were separated by flotation and their clearance was estimated by calculating the area under the 24 h-retinyl palmitate curve (AUC-RP). The factors determining chylomicron and remnant clearance were studied by univariate and multiple regression analysis. RESULTS: Triglyceride clearance in plasma, Sf > 1000 fractions and Sf < 1000 fractions was not significantly different between FH subjects and controls. In subjects with heterozygous FH, chylomicron remnant clearance was two-fold delayed (AUC-RP, 49.39+/-11.61 h.mg L(-1) compared to controls (27.45+/-3.95 h.mg L(-1); P = 0.048). Moreover, 28.4% higher fasting plasma TG in FH resulted in 44.4% higher areas under the remnant-curves compared to controls. The clearance of chylomicron RP was associated to plasma apo E (beta = 0.73, P = 0.011), plasma LDL cholesterol (beta = 0.62, P = 0.018) and plasma TG (beta = 0.58, P = 0.029). The clearance of remnant RP was associated to the diagnosis (FH vs. non-FH), but not to the well-known determinants of remnant clearance like plasma TG. CONCLUSIONS: The clearance of chylomicrons and large remnants isolated in the Sf > fraction depends primarily on the apo B, E (LDL) receptor and to a lesser extent on plasma triglycerides. The clearance of smaller chylomicron remnants isolated in the Sf < 1000 depends to a large extent on the apo B, E (LDL) receptor.     

Long-term results of total penile reconstruction with a prefabricated lateral arm free flap

Trifluoroethanol (TFE) is often used to increase the helicity of peptides to make them usable as models of helices in proteins. We have measured helix propensities for all 20 amino acids in water and two concentrations of trifluoroethanol, 15 and 40% (v/v) using, as a model system, a peptide derived from the sequence of the alpha-helix of ribonuclease T1. There are three main conclusions from our studies. (1) TFE alters electrostatic interactions in the ribonuclease T1 helical peptide such that the dependence of the helical content on pH is lost in 40% TFE. (2) Helix propensities measured in 15% TFE correlate well with propensities measured in water, however, the correlation with propensities measured in 40% TFE is significantly worse. (3) Propensities measured in alanine-based peptides and the ribonuclease T1 peptide in TFE show very poor agreement, revealing that TFE greatly increases the effect of sequence context.     

Target position variability throughout prostate radiotherapy

OBJECTIVE: It was our objective to evaluate the association between early maternal weight gain (before 20 weeks), midpregnancy weight gain (20-28 weeks), and late pregnancy weight gain (28 weeks to birth) with fetal growth and birth weight in twins. STUDY DESIGN: This historic cohort study was based on 1564 births of live twins >/=28 weeks' gestation from Baltimore, Maryland, Miami, Florida, Charleston, South Carolina, and Ann Arbor, Michigan. RESULTS: Early fetal growth was affected only by smoking and chorionicity. Factors in models of both mid and late fetal growth included maternal age, pregravid weight, parity, rates of early pregnancy and midpregnancy maternal weight gain, smoking, and pre-eclampsia. Increased midpregnancy fetal growth was associated with early maternal weight gain (10.91 g/wk per pound per week) and midpregnancy maternal weight gain (15.89 g/wk per pound per week). Increased late fetal growth was associated with early maternal weight gain (16.86 g/wk per pound per week) and midpregnancy maternal weight gain (23.88 g/wk per pound per week). Increased birth weight was associated with early (283.02 g per pound per week), mid (163.58 g per pound per week), and late (69.76 g per pound per week) maternal weight gains. CONCLUSIONS: These findings confirm the importance of early maternal weight gain in twin fetal growth and birth weight.     

