Primaquine radical cure of Plasmodium vivax: a critical review of the literature.
Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001). Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.


Effects of cognitive stimulation therapy Japanese version (CST-J) for people with dementia: a single-blind, controlled clinical trial.
Cognitive stimulation therapy (CST) has shown to have significant benefits in improving the cognitive function and quality of life (QOL) in people with mild-to-moderate dementia in a UK randomized controlled trial (RCT). We developed and examined the Japanese version of group CST (CST-J) in a single-blind, controlled clinical trial. CST-J consisting of 14 sessions was administered to a treatment group (n = 26) twice a week for 7 weeks. The treatment group was compared with a control group (n = 30). Based on single-blindness, cognition was evaluated by a researcher, and QOL and mood were rated by the participants themselves. Additionally, QOL and mood of participants were rated by care workers who were not blind but who observed them most directly in their daily life (important for social validity). A linear mixed model was used for analyses of cognition and QOL. There were significant improvements in cognition [COGNISTAT (Neurobehavioral Cognitive Status Examination) and MMSE (Mini-Mental State Examination)] for the treatment group compared with the control group (p < 0.01). Regarding QOL, the EQ-5D was significant (p = 0.019) and the QoL-AD (Quality of Life - Alzheimer's Disease) showed a positive trend (p = 0.06) when rated by care workers, although not when rated by the participants themselves. Using a nonparametrical analysis, there were significant improvements in the face scale for mood when rated by both the participants (p < 0.01) and the care workers (p = 0.017). The CST-J shows promising improvements in cognition, mood, and aspects of QOL for people with dementia in Japanese care settings. A large RCT is now needed.


The synergy between atomically dispersed Pd and cerium oxide for enhanced catalytic properties.
We report a photochemical synthesis of Pd/CeO2 catalysts with atomically dispersed Pd. Compared to atomically dispersed Pd/CeO2 with a cubic CeO2 support (Pd/CeO2-CP), atomically dispersed Pd/CeO2 with a truncated octahedral CeO2 support (Pd/CeO2-TOP) exhibited higher activity and selectivity, owing to the synergy between Pd atoms and the (111) surface of CeO2. When compared to Pd/CeO2 with Pd clusters and nanoparticles via chemical reduction, Pd/CeO2-TOP showed excellent activity with an enhancement factor of 324 in CO oxidation, as well as an activity enhancement by a factor of 344 in selective oxidation of benzyl alcohol.


Assessment of the Additional Value of Verapamil to a Moxifloxacin and Linezolid Combination Regimen in a Murine Tuberculosis Model.
The favorable treatment outcome rate for multidrug-resistant tuberculosis (MDR-TB) is only 54%, and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the value of the addition of the efflux pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug-sensitive Mycobacterium tuberculosis and were treated with human-equivalent doses of moxifloxacin (200 mg/kg of body weight) and linezolid (100 mg/kg) with or without verapamil (12.5 mg/kg) for 12 weeks. Pharmacokinetic parameters were collected during treatment at the steady state. After 12 weeks of treatment, a statistically significant decline in mycobacterial load in the lungs was observed with the moxifloxacin-linezolid regimen with and without verapamil (5.9 and 5.0 log CFU, respectively), but sterilization was not achieved yet. The spleens of all mice were culture negative after 12 weeks of treatment with both treatment modalities, and the addition of verapamil caused a significant reduction in relapse (14/14 positive spleens without versus 9/15 with verapamil, P = 0.017). In conclusion, treatment with a combination regimen of moxifloxacin and linezolid showed a strong decline in mycobacterial load in the mice. The addition of verapamil to this backbone had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing the spleen relapse rate. These results warrant further studies on the role of efflux pump inhibition in improving the efficacy of MDR-TB backbone regimens.


GRAZING ON GIANT KELP MICROSCOPIC PHASES AND THE RECRUITMENT SUCCESS OF ANNUAL POPULATIONS OF MACROCYSTIS PYRIFERA (LAMINARIALES, PHAEOPHYTA) IN SOUTHERN CHILE(1).
The giant kelp Macrocystis pyrifera (L.) C. Agardh is widely distributed in the Northern Hemisphere and Southern Hemisphere, yet it exhibits distinct population dynamics at local to regional spatial scales. Giant kelp populations are typically perennial with the potential for year-round reproduction and recruitment. In southern Chile, however, annual giant kelp populations exist and often persist entirely on secondary substrata (e.g., shells of the slipper limpet Crepipatella fecunda [Gastropoda, Calyptraeidae]) that can cover up to 90% of the rocky bottom. In these populations, the macroscopic sporophyte phase disappears annually during winter and early spring, leaving a 3-4 month period in which a persistent microscopic phase remains to support the subsequent year's recruitment. We tested the effects of a suite of grazers on the recruitment success of this critical microscopic phase at two sites in southern Chile. Field experiments indicated that the snail Tegula atra negatively impacted M. pyrifera sporophyte recruitment, but that recruitment was highest in the presence of sessile female limpets, C. fecunda. Conversely, small male C. fecunda (biofilm grazers) did not regulate kelp recruitment. Laboratory observations showed that C. fecunda males only grazed on microscopic kelp gametophytes and small (<250 μm) sporophytes, rejecting larger sporophytes, whereas T. atra grazed on all the kelp stages. Recruitment to the C. fecunda treatments far exceeded that to bare rock in the absence of grazers but was not due to the physical presence of C. fecunda shells. We concluded that the key to M. pyrifera recruitment success in southern Chile is its capacity to colonize secondary substrates provided by the slipper limpet C. fecunda.


Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review.
Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.


Factors affecting red blood cell storage age at the time of transfusion.
Clinical trials are investigating the potential benefit resulting from a reduced maximum storage interval for red blood cells (RBCs). The key drivers that determine RBC age at the time of issue vary among individual hospitals. Although progressive reduction in the maximum storage period of RBCs would be expected to result in smaller hospital inventories and reduced blood availability, the magnitude of the effect is unknown. Data on current hospital blood inventories were collected from 11 hospitals and three blood centers in five nations. A general predictive model for the age of RBCs at the time of issue was developed based on considerations of demand for RBCs in the hospital. Age of RBCs at issue is sensitive to the following factors: ABO group, storage age at the time of receipt by the hospital, the restock interval, inventory reserve, mean demand, and variation in demand. A simple model, based on hospital demand, may serve as the basis for examining factors affecting the storage age of RBCs in hospital inventories. The model suggests that the age of RBCs at the time of their issue to the patient depends on factors external to the hospital transfusion service. Any substantial change in the expiration date of stored RBCs will need to address the broad variation in demand for RBCs while attempting to balance considerations of availability and blood wastage.


[Tuberculous prosthetic knee joint infection: a case report and literature review].
Prosthetic late infection occurs in the second month after surgery in the context of haematogenous spread from another source. Prosthetic mycobacterial infection is a rare complication whose clinical management is not standardized. Patient of 77 years with no personal history except for diabetes and a prosthetic replacement of right knee with osteoarthritis three years ago. Patient goes to hospital emergency box for 6 months pain in the right knee with mechanical inflammatory signs but no fever associated. After their return within 5 days and clinical worsening is reporting growth of Mycobacterium tuberculosis in knee aspirate and antitubercular treatment is established for 9 months. Nuclear magnetic resonance imaging studies also confirmed the diagnosis of tuberculosis spondylitis in the clinical context of the patients. After surgery, M. tuberculosis was again isolated from intraoperative samples and therefore the patient received another batch of treatment for 9 months. After a year of monitoring, the development was acceptable but few months later, the patient died for cardiovascular causes. In the literature review, 15 publications with a total of 17 clinical cases of prosthetic infection by M. tuberculosis were found from 1980 to 2014. Prosthetic tuberculous arthritis, although it is a rare presentation, it should be noted, especially in patients with predisposing conditions with a history of tuberculosis infection.


Associations of Adolescents' Cigarette, Waterpipe, and Dual Tobacco Use With Parental Tobacco Use.
Previous studies have demonstrated the influence of parental (both mother and father) cigarette smoking on adolescents' cigarette smoking. Little is known, however, about how parental tobacco use is related to waterpipe and dual waterpipe/cigarette use, which is increasing dramatically in the Arab countries. Study data (n = 34 788, N = 6 109 572) were obtained from nationally representative Global Youth Tobacco Surveys in 17 Arab countries. Study outcome was adolescents' tobacco use categorized into none, cigarette smoking only, waterpipe smoking (WPS) only, and dual use. Primary exposure included parental tobacco use categorized into 10 groups-maternal (mother) cigarette smoking only, maternal WPS only, maternal dual use, paternal (father) cigarette smoking only, paternal WPS only, paternal dual use, parental (both mother and father) cigarette smoking only, parental WPS only, parental dual use, and none. Weighted multinomial regression models were conducted to assess the relationships. Adolescents reported smoking WPS only (5.7%), cigarettes only (2.9%), and dual use (3.5%). Compared to adolescent with no exposure to parental tobacco use, adolescent exposure to parental dual use was associated with significant increase in WPS only (OR = 6.08, 95% CI = 2.38-15.51) and dual use (OR = 3.86, 95% CI = 1.43-10.43). Effect modification of the relationship by adolescents' sex was observed. This is the first study to examine adolescent cigarette, waterpipe, and dual use with parental tobacco use. Study findings may help development of cessation interventions targeting parental tobacco use to prevent the rising waterpipe and dual use strain of the global tobacco epidemic. (1) Influence of parents' cigarette smoking on adolescents' smoking has been demonstrated in earlier studies, however, little is known about how tobacco use behaviors of mother and father influences an adolescent's cigarette, waterpipe and dual cigarette/waterpipe use. (2) Associations of parental (both mother and father) tobacco use with adolescents' tobacco use differed significantly if the adolescent is a waterpipe smoker or dual user compared to an adolescent cigarette smoker. (3) Adolescents' exposed to their mothers' WPS or dual use were more likely to be a waterpipe smoker or dual user. High likelihood of adolescents' cigarette, waterpipe and dual use is found in homes where parental tobacco use is rampant with both parents smoking either cigarette, waterpipe or both.


