The effect of blood transfusion on outcomes among African children admitted to hospital with Plasmodium falciparum malaria: a prospective, multicentre observational study.
Infection with Plasmodium falciparum leads to severe malaria and death in approximately 400 000 children each year in sub-Saharan Africa. Blood transfusion might benefit some patients with malaria but could potentially harm others. The aim of this study was to estimate the association between transfusion and death among children admitted to hospital with P falciparum malaria. In this prospective, multicentre observational study, we analysed admissions to six tertiary care hospitals in The Gambia, Malawi, Gabon, Kenya, and Ghana that participated in the Severe Malaria in African Children network. Patients were enrolled if they were younger than 180 months and had a Giemsa-stained thick blood smear that was positive for P falciparum. Blood transfusion (whole blood at a target volume of 20 mL per kg) was administered at the discretion of the responsible physicians who were aware of local and international transfusion guidelines. The primary endpoint was death associated with transfusion, which was estimated using models adjusted for site and disease severity. We also aimed to identify factors associated with the decision to transfuse. The exploratory objective was to estimate optimal haemoglobin transfusion thresholds using generalised additive models. Between Dec 19, 2000, and March 8, 2005, 26 106 patients were enrolled in the study, 25 893 of whom had their transfusion status recorded and were included in the primary analysis. 8513 (32·8%) patients received a blood transfusion. Patients were followed-up until discharge from hospital for a median of 2 days (IQR 1-4). 405 (4·8%) of 8513 patients who received a transfusion died compared with 689 (4·0%) of 17 380 patients who did not receive a transfusion. Transfusion was associated with decreased odds of death in site-adjusted analysis (odds ratio [OR] 0·82 [95% CI 0·71-0·94]) and after adjusting for the increased disease severity of patients who received a transfusion (0·50 [0·42-0·60]). Severe anaemia, elevated lactate concentration, respiratory distress, and parasite density were associated with greater odds of receiving a transfusion. Among all study participants, transfusion was associated with improved survival when the admission haemoglobin concentration was up to 77 g/L (95% CI 65-110). Among those with impaired consciousness (Blantyre Coma Score ≤4), transfusion was associated with improved survival at haemoglobin concentrations up to 105 g/L (95% CI 71-115). Among those with hyperlactataemia (blood lactate ≥5·0 mmol/L), transfusion was not significantly associated with harm at any haemoglobin concentration-ie, the OR of death comparing transfused versus not transfused was less than 1 at all haemoglobin concentrations (lower bound of the 95% CI for the haemoglobin concentration at which the OR of death equals 1: 90 g/L; no upper bound). Our findings suggest that whole blood transfusion was associated with improved survival among children hospitalised with P falciparum malaria. Among those with impaired consciousness or hyperlactataemia, transfusion was associated with improved survival at haemoglobin concentrations above the currently recommended transfusion threshold. These findings highlight the need to do randomised controlled trials to test higher transfusion thresholds among African children with severe malaria complicated by these factors. US National Institute of Allergy and Infectious Diseases.


Abnormal white matter integrity related to head impact exposure in a season of high school varsity football.
The aim of this study was to determine whether the cumulative effects of head impacts from a season of high school football produce magnetic resonance imaging (MRI) measureable changes in the brain in the absence of clinically diagnosed concussion. Players from a local high school football team were instrumented with the Head Impact Telemetry System (HITS™) during all practices and games. All players received pre- and postseason MRI, including diffusion tensor imaging (DTI). Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) was also conducted. Total impacts and risk-weighted cumulative exposure (RWE), including linear (RWELinear), rotational (RWERotational), and combined components (RWECP), were computed from the sensor data. Fractional, linear, planar, and spherical anisotropies (FA, CL, CP, and CS, respectively), as well as mean diffusivity (MD), were used to determine total number of abnormal white matter voxels defined as 2 standard deviations above or below the group mean. Delta (post-preseason) ImPACT scores for each individual were computed and compared to the DTI measures using Spearman's rank correlation coefficient. None of the players analyzed experienced clinical concussion (N=24). Regression analysis revealed a statistically significant linear relationship between RWECP and FA. Secondary analyses demonstrated additional statistically significant linear associations between RWE (RWECP and RWELinear) and all DTI measures. There was also a strong correlation between DTI measures and change in Verbal Memory subscore of the ImPACT. We demonstrate that a single season of football can produce brain MRI changes in the absence of clinical concussion. Similar brain MRI changes have been previously associated with mild traumatic brain injury.


A real-time respiratory motion monitoring system using KINECT: proof of concept.
The purpose of this study is to investigate the feasibility of a low-cost respiratory motion monitoring system based on the Microsoft KINECT sensor. The authors increased KINECT's inherent depth resolution from 1 cm to 1 mm via a motion magnification system. Using the KINECT software development kit, the authors programmed the KINECT to capture depth images and determine the average depth over a thoracic region of interest, viewed almost parallel to the subject's surface. KINECT respiratory traces (average depth vs time at a rate of 30 Hz) were acquired from four volunteers and compared with those simultaneously acquired using a commercially available strain gauge respiratory gating system. The correlation coefficient (CC) between KINECT and strain gauge traces varied from 0.958 to 0.978, with a mean CC of 0.969. This strong correlation was also demonstrated by the joint probability distribution and visual inspection. It is feasible to use the KINECT for respiratory motion tracking. Traces are similar to those of a clinically used strain gauge system. The KINECT-based system provides a new and economical way to monitor respiratory motion.


