SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats

Intracerebroventricular (i.c.v.) administration of the novel hypothalamic neuropeptide orexin-A stimulates food intake in rats, and delays the onset of behavioural satiety (i.e. the natural transition from feeding to resting). Furthermore, preliminary findings with the selective orexin-1 receptor antagonist, SB-334867, suggest that orexin-A regulation of food intake is mediated via the orexin-1 receptor. At present, however, little is known about either the intrinsic effects of SB-334867 on the normal structure of feeding behaviour, or its effects upon orexin-A-induced behavioural change. In the present study, we have employed a continuous monitoring technique to characterize the effects of SB-334867 (3-30 mg/kg, i.p.) on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Administered alone, SB-334867 (30 mg/kg, but not lower doses) significantly reduced food intake and most active behaviours (eating, grooming, sniffing, locomotion and rearing), while increasing resting. Although suggestive of a behaviourally nonselective (i.e. sedative) action, the structure of feeding behaviour was well-preserved at this dose level, with the reduction in behavioural output clearly attributable to an earlier onset of behavioural satiety. As previously reported, orexin-A (10 microg per rat i.c.v.) stimulated food intake, increased grooming and delayed the onset of behavioural satiety. Pretreatment with SB-334867 dose-dependently blocked these effects of orexin-A, with significant antagonism evident at dose levels (3-10 mg/kg) below those required to produce intrinsic behavioural effects under present test conditions. Together, these findings strongly support the view that orexin-A is involved in the regulation of feeding patterns and that this influence is mediated through the orexin-1 receptor.     

Anxiolytic effects of valproate and diazepam in mice are differentially sensitive to picrotoxin antagonism

Although it is widely believed that the anxiolytic effects of benzodiazepines are mediated through facilitation of GABA(A) receptor function, behavioural studies have to date provided rather weak support for this hypothesis. In particular, considerable inconsistency has been noted both for the effects of GABAergic manipulations in animal models of anxiety and the ability of GABA(A) receptor antagonists to block the anxiolytic effects of diazepam (DZ) and chlordiazepoxide. In view of the sensitivity of the murine plus-maze to the anxiety-modulating effects of GABAergic agents as well as classical benzodiazepines, the current study examined the extent to which the anxiolytic actions of valproic acid (VPA) and DZ in this test involve picrotoxin (PX)-sensitive receptor mechanisms. Subjects were male DBA/2 mice, test duration was 5 min, and ethological scoring methods were employed. Our results show that, while devoid of intrinsic behavioural effects under present test conditions, PX (0.25-0.5 mg/kg) selectively antagonised the anxiolytic-like (but not other) effects of VPA (400 mg/kg). In contrast, the same doses of PX failed to block any of the behavioural changes induced by DZ (1.5 mg/kg), including disinhibition of open arm exploration. These data suggest that the plus-maze anxiolytic effects of DZ in DBA/2 mice are not mediated through PX-sensitive GABA(A) receptors. Further studies will be required to assess the generality of present findings to other mouse strains, species and behavioural paradigms.     

The occurrence of leg ulcers in Auckland: results of a population-based study

AIM: To estimate the cumulative incidence rate and prevalence of leg ulcers in Auckland. METHODS: A cross-sectional study was conducted to identify all individuals who had or developed a leg ulcer in the North Auckland and Central Auckland health districts between 1997 and 1998. Cases were identified through multiple sources, including community-based and hospital-based health professionals and by self-notification. All ulcer types were investigated. RESULTS: 611 individuals with healed or current leg ulcers were identified during the study period, of whom 426 had current leg ulcers. The annual cumulative incidence rate was 32 per 100,000. The point prevalence of current leg ulcers was 39 per 100,000, with a period prevalence of 79 per 100,000 per year. Men had lower age-adjusted incidence rates than women, but a higher age-adjusted point prevalence of leg ulceration, indicating that ulcers take longer to heal in men. Annual cumulative incidence rates increased steeply with age (< 60 years = 4, 60-69 years = 62, 70-79 years = 191, 80+ years = 466 per 100,000 per year), as did point prevalence (< 60 years = 5, 60-69 years = 76, 70-79 years = 238, 80+ years = 564 per 100,000). CONCLUSIONS: These data indicate that the risk of developing leg ulcers increases dramatically with age, with individuals aged 60 years and over particularly at risk. Given New Zealand's rapidly ageing population, the number of older people with leg ulcers each year is expected to double in the next 25 years.     