Xyloglucan endo-transglycosylase-mediated xyloglucan rearrangements in developing wood of hybrid aspen.
Xyloglucan endo-transglycosylases (XETs) encoded by xyloglucan endo-transglycosylases/hydrolase (XTH) genes modify the xyloglucan-cellulose framework of plant cell walls, thereby regulating their expansion and strength. To evaluate the importance of XET in wood development, we studied xyloglucan dynamics and XTH gene expression in developing wood and modified XET activity in hybrid aspen (Populus tremula × tremuloides) by overexpressing PtxtXET16-34. We show that developmental modifications during xylem differentiation include changes from loosely to tightly bound forms of xyloglucan and increases in the abundance of fucosylated xyloglucan epitope recognized by the CCRC-M1 antibody. We found that at least 16 Populus XTH genes, all likely encoding XETs, are expressed in developing wood. Five genes were highly and ubiquitously expressed, whereas PtxtXET16-34 was expressed more weakly but specifically in developing wood. Transgenic up-regulation of XET activity induced changes in cell wall xyloglucan, but its effects were dependent on developmental stage. For instance, XET overexpression increased abundance of the CCRC-M1 epitope in cambial cells and xylem cells in early stages of differentiation but not in mature xylem. Correspondingly, an increase in tightly bound xyloglucan content was observed in primary-walled xylem but a decrease was seen in secondary-walled xylem. Thus, in young xylem cells, XET activity limits xyloglucan incorporation into the tightly bound wall network but removes it from cell walls in older cells. XET overexpression promoted vessel element growth but not fiber expansion. We suggest that the amount of nascent xyloglucan relative to XET is an important determinant of whether XET strengthens or loosens the cell wall.


Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.
The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval [CI], -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient's overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group. Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).


Paeoniflorin prevents endoplasmic reticulum stress-associated inflammation in lipopolysaccharide-stimulated human umbilical vein endothelial cells via the IRE1α/NF-κB signaling pathway.
Endoplasmic reticulum (ER) stress-associated inflammation is a critical molecular mechanism involved in the pathogenesis of endothelial dysfunction (ED). Hence, strategies for alleviating ER stress-induced inflammation may be essential for the prevention of cardiovascular diseases. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora Pallas is known for its functional properties against vascular inflammation. However, to date, PF-mediated protection against ER stress-dependent inflammation has not been identified. Herein, we investigate the protective effect of PF on lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cell (HUVEC) injury and explore its underlying mechanism. The result of the cell viability assay indicates that PF promotes the cell survival rate in LPS-stimulated HUVECs. In addition, the LPS-induced over-production of inflammatory cytokines (interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1)) and ER stress markers (78 kDa glucose regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)) are significantly decreased by PF and the ER stress inhibitor 4-phenylbutric acid (4-PBA). The transmission electron microscopy (TEM) assay implies that the ultrastructural abnormalities in ER are reversed by PF treatment, which is similar to the protective effect of 4-PBA. Impressively, we find that the inositol-requiring enzyme 1α (IRE1α)/nuclear factor-kappa B (NF-κB) pathway is significantly activated and contributes to the progress of LPS-induced HUVEC injury by promoting inflammatory cytokine production. IRE1α siRNA, AEBSF (ATF6 inhibitor), GSK2656157 (PERK inhibitor), PDTC (NF-κB inhibitor) and thapsigargin (TG, IRE1 activator) are used to confirm the role of the IRE1α/NF-κB pathway in PF-mediated protection against LPS-induced HUVEC injury. Our findings indicate that PF has an inhibitory effect on endothelial injury. To summarize, PF might be a potential therapeutic agent to inhibit ER stress-associated vascular inflammation.


Primary Medical Care Provider Accreditation (PMCPA): pilot evaluation.
While practice-level or team accreditation is not new to primary care in the UK and there are organisational indicators in the Quality and Outcomes Framework (QOF) organisational domain, there is no universal system of accreditation of the quality of organisational aspects of care in the UK. To describe the development, content and piloting of version 1 of the Primary Medical Care Provider Accreditation (PMCPA) scheme, which includes 112 separate criteria across six domains: health inequalities and health promotion; provider management; premises, records, equipment, and medicines management; provider teams; learning organisation; and patient experience/involvement, and to present the results from the pilot service evaluation focusing on the achievement of the 30 core criteria and feedback from practice staff. Observational service evaluation using evidence uploaded onto an extranet system in support of 30 core summative pilot PMCPA accreditation criteria. Thirty-six nationally representative practices across England, between June and December 2008. interviews with GPs, practice managers, nurses and other relevant staff from the participating practices were conducted, audiotaped, transcribed, and analysed using a thematic approach. For each practice, the number of core criteria that had received either a 'good' or 'satisfactory' rating from a RCGP-trained assessment team, was counted and expressed as a percentage. Thirty-two practices completed the scheme, with nine practices passing 100% of core criteria (range: 27-100%). There were no statistical differences in achievement between practices of different sizes and in different localities. Practice feedback highlighted seven key issues: (1) overall view of PMCPA; (2) the role of accreditation; (3) different motivations for taking part; (4) practice managers dominated the workload associated with implementing the scheme; (5) facilitators for implementation; (6) patient benefit--relevance of PMCPA to quality improvement; (7) recommendations for improving the scheme. Version 1 of PMCPA has been piloted as a primary care accreditation scheme and shown to be relevant to different types of practice. The scheme is undergoing revision in accordance with the findings from the pilot and ongoing consultation.


Leukocytapheresis in pediatric patients with ulcerative colitis.
Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.


A prospective study of atrial fibrillation and stroke.
In a prospective study of 72 patients with stroke and atrial fibrillation, we classified strokes as cardioembolic or noncardioembolic based on arterial assessment using Doppler sonography and angiography. We analyzed and cross-tabulated 18 clinical characteristics and found four to be significantly associated with a cardioembolic mechanism: stroke with onset during activity and peak deficit at onset (p less than 0.008), previous infarct in a different vascular territory (p less than 0.01), previous transient ischemic attack in a different vascular territory (p less than 0.01), and transient ischemic attack lasting greater than 1 hour (p less than 0.02). Starting with these four characteristics, we used a step-down procedure to select variables for a logistic regression model. Only previous infarct in a different vascular territory (odds ratio = 7.38) and transient ischemic attack lasting greater than 1 hour (odds ratio = 7.89) were selected by the model. Using M-mode and two-dimensional echocardiography, we compared left atrial size in 46 patients with that in 78 controls who had atrial fibrillation without stroke. Left atrial size in patients and controls with mitral valvulopathy was significantly larger than that in patients and controls without mitral valve disease. There was, however, no difference in left atrial size between patients with nonvalvular atrial fibrillation and cardioembolic stroke and controls or patients with nonvalvular atrial fibrillation and noncardioembolic stroke. We concluded that some clinical characteristics are closely related to cardioembolic stroke and that left atrial enlargement reflects underlying cardiopathy rather than atrial emboli-forming capability.


Usability and decision support systems in emergency management.
The actors in charge of an emergency response are confronted with severe difficulties in coordination and decision making, especially in major accidents. To facilitate coordination, various decision support systems (DSS) integrated in communication systems have been developed. However, many DSS in the rescue service organizations are afflicted with under-use and other usability problems. Drawing on both a literature review and an analysis of recently obtained survey data from rescue personnel concerning usability of common communication system in Swedish emergency organizations, this paper addresses the issue of usability of DSS. It is concluded that the impetus for developing DSS in many cases has been the technological possibilities per se, not taking the decision makers task structure and contextual factors into account. It is argued that priority should be given to functions that provide a visual overview of the event and facilitate storing of the series of decisions made during the response.


