Pathogenicity of Field Marek's Disease Virus Serotype-1 and Vaccine Efficacy Test in Chicken in Eastern Shewa Ethiopia.

BACKGROUND: Marek's disease is a chicken lymphoproliferative viral illness. As new viruses emerge, vaccination immunity is being broken and hence pathogenecity assessment and vaccine evaluation related to the pathogen is critical for developing vaccine immunity in the field. METHODS: An experimental investigation was conducted to determine the pathogenicity of field isolates against Marek's disease in antibody-free chicks and to assess the protective efficacy of the Marek's disease vaccination. The viral isolates in question were discovered during an outbreak investigation for a previous study. The pathogenicity and effectiveness trial used a complete random design. RESULTS: In the pathogenicity trial, chickens inoculated with Bishoftu and Mojo field isolate had lower body weight 77.7±3.757 and 78.15±1.95 g at 10 dpi, respectively, when compared to un-inoculated controls, 89.85±3.838 g at 10 dpi. Incidence of early mortality syndrome (35% and 25%), lymphoma (53.8% and 40%), and overall mortality (50% and 45%) between Bishoftu and Mojo isolates, respectively, was discovered. Vaccinations with Herpes virus of turkey challenged chickens were provided complete protection against Marek's disease. CONCLUSION: Based on the findings in pathogenecity assessment experimental trials, Bishoftu and Mojo isolates were designated as virulent Marek's disease viruses. Regular vaccinations with Herpes virus of turkey vaccine and supported by biosecurity measures in poultry farms are important to prevent the disease.

Influence of variation in global sperm DNA methylation level on the expression level of protamine genes and human semen parameters.

An infertility problem is a complex issue that affects 15% approximately of couples worldwide. The current study was designed to evaluate if there is a variation in the status of global DNA methylation among the study groups and to assess their impact on the protamine expression level and human semen parameters. Totalling 200 semen samples were collected from men (50 proved fertile, 60 normospermia and 90 oligospermia) with an average age of 34.9 ± 4.3 years. The DNA and RNA were isolated from purified spermatozoa; then, ELISA and qPCR were applied to estimate the status of global sperm DNA methylation and protamine expression level respectively. Besides that, the sperm chromatin decondensation and sperm DNA fragmentation were assessed. A significant variation was found in the global sperm DNA methylation and the protamine 1 and protamine 2 expression level among the study groups (p ≤ .001). Down-regulation has been found in the protamine 1 and protamine 2 expression levels in the oligospermia group compared to the proved fertile group with fold change (0.001 and 0.0002 respectively). In conclusion, this study proposes that the alteration in global DNA methylation may influence the protamine expression level and may be lead to abnormalities in human semen parameters.

Medium-term outcome of posterior surgery in the treatment of non-tuberculous bacterial spinal infection.

OBJECTIVE: to evaluate the outcome of posterior spinal stabilization surgery for the management of bacterial spinal infection. METHODS: 21 patients with bacterial infection were managed surgically with posterior stabilization. Outcome measures included neurological status. Follow-up data collected using Spine Tango COMI questionnaires and Euro Qol EQ-5D. RESULTS: The mean improvement in neurological deficits was 0.91 Frankel grade. Residual symptoms of pain had no or minor effect on the work or usual activities in 52% of subjects, with 88% reported having either no or mid problems with mobility. CONCLUSION: Posterior surgery can improve neurological outcome in approximately half of the patients.

Serum vitamin D status in type 2 diabetic patients from Gaza Strip.

OBJECTIVE: To assess serum vitamin D status and its relations to other biochemical parameters in type 2 diabetic patients from Gaza Strip. MATERIALS AND METHODS: This case-control study included 58 type 2 diabetic patients as well as 58 non-diabetic controls. Patients and controls were matched for age and gender. Data were obtained from questionnaire interview, and biochemical analysis of blood samples. RESULTS: Serum vitamin D was significantly lower in diabetic patients compared to non-diabetic controls (25.9 ±â€¯11.0 versus 34.6 ±â€¯13.8 ng/dl, % difference = 28.8%, P < 0.001). The number of patients having vitamin D deficient, insufficient and sufficient were 6 (10.4%), 35 (60.3%) and 17 (29.3%) compared to controls of 3 (5.2%), 16 (27.6%) and 39 (67.2%), respectively (χ2 = 14.672, P < 0.001). Serum glucose, glycated hemoglobin (HbA1c), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglycerides were significantly higher in patients than in controls whereas serum insulin, high density lipoprotein cholesterol (HDL-C) and calcium were significantly lower in patients. Serum vitamin D showed significant negative correlations with HbA1c (r = - 0.186, P = 0.046), ALT (r = - 192, P = 0.040) and AST (r = - 0.188, P = 0.044) whereas significant positive correlations were found with HDL-C (r = 0.188, P = 0.044) and calcium (r = 0.239, P = 0.010). CONCLUSION: The significant negative and positive correlations of vitamin D with HbA1c and calcium, respectively suggests that vitamin D supplementation would be of potential therapeutic value in clinical settings for controlling of type 2 diabetes and more importantly its complications. However, a well-designed clinical trials are needed to define the contribution of vitamin D status and therapy in the global diabetes problem.

IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes.

Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (Foral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foral was also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. Foral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.

IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results.

Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, Foral and relative AUC (Frel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.

IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds.

Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.

Physico-chemical and bacteriological quality of drinking water of different sources, Jimma zone, Southwest Ethiopia.

BACKGROUND: The quality of drinking water has always been a major health concern, especially in developing countries, where 80% of the disease cases are attributed to inadequate sanitation and use of polluted water. The inaccessibility of potable water to large segment of a population in the rural communities is the major health concern in most part of developing countries. This study was designed to evaluate the physico-chemical and bacteriological qualities of drinking water of different sources in the study area. METHODS: The study was conducted at Serbo town and selected kebeles around the same town in Kersa district of Jimma Zone, southwest Ethiopia. Socio-demographic characteristics of the study populations were gathered using structured and pre-tested questionnaires. Standard microbiological methods were employed for determination of bacterial load and detection of coliforms. Physico-chemical analyses [including total dissolved substances (TDS), total suspended substances (TSS), biological oxygen demand (BOD), nitrate and phosphate concentrations, turbidity and electrical conductivities] were conducted following guidelines of American Public Health Association and WHO. Correlations among measured parameters of water samples collected from different water sources were computed using SPSS software (version 20). RESULT: Only 18.1% (43/237) of the study population had access to tap water in the study area. More than 50% of the community relies on open field waste disposal. Members of the family Enterobacteriaceae, Bacillus and Pseudomonas were among dominant bacterial isolates in the water samples. All water samples collected from unprotected water sources were positive for total coliforms and fecal coliforms (FC). Accordingly, FC were detected in 80% of the total samples with counts ranging between 0.67 and 266.67 CFU/100 ml although 66.67% of tap water samples were negative for FC. The recorded temperature and pH ranged between 20.1-29.90 °C and 5.64-8.14, respectively. The lowest and highest mean TDS were 116 and 623 mg/l, respectively. Furthermore, the mean concentration of TSS ranged between 2.07 and 403.33 mg/l. Turbidity, electric conductivity, and nitrate concentration of the water samples ranged, respectively, between 0.01-65.4 NTU, 30.6-729 µS/cm, and below detection limit to 95.80 mg/l. In addition, the mean dissolved oxygen values were found to be between 1.62 and 10.71 mg/l; whereas BOD was within the range of 8-77 mg/l. In all water samples, the concentrations of zinc were within the WHO maximum permissible limits (3 mg/l) although the lead concentration in about 66.7% of the samples exceeded the maximum permissible limit (0.01 mg/l). CONCLUSION: The present study has revealed that some of the bacteriological data and physico-chemical parameters of the different water sources had values beyond the maximum tolerable limits recommended by WHO. Thus, it calls for appropriate intervention, including awareness development work and improving the existing infrastructure in order to minimize the potential health problems of those communities currently realizing of the available water sources.

Replacing cottonseed meal with ground Prosopis juliflora pods; effect on intake, weight gain and carcass parameters of Afar sheep fed pasture hay basal diet.

