Does the "script" need a rewrite? Is medication advice in television medical dramas appropriate?

WHAT IS KNOWN AND OBJECTIVE: Television medical dramas depict the healthcare industry and draw considerable interest from the public, while pharmacists play an integral part in providing medication-related advice to the public and other health practitioners in real life. The main objective of this retrospective, observational study was to assess the appropriateness of medication advice given in televised medical dramas and how frequently pharmacists were involved in providing the medication advice. METHODS: Show selection was based on fictional series with a medical drama theme and having the highest viewership. Approximately 100 randomly selected hours of five medical television dramas (House, Grey's Anatomy, Nurse Jackie, Doc Martin and Royal Pains) were assessed for the appropriateness of advice given based on the medication indicated, number of safety checks performed, and the level of adherence to standard clinical guidelines. The appropriateness of medication advice was assessed as appropriate, mostly appropriate, partially appropriate and inappropriate using a piloted, 0-6 point scale. Other parameters recorded included patient demographics, health professionals involved, and the categories of medicines. RESULTS AND DISCUSSIONS: Medications were mentioned on 424 occasions (on average four times per hour), including 239 occasions where medication advice was given. A pharmacist was involved in giving medication advice only 16 times (7%). Using the assessment tool, overall, medication advice was deemed to be appropriate 24% of the time, mostly appropriate 34%, partially appropriate 13% and inappropriate 7%. Although the medication advice given was often for the correct indication and the advice somewhat followed clinical guidelines, it frequently omitted adequate safety checks. Doc Martin had the highest mean appropriateness score, whereas House and Grey's Anatomy had the lowest. WHAT IS NEW AND CONCLUSIONS: Medication was often used for the correct indication in television medical dramas; however, key safety checks were frequently omitted and other medication-related advice, including dose, was less reliable and accurate. Pharmacists were rarely involved in providing medication advice. Viewers should not base medication-related decisions solely on what they see in television medical dramas, and any medication-related advice should be interpreted with extreme caution.

Short-term high-fat diet increases the presence of astrocytes in the hypothalamus of C57BL6 mice without altering leptin sensitivity.

Diet-induced obesity is associated with hypothalamic inflammation and this phenomenon has been proposed to explain leptin resistance. In the present study, we used a short-term high-fat diet (HFD) paradigm for 10 days and analysed the cellular and physiological responses to leptin administration in C57BL6 mice. In parallel, we performed glial fibrillary acidic protein immunostaining to measure the presence of astrocytes in the arcuate nucleus of the hypothalamus (ARH) after 10 days and 20 weeks of HFD. Interestingly, the results obtained demonstrate that the presence of star-like astrocytes is significantly increased after 10 days of HFD, although this is not associated with the absence of cellular and physiological response to leptin administration in mice. Taken together, the results of the present study suggest that star-like astrocytes rapidly increase in numbers in the ARH in response to HFD, although this phenomenon cannot explain the development of leptin resistance by itself.

Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency.

Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with cutis laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine.

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer.

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2-/- mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer.

Weight loss after laparoscopic adjustable gastric band and resolution of the metabolic syndrome and its components.

