Bclx regulates the survival of double-positive thymocytes.

The bclx gene has been shown to regulate programmed cell death in vitro. We now show that Bclx expression increases dramatically when T cells differentiate from CD4- CD8- (double negative) thymocytes to CD4+ CD8+ [double positive (DP)] thymocytes. In contrast single-positive (SP) thymocytes express negligible amounts of Bclx protein. This expression pattern contrasts with that of Bcl2, which is present in double-negative thymocytes, down-regulated in DP thymocytes, and reinduced upon maturation to SP thymocytes. Elimination of Bclx by gene targeting dramatically shortens the survival of DP thymocytes but not the survival of SP thymocytes or peripheral SP T cells. These data suggest that the induction of Bclx during thymic maturation plays a critical role in regulating the length of time DP thymocytes survive in the absence of selection.     

Acute haemodynamic and metabolic effects of dopexamine, a new dopaminergic receptor agonist, in patients with chronic heart failure.

Dopexamine, a new compound with postjunctional dopamine receptor activating and beta adrenoceptor agonist properties, was given to 10 patients with chronic heart failure at diagnostic cardiac catheterisation to investigate its acute haemodynamic and metabolic effects. The drug was administered by intravenous infusion in three incremental doses and produced significant dose related increases in cardiac index, stroke volume index, and heart rate and falls in systemic vascular resistance and left ventricular end diastolic pressure; aortic and pulmonary artery pressures were unchanged. Isovolumic phase (max dP/dt and KVmax) and ejection phase (peak aortic blood velocity, maximum acceleration of blood, and maximum rate of change of power with time during ejection) indices of myocardial contractility were all increased by dopexamine but these changes were hard to interpret in the presence of an increase in heart rate. Myocardial efficiency and ejection fraction were both increased and left ventricular end diastolic and end systolic volumes fell. These largely beneficial changes were achieved without a statistically significant increase in myocardial oxygen consumption or disturbance of myocardial metabolic function. Dopexamine was well tolerated but tremor was reported by two patients at the intermediate dose and mild chest pain by two patients at the high dose.     

Patterns of anismus and the relation to biofeedback therapy

PURPOSE: A study was undertaken to assess physiologic characteristics and clinical significance of anismus. Specifically, we sought to assess patterns of anismus and the relation of these findings to the success of therapy. METHODS: Sixty-eight patients were found to have anismus based on history and diagnostic criteria including anismus by defecography and at least one of three additional tests: anorectal manometry, electromyography, or colonic transit time study. Interpretation of defecography was based on the consensus of at least three of four observers. Anal canal hypertonia (n=32) was defined when mean and maximum resting pressures were at least 1 standard deviation higher than those in 63 controls. There were two distinct defecographic patterns of anismus: Type A (n=26), a flattened anorectal angle without definitive puborectalis indentation but a closed anal canal; Type B (n=42), a clear puborectalis indentation, narrow anorectal angle, and closed anal canal. Outcomes of 57 patients who had electromyographybased biofeedback therapy were reported as either improved or unimproved at a mean follow-up of 23.7 (range, 6–62) months. These two types of anismus were compared with biofeedback outcome to assess clinical relevance. RESULTS: Patients with Type A anismus showed greater perineal descent at rest (mean, 5.1 vs. 3.5 cm;P < 0.01), greater dynamic descent between rest and evacuation (mean, 2.7 vs. 1.4 cm;P <0.01), greater difference of anorectal angle between rest and evacuation (mean, 14.6 vs. ?3.1°;P <0.001), higher mean resting pressure (mean, 77.1 vs. 62.8 mmHg;P <0.05), lower mean squeeze pressure (58.8 vs. 80.7 mmHg;P <0.05), and a higher incidence of anal canal hypertonia (69.2 vs. 33.3 percent;P <0.01) than did patients with Type B anismus. Only 25 percent of patients who had Type A anismus with anal canal hypertonia were improved by biofeedback therapy. Conversely, 86 percent of patients with Type B anismus without anal canal hypertonia were successfully treated with biofeedback (P <0.001; Fisher's exact test). CONCLUSIONS: These two distinct physiologic patterns of anismus correlate with the success of biofeedback treatment. Therefore, knowledge of these patterns may help direct therapy.     