The experiment was conducted to determine the supplementary feeding value of ground Prosopis juliflora pod (Pjp) and cottonseed meal (CSM) and their mixtures on feed intake, body weight gain and carcass parameters of Afar sheep fed a basal diet of pasture hay. Twenty-five yearling fat-tailed Afar rams with mean initial live weight 17.24 ± 1.76 kg (mean ± SD) were used in a randomized complete block design. Animals were blocked on their initial body weight. The experiment was conducted for 12 weeks and carcass evaluation followed. Treatments were hay alone ad libitum (T 1) or with 300 g CSM (T 2), 300 g Pjp (T 5), 2:1 ratio (T 3) and 1:2 ratio of CSM : Pjp (T 4). The CP contents of the hay, CSM and Pjp were 10.5, 44.5 and 16.7 %, respectively. Hay DM intake was higher (P < 0.05) for non-supplemented and total DM intake was lower in non-supplemented. Average daily weight gain (ADG) was lower (P < 0.05) for T 1 compared to all supplemented treatments except T 5. Hot carcass weight and rib-eye muscle area also followed the same trend like that of ADG. Compared with feeding hay alone, supplementing with CSM or a mixture of CSM and Pjp appeared to be a better feeding strategy, biologically, for yearling Afar rams.

Removing the cells from adult bone marrow derived stem cell therapy does not eliminate cardioprotection.

OBJECTIVES: The debate as to whether adult stem cell therapy is regenerative or not continues. The non-regenerative benefits of adult bone marrow-derived stem cell therapy were investigated by testing whether the supernatant derived from unfractionated bone marrow mononuclear cells might be cardioprotective in an animal model of myocardial ischaemia-reperfusion injury. METHODS: Regional myocardial reperfusion injury was acquired by 25 min reversible left anterior descending coronary artery (LAD) occlusion followed by 2 h reperfusion, in anaesthetized Wistar male rats. Unfractionated bone marrow mononuclear cells (BMMNC) isolated from sibling Wistar male rat whole bone marrow were phenotyped by fluorescence activated cell sorting flowcytometry for the haematopoietic stem cell surface markers c-kit, CD34, CD45 and CD133. Animals subjected to regional myocardial reperfusion injury received either 10 million BMMNC or BMMNC supernatant (BMS); both were collected in 0.5 ml phosphate-buffered saline and delivered by intravenous bolus at the onset of reperfusion. The left ventricular region distal to the LAD occlusion point was excised for measurement of myocardial infarct size and proteomic analysis, which was used to identify whether there were any differences in myocardial proteins associated with intravenous injection of either BMMNC or BMS. RESULTS: BMMNC were phenotyped to be c-kit(+) (7 ± 1%), CD34(+) (7 ± 1%), CD45(+) (54 ± 6%), CD133(+) (15 ± 1%). The supernatant reduced myocardial infarct size (BMS 34 ± 2%, n = 15 vs control 57 ± 2%, n = 7, P < 0.0001), which was comparable to the reduction in infarct size afforded by the injection of cells (BMMNC 33 ± 3% vs control 57 ± 2%, n = 10, P < 0.0001). Proteomics of hearts treated with either BMS or BMMNC demonstrated higher expression of (i) anti-apoptotic signal transduction protein: 14-3-3-epsilon (1.5-fold); (ii) anti-oxidants: peroxiredoxin-6 (2.1-fold); (iii) heat shock proteins: alpha B-crystallin (1.7-fold), heat shock protein 72 (2.8-fold), tumour necrosis factor receptor-1 associated protein (2.3-fold), ischaemia responsive protein-94 (1.6-fold); (iv) glycolytic protein: glyceraldehyde-3-phosphate dehydrogenase (2.3-fold); (v) mitochondrial respiratory proteins: mitochondrial aconitase (4.7-fold), voltage-dependent anion-selective channel protein-1 (VDAC-1) (2.7-fold). CONCLUSIONS: Regional myocardial reperfusion injury can be attenuated by intravenous administration of either BMMNC or BMS at the onset of reperfusion, which suggests adult stem cells mediate non-regenerative cardioprotection.

Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery.

In this study an advanced multisampling site pig model, with simultaneous venous blood sampling pre- and post liver, was applied to quantify the role of the intestine in relation to the liver in first-pass glucuronidation of raloxifene in vivo. The pharmacokinetic of raloxifene (a BCS/BDDCS class II compound) in humans is characterized by extensive metabolism (>90%) and the major metabolite is the 4'-ß-glucuronide (R-4-G). Following intra-jejunal (i.j.) single dose administration in pigs raloxifene was metabolized in the gut (E(G)) during first-pass to more than 70% and a high concentration (AUC(0-6 h) ratio R-4-G/raloxifene >100) of R-4-G was reached in the portal vein. The hepatic extraction (E(H)) of raloxifene was ~50% and as in humans the bioavailability become low (~7%) in pigs. Interestingly the E(H) of raloxifene and R-4-G was time-dependent after i.j. administration. It is clear that the gut was the dominating organ in first-pass extraction of raloxifene in vivo in pigs. The quantification in this study support earlier human data and emphasize that intestinal glucuronidation should be considered early in the pharmaceutical development.