BACKGROUND: Substantial weight loss in the setting of obesity has considerable metabolic benefits. Yet some studies have shown improvements in obesity-related metabolic comorbidities with more modest weight loss. By closely monitoring patients undergoing bariatric surgery, we aimed to determine the effects of weight loss on the metabolic syndrome and its components and determine the weight loss required for their resolution. METHODS: We performed a prospective observational study of obese participants with metabolic syndrome (Adult Treatment Panel III criteria) who underwent laparoscopic adjustable gastric banding. Participants were assessed for all criteria of the metabolic syndrome monthly for the first 9 months, then 3-monthly until 24 months. RESULTS: There were 89 participants with adequate longitudinal data. Baseline body mass index was 42.4±6.2 kg m-2 with an average age was 48.2±10.7 years. There were 56 (63%) women. Resolution of the metabolic syndrome occurred in 60 of the 89 participants (67%) at 12 months and 60 of the 75 participants (80%) at 24 months. The mean weight loss when metabolic syndrome resolved was 10.9±7.7% total body weight loss (TBWL). The median weight loss at which prevalence of disease halved was 7.0% TBWL (17.5% excess weight loss (EWL)) for hypertriglyceridaemia; 11% TBWL (26.1-28% EWL) for high-density lipoprotein cholesterol and hyperglycaemia; 20% TBWL (59.5% EWL) for hypertension and 29% TBWL (73.3% EWL) for waist circumference. The odds ratio for resolution of the metabolic syndrome with 10-12.5% TBWL was 2.09 (P=0.025), with increasing probability of resolution with more substantial weight loss. CONCLUSIONS: In obese participants with metabolic syndrome, a weight loss target of 10-12.5% TBWL (25-30% EWL) is a reasonable initial goal associated with significant odds of having metabolic benefits. If minimal improvements are seen with this initial target, additional weight loss substantially increases the probability of resolution.

Hyperphagia in male melanocortin 4 receptor deficient mice promotes growth independently of growth hormone.

KEY POINTS: Loss of function of the melanocortin 4 receptor (MC4R) results in hyperphagia, obesity and increased growth. Despite knowing that MC4Rs control food intake, we are yet to understand why defects in the function of the MC4R receptor contribute to rapid linear growth. We show that hyperphagia following germline loss of MC4R in male mice promotes growth while suppressing the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis. We propose that hyperinsulinaemia promotes growth while suppressing the GH-IGF-1 axis. It is argued that physiological responses essential to maintain energy flux override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. ABSTRACT: Defects in melanocortin-4-receptor (MC4R) signalling result in hyperphagia, obesity and increased growth. Clinical observations suggest that loss of MC4R function may enhance growth hormone (GH)-mediated growth, although this remains untested. Using male mice with germline loss of the MC4R, we assessed pulsatile GH release and insulin-like growth factor-1 (IGF-1) production and/or release relative to pubertal growth. We demonstrate early-onset suppression of GH release in rapidly growing MC4R deficient (MC4RKO) mice, confirming that increased linear growth in MC4RKO mice does not occur in response to enhanced activation of the GH-IGF-1 axis. The progressive suppression of GH release in MC4RKO mice occurred alongside increased adiposity and the progressive worsening of hyperphagia-associated hyperinsulinaemia. We next prevented hyperphagia in MC4RKO mice through restricting calorie intake in these mice to match that of wild-type (WT) littermates. Pair feeding of MC4RKO mice did not prevent increased adiposity, but attenuated hyperinsulinaemia, recovered GH release, and normalized linear growth rate to that seen in pair-fed WT littermate controls. We conclude that the suppression of GH release in MC4RKO mice occurs independently of increased adipose mass, and is a consequence of hyperphagia-associated hyperinsulinaemia. It is proposed that physiological responses essential to maintain energy flux (hyperinsulinaemia and the suppression of GH release) override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. Implications of these findings are likely to extend beyond individuals with defects in MC4R signalling, encompassing physiological changes central to mechanisms of growth and energy homeostasis universal to hyperphagia-associated childhood-onset obesity.

JRK is a positive regulator of ß-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer.

The loss of ß-catenin inhibitory components is a well-established mechanism of carcinogenesis but ß-catenin hyperactivity can also be enhanced through its coactivators. Here we first interrogated a highly validated genomic screen and the largest repository of cancer genomics data and identified JRK as a potential new oncogene and therapeutic target of the ß-catenin pathway. We proceeded to validate the oncogenic role of JRK in colon cancer cells and primary tumors. Consistent with a ß-catenin activator function, depletion of JRK in several cancer cell lines repressed ß-catenin transcriptional activity and reduced cell proliferation. Importantly, JRK expression was aberrantly elevated in 21% of colorectal cancers, 15% of breast and ovarian cancers and was associated with increased expression of ß-catenin target genes and increased cell proliferation. This study shows that JRK is required for ß-catenin hyperactivity regardless of the adenomatous polyposis coli/ß-catenin mutation status and targeting JRK presents new opportunities for therapeutic intervention in cancer.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer.

