Transitioning young adults with neurogenic bladder-Are providers asking too much?

INTRODUCTION: Significant numbers of young adults with chronic health conditions fail to transition. OBJECTIVE: The aim of the study was to evaluate how ready transitioned urologic patients were for that process. Owing to the cognitive impairments frequently seen with spina bifida (SB), it is hypothesized that these individuals will be less prepared to transition their medical care to adult providers compared with their healthy counterparts. METHODS: Participants included consecutive patients in the transitional SB clinic at the study institution and controls (college students without obvious physical disability or interest in healthcare-related fields aged 18-25 years). Both groups were administered the Transition Readiness Assessment Questionnaire (TRAQ) over a nine-month period. Five TRAQ domains assess 20 skills necessary to transition. Likert scale responses range from 1 "no, I do not know how" to 5 "yes, I always do this when I need to" (which the authors considered appropriate for transitioned patients). Demographics and the number of daily medications taken were collected. Patients and healthy controls were compared using (1) total and domain TRAQ scores, (2) the proportion of non-transitioned skills ("1"), and (3) fully transitioned skills ("5"). Non-parametric statistics were used. RESULTS: Forty-three unique SB patients (30.8% shunted, 46.5% female) and 100 controls were enrolled. Patients with SB were older than controls (21 vs 20 years, p < 0.001). There was no gender difference between groups (p = 0.33). Transitioned patients and college students were fully transitioned only in the "Talking with Providers" domain (Figure). College students performed significantly better than patients in the domains of "Appointment Keeping" (p = 0.04) and "Tracking Health Issues" (p = 0.02). Transitioned patients were less likely to be interested in learning how to perform skills in the domains of "Appointment Keeping" and "Tracking Health Issues" (p < 0.001 for both domains). DISCUSSION: The transition readiness of young adults with SB compared to healthy controls and other youths with chronic health conditions is described. The limitations include the small sample size, potentially limiting generalizability, and cross-sectional nature. CONCLUSION: "Transitioned" patients with SB had lower TRAQ scores in some domains compared to healthy college students, who themselves had scores indicating that they were not fully ready for transition. Increased attention to transition readiness in people with SB is necessary, as even healthy young adults struggle with these tasks and are poorly prepared for transition.

Incidence of pathologic postobstructive diuresis after resolution of ureteropelvic junction obstruction with a normal contralateral kidney.

INTRODUCTION: Postobstructive diuresis (POD) after unilateral pyeloplasty or percutaneous nephrostomy (PCN) tube insertion for ureteropelvic junction obstruction (UPJO) in patients with a normal contralateral kidney is not well described. OBJECTIVE: The objective of this study was to determine the incidence and characteristics of POD after relief of unilateral UPJO in patients with a normal contralateral kidney. STUDY DESIGN: Children who underwent a unilateral pyeloplasty or PCN for UPJO from 2010 to 2017 with a normal contralateral kidney were retrospectively reviewed. Postobstructive diuresis was defined as urine output (UO) of >300% of expected UO. Patients with a solitary kidney or those who underwent bilateral pyeloplasty or bilateral PCN tube placement were excluded. RESULTS: Out of 396 children meeting inclusion criteria, seven (1.8%) developed POD (4 after pyeloplasty and 3 after PCN tube placement). Median age at intervention was 1.7 years (range 11 days-18 years); median weight was 11.4 kg (range 3.7-54.2 kg). Postobstructive diuresis was more likely to occur in patients with grade 4 hydronephrosis (3.0%) and larger kidneys and if a PCN tube was placed before pyeloplasty. There was no significant difference in age, gender, kidney laterality, or function between those who developed POD and those who did not. Postobstructive diuresis was managed with additional intravenous fluids and electrolyte monitoring. Median initial postprocedure UO was 5.9 mg/kg/hr (range 3.2-10.0 mg/kg/hr). In five children who underwent PCN in whom UO could be differentiated between kidneys, median initial postprocedure UO was 6.1 mg/kg/hr (range 2.5-9.1 mg/kg/hr) from the affected side and 0.8 mg/kg/hr (range 0.4-0.9 mg/kg/hr) from the unaffected side. The median length of time to resolution of POD was 3 days (range 2-4 days). One patient developed significant acidosis and lethargy that improved with intravenous fluid management. Mild hyponatremia developed in two, hypokalemia in one, hypophosphatemia in one, acidosis in one, and hypoglycemia in 1 patient. DISCUSSION: A low but clinically significant risk of POD occurring after relief of unilateral UPJO in children with a normal contralateral kidney is described. Limitations include retrospective analysis and small sample size due to the rarity of the condition. CONCLUSION: Postobstructive diuresis after decompression of UPJO in patients with a normal contralateral kidney is a rare event (1.8%). However, POD does occur, and patients should be carefully monitored after these procedures given the potential for significant dehydration and electrolyte disturbances.