An investigation into the utility of a multi-compartmental, dynamic, system of the upper gastrointestinal tract to support formulation development and establish bioequivalence of poorly soluble drugs.

In recent years mechanical systems have been developed that more closely mimic the full dynamic, physical and biochemical complexity of the GI Tract. The development of these complex systems raises the possibility that they could be used to support formulation development of poorly soluble compounds and importantly may be able to replace clinical BE studies in certain circumstances. The ability of the TNO Simulated Gastro-Intestinal Tract Model 1 (TIM-1) Dynamic Artificial Gastrointestinal System in the 'lipid membrane' configuration to support the development of Biopharmaceutics Classification System Class 2 compounds was investigated by assessing the performance of various AZD8055 drug forms and formulations in the TIM-1 system under standard fasting and achlorhydric physiological conditions. The performance data were compared with exposure data from the phase 1 clinical study. Analysis of the AZD8055 plasma concentrations after tablet administration supported the conclusions drawn from the TIM-1 experiments and confirmed that these complex systems can effectively support the product development of poorly soluble drugs. Particularly, the TIM-1 system was able to show that AZD8055 exposure would increase in an approximately dose proportional manner and not be limited by the solubility or dissolution. Additionally, the investigations also showed that the exposure produced by a solution and a tablet would be the same. Specific instances when the TIM-1 system may not be predictive of clinical product performance have also been identified.

Early failure of a knee replacement in a neuropathic joint. A case report.

Total knee arthroplasty in neuropathic (Charcot) joints is technically demanding. Most studies report significant improvement in knee function, despite a high incidence of complications. We present a case of idiopathic, unilateral neuropathic arthropathy of the knee treated with a modular stemmed, constrained total knee arthroplasty. Unscrewing of the stem of the tibial component was detected a year following surgery. The tibial component was revised to a custom made monobloc stemmed implant. Satisfactory knee function was noted at short-term follow-up. This case highlights a potential problem of using modular long-stem implants in neuropathic joints and emphasises the need for close follow-up of these difficult cases.

Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway.

OBJECTIVE: Adult bone marrow mononuclear cells (BMMNCs) can restore cardiac function following myocardial necrosis. Protocols used to date have administered cells relatively late after ischaemia/reperfusion injury, but there is the opportunity with elective procedures to infuse cells shortly after restoration of blood flow, for example after angioplasty. Our aim was therefore to try and quantify protection from myocardial injury by early infusion of BMMNCs in a rat ischaemia reperfusion (I/R) model. METHODS AND RESULTS: Male Wistar rats underwent 25 min of ischaemia followed by 2 h reperfusion of the left anterior descending coronary artery. Ten million BMMNCs were injected i.v. at reperfusion. We found BMMNCs caused a significant reduction in infarct size at 2 h when assessed by staining the area at risk with p-nitro blue tetrazolium (42% reduction, P<0.01). Apoptosis and necrosis of isolated cardiomyocytes was significantly reduced in the area at risk. Functional assessment at 7 days using echocardiography and left ventricular catheterisation showed improved systolic and diastolic function in the BMMNC treatment group (LVEF: BMMNC 71 ± 3% vs. PBS 48 ± 4%, P<0.0001). In functional studies BMMNC injected animals showed increased activation of Akt, inhibition of GSK-3ß, amelioration of p38 MAP kinase phosphorylation and NF-κB activity compared to control myocardium. Inhibition of PI3K with LY294002 abolished all beneficial effects of BMMNC treatment. Proteomic analysis also demonstrated that BMMNC treatment induced alterations in proteins within known cardioprotective pathways, e.g., heat shock proteins, stress-70 protein as well as the chaperone protein 14-3-3 epsilon. CONCLUSIONS: Early BMMNC injection during reperfusion preserves the myocardium, with evidence of reduced apoptosis, necrosis, and activation of survival pathways.

Different effects of ketoconazole on the stereoselective first-pass metabolism of R/S-verapamil in the intestine and the liver: important for the mechanistic understanding of first-pass drug-drug interactions.

