Search

Background: Tuberculosis (TB) screening among patients infected with Human Immunodeficiency Virus (HIV) is one of the approaches for controlling TB-HIV co-infection. The absence of typical TB symptoms among HIV-infected patients makes diagnosis challenging. Identifying predisposing risk factors of TB among HIV-infected patients could possibly guide TB diagnosis and treatment. This study was designed to identify some important factors associated with TB among HIV-infected patients and to quantify the strength of this association., Methodology: In 2010, a case control study was conducted in Khartoum State, Sudan. Cases and controls were selected by simple random sampling with a 1:2 ratio; 97 cases and 194 controls were enrolled in the study. A logistic regression model was built to estimate and quantify the strength of the association between the study variables and the outcome; a p -value less than 0.05 was considered the cut-off point for a significant statistical association., Results: Past history of TB, CD4 count < 200 cells/µl, late clinical stages, non-employment, and no formal education were found to be risk factors for developing TB among HIV-infected patients. The adjusted ORs and 95% CIs were (6.9: 3.75-12.99), (4.8: 1.57-15.26), (5.8: 1.88-17.96), (2.5: 1.26-5.03), and (2.5: 1.28-4.63), respectively. Poor adherence, marital status, age, and gender are not associated with developing TB among HIV patients., Conclusion: HIV patients who have at least one of the risk factors found in this analysis are at higher risk of TB; therefore, they should be screened more frequently and treated promptly, especially HIV patients with previous TB., Competing Interests: Conflicts of Interest: All of the authors confirm that they have no reported conflicts. The conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have demonstrated a crucial function for histone acetylation and histone deacetylation in regulating the cellular and behavioral mechanisms underlying synaptic plasticity and learning and memory. In trying to delineate the roles of individual HDACs, genetic tools have been used to manipulate HDAC expression in rodents, uncovering distinct contributions of individual HDACs in regulating the processes of memory formation. Moreover, recent findings have suggested an important role for HDAC inhibitors in enhancing learning and memory processes as well as ameliorating symptoms related to neurodegenerative diseases. In this review, we focus on the role of HDACs in learning and memory, as well as significant data emerging from the field in support of HDAC inhibitors as potential therapeutic targets for the treatment of cognitive disorders., (© 2014 Mahgoub and Monteggia; Published by Cold Spring Harbor Laboratory Press.)

Cannabinoids are among the earliest known drugs to humanity. Cannabis plant contains various phytochemicals that bind to cannabinoid receptors. In addition, synthetic and endogenously produced cannabinoids (endocannabinoids) constitute other classes of cannabinoid receptor ligands. Although many pharmacological effects of these cannabinoids are mediated by the activation of cannabinoid receptors, recent studies indicate that cannabinoids also modulate the functions of various integral membrane proteins including ion channels, receptors, neurotransmitter transporters, and enzymes by mechanism(s) not involving the activation of known cannabinoid receptors. Currently, the mechanisms of these effects were not fully understood. However, it is likely that direct actions of cannabinoids are closely linked to their lipophilic structures. This report will focus on the actions of cannabinoids on nicotinic acetylcholine receptors and will examine the results of recent studies in this field. In addition some mechanistic approaches will be provided. The results discussed in this review indicate that, besides cannabinoid receptors, further molecular targets for cannabinoids exist and that these targets may represent important novel sites to alter neuronal excitability., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The effects of cannabidiol (CBD), a non-psychoactive ingredient of cannabis plant, on the function of the cloned α7 subunit of the human nicotinic acetylcholine (α7 nACh) receptor expressed in Xenopus oocytes were tested using the two-electrode voltage-clamp technique. CBD reversibly inhibited ACh (100 μM)-induced currents with an IC50 value of 11.3 µM. Other phytocannabinoids such as cannabinol and Δ(9)-tetrahydrocannabinol did not affect ACh-induced currents. CBD inhibition was not altered by pertussis toxin treatment. In addition, CBD did not change GTP-γ-S binding to the membranes of oocytes injected with α7 nACh receptor cRNA. The effect of CBD was not dependent on the membrane potential. CBD (10 µM) did not affect the activity of endogenous Ca(2+)-dependent Cl(-) channels, since the extent of inhibition by CBD was unaltered by intracellular injection of the Ca(2+) chelator BAPTA and perfusion with Ca(2+)-free bathing solution containing 2mM Ba(2+). Inhibition by CBD was not reversed by increasing ACh concentrations. Furthermore, specific binding of [(125)I] α-bungarotoxin was not inhibited by CBD (10 µM) in oocytes membranes. Using whole cell patch clamp technique in CA1 stratum radiatum interneurons of rat hippocampal slices, currents induced by choline, a selective-agonist of α7-receptor induced currents were also recoded. Bath application of CBD (10 µM) for 10 min caused a significant inhibition of choline induced currents. Finally, in hippocampal slices, [(3)H] norepinephrine release evoked by nicotine (30 µM) was also inhibited by 10 µM CBD. Our results indicate that CBD inhibits the function of the α7-nACh receptor., (© 2013 Published by Elsevier B.V.)