Early readmission and reoperation characteristics of ambulatory hypospadias repair.

INTRODUCTION AND BACKGROUND: Hypospadias is a common birth defect. It is present in about 34.2 in 10,000 live births in North America. However, few studies have evaluated the immediate reoperation and readmission rates following elective repair. OBJECTIVE: This study aimed to define the rates of readmission and reoperation following elective hypospadias repair, to improve pre-operative counseling on risks of the procedure. STUDY DESIGN: The Pediatric Health Information System (PHIS) was interrogated from 2004 to 2015 for all elective hypospadias repairs (ICD-9-CM code 58.45) performed in the ambulatory surgical setting. The following were then determined: age at initial operation, insurance status, race, presence or absence of readmission or reoperation within 30 days, presence of repeat hypospadias repair (same ICD-9 code), and presence or absence of another urethral operation (ICD-9 CM code 58.XX, excluding 58.45). Mixed effects logistic regression were then performed with dependent variables of 30-day repeat encounter, 30-day emergency department (ED) visit, 30-day readmission, or 30-day reoperation; and independent variables of age, race, ethnicity, and insurance status. RESULTS: The study identified 45,264 hypospadias repairs during 2004-2015 performed in 43 hospitals. Within 30 days of the procedures, 2826 (6.2%) had additional encounters in the ED at the same facilities, and 546 (1.2%) had readmissions. A total of 105 (0.2%) underwent second anesthetic within the first 30 days. With regards to a 30-day repeat encounter, odds of repeat encounter were significantly increased in patients aged <5 years, Black and Asian patients, and those with Medicaid. Of the 4882 repeat encounters, 954 (19.5%) had discharge ICD-9 codes related to the penis, or to postoperative complications in general. DISCUSSION: This study described the epidemiology of clinical events occurring at the same tertiary children's hospital within the first 30 days following more than 45,000 hypospadias repairs. Limitations included a cohort generated from a single set of ICD-9 codes. CONCLUSIONS: Elective hypospadias repair had a low rate of readmission (1.2%) and reoperation (0.2%) within the first 30 days. Patients aged <5 years, of non-white race, Hispanic ethnicity, and on Medicaid had significantly higher odds of 30-day repeat encounters.

Mobility, hydrocephalus and quality of erections in men with spina bifida.

INTRODUCTION: Little is known about erectile dysfunction (ED) among men with spina bifida (SB). The goal of this study was to determine quality of erections and possible factors affecting erections in this population. It was hypothesized that men who ambulate and do not have a ventriculoperitoneal shunt (VPS) are more likely to have erections sufficient for intercourse. METHODS: An online survey was administered over an 18-month period to men aged ≥18 years and with SB. Participants were recruited through local, national and international SB organizations via social media. Exclusion criteria were: poor English proficiency, not completing the questionnaire or missing information regarding erections, VPS or ambulation. Data were collected on demographics, previous surgeries and function. Ambulatory status was classified using the Hoffer classification (Hoffer et al., 1973). Those able to walk at least at home, with or without crutches/braces, were classified as "ambulators." Erections were assessed using a single question from the validated Expanded Prostate Cancer Index Composite questionnaire (e.g. normal: "firm enough for intercourse"). Logistic regression was used for statistical analysis. RESULTS: The median age of 122 participants was 33 years, 53.3% were ambulators and 70.5% had a VPS. Overall, 41.0% reported normal erections. Ambulators were more likely to report normal erections than non-ambulators (63.1% vs 15.8%, P < 0.001) (Table). Those with and without a VPS reported similar rates of normal erections (37.9% vs 48.6%, P = 0.32). On multivariate analysis, ambulators were more likely to have normal erections (OR ≥8.65, P ≤ 0.001) after correcting for age and VPS status. Age and VPS status were not correlated with normal erections on multivariate analysis (P ≥ 0.32 and P = 0.62, respectively). DISCUSSION: Approximately 59% of men with SB reported ED, with ambulators being far more likely to have normal erections. This suggests that ambulatory status, similar to neurological lesion level, is a confounder of erectile function in the SB population. A limitation of the study was that a single item was used to assess erectile function. Rather than performing a comprehensive analysis of sexual health, the study aimed to gauge the prevalence of normal erections and assess possible risk factors. It did not assess sexual activity, erection duration or ED treatments. However, this is the largest study, to date, on SB and erectile quality with international participants. CONCLUSION: About 40% of men with SB reported normal erections. Ambulatory status, rather than hydrocephalus, appeared to be the primary factor associated with erectile function. Approximately 2/3 of ambulators and 1/6 of non-ambulators reported normal erections.