Altered Middle Ear Microbiome in Children With Chronic Otitis Media With Effusion and Respiratory Illnesses.
Chronic otitis media with effusion (COME) is a common childhood disease characterized by an accumulation of fluid behind the eardrum. COME often requires surgical intervention and can also lead to significant hearing loss and subsequent learning disabilities. Recent characterization of the middle ear fluid (MEF) microbiome in pediatric patients has led to an improved understanding of the microbiota present in the middle ear during COME. However, it is not currently known how the MEF microbiome might vary due to other conditions, particularly respiratory disorders. Here, we apply an amplicon sequence variant (ASV) pipeline to MEF 16S rRNA high-throughput sequencing data from 50 children with COME (ages 3-176 months) undergoing tube placement. We achieve a more detailed taxonomic resolution than previously reported, including species and genus level resolution. Additionally, we provide the first report of the functional roles of the MEF microbiome and demonstrate that despite high taxonomic diversity, the functional capacity of the MEF microbiome remains uniform between patients. Furthermore, we analyze microbiome differences between children with COME with and without a history of lower airway disease (i.e., asthma or bronchiolitis). The MEF microbiome was less diverse in participants with lower airway disease than in patients without, and phylogenetic β-diversity (weighted UniFrac) was significantly different based on lower airway disease status. Differential abundance between patients with lower airway disease and those without was observed for the genera Haemophilus, Moraxella, Staphylococcus, Alloiococcus, and Turicella. These findings support previous suggestions of a link between COME and respiratory illnesses and emphasize the need for future study of the middle ear and respiratory tract microbiomes in diseases such as asthma and bronchiolitis.


A first-principles study on the adsorption of ethylenediamine on Ge(100).
We have performed density functional theory (DFT) calculations of the atomic and electronic structures of ethylenediamine on Ge(100). The two amine groups in ethylenediamine can interact with germanium surface atoms through a N-H dissociative nucleophilic reaction and/or N-dative bonding with an electron-deficient down Ge atom. Of the monodentate and row-bridged bidentate structures that formed, the dative-bonded configurations were found to be more stable than the NH dissociative adsorption structures. The formation of row-bridged bidentate, structures is more favorable than that of on-top or end-bridged structures. In simulated STM images, the three types of row-bridged adsorption structure have characteristic features, and the row-bridged dative-bonded configuration gives rise to features due to both adsorbed ethylenediamine molecules and the underlying Ge atoms.


Partnership and depression in Parkinson's disease.
In this study, the influence of partnership on depression and coping with Parkinson's disease has been investigated. Twenty-three single female patients, 46 married patients (23 female, 23 male) with unimpaired partnership and 42 patients (21 female, 21 male) whose partnership had worsened since the onset of disease, were compared with regard to depression and self reported extent of psychosocial distress. Single female patients tended to have higher depression scores than patients in a stable partnership, especially in items concerning personal worthlessness and senselessness of life. Patients differed in the extent of distress concerning social behavior, psychological problems/anxiety and efficiency. Within the group of single female patients two subgroups emerged: (1) patients with low extent of distress in all aspects; (2) patients who were highly distressed by psychological problems and physical disability but weakly distressed from social interaction. Male and female patients living in a stable partnership reported only a generally low to moderate extent of distress. More than half of the male and female patients who reported an impairment of their relationship also had scores of moderate to severe depression. These patients also had the highest extent of distress in each of the aspects assessed. The results are discussed with regard to possible interactive effects of the disease, quality of the partnership and availability of coping strategies.


Graphite exfoliation in cellulose solutions.
Shaking graphite powder dispersed in an aqueous alkaline cellulose solution produces stable dispersions of hydrophilic, thin graphite sheets with lateral dimensions reaching many micrometers. The X-ray diffractogram and Raman spectrum of the exfoliated graphite differ from the well-known graphite patterns. Analytical transmission electron micrographs show cellulose bound to the surface of thin lamellae and this is confirmed by scanning probe micrographs. The dispersant properties of dissolved cellulose are assigned to its adsorption on graphite by juxtaposition of the hydrophobic planes on both substances, forming hydrophilic particles. This method uses only simple and easily accessible chemicals, processed under mild conditions. The resulting nanographite-cellulose dispersions are suitable for making conductive lignocellulosic nanocomposites and coatings.


An experimental study on the application of radionuclide imaging in repair of the bone defect.
The aim of our study was to validate the effect of radionuclide imaging in early monitoring of the bone's reconstruction, the animal model of bone defect was made on the rabbits repaired with HA artificial bone. The ability of bone defect repair was evaluated by using radionuclide bone imaging at 2, 4, 8 and 12 weeks postoperatively. The results indicate that the experimental group stimulated more bone formation than that of the control group. The differences of the bone reconstruction ability were statistically significant (p<0.05). The nano-HA artificial has good bone conduction, and it can be used for the treatment of bone defects. Radionuclide imaging may be an effective and first choice method for the early monitoring of the bone's reconstruction.