NTP Toxicology and Carcinogenesis Studies of Isophorone (CAS No. 78-59-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Toxicology and carcinogenesis studies of isophorone (greater than 94% pure), a widely used solvent and chemical intermediate, were conducted by administering 0, 250, or 500 mg isophorone/kg body weight per day by gavage in corn oil to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Doses selected for the 2-year studies were based on the 16-day studies in which rats and mice of each sex received doses of 0-2,000 mg/kg per day and on 13-week studies in which rats and mice of each sex received doses ranging from 0 to 1,000 mg/kg per day by gavage in corn oil. No chemically related gross or histopathologic effects were observed in the 16-day or 13-week studies, but 1/5 high dose male rats, 4/5 high dose female rats, and all high dose male and female mice died during the 16-day studies. During the 13-week studies, 1/10 high dose female rats and 3/10 high dose female mice died. The high dose for the 2-year studies was set at 500 mg/kg per day for each sex of rats and mice, based mainly on the deaths in the 13-week studies. Throughout the 2-year study, the mean body weights of the high dose male rats averaged 5% lower than those of the vehicle controls. During the second year, the mean body weights of the female high dose rats averaged 8% lower than those of the vehicle controls, and the high dose female mice averaged 5% lower. The survival of high dose male rats was significantly lower than that of the vehicle controls after week 96 (final survival: vehicle control, 33/50; low dose, 33/50; high dose, 14/50). The survival of dosed female rats was poor (30/50; 23/50; 20/50), due in part to 20 gavage-related accidental deaths of dosed animals. The survival of male mice was also low (16/50; 16/50; 19/50), but there was a significant trend toward increased survival of dosed female mice relative to that of the vehicle controls (26/50; 35/50; 34/50). Dosed male rats showed a variety of proliferative lesions of the kidney (tubular cell hyperplasia: 0/50; 1/50; 4/50; tubular cell adenoma: 0/50; 0/50; 2/50; tubular cell adenocarcinoma: 0/50; 3/50; 1/50; epithelial hyperplasia of the renal pelvis: 0/50; 5/50; 5/50). Dosed male rats also exhibited increased mineralization of the medullary collecting ducts (1/50; 31/50; 20/50), and low dose male rats showed a more severe nephropathy than is commonly seen in aging F344/N rats. Carcinomas of the preputial gland were increased in high dose male rats (0/50; 5/50; 5/50). With the exception of a moderate increase in nephropathy (21/50; 39/50; 32/50), female rats did not show chemically related increased incidences of neoplastic or nonneoplastic lesions. In high dose male mice, isophorone exposure was associated with increased incidences of hepatocellular adenomas and carcinomas (18/48; 18/50; 29/50) and of mesenchymal tumors of the integumentary system (fibroma, fibrosarcoma, neurofibrosarcoma, or sarcoma: 6/48; 8/50; 14/50). An increased incidence of lymphomas or leukemias was noted in low dose male mice (8/48; 18/50; 5/50). Coagulative necrosis (3/48; 10/50; 11/50) and hepatocytomegaly (23/48; 39/50; 37/50) were observed more frequently in the livers of dosed male mice than in vehicle controls. No compound-related neoplastic or nonneoplastic lesions associated with isophorone exposure were seen in female mice. Isophorone was not mutagenic in strains TA100, TA1535, TA1537, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9. Isophorone was weakly mutagenic in the mouse L5178Y/TK+/- assay in the absence of S9; it was not tested in the presence of S9. Isophorone induced sister-chromatid exchanges in the absence of S9 in Chinese hamster ovary cells; it did not induce sister-chromatid exchanges in the presence of Aroclor 1254-induced male rat liver S9, and it did not induce chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of S9. An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of isophorcarcinogenesis studies of isophorone. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenicity of isophorone in male F344/N rats as shown by the occurrence of renal tubular cell adenomas and adenocarcinomas in animals given 250 or 500 mg/kg per day; carcinomas of the preputial gland were also observed at increased incidence in male rats given 500 mg/kg. There was no evidence of carcinogenicity in female F344/N rats given 250 or 500 mg/kg per day. For male B6C3F1 mice, there was equivocal evidence of carcinogenicity of isophorone as shown by an increased incidence of hepatocellular adenomas or carcinomas (combined) and of mesenchymal tumors in the integumentary system in animals given 500 mg/kg per day and by an increase in malignant lymphomas in animals given 250 mg/kg per day. There was no evidence of carcinogenicity of isophorone in female B6C3F1 mice given 250 or 500 mg/kg per day. Synonym: 3,5,5-trimethyl-2-cyclohexen-1-one


The role of Vldlr in intraretinal angiogenesis in mice.
PURPOSE. To identify and characterize the r26 mouse line, which displays depigmented patches in the retina, and to determine the causative gene mutation and study the underlying mechanism. METHODS. Fundus examination, fluorescein angiography, histology, and immunostaining were used to determine the retinal phenotypes. Genome-wide linkage analysis, DNA sequencing, and an allelic test were used to identify the causative gene mutation. Wild-type and mutant gene products were examined by Western blot and transient transfection. RESULTS. Homozygous r26/r26 mice displayed depigmented patches in the fundus that overlapped the hyperfluorescent spots in the angiogram. Histology showed overgrown retinal vessels in the subretinal space. Immunostaining verified the presence of endothelial cells in the photoreceptor layer. Chromosome mapping and DNA sequencing revealed a point mutation, c.2239C>T, in the very-low-density lipoprotein receptor (Vldlr) gene. An allelic test in Vldlr knockout (-/-) mice confirmed that r26/(-) mice display a phenotype similar to that of r26/r26 mice. The Vldlr protein was predominantly localized at the plasma membrane of transfected cells, whereas the truncated Vldlr was diffusely expressed in the cell cytosol. The r26 truncated Vldlr was undetectable in mutant retinas by Western blot. CONCLUSIONS. The r26 is a recessive mutant caused by a missense mutation in the Vldlr gene. This results in a truncated Vldlr protein that lacks the C-terminal 127 amino acid residues including the single transmembrane domain and fails to localize at the plasma membrane. Thus, the r26 is a loss-of-function Vldlr mutation. Vldlr on the cell surface probably mediates an antiangiogenic signal to prevent retinal endothelial cells from migrating into the photoreceptor cell layer.


A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators.
Conventional wisdom holds that, owing to the dominance of features such as chromatin level control, the expression of a gene cannot be readily predicted from knowledge of promoter architecture. This is reflected, for example, in a weak or absent correlation between promoter divergence and expression divergence between paralogs. However, an inability to predict may reflect an inability to accurately measure or employment of the wrong parameters. Here we address this issue through integration of two exceptional resources: ENCODE data on transcription factor binding and the FANTOM5 high-resolution expression atlas. Consistent with the notion that in eukaryotes most transcription factors are activating, the number of transcription factors binding a promoter is a strong predictor of expression breadth. In addition, evolutionarily young duplicates have fewer transcription factor binders and narrower expression. Nonetheless, we find several binders and cooperative sets that are disproportionately associated with broad expression, indicating that models more complex than simple correlations should hold more predictive power. Indeed, a machine learning approach improves fit to the data compared with a simple correlation. Machine learning could at best moderately predict tissue of expression of tissue specific genes. We find robust evidence that some expression parameters and paralog expression divergence are strongly predictable with knowledge of transcription factor binding repertoire. While some cooperative complexes can be identified, consistent with the notion that most eukaryotic transcription factors are activating, a simple predictor, the number of binding transcription factors found on a promoter, is a robust predictor of expression breadth.


Patterns of organelle ontogeny through a cell cycle revealed by whole-cell reconstructions using 3D electron microscopy.
The major mammalian bloodstream form of the African sleeping sickness parasite Trypanosoma brucei multiplies rapidly, and it is important to understand how these cells divide. Organelle inheritance involves complex spatiotemporal re-arrangements to ensure correct distribution to daughter cells. Here, serial block face scanning electron microscopy (SBF-SEM) was used to reconstruct whole individual cells at different stages of the cell cycle to give an unprecedented temporal, spatial and quantitative view of organelle division, inheritance and abscission in a eukaryotic cell. Extensive mitochondrial branching occurred only along the ventral surface of the parasite, but the mitochondria returned to a tubular form during cytokinesis. Fission of the mitochondrion occurred within the cytoplasmic bridge during the final stage of cell division, correlating with cell abscission. The nuclei were located underneath each flagellum at mitosis and the mitotic spindle was located along the ventral surface, further demonstrating the asymmetric arrangement of cell cleavage in trypanosomes. Finally, measurements demonstrated that multiple Golgi bodies were accurately positioned along the flagellum attachment zone, suggesting a mechanism for determining the location of Golgi bodies along each flagellum during the cell cycle.


Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.
Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. clinicaltrials.gov Identifier: NCT00603304.


Food affects Zidovudine concentration independent of effects on gastrointestinal absorption.
Food can change drug concentrations by several mechanisms, including some that are independent of absorption effects. This study tests the hypothesis that a meal decreases zidovudine (ZDV) concentration in blood plasma independent of an effect on drug absorption. The study was conducted as a substudy nested in a larger protocol in which ZDV was given to 7 healthy men by continuous infusion for 5 days starting on day 1. The subjects received only a standardized breakfast meal on day 2 and were fasted on day 3 until the 8-hour sampling period each day was finished. Blood samples were collected through an indwelling cannula in the arm contralateral to the ZDV infusion at the same time of day on both days. It was found that food decreased the blood plasma ZDV concentration at 1 hour postprandial by 14% (5.0%-22%; geometric mean change with 95% confidence interval). This decrease recovered by 6 hours postprandial. Similar changes were seen with the ZDV primary metabolite, zidovudine glucuronide. The authors conclude that food decreases blood plasma ZDV concentrations independent of any absorption effects. This effect may be due to the increased hepatic metabolism because feeding increases hepatic blood flow and because ZDV has a high hepatic extraction ratio with low affinity to blood plasma proteins.