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers.

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub-fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats.

OBJECTIVE: Co-administration of amylin and leptin induces synergistic and clinically meaningful (>10%) weight loss that is attenuated as the degree of obesity increases. We explored whether calorie restriction (CR) could restore amylin/leptin synergy in very obese rats. METHODS: Sprague Dawley rats on high-fat diet (696 ± 8 g, n = 72) were randomized to three cohorts (C1-C3). Rats in C1 were administered vehicle, rat amylin (50 µg kg-1 d-1), murine leptin (125 µg kg-1 d-1) or amylin and leptin for 28 days (n = 6 per group) via subcutaneous minipump. Simultaneously, C2 and C3 rats initiated CR. After moderate (12.4 ± 0.3%, 86.7 ± 2.8 g; C2) or severe (24.9 ± 0.3%, 172.7 ± 4.7 g; C3) weight loss, amylin and/or leptin was administered as described. RESULTS: In C1, leptin did not alter weight, and amylin induced 40.2 ± 6.1 g weight loss (-6.0 ± 0.9%), which was not enhanced by leptin (44.4 ± 4.9 g, -6.1 ± 0.8%). In C2, vehicle-treated (75.1 ± 7.8 g weight change from start of treatment, 1.1 ± 0.8% difference from start of pre-CR phase) and leptin-treated rats (68.6 ± 9.2 g, -1.3 ± 1.0%) rebounded to pre-restriction weight that was attenuated by amylin (29.2 ± 11.4 g, -6.2 ± 0.7%). Leptin did not enhance the effect of amylin (22.8 ± 11.7 g, -8.3 ± 1.5%). In C3, vehicle-treated and leptin-treated rats regained most of their weight (161.9 ± 11.8, -2.3 ± 0.8% and 144.6 ± 9.5 g, -2.3 ± 0.9%, respectively), which was attenuated by amylin (91.1 ± 16.8 g, -11.2 ± 0.7%), but not enhanced by leptin (83.0 ± 7.6 g, -10.7 ± 0.8%). CONCLUSIONS: Extreme obesity associated with leptin resistance perturbs amylin/leptin weight loss synergy in rats, which cannot be restored by pre-treatment weight loss.

Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents.

AIM: To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon-like peptide-1 receptor (GLP-1R) agonist on metabolic variables in diet-induced obese (DIO) rodents. METHODS: A stabilized acetylated version of CCK-8 (Ac-Y*-CCK-8), selective CCK1 receptor (CCK1R) or CCK2 receptor (CCK2R) agonists, amylin or the GLP-1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lep(ob) /Lep(ob) mice for 28 days, and metabolic variables were assessed. RESULTS: Combined administration of Ac-Y*-CCK-8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174 + Ac-Y*-CCK-8 treatment. Co-infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174 + Ac-Y*-CCK-8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4 × 4 full-factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R-selective agonist on body weight and food intake was noted. Co-administration of AC3174 and the CCK1R-selective agonist to obese diabetic Lep(ob) /Lep(ob) mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups. CONCLUSIONS: The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.

Interactions of amylinergic and melanocortinergic systems in the control of food intake and body weight in rodents.