Terlipressin versus norepinephrine to prevent milrinone-induced systemic vascular hypotension in cardiac surgery patient with pulmonary hypertension.
Milrinone at inotropic doses requires the addition of a vasoconstrictive drug. We hypothesized that terlipressin use could selectively recover the systemic vascular hypotension induced by milrinone without increasing the pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (MPAP) as norepinephrine in cardiac surgery patients. Patients with pulmonary hypertension were enrolled in this study. At the start of rewarming a milrinone 25 μg/kg bolus over 10 min followed by infusion at the rate of 0.25 μg/kg/min. Just after the loading dose of milrinone, the patients were randomized to receive norepinephrine infusion at a dose of 0.1 μg/kg/min (norepinephrine group) or terlipressin infusion at a dose of 2 μg/kg/h (terlipressin group). Heart rate, mean arterial blood pressure (MAP), central venous pressure, MPAP, systemic vascular resistance (SVR), PVR, cardiac output were measured after induction of anesthesia, after loading dose of milrinone, during skin closure, and in the intensive care unit till 24 h. Milrinone decreased MAP (from 79.56 ± 4.5 to 55.21 ± 2.1 and from 78.46 ± 3.3 to 54.11 ± 1.1) and decreased the MPAP (from 59.5 ± 3.5 to 25.4 ± 2.6 and from 61.3 ± 5.2 to 25.1 ± 2.3) in both groups. After norepinephrine, there was an increase in the MAP which is comparable to terlipressin group (P > 0.05). Terlipressin group shows a significant lower MPAP than norepinephrine group (24.5 ± 1.4 at skin closure vs. 43.3 ± 2.1, than 20.3 ± 2.1 at 24 h vs. 39.8 ± 3.8 postoperatively). There is a comparable increase in the SVR in both group, PVR showed a significant increase in the norepinephrine group compared to the terlipressin group (240.5 ± 23 vs. 140.6 ± 13 at skin closure than 190.3 ± 32 vs. 120.3 ± 10 at 24 h postoperatively). The use of terlipressin after milrinone will reverse systemic hypotension with lesser effect on the pulmonary artery pressure.


Association between the administration of phenylbutazone prior to racing and musculoskeletal and fatal injuries in Thoroughbred racehorses in Argentina.
To examine the association between prerace administration of phenylbutazone and the risk of musculoskeletal injury (MSI) and fatal injury in Thoroughbred racehorses that raced between 2006 and 2015 at 2 of the 4 official racetracks in Argentina. Data from racetrack databases and veterinary reports on 283,193 race starts. Data were collected relating to race performance and injury outcomes for starts at these tracks. The incidence of MSI and fatal injury was calculated for each year, stratified by the declared prerace administration of phenylbutazone. Univariable logistic regression, followed by multivariable logistic regression, was used to identify significant risk factors for both MSI and fatal injury. Analyses identified associations between the declared prerace administration of phenylbutazone and the risk of MSI and fatal injury during racing. Horses with declared prerace phenylbutazone administration had greater odds of MSI (OR, 1.45 [95% CI, 1.03 to 2.04]) and fatal injury (OR, 1.59 [95% CI, 1.1 to 2.27]) than did horses racing without prerace phenylbutazone administration. These associations remained significant when other risk factors were accounted for in both multivariable models. Results suggested an association between the prerace administration of phenylbutazone and the risk of MSI and fatal injury in Thoroughbred racehorses during racing. Although these results did not imply a direct causal relationship between prerace phenylbutazone administration and injury, they may be considered in the development of more conservative medication policies to optimize racehorse welfare in North and Latin America.


Uric Acid is a Useful Tool to Predict Contrast-Induced Nephropathy.
Developing contrast-induced nephropathy (CIN) after primary percutaneous coronary intervention (pPCI) has a negative impact on survival and morbidity. We assessed the predictive value of serum uric acid (SUA) for the development of CIN in patients with ST-segment elevation myocardial infarction (STEMI) who underwent pPCI. Contrast-induced nephropathy was defined an increase of ≥25% or ≥0.5 mg/dL in creatinine concentrations within 72 hours after pPCI. Patients were divided into 2 groups according to admission median SUA level. Serum uric acid level was <5.4 mg/dL (group 1; n = 222) and ≥5.4 mg/dL (group 2; n = 228). Compared to group 1, development of CIN (12% vs 20%, P < .001) was significantly greater in group 2. Using a cut point of >5.45 mg/dL, the SUA level predicted development of CIN with a sensitivity of 70% and specificity of 67%. In multiple logistic regression analysis, SUA level, diabetes mellitus, left ventricular ejection fraction <50%, contrast volume, estimated glomerular filtration rate, and C-reactive protein level emerged as independent predictors of CIN. In conclusion, elevated SUA is an independent risk factor for the development of CIN after pPCI in patients with STEMI.