Psychiatric disorders including major depressive disorder, drug addiction, and schizophrenia are debilitating illnesses with a multitude of complex symptoms underlying each of these disorders. In recent years, it has become appreciated that the onset and development of these disorders goes beyond the one gene-one disease approach. Rather, the involvement of many genes is likely linked to these illnesses, and regulating the activation or silencing of gene function may play a crucial role in contributing to their pathophysiology. Epigenetic modifications such as histone acetylation and deacetylation, as well as DNA methylation can induce lasting and stable changes in gene expression, and have therefore been implicated in promoting the adaptive behavioral and neuronal changes that accompany each of these illnesses. In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment.

Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca(2+)-dependent Cl(-) channels, since menthol inhibition remained unchanged by intracellular injection of the Ca(2+) chelator BAPTA and perfusion with Ca(2+)-free bathing solution containing Ba(2+). Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [(125)I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca(2+) transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner.

Background: Calorie restriction (CR) induces long-term changes in motivation to eat highly palatable food and, in body weight regulation, through an unknown mechanism., Methods: After a period of CR and refeeding, mice were assessed by behavioral and metabolic studies and for levels of the transcription factor ΔFosB. The ΔFosB levels were then increased specifically in nucleus accumbens (NAc) with viral-mediated gene transfer, and behavioral and metabolic studies were conducted., Results: We show that accumulation of ΔFosB in the NAc shell after CR in mice corresponds to a period of increased motivation for high fat reward and reduced energy expenditure. Furthermore, ΔFosB overexpression in this region increases instrumental responding for a high fat reward via an orexin-dependent mechanism while also decreasing energy expenditure and promoting adiposity., Conclusions: These results suggest that ΔFosB signaling in NAc mediates adaptive responses to CR., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Retinoblastoma (RB) is a rare and unique cancer that affects the eyes of very young children. There are few reports on RB in Sudan., Materials and Methods: We performed a retrospective study of data from patients diagnosed with retinoblastoma between January 1999 and December 2009 at the National Cancer Institute in Gezira (NCI-Gezira)., Results: Of the 519 cases of childhood cancer treated at NCI-Gezira during the study period, 25 (4.8%) were retinoblastoma. Of these 25 patients with retinoblastoma, there were 13 boys and 19 cases were unilateral. The median age at diagnosis was 36 months (range, 8-60 months). The disease was localized in 9 patients, regional in 5 patients, and metastatic in 11 patients. The most frequent symptoms were enlarged eye (n = 14) and leukocoria (n = 8). Nine patients (36%) have been lost to follow-up; 9 were alive at last follow-up (7 in remission, 2 progressed); and 7 have died (5 from disease and 2 from unrelated causes). Twenty-two eyes were enucleated in 16 patients (6 bilateral and 10 unilateral). Pathologic examination of the enucleated eyes could only be completed in 11 patients. Diagnostic imaging in the form of computerized tomography scans or ultrasonography of the brain and orbit was done for 10 patients (40%)., Conclusions: Although these findings are not surprising, and similar to reports from other developing countries, we hope our work will provide a foundation for strategies to improve outcome for retinoblastoma in our center such as proper training, public awareness, team approach, and twinning.

