Selective blockade of 5-hydroxytryptamine (5-HT)7 receptors enhances 5-HT transmission, antidepressant-like behavior, and rapid eye movement sleep suppression induced by citalopram in rodents

Evidence has accumulated supporting a role for 5-hydroxytryptamine (5-HT)7 receptors in circadian rhythms, sleep, and mood disorders, presumably as a consequence of the modulation of 5-HT-mediated neuronal activity. We hypothesized that a selective 5-HT7 receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB-269970), should increase activity of 5-HT neurons and potentiate the effect of selective serotonin reuptake inhibitors (citalopram). In rats, administration of 3 mg/kg s.c. citalopram alone increased the extracellular concentration of 5-HT. This effect of citalopram on extracellular 5-HT concentration was significantly enhanced by an ineffective dose of SB-269970. Combining this dose of SB-269970 with a low dose of citalopram also resulted in a significant increase in extracellular concentration of 5-HT, suggesting a potentiation of neurochemical effects. In mice, citalopram and SB-269970 dose-dependently decreased immobility time in the tail suspension test. The dose-effect curve of citalopram was shifted leftward by coadministration of an effective dose of SB-269970. Furthermore, combining ineffective doses of citalopram and SB-269970 also resulted in a significant decrease of immobility time in the tail suspension test, suggesting potentiation of antidepressant-like effects. In rats, SB-269970 potentiated the increase of rapid eye movement (REM) latency and the REM sleep decrease induced by citalopram. SB-269970 also reversed the increase in sleep fragmentation induced by citalopram. Rat plasma and brain concentrations of citalopram were not affected by coadministration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. Overall, these results indicate that selective blockade of 5-HT7 receptors may enhance the antidepressant efficacy of citalopram and may provide a novel therapy to alleviate sleep disturbances associated with depression.     

Pancreaticoduodenectomy: Outcomes in a Low-Volume,Specialised Hepato Pancreato Biliary Unit

Background

This study was designed to evaluate the outcomes of pancreaticoduodenectomy (PD) at a low-volume specialised Hepato Pancreato Biliary (HPB) unit. Volume outcome analyses show significantly better results for patients undergoing PD at high-volume centres (Begg et al. JAMA 280:1747–1751, 1998; Finlayson et al. Arch Surg 138:721–725, 2003; Birkmeyer et al. N Engl J Med 346:1128–1137, 2002; Gouma et al. Ann Surg 232:786–795, 2000). Centralisation of PD seems to be the logical conclusion to be drawn from these results. In countries like Australia with a small and widely dispersed population, centralisation may not be always feasible. Alternative strategy would be to have similar systems in place to those in high-volume centres to achieve similar results at low-volume centres. Many Australian tertiary care centres perform low to medium volumes of PD (Chen et al. HPB 12:101–108, 2010; Kwok et al. ANZ J Surg 80:605–608, 2010; Barnett and Collier ANZ J Surg 76:563–568, 2006; Samra et al. Hepatobiliary Pancreat Dis Int 10:415–421, 2011). Most of these have a specialised HPB unit, accredited by the Australia and New Zealand Hepatic pancreatic and biliary association (ANZHPBA), as training units for post fellowship training in HPB surgery. It is imperative to perform outcome-based analyses in these units to ensure safety and high quality of care.

Methods

Retrospective analysis of database for periampullary carcinoma (1998 till date) was performed in an ANZHPBA accredited HPB unit based at a tertiary care teaching hospital in South Australia. Because age older than 74 years is shown to be a predictive marker of increased morbidity and mortality after a PD, we analysed the outcomes in this subset of patients separately.

Results

Fifty-three patients underwent PD in 14 years. Overall mortality was 3.8 %. The last in hospital mortality was in 1999. The morbidity rates and the oncologic outcomes were similar to those in high-volume units.

Conclusions

PD can be safely performed in a low-volume specialised unit at centres where the amenities and processes at high-volume centres can be replicated.     

Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants

Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds—chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates.     

Abnormal fibrinogens IJmuiden (B beta Arg14----Cys) and Nijmegen (B beta Arg44----Cys) form disulfide-linked fibrinogen-albumin complexes.

The molecular defects in two congenital abnormal fibrinogens, IJmuiden and Nijmegen, were determined by sequence analysis of genomic DNA amplified by the polymerase chain reaction. Both fibrinogens were heterozygous, IJmuiden having a B beta Arg14----Cys substitution and Nijmegen having a B beta Arg44----Cys substitution. Clotting induced by thrombin or Reptilase was impaired in both fibrinogens, indicating defective fibrin polymerization. Immunoblot analysis of both purified fibrinogens demonstrated that some of the abnormal molecules were linked by disulfide bonds to albumin. In addition, abnormal high molecular weight fibrinogen complexes with Mrs between 600,000 and 700,000 were present. Fibrinogen-albumin and high molecular weight complexes were also detected in the patients' plasmas. Quantitative analysis demonstrated that of the total plasma fibrinogen in the IJmuiden patient, 20% was linked to albumin and 10% was present as high molecular weight complexes. In plasma Nijmegen, 13% was linked to albumin and 15% was present as high molecular weight complexes. These results demonstrate that the additional abnormal cysteine in fibrinogens IJmuiden and Nijmegen resulted in the formation of disulfide-linked complexes with other proteins, predominantly albumin. We also found that a significant fraction of the abnormal fibrinogen molecules contained free sulfhydryl groups. These findings complicate interpretation of functional studies of these altered fibrinogens.     

Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation

This report describes the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and platelet function in humans. Subjects with advanced solid tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day 12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold median increase (maximum 10-fold) in platelet count by day 16. The platelets produced in vivo in response to PEG-rHuMGDF showed unchanged aggregation and adenosine triphosphate (ATP)-release responses in in vitro assays. Tests included aggregation and release of ATP in response to adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2 micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and ristocetin (1.5 mg/mL). Administration of aspirin to an individual with platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced ablation of the normal aggregation and ATP-release response to stimulation with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25 mumol/L). There was no change in the expression of the platelet-surface activation marker CD62P (P-selectin) nor induction of the fibrinogen binding site on glycoprotein IIb/IIIa as reported by the monoclonal antibody, D3GP3. An elevation of reticulated platelets was evident after 3 days of treatment with PEG-rHuMGDF and preceded the increase in circulating platelet count by 5 to 8 days; this reflected the production of new platelets in response to PEG-rHuMGDF. At later time points, the mean platelet volume (MPV) decreased in a manner inversely proportional to the platelet count. Levels of plasma glycocalicin, a measure of platelet turnover, rose 3 days after the initial increase in the peripheral platelet count. The level of plasma glycocalicin was proportional to the total platelet mass, suggesting that platelets generated in response to PEG-rHuMGDF were not more actively destroyed. Thus, the administration of PEG-rHuMGDF, to humans, increased the circulating platelet count and resulted in fully functional platelets, which showed no detectable increase in reactivity nor alteration in activation status.     

Skin test studies on close contacts of leprosy patients in India

Skin-test studies with a series of tuberculins have been carried out in close contacts of multibacillary (MB) leprosy patients around three leprosy centers in India, and casual contacts of the disease around two centers. The results show that the rate of acquisition of leprosin A positivity is associated with age and the closeness of contact with MB leprosy. At the age of 15 years, the differences between the two types of contact were highly significant (p less than 0.00001). Many responses to leprosin A are directed toward the group iv species-specific, antigens of the leprosy bacillus, and the significance of positivity is discussed in relation to protective immunity from leprosy. The differences from Iran show that positivity to leprosin A is not solely the effect of the degree of contact with the disease, but must also have a genetic or environmental element, the latter being favored. The results from Miraj show that the high levels of tuberculin, scrofulin, and vaccin positivity seen in Fathimanagar, and to a lesser extent in Karigiri, are not a consequence of contact with leprosy. BCG vaccination made little difference to the leprosin A positivity of close contacts of leprosy patients, although it significantly enhanced positivity among casual contacts around Miraj (p less than 0.002). BCG vaccination significantly increased tuberculin positivity in Miraj and Karigri, and in those under 11 years of age in Fathimanagar. It made no difference to the already high level of positivity found in older persons around Fathimanagar.(ABSTRACT TRUNCATED AT 250 WORDS)     

EXOGEN Ultrasound Bone Healing System for Long Bone Fractures with Non-Union or Delayed Healing: A NICE Medical Technology Guidance

A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC’s findings, and the final NICE guidance issued.     

Determinants of uptake of home modifications and exercise to prevent falls in community‐dwelling older people

Objective: To examine the age‐specific population prevalence and predictors of uptake of home modifications and exercise to prevent falls in the NSW older population. Methods: A total of 5,681 respondents were asked questions on fall prevention activities as part of the 2009 NSW Falls Prevention Survey. Results were weighted to represent the NSW population. Regression analysis was used to determine factors associated with uptake of interventions. Results: Overall, 28.9% of the older population have modified their home, and 35.1% increased exercise to prevent falls. Main predictors of home modification were being aged 85+ (RR 2.04, 95% CI 1.76–2.35) and physiotherapy/occupational therapy intervention (RR 1.57, 95% CI 1.22–2.01). Main predictors of increasing exercise were physiotherapy/OT intervention (RR 2.12, 95% CI 1.86–2.42) and medical advice (RR 1.45, 95% CI1.32–1.60). Older respondents (RR 0.68, 95% CI 0.57–0.81) and those with fair/poor health (RR 0.86, 95% CI 0.77–0.96) were less likely to report increased exercise. Conclusion: More than one‐quarter of the older population of NSW report having made modifications to their home and one‐third increased exercise to prevent falls. There was a clear gradient of increased uptake of home modifications with increasing age, with the reverse trend for increased exercise. Implication: Although fall prevention initiatives are having an impact at the population level, targeted strategies for high‐risk groups are still required.