AIMS: Amylinergic and melanocortinergic systems have each been implicated in energy balance regulation. We examined the interactive effects of both systems using gene knockout and pharmacological approaches. METHODS: Acute food consumption was measured in overnight fasted male wild-type (WT) and melanocortin-4 receptor (MC-4R) deficient rats and in male and female WT and amylin knockout mice (AmyKO). Changes in food intake, body weight and composition in male WT and MC-4R deficient rats and in male diet-induced obese (DIO) rats. Pharmacological treatments included either rat amylin, murine leptin and/or the MC-4R agonist, Ac-R[CEH-dF-RWC]-amide. RESULTS: Amylin (10 µg/kg, IP) decreased food intake in WT but not in MC-4R deficient rats (30 and 60 min post-injection). Ac-R[CEH-dF-RWC]-amide (100 µg/kg, IP) suppressed food intake similarly in male WT and AmyKO, but was ineffective in female AmyKO. Amylin (50 µg/kg/day for 28 days) and leptin (125 µg/kg/day) synergistically reduced food intake and body weight in WT and MC-4R deficient rats to a similar extent. Amylin (100 µg/kg) combined with Ac-R[CEH-dF-RWC]-amide (100 µg/kg, IP) decreased acute food intake over 3 h to a greater extent than either agent alone in fasted mice. In DIO rats, additive anorexigenic, weight- and fat-lowering effects were observed over 12 days with the combination of rat amylin (50 µg/kg/day) and Ac-R[CEH-dF-RWC]-amide (2.3 mg/kg, SC injected daily). CONCLUSIONS: Although amylin's acute anorexigenic effects are somewhat blunted in MC-4R deficiency and those of MC-4R agonism in amylin deficiency, these effects are surmountable with pharmacological administration lending therapeutic potential to combined amylin/melanocortin agonism for obesity.

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight.

OBJECTIVE: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. RESEARCH DESIGN AND METHODS: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. RESULTS: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). CONCLUSION: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

Antiobesity effects of the beta-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats.

OBJECTIVE: To characterize the interactive effects of amylin with phentermine or sibutramine on food intake, body weight/composition and gene expression in diet-induced obese (DIO) rats. DESIGN: DIO rats were intraperitoneally injected with a single dose of amylin (10 microg kg(-1)) and/or phentermine (1 mg kg(-1)) or chronically infused with amylin (100 microg kg(-1) d(-1)) or vehicle with or without phentermine (0.5-10 mg kg(-1) d(-1)) or sibutramine (3 mg kg(-1) d(-1)) using two surgically implanted subcutaneous osmotic mini-pumps. MEASUREMENTS: Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (amylin, phentermine or amylin+phentermine). Body weight and composition (for amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (beta-adrenergic receptors and uncoupling protein-1) were measured (for amylin and/or phentermine) after sustained infusion (2 weeks). RESULTS: Acute co-administration of amylin (10 microg kg(-1)) and phentermine (1 mg kg(-1)) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain ( approximately 4-8%). Phentermine's anorexigenic (10-17%) and weight-reducing effects ( approximately 0-5%) were only evident at the highest dose tested (10 mg kg(-1) d(-1)). Combination of amylin (100 microg kg(-1) d(-1)) and phentermine reduced food intake (30-43%), body weight (8-12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When amylin+sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to amylin+phentermine treatment, amylin+sibutramine mediated weight loss was attributable to significant reductions in fat mass. CONCLUSIONS: Combined treatment of DIO rats with the pancreatic beta-cell hormone amylin and phentermine or sibutramine resulted in additive anorexigenic, weight- and fat-reducing effects.

Comparison of either norepinephrine-uptake inhibitors or phentermine combined with serotonergic agents on food intake in rats.