Lipids,lipoproteins, and exercise

PURPOSE: Dose-response relationships between exercise training volume and blood lipid changes suggest that exercise can favorably alter blood lipids at low training volumes, although the effects may not be observable until certain exercise thresholds are met. METHODS AND RESULTS: Plasma triglyceride reductions are often observed after exercise training regimens requiring energy expenditures similar to those characterized to increase high-density lipoprotein cholesterol (HDL-C). Thresholds established from cross-sectional and longitudinal exercise training studies indicate that 15 to 20 miles/week of brisk walking or jogging, which elicit between 1,200 to 2,200 kcals of energy expenditure per week, is associated with triglyceride reductions of 5 to 38 mg/dL and HDL-C increases of 2 to 8 mg/dL. Exercise training seldom alters total cholesterol and low-density lipoprotein cholesterol (LDL-C) unless dietary fat intake is reduced and body weight loss is associated with the exercise training program, or both. Thus, for most individuals, the positive effects of regular exercise are exerted on blood lipids at low training volumes and accrue so that noticeable differences frequently occur with energy expenditures of 1,200 to 2,200 kcals/week. CONCLUSIONS: It appears that weekly exercise caloric expenditures that meet or exceed the higher end of this range are more likely to produce the desired lipid changes. Regarding hyperlipidemic disorders, the primary means for intervention is pharmacologic, whereas diet modification, weight loss, and exercise, although important, are viewed as adjunctive therapies. Because much is known about the exercise training-induced plasma lipid and lipoprotein modifications as well as the mechanisms responsible for these changes, rehabilitation professionals can better develop a comprehensive medical management plan that optimizes pharmacologic, reduced dietary fat intake, weight loss, and exercise interventions.     

Altered localization and activity of canalicular Mrp2 in estradiol-17beta-D-glucuronide-induced cholestasis

Estradiol-17beta-D-glucuronide (E(2)17G), an endogenous metabolite of estradiol, induces a potent dose-dependent and reversible inhibition of bile flow in the rat. We analyzed the effect of a single dose of E(2)17G (15 micromol/kg, intravenously) to female rats on bile flow and the endocytic retrieval and function of the canalicular multidrug resistance-associated protein 2 (Mrp2) and the effect of pretreatment with dibutyryl-cyclic AMP (DBcAMP; 20 micromol/kg) on these measures. Bile flow was maximally inhibited by 85% within 10 minutes of E(2)17G and returned to 50% and 100% of control levels within 75 and 120 minutes, respectively. Western analysis of total homogenates and mixed plasma and intracellular membranes suggested partial internalization of Mrp2 during the acute phase of cholestasis at 20 minutes and during the period of recovery from cholestasis at 75 minutes, which returned to control levels by 180 minutes after E(2)17G. Confocal analysis confirmed Western studies and demonstrated endocytic retrieval of Mrp2 from the canalicular membrane into pericanalicular and intracellular domains. The biliary concentration and excretion of the model Mrp2 substrate, dinitrophenyl-S-glutathione (DNP-SG), was impaired in parallel with the extent of Mrp2 retrieval. Pretreatment with DBcAMP partially protected against maximal E(2)17G cholestasis and the endocytic retrieval and decreased function of Mrp2 at 20 minutes and significantly accelerated the exocytic insertion of Mrp2 into the canalicular membrane and the recovery of bile flow and biliary excretion of DNP-SG. In conclusion, these data indicate that E(2)17G induces endocytic internalization of Mrp2, which occurs in parallel with decreased bile flow and Mrp2 transport activity.     