Bioremediation and tolerance of humans to heavy metals through microbial processes: a potential role for probiotics?
The food and water we consume are often contaminated with a range of chemicals and heavy metals, such as lead, cadmium, arsenic, chromium, and mercury, that are associated with numerous diseases. Although heavy-metal exposure and contamination are not a recent phenomenon, the concentration of metals and the exposure to populations remain major issues despite efforts at remediation. The ability to prevent and manage this problem is still a subject of much debate, with many technologies ineffective and others too expensive for practical large-scale use, especially for developing nations where major pollution occurs. This has led researchers to seek alternative solutions for decontaminating environmental sites and humans themselves. A number of environmental microorganisms have long been known for their ability to bind metals, but less well appreciated are human gastrointestinal bacteria. Species such as Lactobacillus, present in the human mouth, gut, and vagina and in fermented foods, have the ability to bind and detoxify some of these substances. This review examines the current understanding of detoxication mechanisms of lactobacilli and how, in the future, humans and animals might benefit from these organisms in remediating environmental contamination of food.


Impact of vision impairment and self-reported barriers to vision care: The views of elders in Nuwara Eliya district, Sri Lanka.
The growing burden of vision impairment (VI) among older people is a development challenge in Asian countries. This study aimed to understand older people's views and experiences about the impact of VI and barriers to eye care to inform policies to address this challenge. We conducted 12 focus group discussions in 2013 with retired Tamil and Sinhala elders in Nuwara Eliya district, Sri Lanka (n = 107). Data were analysed thematically. Older people described the broad impacts VI has on their lives. They worry about becoming dependent. VI restricts their ability to contribute to their families and communities, access information, socialise, maintain their health, and earn. Barriers to eye care services include transport difficulties, costs of treatment, fear, lack of knowledge, waiting times, and health staff attitudes. Older people experience and fear the impacts of VI on their health and well-being. Eye health promotion and care services need strengthening and integration with the primary health care system to address the backlog and growing need among older people in an equitable way. Older people should be consulted about how to overcome the economic, social, and cultural barriers to access to eye care and to minimise the impact of VI. FGDs: focus group discussions; GBD: global burden of disease; NCDs: non-communicable diseases; VI: vision impairment.


Heterogeneous and anisotropic integrative model of pulmonary veins: computational study of arrhythmogenic substrate for atrial fibrillation.
Mechanisms underlying the genesis of re-entrant substrate for the most common cardiac arrhythmia, atrial fibrillation (AF), are not well understood. In this study, we develop a multi-scale three-dimensional computational model that integrates cellular electrophysiology of the left atrium (LA) and pulmonary veins (PVs) with the respective tissue geometry and fibre orientation. The latter is reconstructed in unique detail from high-resolution (approx. 70 μm) contrast micro-computed tomography data. The model is used to explore the mechanisms of re-entry initiation and sustenance in the PV region, regarded as the primary source of high-frequency electrical activity in AF. Simulations of the three-dimensional model demonstrate that an initial break-down of normal electrical excitation wave-fronts can be caused by the electrical heterogeneity between the PVs and LA. High tissue anisotropy is then responsible for the slow conduction and generation of a re-entrant circuit near the PVs. Evidence of such circuits has been seen clinically in AF patients. Our computational study suggests that primarily the combination of electrical heterogeneity and conduction anisotropy between the PVs and LA tissues leads to the generation of a high-frequency (approx. 10 Hz) re-entrant source near the PV sleeves, thus providing new insights into the arrhythmogenic mechanisms of excitation waves underlying AF.


Validation of a rheumatoid arthritis health-related quality of life instrument, the CSHQ-RA.
To test the validity and reliability of a newly developed disease-specific multidimensional quality of life instrument: the Cedars-Sinai Health-Related Quality of Life Instrument (CSHQ-RA). A total of 350 rheumatoid arthritis (RA) patients were asked to complete the CSHQ-RA at 2 time points (4 weeks apart). Patients also completed the Medical Outcomes Study Short Form 36 (SF-36) and the Stanford Health Assessment Questionnaire (HAQ) Disability Index (DI) at the second time point. Construct validity was tested, using Pearson's correlations, by comparing subscale scores on the CSHQ-RA to those obtained from the mental component summary (MCS) and physical component summary (PCS) of the SF-36. HAQ DI scores were used to assess the discriminant validity of the CSHQ-RA. Intraclass correlation coefficients (ICCs) were used to assess test-retest reliability. Response rates for the first and second survey were 83% (291) and 93% (276), respectively; 84% of respondents were women, and mean age was 57 years. Mean scores +/- SDs on instruments were: HAQ 0.73 +/- 0.69; MCS 49 +/- 12; and PCS 33 +/- 11. Pearson's correlations between the CSHQ-RA subscale scores and the SF-36 scores ranged from 0.55 to 0.76 (P < 0.001). Analysis of variance indicate that scores on the CSHQ-RA discriminated between levels of physical disability as measured by the HAQ (P < 0.001). Test-retest reliability was demonstrated in the instrument's subscale scores (ICC 0.70-0.90). These results support the construct validity, discriminant validity, and reliability of the CSHQ-RA as a measure that captures the impact of RA on patients' health-related quality of life.


Influence of age on the sympathetic neural adjustments to alterations in systemic oxygen levels in humans.
We tested the hypothesis that aging influences the regulation of sympathetic nervous system activity (SNA) and arterial blood pressure during alterations in systemic O2 levels in humans. To accomplish this, we performed direct (intraneural) measurements of SNA to skeletal muscle (MSNA) in 10 young and 7 older healthy normotensive men during room air breathing (normoxic-control), moderate isocapnic hypoxemia [15 min of 10% fractional inspired O2 (FIO2)], and hyperoxemia (10 min of 50% FIO2). After hypoxemia, arterial O2 saturation (SaO2) declined similarly in the young and older men. MSNA (burst frequency and total minute activity) increased significantly (P < 0.05) in both groups. The magnitudes of the absolute increases in MSNA and the delta MSNA/delta SaO2 were not significantly different in the young and older men; however, because of higher normoxic baseline levels, the percentage increases in burst frequency were smaller (P = 0.02) and those for total minute activity tended to be smaller (P = 0.11) in the older men. Arterial blood pressure increased modestly (P < 0.05) and similarly in both groups, although the older men demonstrated a smaller increase in heart rate. After hyperoxemia [corrected], SaO2 increased and MSNA decreased (both P < 0.05) similarly in the young and older men. Arterial blood pressure did not change significantly from normoxic control levels in either group; however, a small (P < 0.05) reduction in heart rate was observed in both groups. In conclusion, aging does not obviously influence the regulation of absolute levels of MSNA or arterial blood pressure during alterations in systemic O2 levels in healthy men, although older men demonstrate a smaller percentage increase in MSNA from their elevated baseline levels, as well as an attenuated tachycardia in response to acute hypoxemia. As such, the present results are consistent with our previous findings on aging and sympathocirculatory control during other types of acute stress in humans.


The role of HIF-1 in up-regulating MICA expression on human renal proximal tubular epithelial cells during hypoxia/reoxygenation.
Human major histocompatibility complex class I-related chain A (MICA) plays a dual role in adaptive and innate immune responses. Increasing evidence demonstrates that MICA is closely correlated with acute and chronic kidney allograft rejection. Therefore, understanding the activation mechanisms of MICA is important in kidney transplantation. We previously demonstrated that ischemia/reperfusion injury (IRI) could up-regulate MICA expression on mouse kidney allografts. Since hypoxia-inducible factor-1 (HIF-1) is the master regulator of cellular adaptive responses to hypoxia during IRI, here we investigate whether HIF-1 could up-regulate MICA expression and its influence on NK cell cytotoxicity. We find that HIF-1alpha plays an important role in up-regulating MICA expression, inducing IFNgamma secretion and NK cell cytotoxicity during hypoxia/reoxygenation. First, we generated a HIF-1alphaDELTAODD-expressing adenovirus to stably and functionally express HIF-1alpha in human renal proximal tubular epithelial (HK-2) cells under normoxia conditions. HIF-1alpha over-expression in HK-2 cells induces MICA expression and enhances NK cell cytotoxic activity towards cells that express HIF-1alpha. Second, we used a hypoxia/reoxygenation cell model to simulate IRI in vitro and found that the suppression of HIF-1alpha by RNAi induces down-regulation of MICA expression and inhibits NK cytotoxicity. In antibody blocking experiments, an anti-MICA mAb was able to down-regulate NK cell cytotoxic activity towards HK-2 cells that over-expressed HIF-1alpha. Moreover, when NK cells were co-cultured with the HK-2 cells expressing MICA, which was up-regulated by over-expression of HIF-1alpha, there was a significant increase in the secretion of IFNgamma. In the presence of the blocking MICA mAb, IFNgamma secretion was significantly decreased. These results demonstrate that hypoxia/reoxygenation-promoted MICA expression on HK-2 cells is through a HIF-1 pathway. The increased IFNgamma secretion and enhanced NK cell cytotoxicity was mainly due to the surface expression of MICA induced by over-expression of HIF-1alpha. This study enhances our understanding of MICA activation mechanisms during kidney transplantation and provides insights into how IRI can influence transplant outcome. Moreover, these findings might be also important for developing strategies to reduce the effect of MICA in kidney transplant outcomes in the future.