In this acute study a pig jejunal intestinal perfusion model with multiple plasma sampling sites and three different administration routes was used to investigate the quantitative contribution of the intestine versus liver to the first-pass extraction of each enantiomer of verapamil (VER). A subclinical dose of ketoconazole (8 mg) was coadministered in the perfusion solution to selectively inhibit gut wall CYP3A. Both enantiomers of VER and its main metabolite norverapamil (NOR) as well as the inhibitor ketoconazole were quantified in all plasma compartments by liquid chromatography-tandem mass spectrometry. The overall first-pass metabolic extraction of VER and the metabolite NOR was shown to be stereoselective with the S-isomer being more extensively extracted. For VER the ratio of R- enantiomer to S-enantiomer was greater in the hepatic vein than in the portal vein (approximately 2.2 versus 1.4), indicating that the stereoselective metabolism of VER in pigs mainly occurs on the first pass through the liver and not in the intestine. Ketoconazole increased the area under the curve from time 0 to 6 h and C(max) of R- and S-VER at least 3-fold in the portal vein, most likely explained by inhibition of gut wall metabolism. Conversely, hepatic extraction was increased because the effect of gut wall metabolism was not observed at the peripheral sampling sites. In conclusion, this study provided novel and more direct information on the contribution of the intestine and the liver, respectively, to the overall first-pass extraction of racemic VER.

Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R.

Hydrogen sulfide (H2S) is a novel gaseous mediator produced by cystathionine-beta-synthase and cystathionine-gamma-lyase in the cardiovascular system, including the heart. Using a rat model of regional myocardial ischemia/reperfusion, we investigated the effects of an H2S donor (sodium hydrogen sulfide [NaHS]) on the infarct size and apoptosis caused by ischemia (25 min) and reperfusion (2 h). Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by NaHS. Specifically, we demonstrate that NaHS (1) attenuates the increase in caspase 9 activity observed in cardiac myocytes isolated from the area at risk (AAR) of hearts subjected in vivo to regional myocardial I/R and (2) ameliorates the decrease in expression of Bcl-2 within the AAR obtained from rat hearts subjected to regional myocardial I/R. The cardioprotective effects of NaHS were abolished by 5-hydroxydeconoate, a putative mitochondrial adenosine triphosphate-sensitive potassium channel blocker. Furthermore, NaHS attenuated the increase in the I/R-induced (1) phosphorylation of p38 mitogen-activated protein kinase and Jun N-terminal kinase, (2) translocation from the cytosol to the nucleus of the p65 subunit of nuclear factor-kappaB, (3) intercellular adhesion molecule 1 expression, (4) polymorphonuclear leukocyte accumulation, (5) myeloperoxidase activity, (6) malondialdehyde levels, and (7) nitrotyrosine staining determined in the AAR obtained from rat hearts subjected to regional myocardial I/R. In conclusion, we demonstrate that the cardioprotective effect of NaHS is secondary to a combination of antiapoptotic and anti-inflammatory effects. The antiapoptotic effect of NaHS may be in part due to the opening of the putative mitochondrial adenosine triphosphate-sensitive potassium channels.

Segmental radius and ulna fractures with scaphocapitate fractures and bilateral multiple epiphyseal fractures.

Segmental forearm fractures are rare in children, and management is controversial. Epiphyseal injuries further complicate matters. We report the case of a 15-year-old boy who had segmental radius and ulna fractures with a coronal split of a metaphyseal fragment, along with bilateral epiphyseal fractures of the distal radius and ulna as well as ipsilateral scaphocapitate fractures with perilunate dislocation. There was also a contralateral fracture through the radial neck. The patient underwent immediate internal fixation of the forearm fractures and delayed fixation of the scaphocapitate fractures. Results at 12 months showed excellent functional outcome.

Stroke in Qatar: a first prospective hospital-based study of acute stroke.