Effects of single moor baths on physiological stress response and psychological state: a pilot study.
Moor mud applications in the form of packs and baths are widely used therapeutically as part of balneotherapy. They are commonly given as therapy for musculoskeletal disorders, with their thermo-physical effects being furthest studied. Moor baths are one of the key therapeutic elements in our recently developed and evaluated 3-week prevention program for subjects with high stress level and increased risk of developing a burnout syndrome. An embedded pilot study add-on to this core project was carried out to assess the relaxing effect of a single moor bath. During the prevention program, 78 participants received a total of seven moor applications, each consisting of a moor bath (42 °C, 20 min, given between 02:30 and 05:20 p.m.) followed by resting period (20 min). Before and after the first moor application in week 1, and the penultimate moor application in week 3, salivary cortisol was collected, blood pressure and heart rate were measured, and mood state (Multidimensional Mood State Questionnaire) was assessed. A Friedman test of differences among repeated measures was conducted. Post hoc analyses were performed using the Wilcoxon signed-rank test. A significant decrease in salivary cortisol concentration was seen between pre- and post-moor bath in week 1 (Z = -3.355, p = 0.0008). A non-significant decrease was seen between pre- and post-moor bath in week 3. Mood state improved significantly after both moor baths. This pilot study has provided initial evidence on the stress-relieving effects of single moor baths, which can be a sensible and recommendable therapeutic element of multimodal stress-reducing prevention programs. The full potential of moor baths still needs to be validated. A randomized controlled trial should be conducted comparing this balneo-therapeutic approach against other types of stress reduction interventions.


The response regulator SsrB activates expression of diverse Salmonella pathogenicity island 2 promoters and counters silencing by the nucleoid-associated protein H-NS.
The two-component system SsrA-SsrB activates expression of a type III secretion system required for replication in macrophages and systemic infection in mice. Here we characterize the SsrB-dependent regulation of genes within Salmonella pathogenicity island 2 (SPI-2). Primer extension and DNase I footprinting identified multiple SsrB-regulated promoters within SPI-2 located upstream of ssaB, sseA, ssaG and ssaM. We previously demonstrated that ssrA and ssrB transcription is uncoupled. Overexpression of SsrB in the absence of its cognate kinase, SsrA, is sufficient to activate SPI-2 transcription. Because SsrB requires phosphorylation to relieve inhibitory contacts that occlude its DNA-binding domain, additional components must phosphorylate SsrB. SPI-2 promoters examined in single copy were highly SsrB-dependent, activated during growth in macrophages and induced by acidic pH. The nucleoid structuring protein H-NS represses horizontally acquired genes; we confirmed that H-NS is a negative regulator of SPI-2 gene expression. In the absence of H-NS, the requirement for SsrB in activating SPI-2 genes is substantially reduced, suggesting a role for SsrB in countering H-NS silencing. SsrB activates transcription of multiple operons within SPI-2 by binding to degenerate DNA targets at diversely organized promoters. SsrB appears to possess dual activities to promote SPI-2 gene expression: activation of transcription and relief of H-NS-mediated repression.


Role of Early Life Cytotoxic T Lymphocyte and Natural Killer Cell Immunity in Paediatric HIV Cure/Remission in the Anti-Retroviral Therapy Era.
Only three well-characterised cases of functional cure have been described in paediatric HIV infection over the past decade. This underlines the fact that early initiation of combination antiretroviral therapy (cART), whilst minimising the size of the viral reservoir, is insufficient to achieve cure, unless other factors contribute. In this review, we consider these additional factors that may facilitate functional cure in paediatric infection. Among the early life immune activity, these include HIV-specific cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell responses. The former have less potent antiviral efficacy in paediatric compared with adult infection, and indeed, in early life, NK responses have greater impact in suppressing viral replication than CTL. This fact may contribute to a greater potential for functional cure to be achieved in paediatric versus adult infection, since post-treatment control in adults is associated less with highly potent CTL activity, and more with effective antiviral NK cell responses. Nonetheless, antiviral CTL responses can play an increasingly effective role through childhood, especially in individuals expressing then 'protective' HLA-I molecules HLA-B*27/57/58:01/8101. The role of the innate system on preventing infection, in shaping the particular viruses transmitted, and influencing outcome is discussed. The susceptibility of female fetuses to in utero mother-to-child transmission, especially in the setting of recent maternal infection, is a curiosity that also provides clues to mechanisms by which cure may be achieved, since initial findings are that viral rebound is less frequent among males who interrupt cART. The potential of broadly neutralising antibody therapy to facilitate cure in children who have received early cART is discussed. Finally, we draw attention to the impact of the changing face of the paediatric HIV epidemic on cure potential. The effect of cART is not limited to preventing AIDS and reducing the risk of transmission. cART also affects which mothers transmit. No longer are mothers who transmit those who carry genes associated with poor immune control of HIV. In the cART era, a high proportion (>70% in our South African study) of transmitting mothers are those who seroconvert in pregnancy or who for social reasons are diagnosed late in pregnancy. As a result, now, genes associated with poor immune control of HIV are not enriched in mothers who transmit HIV to their child. These changes will likely influence the effectiveness of HLA-associated immune responses and therefore cure potential among children.