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.

Paradoxical effect of gonadotrophin-inhibiting hormone to negatively regulate neuropeptide Y neurones in mouse arcuate nucleus.

Regulation of reproduction and energy homeostasis are linked, although our understanding of the central neural mechanisms subserving this connection is incomplete. Gonadotrophin-inhibiting hormone (GnIH) is a neuropeptide that negatively regulates reproduction and stimulates food intake. Neuropeptide Y (NPY) and products of the pro-opiomelanocortin (POMC) precursor (ß-endorphin melanocortins) are appetite regulating peptides produced in the neurones of the arcuate nucleus; these peptides also regulate reproduction. In the present study, we determined the effects of GnIH on NPY and POMC neurones. Using brain slices from mice with transgenes for fluorescent tags in the two types of neurone and patch clamp electrophysiology, a predominant inhibitory effect of GnIH was observed. GnIH (100 nM) inhibited the firing rate in POMC cells, confirming the results of previous studies and consistent with the stimulatory effect of GnIH on food intake. Paradoxically (i.e. because both GnIH and NPY stimulate food intake), GnIH also had a predominantly inhibitory effect on action potential activity in NPY cells. GnIH also inhibited the secretion of NPY and α-melanocyte-stimulating hormone secretion in incubated hypothalamic blocks. GnIH (100 ng) injected into the cerebral ventricles of mice did not increase the number of NPY cells that were positively immunostained for c-Fos. Finally, dual label immunocytochemistry showed that 20% of NPY neurones had close contacts from GnIH fibres/varicosities. In conclusion, we confirm a negative effect of GnIH on POMC cells and demonstrate a paradoxical reduction of electrophysiological and functional activity in NPY cells.

The role of pharmacotherapy in the prevention and treatment of paediatric metabolic syndrome--Implications for long-term health: part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.

The metabolic syndrome (MetS) is defined as a clustering of risk factors predisposing to the future development of cardiovascular disease and Type 2 diabetes mellitus (T2DM). Its clinical relevance, above and beyond recognition and treatment of each of the component parts, is still hotly debated--especially within paediatric medicine. Prevention and treatment strategies for adult MetS focus on weight management, as obesity and insulin resistance are known to be at the central axis of the definition, alongside pharmacotherapy of integrally linked conditions such as hypertension and dyslipidaemia. In children and adolescents, however, opportunities for pharmacotherapy are currently limited and interventions aimed at weight management remain the sole treatment paradigm in the majority of cases. This is primarily due to a lack of long-term data relating to the degree of cardiovascular disease and T2DM risk from paediatric MetS, as well as concerns relating to safety and side effect profiles of currently available pharmacotherapies in those who are still growing and developing. Coupled with continuing concern about the recently recognised adverse effects of past and proposed anti-obesity drugs, this indicates that a new era of pharmacotherapy for paediatric MetS is unlikely to be imminent. In fact, the overall paucity of effective current interventions for paediatric MetS is concerning, especially given the fact that approximately 25-33% of all obese paediatric patients likely harbour the condition. It is therefore essential at the present time to concentrate efforts on properly testing the safety and efficacy of currently available products in well-constructed randomised controlled trials in obese adolescents. However, not all obese children and adolescents appear equally at-risk of long-term, weight-related morbidity and a change in emphasis is possibly warranted--one that moves away from simple weight reduction for all and more to a model of reducing long-term risk of cardiovascular disease and T2DM in those at greatest metabolic risk.

The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5.

