The role of insulin receptor substrate 2 in hypothalamic and beta cell function

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced P cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis

The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer

Kallikrein-related peptidase 14 (KLK14) is one of several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumour microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analysed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic and in vitro assays with the goal to identify substrates, related-signalling pathways and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neo-adjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression re-occurred in patients who developed castrate-resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14-substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14-regulated genes (Interleukin 32, midkine, Sox9), particularly an involvement of the MAPK1 and IL1RN pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumours. Additional work is necessary to determine the benefits and implications of targeting/co-targeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment

Mathematical Evaluation of Community Level Impact of Combining Bed Nets and Indoor Residual Spraying upon Malaria Transmission in Areas where the main Vectors are Anopheles Arabiensis Mosquitoes.

Indoor residual insecticide spraying (IRS) and long-lasting insecticide treated nets (LLINs) are commonly used together even though evidence that such combinations confer greater protection against malaria than either method alone is inconsistent. A deterministic model of mosquito life cycle processes was adapted to allow parameterization with results from experimental hut trials of various combinations of untreated nets or LLINs (Olyset, PermaNet 2.0, Icon Life nets) with IRS (pirimiphos methyl, lambda cyhalothrin, DDT), in a setting where vector populations are dominated by Anopheles arabiensis, so that community level impact upon malaria transmission at high coverage could be predicted. Intact untreated nets alone provide equivalent personal protection to all three LLINs. Relative to IRS plus untreated nets, community level protection is slightly higher when Olyset or PermaNet 2.0 nets are added onto IRS with pirimiphos methyl or lambda cyhalothrin but not DDT, and when Icon Life nets supplement any of the IRS insecticides. Adding IRS onto any net modestly enhances communal protection when pirimiphos methyl is sprayed, while spraying lambda cyhalothrin enhances protection for untreated nets but not LLINs. Addition of DDT reduces communal protection when added to LLINs. Where transmission is mediated primarily by An. arabiensis, adding IRS to high LLIN coverage provides only modest incremental benefit (e.g. when an organophosphate like pirimiphos methyl is used), but can be redundant (e.g. when a pyrethroid like lambda cyhalothin is used) or even regressive (e.g. when DDT is used for the IRS). Relative to IRS plus untreated nets, supplementing IRS with LLINs will only modestly improve community protection. Beyond the physical protection that intact nets provide, additional protection against transmission by An. arabiensis conferred by insecticides will be remarkably small, regardless of whether they are delivered as LLINs or IRS. The insecticidal action of LLINs and IRS probably already approaches their absolute limit of potential impact upon this persistent vector so personal protection of nets should be enhanced by improving the physical integrity and durability. Combining LLINs and non-pyrethroid IRS in residual transmission systems may nevertheless be justified as a means to manage insecticide resistance and prevent potential rebound of not only An. arabiensis, but also more potent, vulnerable and historically important species such as Anopheles gambiae and Anopheles funestus

A Markov-switching vector equilibrium correction model of the UK labour market

There is a wide literature on the dynamic adjustment of employment and its relationship with the business cycle. In this paper we present a statistical model that offers a congruent representation of part of the UK labour market since the mid 1960s. We use a cointegrated vector autoregressive Markov-switching model in which some parameters change according to the phase of the business cycle. Output, employment, labour supply and real earnings are found to have a common cyclical component. The long run dynamics are characterized by one cointegrating vector relating unemployment to trend-adjusted real wages and output. Despite there having been many changes affecting this sector of the UK economy, the Markov-switching vector-equilibrium-correction model with three regimes (representing recession, normal growth, and high growth) provides a good characterization of the sample data, and performs well relative to alternative linear and non-linear models. The results of an impulse-response analysis highlight the dangers of using VARs when the constancy of the estimated coefficients has not been established, and demonstrate the advantages of generating regime dependent responses

Integrated Mapping of Neglected Tropical Diseases: Epidemiological Findings and Control Implications for Northern Bahr-el-Ghazal State, Southern Sudan

Integrated control of neglected tropical diseases (NTDs) is being scaled up in a number of developing countries, because it is thought to be more cost-effective than stand-alone control programmes. Under this approach, treatments for onchocerciasis, lymphatic filariasis (LF), schistosomiasis, soil-transmitted helminth (STH) infection, and trachoma are administered through the same delivery structure and at about the same time. A pre-requisite for implementation of integrated NTD control is information on where the targeted diseases are endemic and to what extent they overlap. This information is generated through surveys that can be labour-intensive and expensive. In Southern Sudan, all of the above diseases except onchocerciasis require further mapping before a comprehensive integrated NTD control programme can be implemented. To determine where treatment for which disease is required, integrated surveys were conducted for schistosomiasis, STH infection, LF, and loiasis, throughout one of ten states of the country. Our results show that treatment is only required for urinary schistosomiasis and STH in a few, yet separate, geographical area. This illustrates the importance of investing in disease mapping to minimize overall programme costs by being able to target interventions. Integration of survey methodologies for the above disease was practical and efficient, and minimized the effort required to collect these data