Several psychiatric disorders increase the risk of cardiovascular disease, including posttraumatic stress disorder and major depression. While the precise mechanism for this association has not yet been established, it has been shown that certain disorders promote an unfavorable lipid profile. To study the interaction of stress and lipid dysregulation, we utilized chronic social defeat stress (CSDS), a mouse model of chronic stress with features of posttraumatic stress disorder and major depression. Following exposure to CSDS, mice were given access to either regular chow or a Western-style diet high in fat and cholesterol (HFD). The combination of social stress and HFD resulted in significant perturbations in lipid regulation, including two key features of the metabolic syndrome: increased plasma levels of non-HDL cholesterol and intrahepatic accumulation of triglycerides. These effects were accompanied by a number of changes in the expression of hepatic genes involved in lipid regulation. Transcriptional activity of LXR, SREBP1c, and ChREBP were significantly affected by exposure to HFD and CSDS. We present CSDS as a model of social stress induced lipid dysregulation and propose that social stress alters lipid metabolism by increasing transcriptional activity of genes involved in lipid synthesis.

Background: The differential diagnosis of dyspnoea is difficult due to the low predictive value of clinical and laboratory parameters. The elevated levels of NT-proBNP in congestive heart failure may improve diagnostic accuracy. We have evaluated the effect of the introduction of an NT-proBNP assay on hospital length of stay (LOS) and mortality., Methods: There were 11,853 AMAU patient episodes in the 22 months study period (March 2005-Dec 2006). An NT-proBNP assay was requested in 657 (5.5%) of these. Comparison between categorical variables such as diagnosis, NT-proBNP testing, LOS, and in-hospital mortality was made using Chi-square tests. Literature review suggested that an NT-proBNP cut-off >or=5000 ng/L should predict acute in-patient mortality. Logistic regression analysis was used to examine the association between such an elevated NT-proBNP level and outcomes., Results: Of the 396 patients with NT-proBNP <5000 ng/L, 8.1% died compared with 22.5% of the 178 patients dying with values >or=5000 ng/L (p<0.0001). An NT-proBNP >or=5000 ng/L was predictive of both LOS >or=9 days (odds ratios (OR) 1.54 (95% CI 1.06, 2.24: p=0.02) and LOS >or=14 days (OR=1.87 (95% CI 1.29, 2.71: p=0.0009). NT-proBNP requests increased over time, from 2.6% to 8.2% of all patients; the result fell in the diagnostic range for CHF in 60% of requests., Conclusion: The introduction of an NT-proBNP was reflected in an appropriate but rapidly increasing pattern of requests from clinicians. High NT-proBNP levels predicted in-hospital mortality and longer LOS in an acute medical population.

Objective: The aim of this study is to record the observations and experience on the diagnosis and management of abdominal tuberculosis (TB) and to highlight the difficulties in the diagnosis and management of this condition., Methods: Two hundred consecutive patients attending the Gastroenterology Department of the King Khalid National Guard Hospital, Jeddah, Kingdom of Saudi Arabia between May 1991 and May 2001, suspected with abdominal TB were investigated. A detailed clinical history and physical examination were obtained. Data of 75 confirmed cases of abdominal TB were analyzed., Results: The most common presenting symptoms were anorexia (84%), abdominal pain (84%) and weight loss (72%). Abdominal tenderness was the most common clinical finding, followed by ascites and abdominal mass (42%). The chest radiograph suggestive of pulmonary TB was diagnosed in 24 patients (32%). Computed tomographic (CT) scanning revealed abnormalities in all 51 patients who underwent the procedure, while positive findings were observed by abdominal ultrasound in 66% of the tested patients. Histopathological examination of patients showed tuberculous granuloma, while acid fast bacilli were seen in 34%. Mycobacterium tuberculosis was identified by microbiological methods in 60% of patients. The most common presenting symptoms were anorexia (84%), abdominal pain (84%) and weight loss (72%). Abdominal tenderness was the most common clinical finding, followed by ascites and abdominal mass (42%). The chest radiograph suggestive of pulmonary TB was diagnosed in 24 patients (32%). Computed tomographic (CT) scanning revealed abnormalities in all 51 patients who underwent the procedure, while positive findings were observed by abdominal ultrasound in 66% of the tested patients. Histopathological examination of patients showed tuberculous granuloma, while acid fast bacilli were seen in 34%. Mycobacterium tuberculosis was identified by microbiological methods in 60% of patients., Conclusion: A high index of clinical suspicion is required to make an early diagnosis of abdominal TB. Suspicion should be aroused, particularly in patients having a combination of anorexia, abdominal pain, weight loss and ascites. Diagnosis requires the utilization of a combination of various diagnostic procedures especially abdominal ultrasound, CT scan and endoscopy, which provides a high diagnostic yield in this disease. A normal chest radiograph does not exclude the presence of abdominal TB. A timely use of laparoscopy are often required to prevent surgical intervention.