RATIONALE: We have shown previously that the anorectic effects of the catecholamine-releasing agent phentermine (PHEN) and the serotonin (5-HT)-releasing agent dexfenfluramine (DFEN) are greater than additive in rats. In the present study, we examined whether the norepinephrine-uptake inhibitors desmethylimipramine (DMI) and thionisoxetine (TNIX) have additive effects with either DFEN or with the 5-HT-uptake inhibitor fluoxetine (FLX). We also examined whether PHEN interacts with a postsynaptically acting 5-HT agonist. METHODS: Undeprived rats were trained to eat a daily sweet-milk dessert and on test days were systemically administered single or combination drugs and the intakes recorded. RESULTS: Both DMI and TNIX produced dose-related suppressions of food intake. However, by isobolographic analysis, they did not enhance the anorectic actions of either DFEN or FLX. In contrast, confirming and extending our previous work, PHEN had a greater potentiating effect on the anorectic actions of DFEN and FLX than TNIX. Further, the anorectic action of the 5-HT2c receptor agonist TFMPP was enhanced by PHEN. CONCLUSIONS: These and other data are consistent with the idea that 5-HT agents may work "upstream" of critical catecholaminergic synapses in the production of anorexia, and explain the diminished efficacy of norepinephrine-uptake inhibitors relative to PHEN. The implications for clinically useful anorectic agents are discussed briefly.

Dexfenfluramine and norfenfluramine: comparison of mechanism of action in feeding and brain Fos-ir studies.

Dexfenfluramine (dF) and dexnorfenfluramine (dNF), its metabolite, are anorectic agents that release serotonin (5-HT) and may have a direct postsynaptic action. The effects on the anorectic effects of dF and dNF of either acute (p-chlorophenylalanine, PCPA) or chronic (5,7-dihydroxytryptamine, 5,7-DHT) brain 5-HT depletions were studied in rats and compared with the actions of a 5-HT uptake inhibitor (fluoxetine) and 5-HT(1B/2C) receptor agonists [1-(3-trifluoromethyl-phenyl)-piperazine and 1-(3-chlorophenyl) piperazine]. The anorexia caused by these agonists was enhanced in rats with 5,7-DHT lesions, possibly a result of receptor supersensitivity. In contrast, fluoxetine anorexia was somewhat reduced in one study and was unchanged in a second. Both dF and dNF anorexias were enhanced in rats with 5,7-DHT lesions. In contrast, the anorectic effects of either dF or dNF were unchanged in PCPA-treated rats relative to controls. Compared with controls, 5, 7-DHT-lesion rats showed greatly increased dF- and dNF-induced Fos-like immunoreactivity (ir) in the paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei, and in the median preoptic area (MnPO), but were similar to controls in most other areas. PCPA pretreatment increased dF- and dNF-induced Fos-ir in the PVN, SON, and MnPO. In controls, equianorectic doses of dF and dNF induced Fos-ir in similar brain regions, but dNF produced relatively larger effects than dF in SON, PVN, and MnPO. The data are discussed in terms of multiple pathways in the anorectic actions of dF and dNF.

Interactive Effects of Neurochemicals on Ingestive Behavior.

Most previous research has focused on the effects of single neurotransmitters and neuropeptides on ingestive behavior. An important next step in the advancement of the science of ingestive behavior is to gain an understanding of how these different systems interact with one another. The present article is designed as an introduction to interacting systems involved in the regulation of food intake. Specifically, we review recent research on several neurochemicals that have emerged as good candidates for further study of interactions because they appear to serve integrative roles.

Anorectic efficacy of the fenfluramine/phentermine combination in rats: additivity or synergy?

Fenfluramine + phentermine was a widely used combination for weight loss. Fenfluramine and phentermine are believed to act via serotonin and catecholamines, respectively. To what extent these drugs interact has not been well-established. We compared the anorectic efficacy of a range of doses of the combination (using dexfenfluramine instead of fenfluramine) relative to a range of doses of the individual drugs in 90 min sweetened milk intake tests in deprived and nondeprived rats. Results were plotted on isobolograms to determine whether the anorectic effects of the combination were either additive or synergistic. Collectively, the isobolographic analysis revealed that: (1) under acute conditions, dexfenfluramine and phentermine interact for the most part in a synergistic manner, and (2) with the exception of phentermine alone, deprivation state at time of testing did not alter the efficacy of the anorectics. These findings suggest that combined drug treatment for obesity is a theoretical approach that merits further investigation.

Efficacy of administration of dexfenfluramine and phentermine, alone and in combination, on ingestive behavior and body weight in rats.