Prolactin and progesterone act together to regulate mammary alveolar development, and both hormones have been implicated in breast cancer initiation and progression. Here we show that Elf5, a prolactin-induced ETS transcription factor that specifies the mammary secretory cell lineage, is also induced by progestins in breast cancer cells via a direct mechanism. To define the transcriptional response to progestin elicited via Elf5, we made an inducible Elf5 short hairpin-RNA knock-down model in T47D breast cancer cells and used it to prevent the progestin-induction of Elf5. Functional analysis of Affymetrix gene expression data using Gene Ontologies and Gene Set Enrichment Analysis showed enhancement of the progestin effects on cell cycle gene expression. Cell proliferation assays showed a more efficacious progestin-induced growth arrest when Elf5 was kept at baseline levels. These results showed that progestin induction of Elf5 expression tempered the antiproliferative effects of progestins in T47D cells, providing a further mechanistic link between prolactin and progestin in the regulation of mammary cell phenotype.

Iron deficiency anemia and cardiac mortality in patients with left ventricular systolic dysfunction undergoing coronary stenting.

AIM: The aim of this study was to assess cardiac mortality in patients with reduced ejection fraction (EF< or =45%) and anemia (Hb< or =12 g/dL) undergoing coronary stenting and to investigate whether iron-deficiency anemia influenced outcome when compared to non-anemic patients or patients with other types of anemia. METHODS: One hundred twenty consecutive patients undergoing percutaneous coronary intervention (PCI) between April 2003 and December 2005 were identified and followed for a median of 30 months. Patients were divided into 2 groups, anemic (Hb< or =12 g/dL) and non-anemic. Anemic patients were then divided into 3 sub-groups based on laboratory analysis and anemia work-up: iron-deficiency, malignancy-associated, and anemia of chronic disease (including chronic kidney disease). Mortality rates and cause of death were retrieved using both the Social Security database and the hospital records. RESULTS: Thirty-one percent of patients had iron deficiency, 24% had a malignancy-associated anemia and 45% had anemia of chronic disease. Overall mortality was 12% of which 29% was cardiac death. All-cause and cardiac mortality were significantly higher in anemic vs. non-anemic patients, (31% vs. 6%, P<0.001, and 10% vs. 1%, P=0.016, respectively). Iron-deficiency anemia strongly predicted cardiac mortality (33% vs. 1% in non-anemic patients, P<0.001), while malignancy-associated anemia was the strongest predictor of non-cardiac death (57% vs. 4% in non-anemic patients, P<0.001). Anemia of chronic disease neither predicted cardiac nor non-cardiac death. CONCLUSIONS: To the authors' knowledge, this is the first study to show that iron-deficiency anemia is a strong predictor of cardiac death when compared to patients with other types of anemia or to non-anemic patients.

Using intranasal lidocaine to reduce food intake.

OBJECTIVE: Develop a dose-response curve for the effect of intranasal lidocaine on food intake. DESIGN: Healthy obese subjects had food intake, ratings of hunger, desire to eat, craving and fullness measured at lunch after an overnight fast. Four treatments were given as nose drops (0.5-0.6 ml per nostril) 5 min before the meal in a double-blind manner with a four period crossover design including a 7-day washout between periods. The treatments were saline, 2.5, 10 and 25 mg lidocaine per nostril. The order of administration was randomly assigned to each subject. Electrocardiograms, vital signs, chemistry panels, complete blood counts (CBC) and nasal inspections were carried out before and after each dose. SUBJECTS: Forty-seven subjects were screened, 34 were randomized and 20 subjects completed all four study periods in the trial. The subjects were 39+/-12.5 (s.d) years of age, had a weight of 91+/-13.0 kg, a height of 167+/-10.3 cm, 56% were women, 47% were African-American and 53% were Caucasian. MEASUREMENTS: Food intake, rating of hunger, desire to eat, craving and fullness are measures of efficacy. Adverse events, electrocardiograms, vital signs, chemistry panels, nasal inspections, CBC and physical exams are measures of safety. RESULTS: The mean reduction in food intake vs saline control in the 20 subjects completing all four study periods was 3.3+/-7% (s.d), 4.2+/-8.5% and 7.4+/-7.3% in the 2.5 mg, 10 and 25 mg per nostril groups, respectively (P=NS). Hunger and desire to eat in subjects who completed at least one study period decreased dose dependently (P<0.03, at the 25 mg per nostril dose). There were no clinically significant changes in safety measures, electrocardiograms, vital signs, chemistry panels, CBC or nasal inspections. CONCLUSION: Intranasal lidocaine reduced hunger and the desire to eat, but this did not translate into a significant reduction in food intake suggesting that intranasal lidocaine will not have value in treating obesity.

