Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥ 30 kg m(-2) and binge eating scale scores ≥ 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day(-1) GSK1521498, 5 mg day(-1) GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day(-1) caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day(-1) on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

Potential for pharmacokinetic interactions between ambrisentan and cyclosporine.

Ambrisentan (ABS), approved for the treatment of pulmonary arterial hypertension and administered as an oral dose once daily, is an ET(A)-selective endothelin receptor antagonist (ERA) and a potential substrate for cytochrome P450 (CYP) 3A4, organic anion-transporting polypeptide (OATP), and P-glycoprotein (P-gp). Cyclosporin A (CsA), an inhibitor of CYP3A4, P-gp, and OATP, may be used concomitantly with ABS. In this open-label, parallel-treatment study, 28 healthy subjects received steady-state ABS (5 mg q.d.) either alone or with steady-state CsA (100-150 mg b.i.d.), and 24 other subjects received steady-state CsA either alone or with steady-state ABS. In the presence of CsA, ABS maximum plasma concentration (C(max)) increased 1.5-fold, and area under the plasma concentration-time curve (AUC)(0-τ) increased twofold. Marginal increases were observed for CsA C(max) (906 vs. 1,014 ng/ml) and AUC(0-τ) (3.05 vs. 3.37 µg·h/ml) in the presence of ABS. Frequent adverse events (AEs) were headache and gastrointestinal disorders. The addition of ABS to steady-state CsA appeared less tolerable as compared with the addition of CsA to steady-state ABS. A maximum ABS dose of 5 mg is recommended if it is coadministered with CsA. No change in CsA dose is recommended if it is coadministered with ABS.

Documentation of positive blood culture results in a London teaching hospital.

OBJECTIVES: Our current practice is that initial (day 1) positive blood culture results are communicated to clinical teams; the task of recording those results in the notes is left to the clinical team. Microbiological information may be of crucial importance to an on-call doctor asked to review an unwell patient. We therefore sought to establish the extent to which day 1 positive blood culture information is available in patients' notes and its accuracy. METHODS: There were 51 positive blood cultures over a 14-day period. Patient notes of 39 of these were available for examination for evidence of the day 1 culture report, the accuracy of that report and evidence of clinical interpretation. RESULTS: The proportion of notes with a record was disappointingly low (54%), although the record was almost always accurate. Results reported at the weekend were as likely to be recorded in the notes as those given during the week. CONCLUSION: On-call doctors, not previously acquainted with a patient, will find that important information about day 1 positive blood culture results is not available to them in patient notes in around half of all cases. This adds weight to the view that medical microbiologists should give greater priority to ward visits and documentation of significant results, thus ensuring continuity of care from the laboratory bench to the bedside.

Injuries to the glenoid labrum: a diagnostic and treatment challenge.

The glenoid labrum contributes to shoulder stability by increasing the glenoid surface and providing attachments for the shoulder capsule and various ligaments and tendons. Overhead arm activities, especially throwing, can stress the shoulder excessively and cause labral injury. Symptoms include poorly localized pain, exacerbated by overhead and behind-the-back motions, and popping, catching, or grinding. Imaging includes AP, outlet, and axillary radiographs, but CT arthrogram or MR arthrogram is also recommended. Fractures and dislocations should be referred. In other labral injuries, 2 to 4 weeks of rest and physical therapy may resolve symptoms. If not, patients should be referred for further testing and possible surgery.

Early operative reconstruction of severe ligamentous knee injuries in patients with multiple trauma.

Although operative reconstruction of severe knee ligament injuries has been the preferred method of treatment, the timing of that reconstruction relative to the injury has not been previously addressed. In a retrospective review of multitrauma cases, we identified 32 patients with 34 severe knee ligament injuries. Of these 34 knees, 19 (56%) were treated with early reconstruction (within 2 weeks of injury). Of the remaining 15 knees, 8 were managed by delayed reconstruction at an average of 4.8 months after injury, and 7 knees were not surgically treated. All 19 knees treated by early operation were clinically stable, and 89% were pain free at an average of 25 months' follow-up. In contrast, only 13% of the knees treated by delayed or no reconstruction were clinically stable, 33% were persistently painful, and 40% required bracing intermittently to allow activities of daily living. In this study, patients treated by delayed reconstruction or non-operatively had poor functional results. We believe early operative reconstruction of severe knee injuries in multitrauma patients is crucial to maximize functional outcome and minimize long-term sequelae.