An evaluation of a nurse-led Comprehensive Child Development Service in Hong Kong

Objective: The objectives of this study were to evaluate a nurse-led Comprehensive Child Development Service aimed at reducing depression and increasing satisfaction with care among a group of high-risk pregnant women. Background: Many studies have indicated that mental health problems, substance abuse, teenage pregnancy and poor social support for single mothers are associated with poor outcomes in fetal and child development. Pre-term delivery and low birth weight can be found in mothers engaging in substance abuse. The nurse-led Comprehensive Child Development Service includes an early identification and referral system for families in need that is geared towards providing better care and ensuring better health outcomes and positive life courses for children and families. Methods: A single group pre-test post-test design was used and participants – 74 pregnant women who presented with symptoms of low mood, had separated from their partners or had a history of illicit drug use – were recruited from an outpatient clinic in Hong Kong. Depression and satisfaction were measured by the Edinburgh Postnatal Depression Scale and a self-developed questionnaire respectively. Results: Participants reported a significant reduction in depression and a high level of satisfaction with the service. Conclusion: The study demonstrates that the Comprehensive Child Development Service has a positive impact on pregnant women.     

Pneumatic dilation for the treatment of achalasia in untreated patients and patients with failed Heller myotomy

BACKGROUND: Laparoscopic Heller myotomy (HM) has become an increasingly preferred modality to treat achalasia. However, the treatment course after a failed myotomy is controversial with fears that pneumatic dilation (PD) has high perforation risk. GOAL: To compare success and safety of graded PD with Rigiflex balloons in achalasia patients without a prior HM (untreated cases) and those with a failed HM. STUDY: A total of 108 patients were retrospectively evaluated: 96 untreated cases (53 male, 43 female, mean age 51 years) and 12 failed HM(7 male, 5 female, mean age 54 years). Symptoms (dysphagia and regurgitation) and physiologic studies, lower esophageal sphincter pressure (LESP) and timed barium swallow, assessed pre- and post-PD. Success was defined as: 1) symptom improvement to /=80% decrease in 5-minute barium column height from initial timed barium swallow. RESULTS: A total of 139 PDs performed (117 untreated cases, 22 failed HM): 2 perforations in untreated cases and none in failed HM group. Baseline demographics were similar, but failed HM patients had significantly lower LESP and timed barium swallow columns. Despite less LES resistance, failed HM group (symptom and physiologic success: 50% and 10%) did not do as well after PD as compared with untreated cases (symptom and physiologic success: 74% and 52%, respectively). Five failed HM patients had good symptom relief after PD compared with poor responders these patients were older (>50 years) and had LESP >17 mm Hg. CONCLUSIONS: PD perforation risk is not higher after HM. Despite lower LES pressure, patients undergoing PD after failed HM do not do as well as untreated cases. Factors predicting better outcome include older age and higher LES pressure.     

Estrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1

Estrogen and insulin/insulin-like growth factor-I (IGF-I) are major mitogens for breast epithelial cells and when co-administered, synergistically induce G(1)-S phase cell cycle progression. We investigated this cooperativity by evaluating if the key cell cycle regulators, c-Myc and cyclin D1, represent points of convergence in the action of these mitogens in MCF-7 breast cancer cells. These studies demonstrated that estrogen significantly increased both c-Myc and cyclin D1 protein, while insulin predominantly increased cyclin D1 levels. This cumulative increase in c-Myc and cyclin D1 contributes to the cooperativity of these mitogens, since ectopic expression of c-Myc or cyclin D1 cooperates with either the estrogen or insulin signaling pathways to increase cell cycle progression. Inhibition of the MAPK or PI3-kinase pathways significantly reduced c-Myc and cyclin D1 protein levels and cell cycle progression. Ectopic expression of cyclin D1 partially overcame this inhibition, while ectopic expression of c-Myc partially overcame MAPK but not PI3-kinase inhibition. Therefore, estrogen and insulin/IGF-1 differentially regulate c-Myc and cyclin D1 to cooperatively stimulate breast cancer cell proliferation.