Pancreatic polypeptide in obese children before and after weight loss.

OBJECTIVE: Little is known concerning pancreatic polypeptide (PP) in weight loss and in childhood obesity. METHODS: Fasting PP, leptin and insulin concentrations were determined in 38 obese children and compared with 35 lean children of the same age, gender and pubertal stage. Furthermore, changes of PP concentrations over a 1-year period were analyzed in the obese children participating in a weight loss intervention program. RESULTS: Obese children had significantly (P<0.01) lower PP, and higher leptin and insulin levels compared to lean children. In multiple linear regression analysis, PP was significantly negatively correlated to body mass index (P<0.01), but not to leptin, insulin, age, gender and pubertal stage. Changes of PP did not significantly correlate to changes of insulin (r=0.07, P=0.343) and leptin (r=-0.02, P=0.459). The substantial weight loss in 17 children led to a significant (P<0.05) increase in PP and decrease in insulin and leptin. In the 21 children without substantial weight loss, there were no significant changes in PP, insulin and leptin. CONCLUSIONS: PP concentrations are decreased in obese children and independent of age, gender, pubertal stage, leptin and insulin. The decrease of PP in obese children normalized after weight loss. Therefore, low PP concentrations reflect the overweight status, rather than cause it.

Hypothalamic circuitry of neuropeptide Y regulation of neuroendocrine function and food intake via the Y5 receptor subtype.

Neuropeptide Y (NPY) displays diverse modes of action in the CNS including the modulation of feeding behavior, gonadotropin releasing hormone release, and stress responses. Many of the above physiological actions have been at least partially attributed to actions of NPY on the NPY Y5 receptor subtype. We utilized an antibody directed against the NPY Y5 receptor to characterize the distribution of this receptor in the rat brain. Using Western blot analysis, this antibody recognized a single major band at approximately 57 kD. To further verify the specificity of the antibody, animals were treated for 5 days with antisense oligonucleotides for the Y5 receptor. The antisense treatment significantly reduced food intake and body weight. Furthermore, the Y5 antibody detected a significant decrease in Y5 receptor protein. Y5-like immunoreactivity (-ir) was observed throughout the hypothalamus, thalamus, hippocampus and cortex. Double-label immunofluorescence demonstrated that Y5-ir was colocalized with the following neuronal phenotypes in the hypothalamus, gonadotropin-releasing hormone, neurophysins, corticotropin-releasing hormone, and gamma-amino butyric acid. In addition, functional interactions were demonstrated by the presence of close appositions of NPY fibers with Y5-ir expressing cells. The wide distribution of the Y5 receptor-ir, as well as the colocalization within specific neuronal populations, agrees with the distribution of the Y5 receptor mRNA and the known physiological roles of the NPY/Y5 system. The role of the NPY/Y5 receptor system as a mediator between signals of peripheral energy availability and reproductive neuroendocrine function is discussed.

Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus.

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.

Results of the study to determine rotablator and transluminal angioplasty strategy (STRATAS).