Antegrade drilling for osteochondritis dissecans of the knee.

Twenty-four knees with osteochondritis dissecans of the femoral condyles failed a conservative program and were treated with antegrade drilling. To our knowledge, this represents the largest reported series using this technique. The average age at the time of surgery was 13 years 6 months. Seventeen patients had open physes, and four were skeletally mature. Nineteen lesions involved the medial femoral condyle, and five involved the lateral femoral condyle. The average follow-up was 5 years. Postoperative evaluation included rating by the International Knee Documentation Committee (IKDC) form and the Hughston Rating Scale for osteochondritis dissecans. Twenty of the 24 lesions healed after antegrade drilling, and the average time of healing was 4 months. According to the criteria on the IKDC grading form, 14 were normal, 6 nearly normal, three abnormal, and one severely abnormal. The results of the Hughston Rating Scale were similar: 15 were excellent, seven good, one fair, and one poor. Only two of the four skeletally mature patients healed after antegrade drilling. Antegrade drilling is an effective method of treatment for osteochondritis dissecans of the knee that occurs in adolescents with open physes. This operation is not as likely to result in a successful outcome in patients with closed physes; consequently, other methods should be considered in skeletally mature patients.

Effect of alpha-MSH 11-13 (lysine-proline-valine) on fever in the rabbit.

In previous experiments, alpha-MSH (1-13) and ACTH (1-24), which contains the alpha-MSH 1-13 amino acid sequence, were found to reduce fever after central and peripheral administration of low, non-hypothermic doses. Shorter molecules, including alpha-MSH 1-10, had no effect. The idea that the 11-13 amino acid sequence is important to the effect of the parent molecule was tested by giving lysine-proline-valine both centrally and peripherally to rabbits made febrile by IV administration of leukocytic pyrogen. The tripeptide reduced fever after both central (0.5-2.0 mg) and peripheral (2-200 mg) administration. It appears that the 11-13 sequence is part of the message sequence of alpha-MSH with regard to antipyretic activity. However, the lower potency relative to that of the parent molecule suggests that other portions of the molecule are essential to full expression of the antipyretic effect.

Antipyretic effect of centrally administered CRF.

CRF injected into the third cerebral ventricle (0.5-2.5 micrograms) caused dose-related reductions in fever induced in rabbits by IV administration of leukocytic pyrogen. Control injections of CRF when the same animals were afebrile did not alter normal body temperature. Intravenous injections of 5 and 20 micrograms CRF, doses known to release ACTH and corticosteroids into the bloodstream in other species, did not reduce fever. CRF injected into the cerebral ventricles may be antipyretic per se, or it may reduce fever by virtue of central release of the antipyretic peptides ACTH and alpha-MSH.

Antipyretic potency of centrally administered alpha-melanocyte stimulating hormone.

Centrally administered alpha-melanocyte stimulating hormone is much more potent in reducing fever than the widely used antipyretic acetaminophen. This finding supports the hypothesis that the endogenous neuropeptide has a role in the limitation of fever and suggests that it may be clinically useful as an antipyretic.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case with widespread nodal and extra nodal dissemination.

A fatal case of sinus histiocytosis with massive lymphadenopathy (SHML) is described in a male patient who presented at 11 years-of-age with swelling of the malar region and nasal obstruction due to the disease and who died aged 28 in uraemic coma following renal involvement. At autopsy SHML tissue extended into the hilum of both lungs and from the retroperitoneal tissue into the pancreas and kidneys. The appearances suggest that the extension of the disease into these organs may have been due to retrograde lymphatic spread from involved lymph nodes. Replacement of the atypical sinus histiocyte by fibrous tissue was seen in the cervical lymph nodes and this may be the usual mode of resolution of the lesion. The nature of SHML is discussed in relation to a possible infectious aetiology and defects in the host immune system. Finally, it is noted that the term 'massive lymphadenopathy' is not applicable to all cases and that sinus histiocytosis in not appropriate for the now frequently recognized extranodal manifestations of the disease. It is proposed that the term 'lymphophagocytic histiocytosis syndrome' should be adopted or that the eponymous title 'Rosai-Dorfman disease' should be used.