A longitudinal study of the long-term consequences of drinking during pregnancy: heavy in utero alcohol exposure disrupts the normal processes of brain development.
Exposure to alcohol in utero can cause birth defects, including face and brain abnormalities, and is the most common preventable cause of intellectual disabilities. Here we use structural magnetic resonance imaging to measure cortical volume change longitudinally in a cohort of human children and youth with prenatal alcohol exposure (PAE) and a group of unexposed control subjects, demonstrating that the normal processes of brain maturation are disrupted in individuals whose mothers drank heavily during pregnancy. Trajectories of cortical volume change within children and youth with PAE differed from those of unexposed control subjects in posterior brain regions, particularly in the parietal cortex. In these areas, control children appear to show a particularly plastic cortex with a prolonged pattern of cortical volume increases followed by equally vigorous volume loss during adolescence, while the alcohol-exposed participants showed primarily volume loss, demonstrating decreased plasticity. Furthermore, smaller volume changes between scans were associated with lower intelligence and worse facial morphology in both groups, and were related to the amount of PAE during each trimester of pregnancy in the exposed group. This demonstrates that measures of IQ and facial dysmorphology predict, to some degree, the structural brain development that occurs in subsequent years. These results are encouraging in that interventions aimed at altering "experience" over time may improve brain trajectories in individuals with heavy PAE and possibly other neurodevelopmental disorders.


Strategies to combat antimicrobial resistance: anti-plasmid and plasmid curing.
Antimicrobial resistance (AMR) is a global problem hindering treatment of bacterial infections, rendering many aspects of modern medicine less effective. AMR genes (ARGs) are frequently located on plasmids, which are self-replicating elements of DNA. They are often transmissible between bacteria, and some have spread globally. Novel strategies to combat AMR are needed, and plasmid curing and anti-plasmid approaches could reduce ARG prevalence, and sensitise bacteria to antibiotics. We discuss the use of curing agents as laboratory tools including chemicals (e.g. detergents and intercalating agents), drugs used in medicine including ascorbic acid, psychotropic drugs (e.g. chlorpromazine), antibiotics (e.g. aminocoumarins, quinolones and rifampicin) and plant-derived compounds. Novel strategies are examined; these include conjugation inhibitors (e.g. TraE inhibitors, linoleic, oleic, 2-hexadecynoic and tanzawaic acids), systems designed around plasmid incompatibility, phages and CRISPR/Cas-based approaches. Currently, there is a general lack of in vivo curing options. This review highlights this important shortfall, which if filled could provide a promising mechanism to reduce ARG prevalence in humans and animals. Plasmid curing mechanisms which are not suitable for in vivo use could still prove important for reducing the global burden of AMR, as high levels of ARGs exist in the environment.


KinoHaptics: An Automated, Wearable, Haptic Assisted, Physio-therapeutic System for Post-surgery Rehabilitation and Self-care.
A carefully planned, structured, and supervised physiotherapy program, following a surgery, is crucial for the successful diagnosis of physical injuries. Nearly 50 % of the surgeries fail due to unsupervised, and erroneous physiotherapy. The demand for a physiotherapist for an extended period is expensive to afford, and sometimes inaccessible. Researchers have tried to leverage the advancements in wearable sensors and motion tracking by building affordable, automated, physio-therapeutic systems that direct a physiotherapy session by providing audio-visual feedback on patient's performance. There are many aspects of automated physiotherapy program which are yet to be addressed by the existing systems: a wide classification of patients' physiological conditions to be diagnosed, multiple demographics of the patients (blind, deaf, etc.), and the need to pursue patients to adopt the system for an extended period for self-care. In our research, we have tried to address these aspects by building a health behavior change support system called KinoHaptics, for post-surgery rehabilitation. KinoHaptics is an automated, wearable, haptic assisted, physio-therapeutic system that can be used by a wide variety of demographics and for various physiological conditions of the patients. The system provides rich and accurate vibro-haptic feedback that can be felt by the user, irrespective of the physiological limitations. KinoHaptics is built to ensure that no injuries are induced during the rehabilitation period. The persuasive nature of the system allows for personal goal-setting, progress tracking, and most importantly life-style compatibility. The system was evaluated under laboratory conditions, involving 14 users. Results show that KinoHaptics is highly convenient to use, and the vibro-haptic feedback is intuitive, accurate, and has shown to prevent accidental injuries. Also, results show that KinoHaptics is persuasive in nature as it supports behavior change and habit building. The successful acceptance of KinoHaptics, an automated, wearable, haptic assisted, physio-therapeutic system proves the need and future-scope of automated physio-therapeutic systems for self-care and behavior change. It also proves that such systems incorporated with vibro-haptic feedback encourage strong adherence to the physiotherapy program; can have profound impact on the physiotherapy experience resulting in higher acceptance rate.


Effects of 2-ketoisocaproate on insulin release and single potassium channel activity in dispersed rat pancreatic beta-cells.
1. The effects of the insulin secretagogue 2-ketoisocaproate, and of arginine, on insulin release, intracellular adenosine triphosphate (ATP) concentration and the activity of single K channels in cell-attached membrane patches have been studied in primary cultures of beta-cells from adult rat islets of Langerhans. 2. Insulin secretion was significantly increased by 2-ketoisocaproate (20 mM). The time course of this release was biphasic. Arginine (20 mM) did not stimulate insulin secretion. 3. In the absence of 2-ketoisocaproate (or arginine), two kinds of K channel were regularly observed in cell-attached membrane patches held at the cell resting potential: a channel of approximately 20 pS conductance and a channel of 50 pS conductance ([K]o = 140 mM, room temperature). 4. Addition of 2-ketoisocaproate (20 mM) to the bath suppressed the activity of the 50 pS channel and initiated action potentials. Arginine (20 mM) was without effect. 5. The intracellular concentration of ATP was increased significantly by 2-ketoisocaproate (20 mM) but not by arginine (20 mM). 6. It is suggested that, like glucose, 2-ketoisocaproate depolarizes the beta-cell and mediates insulin secretion by reducing the open probability of the 50 pS K channel. The results are also consistent with the idea that both secretagogues inhibit this channel by increasing the cytoplasmic concentration of ATP.


NirJ, a radical SAM family member of the d1 heme biogenesis cluster.
NirJ is involved in the transformation of precorrin-2 into heme d(1), although its precise role in the process has not been established. The purified protein was found to contain a 4Fe-4S centre, in line with the prediction that it belongs to the radical SAM class of enzymes. This was further confirmed by binding of S-adenosyl-L-methionine (SAM) to dithionite-reduced NirJ, which resulted in a decrease in the signal intensity and in a shift to higher field of the [4Fe-4S](1+) EPR signal. Significantly, though, this approach also led to the appearance of a small but reproducible organic radical signal that was associated with about 2% of the NirJ molecules and was affected by the incorporation of SAM deuterated at the 5' adenosyl group.


Cognitive dysfunction in lower motor neuron disease: executive and memory deficits in progressive muscular atrophy.
In contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of this study was to investigate cognitive function in PMA and to compare the cognitive profile with that of ALS. In addition, visuospatial functions were assessed comprehensively; these tests are underrepresented in earlier neuropsychological investigations in ALS. 23 PMA and 30 ALS patients (vital capacity >70% of predicted value) underwent a neuropsychological assessment adapted to motor impairments: global cognitive and executive functioning, psychomotor speed, memory, language, attention and visuospatial skills. The results were compared with age, education and sex matched controls and with normative data. Compared with controls, PMA patients performed worse on attention/working memory (digit span backward), category fluency and the Mini-Mental State Examination. Compared with normative data, PMA patients most frequently showed impairment on three measures: letter-number sequencing, and immediate and delayed story recall. 17% of PMA patients showed cognitive impairment, defined as performance below 2 SDs from the mean of normative data on at least three neuropsychological tests. In ALS, similar but more extensive cognitive deficits were found. Visuospatial dysfunction was not found in PMA and ALS. 17% of PMA patients have executive and memory impairments. PMA with cognitive impairment adds a formerly unknown phenotype to the existing classification of motor neuron diseases.