The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.
The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.


Anterior corneal and internal contributions to peripheral aberrations of human eyes.
Anterior corneal and internal component contributions to overall peripheral aberrations of five human eyes were determined, based on corneal topography and overall aberration measurements. Anterior corneal position and orientation (tilt) were referenced to the line of sight. Ray tracing was performed through the anterior cornea for 6-mm-diameter pupils at angles out to 40 degrees in both the temporal and the nasal visual fields. In general, both component and overall Zernike aberrations were greater for the nasal than for the temporal visual field. In general, the anterior corneal aberration components were considerably higher than the overall aberrations across the visual field and were balanced to a considerable degree by the internal ocular aberration components. The component and overall levels of Zernike third-order aberrations showed linear trends away from the fixation axis, and the component levels of Zernike fourth-order aberrations showed quadratic trends away from the fixation axis. The second-order, but not higher-order, aberration components were susceptible to the choice of image radius of curvature, while disregarding corneal position and orientation affected second- and higher-order aberration components.


Effect of prior authorization of second-generation antipsychotic agents on pharmacy utilization and reimbursements.
Medicaid expenditures for antipsychotic medications have risen rapidly, from under $1.0 billion in 1995 to over $5.5 billion in 2005. In response, at least ten states have implemented prior-authorization programs that restrict access to particular second-generation antipsychotic agents (aripiprazole and olanzapine). Twenty-two states restrict particular dosing forms (injections). This study examined the impact of such restrictions. The authors used interrupted time-series analysis of quarterly state-level drug utilization data to examine the impact of prior authorization for particular agents in West Virginia and Texas. Changes in market share of nonpreferred medications and total pharmacy costs were compared with changes in states without similar prior-authorization requirements. The West Virginia policy led to an immediate 3.5% reduction in market share level (p<.01) and a 1.3% decrease in trend per quarter in market share (p<.001) for nonpreferred antipsychotics, leading to a 13.9% reduction after two years. In Texas, prior authorization reduced the market share level of nonpreferred agents by 2.6% (p=.055). However, prior authorization did not lead to a significant decrease in pharmacy reimbursements in either state. Current prior-authorization policies for second-generation antipsychotics do not appear to reduce pharmacy reimbursement, probably because alternative medications are costly. These findings suggest that any cost savings from prior-authorization policies would accrue largely through supplemental rebate agreements with manufacturers, which are likely reduced by the transfer of dually eligible Medicaid enrollees to Medicare Part D plans. Further evaluation of the clinical consequences resulting from such policies is urgently needed to determine whether the minimal cost savings outweigh the potential clinical risks.


Information sharing with rural family caregivers during care transitions of hip fracture patients.
Following hip fracture surgery, patients often experience multiple transitions through different care settings, with resultant challenges to the quality and continuity of patient care. Family caregivers can play a key role in these transitions, but are often poorly engaged in the process. We aimed to: (1) examine the characteristics of the family caregivers' experience of communication and information sharing and (2) identify facilitators and barriers of effective information sharing among patients, family caregivers and health care providers. Using an ethnographic approach, we followed 11 post-surgical hip fracture patients through subsequent care transitions in rural Ontario; in-depth interviews were conducted with patients, family caregivers (n = 8) and health care providers (n = 24). Priority areas for improved information sharing relate to trust and respect, involvement, and information needs and expectations; facilitators and barriers included prior health care experience, trusting relationships and the rural setting. As with knowledge translation, effective strategies to improve information sharing and care continuity for older patients with chronic illness may be those that involve active facilitation of an on-going partnership that respects the knowledge of all those involved.


Pain-related changes in cutaneous innervation of patients suffering from bortezomib-induced, diabetic or chronic idiopathic axonal polyneuropathy.
Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age-matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CIAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between IENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology.


Development and Usability Evaluation of a Facebook-Based Intervention Program for Childhood Cancer Patients: Mixed Methods Study.
Childhood cancers previously considered to be incurable now have 5-year survival rates up to 84%. Nevertheless, these patients remain at risk of morbidity and mortality from therapy-related complications. Thus, patient education and self-management strategies for promoting a healthy lifestyle are of tantamount importance for improving short- and long-term health outcomes. A Facebook-based "Healthy Teens for Soaam" (a Korean term for childhood cancers) program was developed to help improve knowledge and self-management practices of teens with cancer related to their disease and treatment. The two-fold purpose of this usability study was (1) to describe the process of developing an 8-week Facebook-based intervention program for teens with cancer, and (2) to evaluate its usability to refine the program. Multiple phases and methods were employed to develop and evaluate the usability of the program. Study phases included: (1) needs assessment through focus group interviews and qualitative content analysis, (2) development of module content, (3) expert review and feedback on module content, (4) Facebook-based program development, (5) usability evaluation by heuristic evaluation, (6) usability evaluation by targeted end-user testing, and (7) modification and final version of the program. Usability of the final version was confirmed through feedback loops of these phases. Based on 6 focus group discussion sessions, it was determined that teens with cancer were interested in seeing stories of successful childhood cancer cases and self-management after discharge, and preferred multimedia content over text. Therefore, each Facebook module was redesigned to include multimedia materials such as relevant video clips tailored for teens. Usability assessed by heuristic evaluation and user testing revealed several critical usability issues, which were then revised. Potential end users tested the final program and perceived it to be usable and useful for teens with cancer. To our knowledge, "Healthy Teens for Soaam" is the first Facebook-based intervention program for teens with cancer. We actively worked with current childhood cancer patients and survivors to develop and improve this program, achieved good usability, and met the expressed needs and preferences of target end users. This 8-week Facebook-based educational program for teens with cancer, developed as the first step of an upcoming intervention study, will be useful for improving knowledge and self-management strategies of teens.


Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways.
Brown adipose tissue plays an important role in obesity, insulin resistance, and diabetes. We have previously shown that the transition from brown preadipocytes to mature adipocytes is mediated in part by insulin receptor substrate (IRS)-1 and the cell cycle regulator protein necdin. In this study, we used pharmacological inhibitors and adenoviral dominant negative constructs to demonstrate that this transition involves IRS-1 activation of Ras and ERK1/2, resulting in phosphorylation of cAMP response element-binding protein (CREB) and suppression of necdin expression. This signaling did not include an elevation of intracellular calcium. A constitutively active form of CREB expressed in IRS-1 knockout cells decreased necdin promoter activity, necdin mRNA, and necdin protein levels, leading to a partial restoration of differentiation. By contrast, forkhead box protein (Fox)O1, which is regulated by the phosphoinositide 3 kinase-Akt pathway, increased necdin promoter activity. Based on reporter gene assays using truncations of the necdin promoter and chromatin immunoprecipitation studies, we demonstrated that CREB and FoxO1 are recruited to the necdin promoter, likely interacting with specific consensus sequences in the proximal region. Based on these results, we propose that insulin/IGF-I act through IRS-1 phosphorylation to stimulate differentiation of brown preadipocytes via two complementary pathways: 1) the Ras-ERK1/2 pathway to activate CREB and 2) the phosphoinositide 3 kinase-Akt pathway to deactivate FoxO1. These two pathways combine to decrease necdin levels and permit the clonal expansion and coordinated gene expression necessary to complete brown adipocyte differentiation.


Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence.
Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence. Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users. During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1-4 (oestrogen-progestagen RR 1·60, 95% CI 1·52-1·69; oestrogen-only RR 1·17, 1·10-1·26), and were twice as great during years 5-14 (oestrogen-progestagen RR 2·08, 2·02-2·15; oestrogen-only RR 1·33, 1·28-1·37). The oestrogen-progestagen risks during years 5-14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21-2·40 vs 1·93, 1·84-2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5-14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40-44, 45-49, 50-54, and 55-59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use. If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50-69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great. Cancer Research UK and the Medical Research Council.


Elevated HIV prevalence and risk behaviours among men who have sex with men (MSM) in Vietnam: a systematic review.
To review and analyse original studies on HIV prevalence and risk behaviours among men who have sex with men (MSM) in Vietnam. Systematic literature review. Comprehensive identification of material was conducted by systematic electronic searches of selected databases. Inclusion criteria included studies conducted from 2002 onwards, following a systematic review concluding in 2001 conducted by Colby, Nghia Huu and Doussantousse. Data analysis was undertaken through the application of both the Cochrane Collaboration and ePPI Centre approaches to the synthesis of qualitative and quantitative studies. Vietnam. Sixteen studies, undertaken during 2005-2011, were identified that met the inclusion criteria. The analysis showed that HIV prevalence among MSM in Vietnam has increased significantly (eg, from 9.4% in 2006 to 20% in 2010 in Hanoi) and that protective behaviours, such as condom use and HIV testing and counselling, continue at inadequately low levels. Increasing HIV prevalence and the lack of effective protective behaviours such as consistent condom use during anal sex among MSM in Vietnam indicate a potential for a more severe HIV epidemic in the future unless targeted and segmented comprehensive HIV prevention strategies for MSM in Vietnam are designed and programmes implemented.


Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment.
Many patients with unilateral breast cancer choose contralateral prophylactic mastectomy to prevent cancer in the opposite breast. The purpose of our study was to determine the use and trends of contralateral prophylactic mastectomy in the United States. We used the Surveillance, Epidemiology and End Results database to review the treatment of patients with unilateral breast cancer diagnosed from 1998 through 2003. We determined the rate of contralateral prophylactic mastectomy as a proportion of all surgically treated patients and as a proportion of all mastectomies. We identified 152,755 patients with stage I, II, or III breast cancer; 4,969 patients chose contralateral prophylactic mastectomy. The rate was 3.3% for all surgically treated patients; 7.7%, for patients undergoing mastectomy. The overall rate significantly increased from 1.8% in 1998 to 4.5% in 2003. Likewise, the contralateral prophylactic mastectomy rate for patients undergoing mastectomy significantly increased from 4.2% in 1998 to 11.0% in 2003. These increased rates applied to all cancer stages and continued to the end of our study period. Young patient age, non-Hispanic white race, lobular histology, and previous cancer diagnosis were associated with significantly higher rates. Large tumor size was associated with a higher overall rate, but with a lower rate for patients undergoing mastectomy. The use of contralateral prophylactic mastectomy in the United States more than doubled within the recent 6-year period of our study. Prospective studies are needed to understand the decision-making processes that have led to more aggressive breast cancer surgery.


