Interaction of PACAP with Sonic hedgehog reveals complex regulation of the Hedgehog pathway by PKA

AbstractSonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (cGCPs) and its aberrant activation causes a cerebellar cancer medulloblastoma. Pituitary adenylate cyclase activating polypeptide (PACAP) inhibits Shh-driven proliferation of cGCPs and acts as tumor suppressor in murine medulloblastoma. We show that PACAP blocks canonical Shh signaling by a mechanism that involves activation of protein kinase A (PKA) and inhibition of the translocation of the Shh-dependent transcription factor Gli2 into the primary cilium. PKA is shown to play an essential role in inhibiting gene transcription in the absence of Shh, but global PKA activity levels are found to be a poor predictor of the degree of Shh pathway activation. We propose that the core Shh pathway regulates a small compartmentalized pool of PKA in the vicinity of primary cilia. GPCRs that affect global PKA activity levels, such as the PACAP receptor, cooperate with the canonical Shh signal to regulate Gli protein phosphorylation by PKA. This interaction serves to fine-tune the transcriptional and physiological function of the Shh pathway

Optimization techniques for time-shared computer systems

The inefficiency of time-shared computer systems compared to batch processing systems is in the time lost in swapping operations. The larger the allocated quantum size, the less swap time is incurred. In order to guard against intolerable response time while lengthening the quantum size, the response time of a common request must be regulated. The criteria used in this paper to regulate the response time is to vary the quantum, with the number of users in the system, in such a way that the computer response time approaches the human response time. Based upon this concept, models are designed and analyzed to design an optimal scheduling algorithm which allocates the quantum dynamically. The models proposed are based upon Markovian assumptions for both arrival and service times. The priority discipline is round robin with dynamic quantum allocation. The swap time is assumed to be constant and the overhead time is zero. The inverse measure of performance is assumed to be the expected square difference between the cycle time and the mean human response time. In order to optimize these models two techniques are discussed. In the first, a mathematical optimization model is formulated in which a Markov chain is imbedded at the epochs of the beginning of a cycle. The cost function is assumed to be the inverse measure of performance. A technique suggested by Howard for optimizing a stochastic system under Markovian assumptions provides an optimal policy by which the scheduling algorithm allocates the quantum. The second technique discussed is based upon an optimal control system approach. The quantum size is chosen in such a way as to assure some stability property while improving system performance. A numerical example which illustrates these methods is provided

Recurrent Hepatocellular Carcinoma in Patient with Crohn\u27s Disease: Incidental or Expected Outcome of Azathioprine?

Hepatocellular carcinoma (HCC) usually occurs in patients with underlying risk factors such as liver cirrhosis and chronic hepatitis B. Although patients with Crohn’s disease (CD) are at an increased risk to develop malignancies such as colon cancer, the incidence of HCC in this population is extremely rare. We report a case of 62-year-old male with long history of CD treated with azathioprine (AZA) and aminosalicylic acid (ASA) who was incidentally diagnosed with HCC, for which left hepatectomy was done. Four years later during routine follow-up, patient had another hepatic lesion and underwent resection of the mass. The mechanism of occurrence of HCC in patient with CD is still controversial and may include immune mediated changes and medication related complications. AZA was reported in all case reports of CD that developed HCC.Through this report we hope to explore the complex pathophysiological mechanisms contributing to the development of HCC in the Crohn’s disease patient population

RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss

Precisely deciphering the molecular mechanisms of age-related memory loss is crucial to create appropriate therapeutic interventions. We have previously shown that the histone-binding protein RbAp48/Rbbp4 is a molecular determinant of Age-Related Memory Loss. By exploring how this protein regulates the genomic landscape of the hippocampal circuit, we find that RbAp48 controls the expression of BDNF and GPR158 proteins, both critical components of osteocalcin (OCN) signaling in the mouse hippocampus. We show that inhibition of RbAp48 in the hippocampal formation inhibits OCN’s beneficial functions in cognition and causes deficits in discrimination memory. In turn, disruption of OCN/GPR158 signaling leads to the downregulation of RbAp48 protein, mimicking the discrimination memory deficits observed in the aged hippocampus. We also show that activation of the OCN/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues age-related memory loss

Recurrent Hepatocellular Carcinoma in Patient with Crohn’s Disease: Incidental or Expected Outcome of Azathioprine?

Hepatocellular carcinoma (HCC) usually occurs in patients with underlying risk factors such as liver cirrhosis and chronic hepatitis B. Although patients with Crohn\u27s disease (CD) are at an increased risk to develop malignancies such as colon cancer, the incidence of HCC in this population is extremely rare. We report a case of 62-year-old male with long history of CD treated with azathioprine (AZA) and aminosalicylic acid (ASA) who was incidentally diagnosed with HCC, for which left hepatectomy was done. Four years later during routine follow-up, patient had another hepatic lesion and underwent resection of the mass. The mechanism of occurrence of HCC in patient with CD is still controversial and may include immune mediated changes and medication related complications. AZA was reported in all case reports of CD that developed HCC. Through this report we hope to explore the complex pathophysiological mechanisms contributing to the development of HCC in the Crohn\u27s disease patient population

Prevalence of HIV infection and median CD4 counts among health care workers in South Africa