Predictors and prevalence of obstructive sleep apnoea and snoring in 1001 middle aged men.
One thousand and one men, aged 35-65 years, were identified from the age-sex register of one group general practice. Over four years 900 men were visited at home and asked questions about symptoms potentially related to sleep apnoea and snoring. Height, weight, neck circumference, resting arterial oxygen saturation (SaO2), and spirometric values were also determined. All night oximetry was then performed at home and the tracing analysed for the number of dips in SaO2 of more than 4%. Subjects with more than five dips of 4% SaO2 or more per hour were invited for sleep laboratory polysomnography. Seventeen per cent of the men admitted to snoring "often." Multiple linear regression techniques identified and ranked neck circumference (r2 = 7.2%), cigarette consumption (r2 = 3.4%), and nasal stuffiness (r2 = 2%) as the only significant independent predictors of snoring. Together these account for at least a sixfold variation in the likelihood of being an "often" snorer. Forty six subjects (5%) had greater than 4% SaO2 dip rates of over five an hour and 31 of these had full sleep studies. Three subjects had clinically obvious and severe symptomatic obstructive sleep apnoea, giving a prevalence of three per 1001 men (0.3%; 95% confidence interval 0.07-0.9%). Eighteen men had obstructive sleep apnoea only when supine and in 10 the cause of the SaO2 dipping on the original home tracing was not elucidated. The greater than 4% SaO2 dip rates correlated with the history of snoring. Multiple linear regression techniques identified and ranked neck circumference (r2 = 7.9%), alcohol consumption (r2 = 3.7%), age (r2 = 1%) and obesity (r2 = 1%) as the only significant independent predictors of the rate of overnight hypoxic dipping. This study shows that snoring in this randomly selected population correlates best with neck size, smoking, and nasal stuffiness. Obstructive sleep apnoea, defined by nocturnal hypoxaemia, correlates best with neck size and alcohol, and less so with age and general obesity.


A new stem-neopterygian fish from the Middle Triassic of China shows the earliest over-water gliding strategy of the vertebrates.
Flying fishes are extraordinary aquatic vertebrates capable of gliding great distances over water by exploiting their enlarged pectoral fins and asymmetrical caudal fin. Some 50 species of extant flying fishes are classified in the Exocoetidae (Neopterygii: Teleostei), which have a fossil record no older than the Eocene. The Thoracopteridae is the only pre-Cenozoic group of non-teleosts that shows an array of features associated with the capability of over-water gliding. Until recently, however, the fossil record of the Thoracopteridae has been limited to the Upper Triassic of Austria and Italy. Here, we report the discovery of exceptionally well-preserved fossils of a new thoracopterid flying fish from the Middle Triassic of China, which represents the earliest evidence of an over-water gliding strategy in vertebrates. The results of a phylogenetic analysis resolve the Thoracopteridae as a stem-group of the Neopterygii that is more crown-ward than the Peltopleuriformes, yet more basal than the Luganoiiformes. As the first record of the Thoracopteride in Asia, this new discovery extends the geographical distribution of this group from the western to eastern rim of the Palaeotethys Ocean, providing new evidence to support the Triassic biological exchanges between Europe and southern China. Additionally, the Middle Triassic date of the new thoracopterid supports the hypothesis that the re-establishment of marine ecosystems after end-Permian mass extinction is more rapid than previously thought.


Investigation of induced recirculation during planned ventilation system maintenance.
The Office of Mine Safety and Health Research (OMSHR) investigated ways to increase mine airflow to underground metal/nonmetal (M/NM) mine working areas to improve miners' health and safety. One of those areas is controlled recirculation. Because the quantity of mine air often cannot be increased, reusing part of the ventilating air can be an effective alternative, if implemented properly, until the capacity of the present system is improved. The additional airflow can be used to provide effective dilution of contaminants and higher flow velocities in the underground mine environment. Most applications of controlled recirculation involve taking a portion of the return air and passing it back into the intake to increase the air volume delivered to the desired work areas. OMSHR investigated a Nevada gold mine where shaft rehabilitation was in progress and one of the two main fans was shut down to allow reduced air velocity for safe shaft work. Underground booster fan operating pressures were kept constant to maintain airflow to work areas, inducing controlled recirculation in one work zone. Investigation into system behavior and the effects of recirculation on the working area during times of reduced primary ventilation system airflow would provide additional information on implementation of controlled recirculation into the system and how these events affect M/NM ventilation systems. The National Institute for Occupational Safety and Health monitored the ventilation district when both main fans were operating and another scenario with one of the units turned off for maintenance. Airflow and contaminants were measured to determine the exposure effects of induced recirculation on miner health. Surveys showed that 19% controlled recirculation created no change in the overall district airflow distribution and a small reduction in district fresh air intake. Total dust levels increased only modestly and respirable dust levels were also low. Diesel particulate matter (DPM) levels showed a high increase in district intake mass flow, but minor increases in exposure levels related to the recirculation percentage. Utilization of DPM mass flow rates allows input into ventilation modeling programs to better understand and plan for ventilation changes and district recirculation effects on miners' health.


The assesment of follicular fluid presepsin levels in poor ovarian responder womenandits relationship with the reproductive outcomes.
A considerable proportion of all women undergoing IVFrespond poorly to gonadotropin stimulation. These women are reported to be associated with increased cancellation rates and lower pregnancy rates. It has been hypothesized that poor response to ovarian stimulation is a first sign of ovarian ageing or premature ovarian failure, which might be related to altered inflammatory response in the body. We aimed to compare follicular fluid presepsin levels between poor- and normo-responder patients to ovarian stimulation, to assess its relationship with reproductive outcomes. This study included infertility patients who underwent ovulation induction with either long GnRH agonist or GnRH antagonist protocols and who subsequently underwent IVF/ICSI. Included patients were assigned to two groups according to the Bologna criteria for poor ovarian response. Group 1 and 2 consisted of normo- and poor-responder patients, respectively.The 2 groups were compared in terms of FF presepsin levels. Also, any relationship between the FF presepsin levels and fertility outcomes was assessed within the groups. The groups were compared by using student's t-test, Mann-Whitney U test and X(2) test, where appropriate. Pregnancy rates were not significantly different between the groups (22.6% and 17.6%; P=0.650, respectively). FF presepsin levels were higher in Group 1, however, the difference was not statistically significant (298.0±797.4 and 149.2±422.3; P=0.190, respectively). FF presepsin levels did not significantly differ between pregnancy positive and the pregnancy negative patients in both Group 1 (243.6±531.1 and 314.3±866.5; P=0.055, respectively) and Group 2 (112.2±79.8 and 157.1±464.3; P=0.394, respectively). Consequently, FF presepsin seems not to be a reliable marker in predicting pregnancy in both normo-responder and poor-responder infertility groups.


Public autonomous hospitals in sub-Saharan Africa: trends and issues.
Since the late 1980s, many countries in Africa have been granting increased autonomy to their main teaching hospitals. This policy has significant international support but has been evaluated little from either theoretical or empirical perspectives. This paper attempts to fill this gap by assembling evidence from policy documents, theoretical debates and empirical evidence of related policy changes in other contexts such as the development of trust hospitals in the UK NHS. The paper attempts to locate the policy in the broader context of the package of health sector reform measures proposed at international level, and to identify the role it is intended to play in the achievement of the implicit objectives of that package. The objectives identified are improvements in allocative efficiency and equity, improvements in internal efficiency and improvements in responsiveness, accountability and choice. Each of these objectives presents difficulties which suggest that only modest short-term expectations of the policy can be justified. Given the lack of evidence from existing experience, a research agenda is suggested, which aims to provide information to guide further implementation of the policy.


Cost-effective side-illumination darkfield nanoplasmonic marker microscopy.
We present the development of an innovative technology for quantitative multiplexed cytology analysis based on the application of spectrally distinctive plasmonic nanoparticles (NPs) as optical probes and on cost-effective side-illumination multispectral darkfield microscopy (SIM) as the differential NP imaging method. SIM is based on lateral illumination by arrays of discrete color RGB light emitting diodes (LEDs) of spectrally adjusted plasmonic NPs and consecutive detection by the conventional CMOS color camera. We demonstrate the enhanced contrast and higher resolution of our method for individual NP detection in the liquid medium and of NP markers attached on the cell membrane in a cytology preparation by comparing it to the conventional darkfield microscopy (DFM). The proposed illumination and detection system is compatible with current clinical microscopy equipment used by pathologists and can greatly simplify the adaptation of plasmonic NPs as novel reliable and stable biological multiplexed chromatic markers for biodetection and diagnosis.


A widespread glutamine-sensing mechanism in the plant kingdom.
Glutamine is the primary metabolite of nitrogen assimilation from inorganic nitrogen sources in microorganisms and plants. The ability to monitor cellular nitrogen status is pivotal for maintaining metabolic homeostasis and sustaining growth. The present study identifies a glutamine-sensing mechanism common in the entire plant kingdom except Brassicaceae. The plastid-localized PII signaling protein controls, in a glutamine-dependent manner, the key enzyme of the ornithine synthesis pathway, N-acetyl-l-glutamate kinase (NAGK), that leads to arginine and polyamine formation. Crystal structures reveal that the plant-specific C-terminal extension of PII, which we term the Q loop, forms a low-affinity glutamine-binding site. Glutamine binding alters PII conformation, promoting interaction and activation of NAGK. The binding motif is highly conserved in plants except Brassicaceae. A functional Q loop restores glutamine sensing in a recombinant Arabidopsis thaliana PII protein, demonstrating the modular concept of the glutamine-sensing mechanism adopted by PII proteins during the evolution of plant chloroplasts.