Recently, a combination of the anorectics fenfluramine (FEN) and phentermine (PHEN) has been used to treat obesity. While each of these agents has been investigated in animals, little is known concerning the effects of the combination on ingestive behavior and body weight. In the present experiments, we report: (1) the effects of acute administration of dexfenfluramine (DFEN) and PHEN individually and in combination on sweetened milk intake and body weight in non-deprived rats and (2) the effects of chronic administration (7 day minipump) of DFEN, PHEN, and their combination on daily food intake and body weight both during and after the treatment period. Additionally, the effects of the 5-HT2C agonist 1-[3-(trifluoromethyl)-phenyl]piperazine (TFMPP) alone and in combination with PHEN on food intake and body weight were assessed. Both acute and chronic administration of DFEN and PHEN revealed that in combination they are more effective than when given individually. However, the DFEN/ PHEN combination does not appear to exert effects that are selective for food intake because water intake was markedly suppressed in water-deprived rats. PHEN alone or in combination with either DFEN or TFMPP also produced increased activity or alertness during the day when controls normally were asleep. While anorectic combinations such as DFEN/PHEN may be effective at promoting weight loss and reducing food intake, future studies on their specificity, safety and efficacy are warranted.

Effects of L-arginine on angiotensin II-related water and salt intakes.

Nitric oxide (NO) has been implicated centrally as an inhibitory neuromodulator, acting in short feedback loops. Neurons capable of NO synthesis have been localized in various thirst-related hypothalamic nuclei. Intracerebroventricular (icv) injection of L-arginine (L-arg), the precursor for NO, has previously been shown to attenuate both dehydration- and angiotensin II (Ang II)-induced drinking behavior. The present study further examines the effects of L-arg on drinking. We confirmed that icv administration of L-arg (50 microg) reduced water intakes induced by both 24 h water deprivation and icv Ang II (250 ng). We additionally showed that L-arg inhibited the water intake induced by peripheral injection of Ang II and the intake of 0.3 M NaCl following 24 h sodium depletion. We demonstrated the behavioral specificity of L-arg treatment by showing that it did not inhibit the intake of sucrose in food deprived rats and did not act as an unconditional stimulus for the formation of a conditioned taste aversion. These results lend further support to the idea that NO plays a role in modulating fluid balance and drinking behavior.

Famotidine-induced mixed hepatocellular jaundice.

OBJECTIVE: To report a case of probable famotidine-induced mixed hepatocellular jaundice. CASE SUMMARY: A 55-year-old man presented with a one-month history of mid-epigastric pain. Initial physical examination and laboratory studies, including liver enzyme concentration tests, were unrevealing. A diagnosis of gastritis was made and ranitidine was prescribed. Following one week of therapy, the patient's symptoms had not improved and therapy was changed to famotidine and sucralfate. Approximately one week later the patient presented with jaundice. Liver enzyme concentrations were elevated and the patient was hospitalized for further evaluation. Five days following discontinuation of famotidine, liver enzyme concentrations were normal and jaundice had resolved. Further tests did not reveal any pathologic etiology. DISCUSSION: Hepatic changes have occurred in patients receiving histamine2-antagonists; ranitidine and cimetidine have been cited most frequently. In general, the elevations are mild, transient, and return to baseline with continued therapy. This is one of the first case reports of probable famotidine-induced mixed hepatocellular jaundice. CONCLUSIONS: There was a temporal relationship between the patient's signs and symptoms and initiation of famotidine. No identifiable factors contributed to the elevated liver enzyme concentrations and jaundice.

Long-lasting inhibition of neuron R15 of Aplysia: role of the interneuron II network.

Stimulation of the branchial or either connective nerve of the abdominal ganglion of Aplysia californica evokes simultaneous responses in cells R15, L8, L9, and L11 which are indistinguishable from those arising from spontaneous interneuron II (INT II) activity. Threshold for the INT II-like response in all cells is identical, suggesting that the response is mediated by INT II activity. The magnitude of the response in each cell increases with stimulus intensity and is subject to both temporal and spatial summation, implying the existence of multiple fibres in each nerve which converge on INT II. Repetitive stimulation evokes long-lasting inhibition in R15. The onset of this phenomenon is always accompanied by an INT II burst in the other follower cells. Long-lasting inhibition in R15 is not accompanied by prolonged INT II activity, suggesting an endogenous mechanism of inhibition. The phosphodiesterase inhibitor, IBMX, potentiates the response of R15 to nerve stimulation without affecting threshold for the response. This is consistent with inhibition by a mechanism endogenous to R15.