Rotational atherectomy is used to debulk calcified or complex coronary stenoses. Whether aggressive burr sizing with minimal balloon dilation (<1 atm) to limit deep wall arterial injury improves results is unknown. Patients being considered for elective rotational atherectomy were randomized to either an "aggressive" strategy (n = 249) (maximum burr/artery >0.70 alone, or with adjunctive balloon inflation < or = 1 atm), or a "routine" strategy (n = 248) (maximum burr/artery < or =0.70 and routine balloon inflation > or =4 atm). Patient age was 62 +/- 11 years. Fifty-nine percent routine and 60% aggressive strategy patients had class III to IV angina. Fifteen percent routine and 16% aggressive strategy patients had a restenotic lesion treated; lesion length was 13.6 versus 13.7 mm. Reference vessel diameter was 2.64 mm. Maximum burr size (1.8 vs 2.1 mm), burr/artery ratio (0.71 vs 0.82), and number of burrs used (1.9 vs 2.7) were greater for the aggressive strategy, p <0.0001. Final minimum lumen diameter and residual stenosis were 1.97 mm and 26% for the routine strategy versus 1.95 mm and 27% for the aggressive strategy. Clinical success was 93.5% for the routine strategy and 93.9% for the aggressive strategy. Creatine kinase-myocardial band (CK-MB) was >5 times normal in 7% of the routine versus 11% of the aggressive group. CK-MB elevation was associated with a decrease in rpm of >5,000 from baseline for a cumulative time >5 seconds, p = 0.002. At 6 months, 22% of the routine patients versus 31% of the aggressive strategy patients had target lesion revascularization. Angiographic follow-up (77%) showed minimum lumen diameter to be 1.26 mm in the routine group versus 1.16 mm in the aggressive group, and the loss index 0.54 versus 0.62. Dichotomous restenosis was 52% for the routine strategy versus 58% for the aggressive strategy. Multivariable analysis indicated that left anterior descending location (odds ratio 1.67, p = 0.02) and operator-reported excessive speed decrease >5,000 rpm (odds ratio 1.74, p = 0.01) were significantly associated with restenosis. Thus, the aggressive rotational atherectomy strategy offers no advantage over more routine burr sizing plus routine angioplasty. Operator technique reflected by an rpm decrease of >5,000 from baseline is associated with CK-MB elevation and restenosis.

The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis.

Arcuate nucleus neurons are known to be responsive to a wide array of hormones and nutrients, including leptin, insulin, gonadal steroids and glucose. In addition to potential transport mechanisms, peripheral substances may access these neurons via arcuate cell bodies in and projections to the median eminence, a region considered to be a circumventricular organ. The arcuate is a potent site of leptin action, probably mediating a component of leptin's effects via arcuate neuropeptide Y/agouti-related peptide (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons, and implicating this structure in the long-term control of energy stores. However, ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, may also stimulate feeding and weight gain, in part through action on receptors in arcuate NPY neurons. Since ghrelin is secreted by the stomach upon content depletion, with a half-life of no more than an hour, the arcuate nucleus may also be important in sensing and responding to acute changes in nutrients. We have developed a system for recording from arcuate POMC neurons using a mouse containing a transgene in which the POMC promoter is driving expression of the green fluorescent protein (GFP). In these mice, 99% of the beta-endorphin positive neurons express GFP, making whole cell patch clamp recordings from the sparsely distributed POMC neurons facile. All of the POMC neurons appear to be activated by leptin, via two different mechanisms, while approximately 30-50% of the neurons appear to be inhibited by a gamma-melanocyte stimulating hormone (MSH) specific agonist. The latter result suggests that the melanocortin-3 receptor (MC3-R) may act as an autoinhibitory receptor on some POMC neurons. This hypothalamic slice preparation also confirms the responsiveness of arcuate POMC neurons to a wide variety of nutrients and hormones. Thus the arcuate melanocortin system is best described as a conduit of many diverse signals involved in energy homeostasis, with leptin acting tonically to regulate the responsiveness of the circuit to a wide variety of hormones and nutrients.