Carcinoid tumor of the minor papilla in complete pancreas divisum presenting as recurrent abdominal pain

<p>Abstract</p> <p>Background</p> <p>Tumors of the minor papilla of the duodenum are extremely rare, and they are mostly neuroendocrine tumors, such as somatostatinomas and carcinoid tumors. However, true incidence of carcinoid tumors in minor papilla might be much higher, because patients with minor papillary tumors usually remain asymptomatic. We report a very unusual case of carcinoid tumor in a patient with complete pancreas divisum with a review of the literature.</p> <p>Case presentation</p> <p>A 56-year-old female patient was referred for evaluation of pancreatic duct dilatation noted on abdominal ultrasonography and computerized tomography. She complained of intermittent epigastric pain for 6 months. A MRCP and ERCP revealed complete pancreas divisum with dilatation of the main pancreatic duct. On duodenoscopy, a small, yellows, subepithelial nodule was visualized at the minor papilla; biopsy of this lesion revealed a carcinoid tumor. She underwent a pylorus-preserving pancreaticoduodenectomy. The histologic evaluation showed a single nodule, 1 cm in diameter, in the submucosa with duodenal and vascular invasion and metastasis to the regional lymph nodes.</p> <p>Conclusion</p> <p>Although the size of the carcinoid tumor was small and the tumor was hormonally inactive, the concomitant pancreas divisum led to an early diagnosis, the tumor had aggressive behavior. Carcinoid tumors of the minor papilla should be included in the differential diagnosis of recurrent abdominal pain or pancreatitis of unknown cause.</p

Lessons Learned in Conducting Mass Drug Administration for Schistosomiasis Control and Measuring Coverage in an Operational Research Setting

The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was created to conduct research that could inform programmatic decision-making related to schistosomiasis. SCORE included several large cluster randomized field studies involving mass drug administration (MDA) with praziquantel. The largest of these were studies of gaining or sustaining control of schistosomiasis, which were conducted in five African countries. To enhance relevance for routine practice, the MDA in these studies was coordinated by or closely aligned with national neglected tropical disease (NTD) control programs. The study protocol set minimum targets of at least 90% for coverage among children enrolled in schools and 75% for all school-age children. Over the 4 years of intervention, an estimated 3.5 million treatments were administered to study communities. By year 4, the median village coverage was at or above targets in all studies except that in Mozambique. However, there was often a wide variation behind these summary statistics, and all studies had several villages with very low or high coverage. In studies where coverage was estimated by comparing the number of people treated with the number eligible for treatment, denominator estimation was often problematic. The SCORE experiences in conducting these studies provide lessons for future efforts that attempt to implement strong research designs in real-world contexts. They also have potential applicability to country MDA campaigns against schistosomiasis and other NTDs, most of which are conducted with less logistical and financial support than was available for the SCORE study efforts

Survivorship of Anopheles darlingi (Diptera: Culicidae) in Relation with Malaria Incidence in the Brazilian Amazon

We performed a longitudinal study of adult survival of Anopheles darlingi, the most important vector in the Amazon, in a malarigenous frontier zone of Brazil. Survival rates were determined from both parous rates and multiparous dissections. Anopheles darlingi human biting rates, daily survival rates and expectation of life where higher in the dry season, as compared to the rainy season, and were correlated with malaria incidence. The biting density of mosquitoes that had survived long enough for completing at least one sporogonic cycle was related with the number of malaria cases by linear regression. Survival rates were the limiting factor explaining longitudinal variations in Plasmodium vivax malaria incidence and the association between adult mosquito survival and malaria was statistically significant by logistic regression (P<0.05). Survival rates were better correlated with malaria incidence than adult mosquito biting density. Mathematical modeling showed that P. falciparum and P. malariae were more vulnerable to changes in mosquito survival rates because of longer sporogonic cycle duration, as compared to P. vivax, which could account for the low prevalence of the former parasites observed in the study area. Population modeling also showed that the observed decreases in human biting rates in the wet season could be entirely explained by decreases in survival rates, suggesting that decreased breeding did not occur in the wet season, at the sites where adult mosquitoes were collected. For the first time in the literature, multivariate methods detected a statistically significant inverse relation (P<0.05) between the number of rainy days per month and daily survival rates, suggesting that rainfall may cause adult mortality