The clinical application of islet transplantation is limited due to the limited source and the morbidity of systemic immunosuppression to prevent rejection. The two problems can be solved by using encapsulated islets. We have used amniotic membranes as biocompatible natural immune barriers. The objective of this study was to assess the revascularization of the membrane, which is necessary to ensure islet viability when the membrane is used for islet encapsulation. The amniotic membranes, obtained from full-term pregnant female dogs, were molded to form macrocapsules, which were implanted in the peritoneal cavity. The capsules were removed after 3, 10, 15, and 30 days and examined histopathologically using hematoxylin and eosin and by immunohistochemistry for neovascularization using factor VIII to detect angiogenesis. Upon histopathological examination, all specimens showed localized, moderate inflammation and congested blood vessels with no thrombosis or rejection. There was a mild degree of fibroblast proliferation starting from day 10 to day 30. Immunohistochemical staining revealed that the number of blood vessels was 7, 11, 13, 10 per high-power microscopic field on days 3, 10, 15, and 30, respectively. We concluded from this study that implanted amniotic sac capsules were vascularized within the omental tissue from day 10 on with significant blood vessel formation starting on day 3 by immunohistochemical study.

Background: Monophosphoryl lipid-A (MLA) has a late window (24 hours) of cardioprotection against acute myocardial infarction. It is not known whether MLA, administered, 24 hours before surgery, attenuates intraoperative ventricular dysfunction "stunning" associated with aortic cross-clamping and reperfusion during elective cardiac surgery. We determined the dose-response relationship between MLA and ventricular function in a canine model of global myocardial stunning in the absence of necrosis. The role of expression of inducible heat shock protein 70 (HSP 70i) was also investigated., Methods: Mongrel dogs (n = 32) were intravenously injected with either a vehicle solution or 3, 5, 10, 35 ug/kg MLA. Twenty four hours later, dogs were anesthetized and instrumented, in situ, to monitor the left ventricular performance (the slope of regression between stroke-work and end diastolic length). Tissue samples were obtained to determine HSP70i using immunoblot analysis. After a period of equilibration on cardiopulmonary bypass, the aortic cross-clamp was applied at normothermia for 30 minutes followed by 60 minutes of reperfusion. ATP and catabolites were determined in transmural myocardial biopsies. Triphenyl-tetrazolium chloride (TTC) staining was used to determine myocardial necrosis., Results: MLA treatment did not alter myocardial contractility or ATP metabolism. Global ischemia resulted in about 50% depletion of ATP and remained depressed during reperfusion in all groups. MLA-treated hearts had improved functional recovery in a dose dependent-manner. Significant recovery was observed at the highest dose (35 ug/kg) compared to the control group. Immunoblot analysis demonstrated significant increase in HSP 70i in the MLA-treated hearts., Conclusions: MLA exhibits a delayed (24 hours) window of protection against myocardial stunning associated with aortic cross-clamping. HSP70i expression may play a role in MLA-mediated cardioprotection.

Background: Chronic arteriovenous fistulae (AVF) create sustained hyperdynamic circulation. It is not known whether hyperdynamic circulation alters myocardial sensitivity to ischemia and reperfusion injury. We tested the hypothesis that AVF activate molecular responses that increase tolerance to infarction in dogs., Methods: Twelve dogs were divided into two groups: 1) AVF group, where an AVF in the femoral region was done; and 2) sham-operated group (each n = 6). After 8 weeks, left ventricular performance was determined from stroke work/end-diastolic length relationship. Myocardial biopsy was obtained to determine heat-shock protein 70 and adenosine triphosphate (ATP) pool. Left anterior descending coronary artery was occluded for 90 minutes at 37 degrees C, followed by 4 hours of reperfusion. Coronary blood flow was determined using different colored microspheres., Results: The fistula group showed improvement of left ventricular performance (p = 0.03). The infarct size was significantly lower in the fistula group; it was 9.2+/-2.0% in the fistula group versus 28.4+/-5.2% in the sham group (p < 0.05). ATP depletion during ischemia was less in the fistula group (p = 0.02). Regional myocardial blood flow was significantly higher in the fistula group (p = 0.03)., Conclusions: Peripheral AVF improve the left ventricular performance, and decrease infarct size and ATP depletion. This protective effect is caused by the development of collaterals in the coronary circulation without expression of heat-shock protein 70.