Predicted v. real prevalence of the 22q11.2 deletion syndrome in children with congenital heart disease presenting to Red Cross War Memorial Children's Hospital, South Africa: A prospective study.
The 22q11.2 deletion syndrome (22qDS) has more than 180 associated phenotypic features, yet genotype-phenotype correlation remains obscure. Since many of the clinical characteristics are serious, yet treatable (including congenital heart disease), clinicians must maintain a high index of clinical suspicion to recognise a suite of co-occurring phenotypic features that suggest a diagnosis of 22qDS. Óskarsdottir's scoring schedule (the 'O score') is generally used to suggest the need for confirmatory fluorescent in situ hybridisation (FISH) testing, using the TUPLE 1 probe. An O score of two or more indicates the need for FISH testing. Objectives. A previous audit of FISH-positive results of patients with congenital heart disease at Red Cross War Memorial Children's Hospital (RCWMCH) revealed a clinical recognition rate of 1.7%. However, we were concerned that the syndrome may be under-recognised in our setting. Our aims were therefore to assess the predictive value of 'O scoring' and to accurately determine the prevalence of 22qDS in our patient population. Methods. A prospective trial of FISH testing every new patient with congenital heart disease presenting to RCWMCH was undertaken to accurately determine the prevalence of 22qDS. The results were then compared with the ability of the O score to indicate the need for FISH testing. Testing of 125 patients detected deletions in six (4.8%, 2.8 times the previously determined clinical detection rate), thereby vindicating our concern that 22qDS is under-diagnosed. Of these 125 patients, 37 had an O score of 2 or 3, yet only 6 were FISH-positive, giving the O score a positive predictive value of only 14%. Conclusion. Until a more robust alternative recognition tool is available, South African clinicians should use all clinical recognition criteria liberally to suggest the need for formal testing for 22qDS.


Immunosuppressive effect of subchronic exposure to a mixture of eight heavy metals, found as groundwater contaminants in different areas of India, through drinking water in male rats.
Immunotoxicity is an important health hazard of heavy metal exposure. Because the risk of combined exposure in the population cannot be neglected, we examined whether subchronic exposure to a mixture of metals (arsenic, cadmium, lead, mercury, chromium, nickel, manganese, and iron) via drinking water at contemporary Indian groundwater contamination levels and at concentrations equivalent to the WHO maximum permissible limit (MPL) in drinking water can induce immunotoxicity in male rats. Data on groundwater contamination with metals in India were collected from literature and metals were selected on the basis of their frequency of occurrence and contamination level above the MPL. Male albino Wistar rats were exposed to the mixture at 0, 1, 10, and 100 times the mode concentrations (the most frequently occurring concentration) of the individual metals in drinking water for 90 days. In addition, one group was exposed to the mixture at a concentration equal to the MPL of the individual metal and another group was used as positive control for immune response studies. The end points assessed were weights of organs, hematological indices, humoral and cell-mediated immune responses, and histopathology of skin and spleen. The MPL and 1x doses did not significantly affect any of the parameters and none of the doses induced any significant changes after 30 days of exposure. The mixture at 10x and 100x doses increased the relative weight of the spleen, but that of thymus, adrenals, and popliteal lymphnodes were increased with the 100x dose. After 90 days, 10x and 100x doses decreased serum protein and globulin contents and increased the albumin:globulin ratio; the albumin level was decreased only with the 100x dose. After 60 days, the total erythrocyte count (TEC), hemoglobin (Hb) level, and packed cell volume (PCV) were decreased with the 100x dose, whereas after 90 days, 10x and 100x doses reduced the TEC, total leukocyte count, Hb level, PCV, mean corpuscular volume, and mean corpuscular hemoglobin. With the 100x dose, the lymphocyte count was decreased after 60 and 90 days, but the neutrophil number was increased after 90 days. Antibody titer was decreased after 75 days with the 100x dose, but after 90 days, it was decreased with both the 10x and 100x doses. In delayed-type hypersensitivity response, these two doses decreased ear thickness after 24 and 48 h and skin biopsies showed a dose-dependent decrease in inflammatory changes. Histologically, the spleen revealed depletion of lymphoid cells and atrophic follicles with reduced follicular activity with higher doses. The findings suggest that hematopoietic and immune systems are toxicologically sensitive to the mixture, which could lead to anemia and suppression of humoral and cell-mediated immune responses in male rats at 10 and 100 times the mode concentrations of the individual components in contaminated groundwater.