Physical limits to spatial resolution of optical recording: clarifying the spatial structure of cortical hypercolumns.
Neurons in macaque primary visual cortex are spatially arranged by their global topographic position and in at least three overlapping local modular systems: ocular dominance columns, orientation pinwheels, and cytochrome oxidase (CO) blobs. Individual neurons in the blobs are not tuned to orientation, and populations of neurons in the pinwheel center regions show weak orientation tuning, suggesting a close relation between pinwheel centers and CO blobs. However, this hypothesis has been challenged by a series of optical recording experiments. In this report, we show that the statistical error associated with photon scatter and absorption in brain tissue combined with the blurring introduced by the optics of the imaging system has typically been in the range of 250 microm. These physical limitations cause a systematic error in the location of pinwheel centers because of the vectorial nature of these patterns, such that the apparent location of a pinwheel center measured by optical recording is never (on average) in the correct in vivo location. The systematic positional offset is approximately 116 microm, which is large enough to account for the claimed misalignment of CO blobs and pinwheel centers. Thus, optical recording, as it has been used to date, has insufficient spatial resolution to accurately locate pinwheel centers. The earlier hypothesis that CO blobs and pinwheel centers are coterminous remains the only hypothesis currently supported by reliable observation.


The STING in the tail for cytosolic DNA-dependent activation of IRF3.
Cytosolic pattern recognition receptors (PRRs) sense intracellular nucleic acids from pathogens such as bacteria and viruses, which leads to the induction of type I interferon (IFN) responses that are essential for an effective immune response. Further, these PRR pathways can be aberrantly activated by self DNA, which leads to autoimmunity. Therefore, understanding the signaling mechanisms that underlie PRR-induced production of IFN is vital to health and disease. A key transcription factor that is involved in these pathways is IFN regulatory factor 3 (IRF3), which is often activated by the kinase TANK-binding kinase 1 (TBK1). STING (stimulator of interferon genes) is a master regulator for the cyto-solic nucleic acid-mediated activation of IRF3 through TBK1 stimulation, but how the STING-TBK1-IRF3 signaling axis operates has been unclear. A study now shows that in response to cytosolic double-stranded DNA, the C-terminal tail of STING provides a scaffold to assemble IRF3 and TBK1, which leads to TBK1-dependent phosphorylation of IRF3. Thus, STING directs TBK1 to activate IRF3 in DNA-sensing pathways.


Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation.
To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5-HT(1A) receptor activation in animal models. We investigated the effect of CBDA on (i) lithium chloride (LiCl)-induced conditioned gaping to a flavour (nausea-induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion-, LiCl- or cisplatin-induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5-HT(1A) receptor activation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and mouse whole brain CB(1) receptor activation by CP55940, using [³⁵S]GTPγS-binding assays. In shrews, CBDA (0.1 and/or 0.5 mg·kg⁻¹ i.p.) reduced toxin- and motion-induced vomiting, and increased the onset latency of the first motion-induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg⁻¹ i.p.) suppressed LiCl- and context-induced conditioned gaping, effects that were blocked by the 5-HT(1A) receptor antagonist, WAY100635 (0.1 mg·kg⁻¹ i.p.), and, at 0.01 mg·kg⁻¹ i.p., enhanced saccharin palatability. CBDA-induced suppression of LiCl-induced conditioned gaping was unaffected by the CB₁ receptor antagonist, SR141716A (1 mg·kg⁻¹ i.p.). In vitro, CBDA (0.1-100 nM) increased the E(max) of 8-OH-DPAT. Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5-HT(1A) receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.


Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin.
The rate of stroke in atrial fibrillation (AF) depends on the presence of comorbid conditions and the use of antithrombotic therapy. Although adjusted-dose warfarin is superior to aspirin for reducing stroke in AF, the absolute risk reduction of warfarin depends on the stroke rate with aspirin. This prospective cohort study tested the predictive accuracy of 5 stroke risk stratification schemes. The study pooled individual data from 2580 participants with nonvalvular AF who were prescribed aspirin in a multicenter trial (Atrial Fibrillation, Aspirin, Anticoagulation I study [AFASAK-1], AFASAK-2, European Atrial Fibrillation Trial, Primary Prevention of Arterial Thromboembolism in patients with nonrheumatic Atrial Fibrillation in primary care study, and Stroke Prevention and Atrial Fibrillation [SPAF]-III high risk or SPAF-III low risk). There were 207 ischemic strokes during 4887 patient-years of aspirin therapy. All schemes predicted stroke better than chance, but the number of patients categorized as low and high risk varied substantially. AF patients with prior cerebral ischemia were classified as high risk by all 5 schemes and had 10.8 strokes per 100 patient-years. The CHADS(2) scheme (an acronym for Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack) successfully identified primary prevention patients who were at high risk of stroke (5.3 strokes per 100 patient-years). In contrast, patients identified as high risk by other schemes had 3.0 to 4.2 strokes per 100 patient-years. Low-risk patients identified by all schemes had 0.5 to 1.4 strokes per 100 patient-years of therapy. Patients with AF who have high and low rates of stroke when given aspirin can be reliably identified, allowing selection of antithrombotic prophylaxis to be individualized.


Pyoderma gangrenosum occurring in a lower limb fasciocutaneous flap--a lesson to learn.
Pyoderma gangrenosum is a destructive cutaneous disease characterised by progressive painful ulceration. The occurrence of pyoderma gangrenosum at a surgical site is rare (especially if there is no predisposing illness), but is well recognised. We present a case of a 63-year-old man who developed erythematous ulcerative lesions due to pyoderma gangrenosum in and around a lower limb fasciocutaneous flap used to cover an exposed total knee prosthesis. The lesions were initially confused with postoperative wound infection. No predisposing disorder, other than the rarely reported association with osteoarthritis, was found. The diagnosis is important because its rapid detection not only avoids unnecessary treatment but also allows for prompt intervention with oral steroids. This case is presented to alert surgeons to the presence of pyoderma gangrenosum and its diagnostic confusion with postoperative wound infection.


Gene translocations in musculoskeletal neoplasms.
Establishing the best diagnosis for musculoskeletal neoplasms requires a multidisciplinary approach using clinical, radiographic, and histologic analyses. Despite this rigorous approach, establishing accurate diagnoses and prognoses remains challenging. Improved diagnostic methods are expected as unique molecular signals for specific bone and soft tissue cancers are identified. We performed a systematic review of the best available evidence to explore three major applications of molecular genetics that will best benefit clinical management of musculoskeletal neoplasms: diagnostic, prognostic, and therapeutic applications. The specific questions addressed in this systematic review are: (1) What sets of histopathologic sarcoma subtypes will benefit from molecular evaluation and diagnosis? (2) What molecular methods are best applied to histopathologic sarcomas to distinguish between major subtypes? (3) How do the molecular patterns discovered on genetic diagnosis affect prognosis of certain sarcomas? (4) Which sarcoma translocations can benefit from an improved response and outcome using existing and forthcoming pharmacogenetic approaches targeting molecular events? This review summarizes recent advances in molecular genetics that are available and will soon be available to clinicians to better predict outcomes and subsequently help make future treatment decisions. Level IV, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.


Agreement Between Self-Reported and Device-Based Sedentary Time among Eight Countries: Findings from the ELANS.
The purpose of this study was to analyze the agreement between self-reported and device-based sedentary time among eight countries in Latin America. As part of the Latin American Study of Nutrition and Health (ELANS), data were collected from 2524 participants (18-65 years) across eight countries. Participants reported time spent sedentary in different activities (computer use at home, videogame use, reading, sitting down to chat with friends/relatives or listening to music, speaking on the phone, watching TV, and riding in a car). Overall sitting time was assessed using a single item from the International Physical Activity Questionnaire (IPAQ). Device-based sedentary time was assessed using Actigraph GT3X accelerometers. Self-reported overall sitting time (227.1 min/day) produced the lowest values of the three assessment methods, followed by self-reported sum of different types of sedentary behavior (364.1 min/day) and device-based sedentary time (568.6 min/day). Overall, correlation coefficients and ICC varied from weak to moderate (rho: 0.25-0.39; ICC: 0.21:0.39) between self-reported sum of different types of sedentary behavior, self-reported overall sitting time, and device-based sedentary time. The Bland-Altman plots indicated low to moderate agreement between self-reported overall sitting time and device-based sedentary time by sex. Self-report measures underestimate sedentary behavior and overall sitting time when compared with device-based measures. The weak and moderate level of agreement between methods indicates that caution is required when comparing associations between different self-report and device-based measures of sedentary behavior with health outcomes.


Renal sodium retention in cirrhosis: relation to aldosterone and nephron site.
1. In a group of patients with cirrhosis who showed a wide range of values for the rate of renal sodium excretion, the latter was found to be inversely related to both the plasma concentration and rate of renal excretion of aldosterone. However, for a given sodium excretion the values for aldosterone were significantly lower in the patients than for a group of healthy control subjects. These findings suggest either an increased renal tubular sensitivity to aldosterone or the participation of other factors in the pathogenesis of the sodium retention. 2. Based on measurements of the rate of urine flow and the clearances of free water and inulin during a maximal water diuresis, the fractional reabsorption of sodium by the 'proximal', 'diluting segment' and 'distal' segments of the nephron was estimated. For patients retaining sodium the enhanced reabsorption occurred at both proximal and distal sites, the latter being quantitatively more important. There was no significantly enhanced sodium reabsorption in the diluting segment.