Objective. To determine the prevalence of HIV infection and the extent of  disease progression based on CD4 count in a public health system workforce in southern Africa.Design. Cross-sectional voluntary, anonymous, unlinked survey including an oral fluid or blood sample and a brief demographic questionnaire.Setting. Two public hospitals in Gauteng, South Africa.SubJects. All 2 032 professional and support staff employed by the two hospitals.Outcome measures. HIV prevalence and CD4 cell count distribution.Results. Overall prevalence of HIV was 11.5%. By occupation, prevalence was highest among student nurses (13.8%) and nurses (13.7%). The  highest prevalence by age was in the 25- 34-year group (15.9%). Nineteen per cent of HIV-positive participants who provided blood samples had CD4  counts less than or equal to 200 cells/µl, 28% had counts 201 - 350  cells/pi, 18% had counts 351 - 500 cells/µl, and 35% had counts above 500 cells /µl.Conclusions. One out of 7 nurses and nursing students in this public sector workforce was HIV-positive. A high proportion of health care workers had CD4 counts below 350 cells/µl, and many were already eligible for  antiretroviral therapy under South African treatment guidelines. Given the short supply of nurses in South Africa, knowledge of prevalence in this workforce and provision of effective AIDS treatment are crucial for meeting future staffing needs

Recurrent Hepatocellular Carcinoma in Patient with Crohn’s Disease: Incidental or Expected Outcome of Azathioprine?

Hepatocellular carcinoma (HCC) usually occurs in patients with underlying risk factors such as liver cirrhosis and chronic hepatitis B. Although patients with Crohn’s disease (CD) are at an increased risk to develop malignancies such as colon cancer, the incidence of HCC in this population is extremely rare. We report a case of 62-year-old male with long history of CD treated with azathioprine (AZA) and aminosalicylic acid (ASA) who was incidentally diagnosed with HCC, for which left hepatectomy was done. Four years later during routine follow-up, patient had another hepatic lesion and underwent resection of the mass. The mechanism of occurrence of HCC in patient with CD is still controversial and may include immune mediated changes and medication related complications. AZA was reported in all case reports of CD that developed HCC. Through this report we hope to explore the complex pathophysiological mechanisms contributing to the development of HCC in the Crohn’s disease patient population

High-resolution Imaging of Myeloperoxidase Activity Sensors in Human Cerebrovascular Disease

Progress in clinical development of magnetic resonance imaging (MRI) substrate-sensors of enzymatic activity has been slow partly due to the lack of human efficacy data. We report here a strategy that may serve as a shortcut from bench to bedside. We tested ultra high-resolution 7T MRI (microMRI) of human surgical histology sections in a 3-year IRB approved, HIPAA compliant study of surgically clipped brain aneurysms. microMRI was used for assessing the efficacy of MRI substrate-sensors that detect myeloperoxidase activity in inflammation. The efficacy of Gd-5HT-DOTAGA, a novel myeloperoxidase (MPO) imaging agent synthesized by using a highly stable gadolinium (III) chelate was tested both in tissue-like phantoms and in human samples. After treating histology sections with paramagnetic MPO substrate-sensors we observed relaxation time shortening and MPO activity-dependent MR signal enhancement. An increase of normalized MR signal generated by ultra-short echo time MR sequences was corroborated by MPO activity visualization by using a fluorescent MPO substrate. The results of microMRI of MPO activity associated with aneurysmal pathology and immunohistochemistry demonstrated active involvement of neutrophils and neutrophil NETs as a result of pro-inflammatory signalling in the vascular wall and in the perivascular space of brain aneurysms

Multivariate epidemiologic analysis of type 2 diabetes mellitus risks in the Lebanese population

Background: The burden of diabetes in Lebanon requires well-targeted interventions for screening type 2 diabetes mellitus (T2DM) and prediabetes and prevention of risk factors. Newly recruited 998 Lebanese individuals, in addition to 7,292 already available, were studied to investigate the prevalence of diabetes, prediabetes and their associated risk factors. Methods: Participants had fasting blood sugar and glycohemoglobin tests in addition to a lipid profile. Clinical and demographic information were obtained from a detailed questionnaire. The relationship between T2DM, its risk factors, and its complications were tested. Comparisons of these risk factors among diabetics, healthy, and coronary artery disease (CAD) patients were performed. Results: The prevalence of T2DM significantly increased with increasing BMI (p < 0.0001). Exercise activity level negatively correlated with the disease (p = 0.002), whereas the prevalence of T2DM (p < 0.0001) and CAD family history (p = 0.006) positively correlated with the affection status. The mean levels of triglycerides and LDL-C were significantly higher in diabetics (1.87; 1.35) compared to individuals with prediabetes (1.63; 1.26) and unaffected controls (1.49; 1.19). People with T2DM showed a significant decrease in HDL-C levels. A strong correlation of overall hyperlipidemia with the diabetes affection status was shown (p < 0.0001). Other comorbid factors such as hypertension (p < 0.0001) and self-reported obesity (p < 0.0001) were highly associated with T2DM and prediabetes. Reproductive health of women showed a strong correlation between giving birth to a baby with a high weight and the occurrence of T2DM and prediabetes later in life (p < 0.0001). Retinopathy and peripheral neuropathy were significantly correlated with diabetes and prediabetes (p < 0.0001). Conclusions: The present study shows an alarming prevalence of diabetes and prediabetes in the studied subgroups representative of the Lebanese population. Electronic supplementary material The online version of this article (doi:10.1186/1758-5996-6-89) contains supplementary material, which is available to authorized users