The laminins in the murine inner ear: developmental transitions and expression in cochlear basement membranes

The laminins are a family of heterotrimeric extracellular matrix molecules that form suprastructural networks in basement membranes and elsewhere. They interact with integrin receptors, playing key roles in modulating programs of cytodifferentiation and maintaining tissue homeostasis in animals. Earlier studies have demonstrated an extensive laminin network in both the developing and adult cochlea, primarily associated with the basement membranes. These studies, however, did not address the laminin chain composition of these networks. In this study, we used antibodies specific for the known laminin chains to examine the composition of laminins in both the developing and adult murine cochlea. The results illustrate a complex and dynamic postnatal developmental regulation pattern for most of these chains, and suggest that an unusually large number of laminin heterotrimers are present in both the developing and adult cochlea. The laminin composition at postnatal day 2 is relatively simple. By postnatal day 7, however, activation of several laminin chains results in a very complex laminin composition. In the basement membrane underlying the region of the basilar membrane under the developing organ of Corti, eight of the 11 known basement membrane laminins are possible by co-localization inference. Dynamic changes in expression continue through day 14, but simplify by adulthood. Thus, the most dynamic period for laminin expression in the mouse cochlea coincides with terminal cytodifferentiation of the cochlear epithelial structures. Considering the well established role of laminins in regulating both embryonic and organ development in other systems, these data suggest a closer look at the role of the laminins in cochlear development and function may be warranted.     

Management of thrombosis in women with antiphospholipid syndrome

1) Antiphospholipid antibody syndrome may be associated with unusual sites of thrombosis. 2) Laboratory evaluation involves testing for antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibodies. 3) Acute management of thrombosis involves immediate anticoagulation. Low-molecular-weight heparins are as safe and effective as unfractionated heparin in this setting. Arterial events may require emergent thrombolytic therapy. Monitoring of the APTT with unfractionated heparin in the presence of a lupus anticoagulant is ineffective; these patients require monitoring of antifactor Xa levels or the use of LMWH, which does not require monitoring. 4) The pharmacokinetics of LMWH change in pregnancy, resulting in a shorter plasma half-life and larger volume of distribution. Monitoring of antifactor Xa levels is necessary. 5) Chronic anticoagulation is best achieved with warfarin, with significantly decreased rates of recurrent events when the INR is > or = 3.0. Long-term, if not life-long, anticoagulation is often necessary. Warfarin is teratogenic, and individuals desiring pregnancy will need to convert to therapeutic, not prophylactic, doses of either unfractionated heparin or LMWH. 6) As part of optimal management of thrombosis in APS, additional risk factors for thrombosis should be eliminated or reduced. These include comorbid illnesses such as hypertension and hyperlipidemia, as well as smoking. 7) Tamoxifen, raloxifene, oral contraceptives, and hormone replacement therapy are all associated with an increased risk of DVT in the general population. In APS patients receiving therapeutic anticoagulation, the addition of these drugs should not increase thrombosis risk. In APS patients not receiving anticoagulant therapy, these hormonal therapies may increase the thrombosis risk.     