Highly sensitive thromboplastins do not improve INR precision

OBJECTIVE: Severe obesity (ie, at least 100% overweight or body mass index > or =40 kg/m2) is associated with significant morbidity and increased mortality. It is apparently becoming more common in this country. Conventional weight-loss treatments are usually ineffective for severe obesity and bariatric surgery is recommended as a treatment option. However, longitudinal data on the long-term outcome of bariatric surgery are sparse. Available data indicate that the outcome of bariatric surgery, although usually favorable in the short term, is variable and weight regain sometimes occurs at 2 years after surgery. The objective of this study is to present a review of the outcome of bariatric surgery in three areas: weight loss and improvement in health status, changes in eating behavior, and psychosocial adjustment. The study will also review how eating behavior, energy metabolism, and psychosocial functioning may affect the outcome of bariatric surgery. Suggestions for additional research in these areas are made. METHOD: Literature review. RESULTS: On average, most patients lose 60% of excess weight after gastric bypass and 40% after vertical banded gastroplasty. In about 30% of patients, weight regain occurs at 18 months to 2 years after surgery. Binge eating behavior, which is common among the morbidly obese, may recur after surgery and is associated with weight regain. Energy metabolism may affect the outcome of bariatric surgery, but it has not been systematically studied in this population. Presurgery psychosocial functioning does not seem to affect the outcome of surgery, and psychosocial outcome is generally encouraging over the short term, but there are reports of poor adjustment after weight loss, including alcohol abuse and suicide. CONCLUSIONS: Factors leading to poor outcome of bariatric surgery, such as binge eating and lowered energy metabolism, should be studied to improve patient selection and outcome. Long-term outcome data on psychosocial functioning are lacking. Longitudinal studies to examine the long-term outcome of bariatric surgery and the prognostic indicators are needed.     

A randomized, placebo-controlled trial of topical cyclosporin A in steroid-dependent atopic keratoconjunctivitis

OBJECTIVE: This study aimed to investigate the therapeutic effect of topical cyclosporin A (CsA) 2% in maize oil as a steroid-sparing agent in steroid-dependent atopic keratoconjunctivitis. DESIGN: Prospective, randomized, double-masked, placebo-controlled trial. PARTICIPANTS: Twenty-one patients with steroid-dependent atopic keratoconjunctivitis were studied. INTERVENTION: Patients used either topical CsA or vehicle four times daily for 3 months in addition to their usual therapy, and the clinical response was used to taper or stop topical steroids when possible. MAIN OUTCOME MEASURES: Steroid drop usage per week, ability to cease steroid use, scores for symptoms and clinical signs, drop side effects, and overall subjective rating of trial drop by patients and clinician were measured. RESULTS: Cyclosporin A had a greater steroid-sparing effect than did placebo. Nine of 12 CsA patients ceased steroids compared to 1 of 9 placebo patients (P = 0.01), the final steroid use was lower in the CsA group (2.6 +/- 1.4 vs. 27.7 +/- 17.7, P = 0.005), and the mean reduction in steroid use was greater for CsA (85.5 +/- 14.7 vs. 13.9 +/- 16.0, P = 0.005). Clinical signs and symptom scores were reduced to a greater level for CsA. Serious side effects were lid skin maceration in one patient using CsA and an allergic reaction in one placebo patient. Marked blurring of vision after drop instillation was common in both groups, but intense stinging was more common in CsA patients (9/12 vs. 1/9, P = 0.01), limiting frequency of drop use. The clinician rated the trial drops as good or excellent more frequently for CsA (11/12 vs. 0/9, P < 0.0001). CONCLUSIONS: Topical CsA is an effective and safe steroid-sparing agent in atopic keratoconjunctivitis and, despite difficulties in patient tolerance, also improves symptoms and signs.     

Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 1996. Report of the Australian Mycobacterium Reference Laboratory Network

The Australian Mycobacterium Reference Laboratory Network collected and analysed laboratory data on new diagnoses of infection with Mycobacterium tuberculosis complex during 1996. A total of 750 cases were identified, representing an annual incidence of 4.1 cases of laboratory confirmed tuberculosis per 100,000 population. The incidence rate varied between States, reflecting differences in the distribution of persons belonging to 'high-risk' categories for tuberculosis. Incidence statistics were almost identical to those recorded by the Network in 1994 and 1995. The male:female ratio remained at around 1.2:1. As was the case in 1995, the median age group for males was 45-49 years and for females 35-39 years. The frequency of positive microscopy in pulmonary samples was stable at around 55%. Lymphatic disease accounted for 19% of the total cases in 1996 compared with 15% in the previous year, confirming that lymphadenitis is becoming more common in females with tuberculosis in Australia. Approximately 11% of isolates had in vitro resistance to at least one of the four standard anti-tuberculosis drugs, an increase from 8% in 1994-95. Fifteen isolates were multi-drug resistant, compared with a total of only 38 during the previous seven years. Thus, the 1996 data points to an increasing frequency of multi-drug resistant strains among isolates from Australian patients with tuberculosis.