The biology of leptin: a review

Leptin, a 16-kDa protein secreted from white adipocytes, has been implicated in the regulation of food intake, energy expenditure, and whole-body energy balance in rodents and humans. The gene encoding leptin was identified by positional cloning and is the mutation leading to the profound obese phenotype of the ob/ob mouse. Exogenous administration of leptin to ob/ob mice leads to a significant improvement in reproductive and endocrine status as well as reduced food intake and weight loss. The expression and secretion of leptin is highly correlated with body fat mass and adipocyte size. Cortisol and insulin are potent stimulators of leptin expression, and expression is attenuated by beta-adrenergic agonists, cAMP, and thiazolidinediones. The role of other hormones and growth factors in the regulation of leptin expression and secretion is emerging. Leptin circulates specifically bound to proteins in serum, which may regulate its half-life and biological activity. Isoforms of the leptin receptor, members of the interleukin-6 cytokine family of receptors, are found in multiple tissues, including the brain. Many of leptin's effects on food intake and energy expenditure are thought to be mediated centrally via neurotransmitters such as neuropeptide Y. Multiple peripheral effects of leptin have also been recently described, including the regulation of insulin secretion by pancreatic beta cells and regulation of insulin action and energy metabolism in adipocytes and skeletal muscle. Leptin is thought to be a metabolic signal that regulates nutritional status effects on reproductive function. Leptin also plays a major role in hematopoeisis and in the anorexia accompanying an acute cytokine challenge. The profound effects of leptin on regulating body energy balance make it a prime candidate for drug therapies for humans and animals.     

Selective loss of [3H]kainic acid and [3H]AMPA binding in layer VI of frontal cortex in Huntington's disease

Excitatory amino acid neurotoxicity has been proposed to cause the neostriatal neuronal degeneration of Huntington's disease (HD); N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors have been hypothesized to play important roles in this process. We have recently reported a loss of neurons in layer VI of the cerebral cortex in HD. Using quantitative autoradiographic methods, we have now measured NMDA, AMPA, and kainate receptor binding in the frontal cerebral cortex of the brains of controls and individuals with HD. We find no change in NMDA receptor binding but a selective decrease in kainate and AMPA receptor binding in layer VI. These data suggest that cerebral cortical neurons possessing kainate or AMPA receptors may be selectively vulnerable in individuals with HD.     

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Five percent of live-born human offspring will have a genetic disorder. Of these, 20% are because of germ-line de novo mutations. Several genetic diseases, such as neurofibromatosis and Duchenne muscular dystrophy, are associated with a high percentage of de novo germ-line mutations. Until recently, a direct analysis of spontaneous mutation frequencies in mammalian germ cells has been prevented by technical limitations. We have measured spontaneous mutation frequencies in a lacI transgene by using enriched populations of specific spermatogenic cell types. Similar to previously published results, we observed a lower mutation frequency for seminiferous tubule cell preparations, which contain all stages of spermatogenesis, relative to somatic tissues. We made the unexpected observation of a decline in mutation frequency during spermatogenesis, such that the mutation frequencies of type B spermatogonia and all subsequent stages of spermatogenesis are lower than the frequency for primitive type A spermatogonia. In addition, spermatogenic cells from old mice have significantly increased mutation frequencies compared with spermatogenic cells from young or middle-aged mice. Finally, the mutation frequency was observed to increase during spermiogenesis in postreplicative cell types when spermatogenic cells were obtained from old mice.     

Wasp and bee venom allergy

To diagnose insect venom allergy a good patient history is important. Allergological tests (skin test, specific IgE titre) confirm the diagnosis. Patients are advised on preventive measures (e.g. with respect to clothing and use of perfume). They are also instructed on medical treatment (antihistaminics, epinephrine) in case they are stung again. In patients having had a serious systemic reaction immunotherapy should be considered. Immunotherapy leads to complete protection in more than 98% of patients with wasp (yellow jacket) venom allergy and in 75-80% of patients with bee venom allergy. Serious adverse reactions to immunotherapy are rare. Immunotherapy lasts at least 3 to 5 years. After cessation of immunotherapy the frequency of systemic reactions to the sting of a wasp or bee is in the range of 5-15%. There are insufficient data on the long-term effect of immunotherapy.     