Heparin-induced thrombocytopenia is rare in pregnancy

OBJECTIVE: The indications for heparin use during pregnancy are expanding; however, heparin is associated with serious adverse effects including heparin-induced thrombocytopenia. Low-molecular-weight heparin is expensive but is associated with less frequent occurrences of heparin-induced thrombocytopenia in the nonpregnant population. However, the incidence of heparin-induced thrombocytopenia during pregnancy is unknown. The purpose of this study was to compare the incidence of heparin-induced thrombocytopenia in pregnant and nonpregnant women. STUDY DESIGN: This is a retrospective cohort comparison. Pregnant and nonpregnant women were identified by means of diagnosis related group and Current Procedural Terminology code searches at three medical centers in Utah; the incidence of heparin-induced thrombocytopenia in the two groups was compared. RESULTS: There were 10 (4%) cases of thrombocytopenia among 244 heparin-treated pregnant patients and 26 (11%) cases among the 244 nonpregnant controls. There were no cases of heparin-induced thrombocytopenia in the pregnant group, but there were 10 (4%) cases in the control group (P =.0014). CONCLUSION: Heparin-induced thrombocytopenia is extremely rare in pregnant women.     

The impact of a clinical pathway for gastric bypass surgery on resource utilization

BACKGROUND: Clinical pathways are believed to improve patient care and reduce costs. Our hypothesis was that a gastric bypass pathway would decrease hospital resource utilization and cost of care without adversely affecting patient care. METHODS: The prepathway (Pre) group consisted of 16 gastric bypasses (6/98 to 3/99). The postpathway (Post) group includes 12 gastric bypass procedures performed after institution of the clinical pathway (4/99 to 12/99). The impact of the clinical pathway on hospital length of stay (LOS) and resource utilization was investigated. A comparison of costs was performed using cost/charge ratios. Hospital readmissions and postoperative complications were also examined. RESULTS: Despite increased obesity/medical acuity of the Post group, hospital LOS decreased by 3 days (P < 0.0001). Total hospital costs decreased by over $1600/case (>15%). Postpathway savings were greatest for room and board (34%), supplies (41%), and lab/radiology costs (50%). An increase in OR costs (22%) was observed in the Post group. This was due to an increase in anesthesia time (epidural catheter placement) and equipment costs (ultrasonic shears). Despite reductions in hospital LOS and resource utilization, the complication rate (Pre 12%, Post 16%) was similar and two patients in each group required brief readmission. CONCLUSIONS: A pathway for gastric bypass decreased hospital LOS and resource utilization. OR-related expenses account for 34-50% of total costs and must be monitored closely for surgical patients. The reduction in costs observed with this clinical pathway was not associated with an increase in postoperative complications or hospital readmission.     

Energy expended playing video console games: an opportunity to increase children's physical activity?

This study sought to quantify the energy expenditure and physical activity associated with playing the "new generation" active and nonactive console-based video games in 21 children ages 10-14 years. Energy expenditure (kcal) derived from oxygen consumption (VO2) was continuously assessed while children played nonactive and active console video games. Physical activity was assessed continuously using the Actigraph accelerometer. Significant (p < .001) increases from baseline were found for energy expenditure (129-400%), heart rate (43-84%), and activity counts (122-1288 versus 0-23) when playing the active console video games. Playing active console video games over short periods of time is similar in intensity to light to moderate traditional physical activities such as walking, skipping, and jogging.     

Splenic papillary angioendothelioma in a 6-year-old girl

Papillary angioendothelioma is a rare, low-grade neoplasm of lymphatic channels that usually presents intradermally. We report the case of a 6-year-old girl with isolated splenomegaly and symptoms of early satiety and weight loss, whom was found to have a splenic papillary angioendothelioma. Preoperative abdominal computed tomography scan showed an irregular, heterogeneous mass; a tagged red cell scan ruled out a hemangioma, whereas a positron emission tomography scan showed mildly increased uptake. Subsequent surgery and pathologic assessment revealed a papillary angioendothelioma (Dabska tumor) within lymphatic spaces. The child has no evidence of recurrence or metastases 1 year postoperatively.