Decrease in intracellular thiols leads to oxidative stress and thus may cause alterations in the activity of redox-sensitive enzymes required for signal transduction. Here, we report that, N-ethylmaleimide and phenylarsine oxide, which are known to oxidize free thiols as well as protein thiols, induced phosphatidyl ethanol generation in the micromolar range suggesting activation of phospholipase D in vascular smooth muscle cells. These agents also induced significant phosphatidic acid and diacylglycerol generation without causing protein kinase C activation. Phenylarsine oxide and N-ethyl maleimide induced phospholipase D activation is protein kinase C independent as it was not inhibited by compound-3 and bisindolylmaleimide, potent protein kinase C inhibitors. Tyrosine kinase inhibitor herbimycin A by itself activated PLD, but inhibited the phospholipase D activation by phenylarsine oxide and N-ethylmaleimide. These results suggest that oxidation of the cellular thiols activates phospholipase D independent of protein kinase C.

Cardiovascular complications are the most common causes of morbidity and mortality in diabetic patients. Coronary atherosclerosis is enhanced in diabetics, whereas myocardial infarction represents 20% of deaths of diabetic subjects. Furthermore, re-infarction and heart failure are more common in the diabetics. Diabetic cardiomyopathy is characterized by an early diastolic dysfunction and a later systolic one, with intracellular retention of calcium and sodium and loss of potassium. In addition, diabetes mellitus accelerates the development of left ventricular hypertrophy in hypertensive patients and increases cardiovascular mortality and morbidity. Treating the cardiovascular problems in diabetics must be undertaken with caution. Special consideration must be given with respect to the ionic and metabolic changes associated with diabetes. For example, although ACE inhibitors and calcium channel blockers are suitable agents, potassium channel openers cause myocardial preconditioning and decrease the infarct size in animal models, but they inhibit the insulin release after glucose administration in healthy subjects. Furthermore, potassium channel blockers abolish myocardial preconditioning and increase infarct size in animal models, but they protect the heart from the fatal arrhythmias induced by ischemia and reperfusion which may be important in diabetes. For example, diabetic peripheral neuropathy usually presents with silent ischemia and infarction. Mechanistically, parasympathetic cardiac nerve dysfunction, expressed as increased resting heart rate and decreased respiratory variation in heart rate, is more frequent than the sympathetic cardiac nerve dysfunction expressed as a decrease in the heart rate rise during standing.

Reactive oxygen species function as signaling molecules, and are known to be generated under both normal and pathological conditions. Using vascular smooth muscle cells, we have demonstrated an increase in mitogen activated protein kinase activity in response to oxidants. Mitogen activated protein kinase activity increased linearly with time in cells treated with pervanadate. Hydrogen peroxide also caused rapid induction of mitogen activated protein kinase. Protein kinase C down regulation partially decreased induction of mitogen activated protein kinase activity by oxidants, and the Ca2+ ionophore, ionomycin. Protein kinase C inhibitors, compound-3 and bisindolylmaleimide did not inhibit oxidant induced mitogen activated protein kinase activity, where as calphostin C activated it. The tyrosine kinase inhibitors genistein, herbimycin A and tyrphostin caused 50% inhibition of oxidant induced mitogen activated protein kinase activation. These results suggest that oxidant-induced mitogen activated protein kinase is protein kinase C independent.

Twenty patients with bilharzial periportal fibrosis (group I); 20 patients with post hepatitic cirrhosis (group II) and 20 normal controls were chosen to study the correlation between the serum level of human growth hormone (GH) and Somatomedin-C (Sm-C); and the anthropometric measurements; liver function tests and various haematological parameters. Group I showed no statistically significant difference in the mean values of serum GH before and after insulin induced hypoglycemia. The basal serum level of Sm-C showed a statistically significant decrease and highly significant decrease after insulin test. A statistically significant positive correlation was evident between the individual values of serum level of GH and Sm-C and the anthropometric measurements, haematological values and liver function tests (r = 0.41). The mean serum level of GH in group 2, showed statistically significant increase before and after insulin test. The mean serum level of Sm-C showed a statistically significant decrease before and after insulin test. A statistically significant negative correlation was found between the individual values of the serum level of GH and Sm-C and the anthropometric measurements, haematological values and liver function tests (r = 0.16).