Baroreflex setting and sensitivity after acute and chronic nicardipine therapy.
Intra-arterial pressure, baroreflex sensitivity and the baroreflex set point were measured in eight patients with essential hypertension during a control period and then after acute treatment (2 h after a 30 mg oral dose) and after chronic treatment (at least 2 months) with nicardipine hydrochloride, a calcium channel antagonist. Mean intra-arterial blood pressure fell after the acute treatment from 130 +/- 14 (SD) control to 118 +/- 11 mmHg, P less than 0.05, and after chronic treatment to 112 +/- 19 mmHg, P less than 0.05. Heart rate increased from 72 +/- 11 control to 81 +/- 16 beats/min, P less than 0.05, during acute treatment indicating activation of the baroreflex control mechanism, but returned to control values with chronic treatment (72 +/- 11 control vs 69 +/- 9 beats/min chronic), indicating a significant shift to the left of the baroreflex set point. There was no change in baroreflex sensitivity after either acute or chronic treatment (control 4.7, acute 4.3, chronic 5.1 ms/mmHg, P not significant for all values). Nicardipine significantly reduces mean intra-arterial pressure both acutely and chronically; the latter is associated with a return of the heart rate to control values due to resetting of the baroreflex control mechanism.


Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines).
This article reviews clinical pharmacokinetic data on the H1-receptor antagonists, commonly referred to as the antihistamines. Despite their widespread use over an extended period, relatively little pharmacokinetic data are available for many of these drugs. A number of H1-receptor antagonists have been assayed mainly using radioimmunoassay methods. These have also generally measured metabolites to greater or lesser extents. Thus, the interpretation of such data is complex. After oral administration of H1-receptor antagonists as syrup or tablet formulations, peak plasma concentrations are usually observed after 2 to 3 hours. Bioavailability has not been extensively studied, but is about 0.34 for chlorpheniramine, 0.40 to 0.60 for diphenhydramine, and about 0.25 for promethazine. Most of these drugs are metabolised in the liver, this being very extensive in some instances (e.g. cyproheptadine and terfenadine). Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg (for astemizole, brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine and triprolidine), while their elimination half-lives range from about 3 hours to about 18 days [cinnarizine about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole and its active metabolites about 7 to 20 days (after long term administration); flunarizine about 18 to 20 days]. They also have relatively large apparent volumes of distribution in excess of 4 L/kg. In children, the elimination half-lives of chlorpheniramine and hydroxyzine are shorter than in adults. In patients with alcohol-related liver disease, the elimination half-life of diphenhydramine was increased from 9 to 15 hours, while in patients with chronic renal disease that of chlorpheniramine was very greatly prolonged. Little, if any, published information is available on the pharmacokinetics of these drugs in neonates, pregnancy or during lactation. The relatively long half-lives of a number of the older H1-receptor antagonists such as brompheniramine, chlorpheniramine and hydroxyzine suggest that they can be administered to adults once daily.


Striatal alcohol cue-reactivity is stronger in male than female problem drinkers.
Despite apparent sex differences in the development and treatment of alcohol use disorder, relatively little is known about the underlying neural mechanisms. In this study, we therefore investigated neural cue-reactivity in a sample of male (n = 28) and female (n = 27) problem drinkers (matched on age and alcohol use severity) with an average alcohol use disorder identification test score of 12 which is indicative of a likely alcohol use disorder. Neural cue-reactivity data were extracted from four regions of interest: the ventral and dorsal striatum and the ventral and dorsal anterior cingulate cortex, with a significance level set at p < 0.05. While the cue-reactivity paradigm induced similar levels of self-reported craving in men and women, visual alcohol cues induced significantly stronger striatal activation in men compared to drinkers. While sex differences in ventral striatal cue-reactivity were partly explained by sex differences in alcohol intake, cannabis use, negative affect and anxiety, this was not the case for sex differences in dorsal striatal cue-reactivity. These results suggest that alcohol cues are differentially processed by men and women and that the neurobiological mechanisms behind cue-reactivity differ between the sexes. Consequently, paradigms using alcohol-related pictures may not be optimal to induce cue-reactivity in female drinkers and may not be optimal to measure neurobiological markers of alcohol use severity and relapse. Future alcohol cue-reactivity studies should, in addition to including both men and women, include different types of cues (e.g., stressors and imagery in addition to pictures) to assess sex differences in alcohol cue-reactivity.


Social models of HIV risk among young adults in Lesotho.
Extensive research over the past 30 years has revealed that individual and social determinants impact HIV risk. Even so, prevention efforts focus primarily on individual behaviour change, with little recognition of the dynamic interplay of individual and social environment factors that further exacerbate risk engagement. Drawing on long-term research with young adults in Lesotho, I examine how social environment factors contribute to HIV risk. During preliminary ethnographic analysis, I developed novel scales to measure social control, adoption of modernity, and HIV knowledge. In survey research, I examined the effects of individual characteristics (i.e., socioeconomic status, HIV knowledge, adoption of modernity) and social environment (i.e., social control) on HIV risk behaviours. In addition, I measured the impact of altered environments by taking advantage of an existing situation whereby young adults attending a national college are assigned to either a main campus in a metropolitan setting or a satellite campus in a remote setting, irrespective of the environment in which they were socialised as youth. This arbitrary assignment process generates four distinct groups of young adults with altered or constant environments. Regression models show that lower levels of perceived social control and greater adoption of modernity are associated with HIV risk, controlling for other factors. The impact of social control and modernity varies with environment dynamics.


Integrating distributed data sources with OGSA-DAI DQP and VIEWS.
OGSA-DAI (Open Grid Services Architecture Data Access and Integration) is a framework for building distributed data access and integration systems. Until recently, it lacked the built-in functionality that would allow easy creation of federations of distributed data sources. The latest release of the OGSA-DAI framework introduced the OGSA-DAI DQP (Distributed Query Processing) resource. The new resource encapsulates a distributed query processor, that is able to orchestrate distributed data sources when answering declarative user queries. The query processor has many extensibility points, making it easy to customize. We have also introduced a new OGSA-DAI Views resource that provides a flexible method for defining views over relational data. The interoperability of the two new resources, together with the flexibility of the OGSA-DAI framework, allows the building of highly customized data integration solutions.


Dynamic miRNA changes during the process of epileptogenesis in an infantile and adult-onset model.
Temporal lobe epilepsy (TLE) is the most common epilepsy type. TLE onset in infancy aggravates features like severity, drug responsiveness, or development of comorbidities. These aggravations may arise from altered micro RNA (miRNA) expression specific to the early onset of the disease. Although the miRNA involvement in TLE is widely studied, the relationship between the onset-age and miRNA expression has not been addressed. Here, we investigated the miRNA profile of infantile and adult-onset TLE in rats combining sequencing and PCR. Since miRNA expression changes with the disease progression, we scrutinized miRNA dynamics across three stages: acute, latent, and chronic. We report that infantile-onset TLE leads to changes in the expression of fewer miRNAs across these stages. Interestingly, the miRNA profile in the acute stage of infantile-onset TLE overlaps in dysregulation of miR-132-5p, -205, and -211-3p with the chronic stage of the disease starting in adulthood. The analysis of putative targets linked the majority of dysregulated miRNAs with pathways involved in epilepsy. Our profiling uncovered miRNA expression characteristic for infantile and adulthood-onset epileptogenesis, suggesting the distinct biology underlying TLE in the onset age-dependent matter. Our results indicate the necessity of addressing the onset age as an important parameter in future epilepsy research.


Functional connectivity, behavioral and dopaminergic alterations 24 hours following acute exposure to synthetic bath salt drug methylenedioxypyrovalerone.
Among cathinone drugs known as bath salts, methylenedioxypyrovalerone (MDPV) exerts its potent actions via the dopamine (DA) system, and at intoxicating doses may produce adverse behavioral effects. Previous work by our group suggests that prolonged alterations in correlated neural activity between cortical and striatal areas could underlie, at least in part, the adverse reactions to this bath salt drug. In the present study, we assessed the effect of acute MDPV administration on brain functional connectivity at 1 and 24 h in rats. Using graph theory metrics to assess in vivo brain functional network organization we observed that 24 h after MDPV administration there was an increased clustering coefficient, rich club index, and average path length. Increases in these metrics suggests that MDPV produces a prolonged pattern of correlated activity characterized by greater interactions between subsets of high degree nodes but a reduced interaction with regions outside this core subset. Further analysis revealed that the core set of nodes include prefrontal cortical, amygdala, hypothalamic, somatosensory and striatal areas. At the molecular level, MDPV downregulated the dopamine transporter (DAT) in striatum and produced a shift in its subcellular distribution, an effect likely to involve rapid internalization at the membrane. These new findings suggest that potent binding of MDPV to DAT may trigger internalization and a prolonged alteration in homeostatic regulation of DA and functional brain network reorganization. We propose that the observed MDPV-induced network reorganization and DAergic changes may contribute to previously reported adverse behavioral responses to MDPV.