BACKGROUND: Stroke is a major cause of morbidity and mortality in Qatar. OBJECTIVES: The aim of our study was to determine types of strokes, the associated risk factors, clinical presentation, outcome, and time to hospital admission among Qatari and non-Qatari patients as well as young and nonyoung patients. METHODS: We conducted a hospital-based prospective observational study including all patients admitted to Hamad Medical Corporation with first-ever stroke from September 15, 2004, to September 14, 2005. A stroke was defined according to World Health Organization criteria. RESULTS: Stroke was confirmed in 270 patients of whom 217 (80.4%) had ischemic stroke and 53 (19.6%) had hemorrhagic stroke. Male patients predominated in all types of stroke. The main risk factors for stroke were hypertension and diabetes, whereas lacunar infarct was the most common subtype of ischemic stroke. Risk factor profiles were similar between Qatari and non-Qatari patients except for hypercholesterolemia, which was observed with a higher frequency in Qatari compared with non-Qatari patients with ischemic stroke. There were significant differences between the young and nonyoung patients with ischemic stroke with respect to risk factors, ejection fraction, ventricular wall-motion abnormalities, time to hospital admission, and outcome. Most patients arrived at the hospital more than 3 hours from stroke onset because of unawareness of stroke symptoms. The overall in-hospital mortality was 9.3%. CONCLUSIONS: Hypertension and diabetes mellitus were the main risk factors for stroke in Qatar, whereas lacunar infarct was the most common subtype. Significant differences between the young and nonyoung patients were observed with respect to risk factors, ejection fraction, ventricular wall-motion abnormalities, time to hospital admission, and outcome.

An investigation into the influence of drug lipophilicity on the in vivo absorption profiles from subcutaneous microspheres and in situ forming depots.

Drug lipophilicity is known to have a major influence on in vivo drug absorption from intramuscularly and subcutaneously administered solutions. Indeed, chemical modification to increase drug lipophilicity is used to enable sustained drug release from solutions. In contrast to the wealth of knowledge on drug release from simple solutions, the influence of drug lipophilicity on its release from controlled release formulations, such as, microparticles and in situ forming depots, have not been systematically studied. Controlled release vehicles are designed to 'control' drug release, hence, in vitro studies show negligible influence of drug lipophilicity on release. The situation could however be different in vivo, due to interactions between the vehicle and biological tissue. We therefore investigated the influence of drug lipophilicity on its in vivo release in rats from two controlled release formulations, PLGA microparticles and in situ forming depots. Both systems exhibited a burst drug release. Subsequent to the burst release, we found that lipophilicity did not influence the rate or extent of drug absorption from the two formulations over a 10-day study period, which would imply that drug partitioning out of the depots was not the main mechanism of drug release from both formulations. This study must however be repeated with a greater number of animals to increase its power.

MUC4 and ErbB2 expression in squamous cell carcinoma of the upper aerodigestive tract: correlation with clinical outcomes.

OBJECTIVES/HYPOTHESIS: Expression of the membrane mucin MUC4 has been associated with a variety of malignancies, including squamous cell carcinoma of the upper aerodigestive tract. MUC4 modulates cell signaling pathways as an intramembrane ligand of ErbB2. The hypotheses of the study were that MUC4 expression would correlate with ErbB2 expression and that MUC4 expression would correlate with clinical outcomes in squamous cell carcinoma of the upper aerodigestive tract. STUDY DESIGN: Retrospective chart review was combined with immunohistochemical analysis of paraffin-embedded tumor specimens from patients treated with initial definitive surgical resection at an academic tertiary care medical center. METHODS: MUC4 and ErbB2 receptor expression was localized by immunohistochemical studies using archival formalin-fixed and paraffin-embedded tissue. A limited number of fresh-frozen tissues were further analyzed by Western blot. Clinical outcomes and histopathological parameters were determined by retrospective chart review and correlated with immunohistochemical findings. RESULTS: One hundred fifty-four patients were analyzed with a median follow-up of 12 months among 54 patients who died and 49 months among 100 surviving patients. Membrane expression of MUC4 and ErbB2 was seen in 12% and 13% of tumors, respectively. MUC4 expression was not correlated with pathological grade. A significant correlation was found between MUC4 expression and ErbB2 expression. Multivariate survival analyses revealed that patients whose tumors exhibited MUC4 membrane expression had statistically significant improvement in survival and longer time to recurrence compared with patients whose tumors did not express MUC4 as defined by immunohistochemical staining patterns. No correlations between ErbB2 expression and survival or recurrence were observed. CONCLUSION: Patients with tumors that retain MUC4 expression exhibit improved survival and decreased recurrence in squamous cell carcinoma of the upper aerodigestive tract. Correlations between MUC4 expression patterns and ErbB2 expression are also observed, suggesting that MUC4-ErbB2 mediated cell signaling pathways may provide insights into this clinical result.