Synthesis and pharmacological evaluation of new flosulide analogues, synthesized from natural safrole

OBJECTIVE: To study the effect of adjuvant chemotherapy after curative hepatic resection in patients with hepatocellular carcinoma. DESIGN: A randomized controlled trial. SETTING: A tertiary referral center. PATIENTS: During a 54-month period, 142 patients with hepatocellular carcinoma underwent hepatic resection at 1 institution. Sixty-six patients who survived the operation and had no demonstrable evidence of residual disease on ultrasonographic examination and hepatic angiographic testing at 1 month after surgery agreed to participate in the study. The median follow-up time was 28.3 months. INTERVENTION: Thirty patients received a combination of intravenous epirubicin hydrochloride (8 doses of 40 mg/m2 each at 6-week intervals) and transarterial chemotherapy using an emulsion of iodized oil and cisplatin (3 courses with a maximum dose of 20 mL each at 2-month intervals). Thirty-six patients had no adjuvant treatment. MAIN OUTCOME MEASURES: Recurrence rate and disease-free survival. RESULTS: A total of 138 courses of intravenous epirubicin was given to the 30 patients. Sixty-one courses of transarterial chemotherapy were given to only 29 of the 30 patients assigned to the treatment group, because the hepatic artery in 1 patient was thrombosed. Six patients (20%) had chemotherapy-related complications with no mortality. Twenty-three of 30 patients in the treatment group and 17 of 36 patients in the control group had recurrences (P=.01). Patients who received adjuvant chemotherapy had a higher incidence of extrahepatic metastases (11 patients vs 5 patients; P=.03). The respective disease-free survival rates at 1, 2, and 3 years were 50%,36%, and 18% for the treatment group and 69%, 53%, and 48% for the control group (P=.04). CONCLUSION: In a group of patients who underwent curative resection of hepatocellular carcinoma, postoperative adjuvant chemotherapy using the present regimen was associated with more frequent extrahepatic recurrences and a worse outcome.     

Economic evaluation of cancer treatments: methodological and practical issues

Economic evaluation is a comparative analysis of alternatives in terms of both their costs and consequences. Therefore, the basic task of economic evaluation is to identify, measure, value and compare the costs and effects of the alternatives being considered. In this paper, the methodology of economic evaluation in general and in cancer in particular is reviewed and practical issues are illuminated. In the treatment of cancer patients not only survival and disease-free survival are important outcome parameters, but also quality of years alive. Hence, specific attention is given to the measurement and valuation of quality of life. Economic evaluation is intended to support health policy at different levels of decision making. In cancer treatment, health policy concerns both preventive, curative and palliative strategies, and decisions are often made at the micro and macro level. Economic evaluation can provide essential information on the costs and benefits of each option, and consequently on the optimal policy mix, and thus support decisions on the adoption and utilization of new treatments. Such information may assist policy makers in formulating regulatory policies and legislation, industry in developing products, health professionals in treating and serving patients, and consumers in making personal health decisions.     

Cerebral microembolism in patients with retinal ischemia

BACKGROUND AND PURPOSE: We investigated the frequency of cerebral microembolism detected by transcranial Doppler ultrasonography in patients with clinical evidence of retinal ischemia, including transient monocular blindness, central and branch retinal artery infarction, and ischemic oculopathy, and assessed its correlation with carotid artery stenosis. METHODS: Records of 331 consecutive patients examined during a 47-month period at the Neurovascular Laboratory were reviewed. Of the original 453 intracranial arteries, 186 middle cerebral arteries (MCAs) satisfied qualifying criteria that excluded patients with cardiac embolic sources. Forty-five MCAs ipsilateral to the symptomatic eye constituted the study group. The control group consisted of 141 asymptomatic MCAs. Microembolus detection studies were performed on transcranial Doppler instruments equipped with special software, and the degree of carotid artery stenosis was measured by cerebral or MR angiography or by color duplex studies. RESULTS: Microembolism was detected in 40.0% of study MCAs and 9.2% of controls (P < 0.001). In the study group, microembolic signals were detected in 61.9% of MCAs tested within a week of symptom onset and 20.8% of those tested afterward (P < 0.001). Severe (> or = 70%) carotid stenosis or occlusion was more frequent in the study group (P < 0.001). Microembolic signals were detected in 25.3% and 11.2%, respectively, of MCAs distal to carotid arteries with 70% to 100% and 0% to 69% stenosis (P = 0.013). CONCLUSIONS: In patients without cardiac embolic sources, cerebral microembolism is frequently present on the side of retinal ischemia, particularly during the week after onset of symptoms. It is often associated with severe stenosis or occlusion of the ipsilateral carotid artery.     

Effects of the PIPC model on outcome measures of productivity and costs

The purpose of this experimental research was to determine the effects of the Partners in Care Practice Model (PIPC) on the outcomes of productivity and costs. Over an 18-month study period, no significant differences were found in costs per patient day between the pilot and control units; however, significant differences were found in actual salaries, amount of time spent in documentation, and supply costs. Differences in costs and productivity reflected increased training costs and costs for additional supplies on the pilot unit.