Genotoxicity and DNA adduct formation of incense smoke condensates: comparison with environmental tobacco smoke condensates.
Indoor air pollution has now been recognized as a potentially important problem for public health, since people spend most of their day in closed environments. Incense burning is possibly associated with elevated risks of leukemia and brain tumor in children from the epidemiological studies. Thus, evaluation of the genotoxicity of smoke condensates from incense burning is needed. We examined the genotoxicity of incense smoke condensates (ISC) using the Ames test in S. typhimurium strains with different mutagenic specificity and level of metabolic enzyme, the SOS chromotest in E. coli PQ37, and sister chromatid exchange assay in Chinese hamster ovary cells (SCE/CHO). The genotoxicity of environmental tobacco smoke condensates (TSC) was also evaluated by the three assays to compare with the genotoxicity of ISC. ISC showed a positive response in TA98, but not in TA100. It suggested that ISC only contained frame shift mutagens. The mutagenicity of ISC in both strains of TA98NR with deficient nitroreductase and TA98/1,8-DNP6 with deficient O-acetyltransferase was markedly decreased compared to that in TA98 strain. However, the mutagenicity was enhanced in YG1024 with overexpression of O-acetyltransferase activity. Thus, nitroarenes seemed to be responsible in part for the mutagenicity of ISC. Interestingly, all of the four ISC and two TSC samples showed a dose-dependent genotoxic response in the SOS chromotest with E. coli PQ37 but a low SCE induction of those samples were observed in CHO cells. When the genotoxicity was analyzed based on the condensates per one gram of original samples, the genotoxicity of two TSC condensates in prokaryotic cells was higher than that of four ISC samples except for the genotoxicity of TSC-2 in TA98 strain. However, the genotoxicity of certain ISC in eukaryotic cells based on the SCE/CHO assay was higher than that of TSC. To compare the covalent binding of DNA reactive intermediates of ISC and TSC to S. typhimurium TA98, the DNA adducts were evaluated by the 32P-postlabeling method with butanol extraction version. Similar diagonal radioactive zone (DRZ) was observed between ISC and CSC. However, DNA adduct levels induced by TSC were much greater than that of ISC.


Role of adenosine in NMDA receptor modulation in the cerebral cortex of an anoxia-tolerant turtle (Chrysemys picta belli).
Accumulation of the neuromodulator adenosine in the anoxia-tolerant turtle brain may play a key role in a protective decrease in excitatory neurotransmission during anoxia. Since excitatory neurotransmission is mediated largely by Ca2+ entry through N-methyl-D-aspartate (NMDA) receptors, we measured the effect of adenosine on NMDA-mediated Ca2+ transients in normoxic and anoxic turtle cerebrocortical sheets. Intracellular [Ca2+] was measured fluorometrically with the Ca2+-sensitive dye Fura-2. Baseline intracellular [Ca2+] and [ATP] were also measured to assess cortical sheet viability and potential toxic effects of NMDA. Baseline [Ca2+] did not change significantly under any condition, ranging from 109 +/- 22 to 187 +/- 26 nmoll-1. Throughout normoxic and 2h anoxic protocols, and after single and multiple NMDA exposures, [ATP] did not change significantly, ranging from 16.0 +/- 1.9 to 25.3 +/- 4.9 nmol ATP mg-1 protein. Adenosine caused a reduction in the normoxic NMDA-mediated increase in [Ca2+] from a control level of 287 +/- 35 to 103 +/- 22 nmoll-1 (64%). This effect is mediated by the A1 receptor since 8-phenyltheophylline (a specific A1 antagonist) effectively blocked the adenosine effect and N6-cyclopentyladenosine (a specific A1 agonist) elicited a similar decrease in the NMDA-mediated response. Cortical sheets exposed to anoxia alone exhibited a 52% decrease in the NMDA-mediated [Ca2+] rise, from 232 +/- 30 to 111 +/- 9 nmoll-1. The addition of adenosine had no further effect and 8-phenyltheophylline did not antagonize the observed decrease. Therefore, the observed down-regulation of NMDA receptor activity during anoxia must involve additional, as yet unknown, mechanisms.


Identification and characterisation of novel mammalian homologues of Drosophila polyhomeoticpermits new insights into relationships between members of the polyhomeotic family.
We have identified and characterised novel members of the mammalian polyhomeotic gene family, comprising a third human homologue, PHC3, and its mouse counterpart, Phc3. The two new genes have essentially the same genomic organisation, with 15 exons specifying proteins of 983 (PHC3) or 981 (Phc3) amino acids, with an overall sequence identity of 93%. Northern blot hybridisations have identified a single large transcript in a variety of adult mouse tissues and in situ hybridisation analyses indicate apparently ubiquitous expression during early human and mouse development. Exhaustive database screening suggests a maximum of three polyhomeotic homologues in humans and in mice and, for completeness, we have also derived the full-length coding sequence of the PHC2 gene (formerly called EDR2). The availability of full-length coding sequences for PHC2, PHC3 and Phc3 completes the profile of human and mouse polyhomeotic homologues and has enabled comprehensive comparative analyses of the human, mouse and Drosophilapolyhomeotic proteins. The mammalian paralogues are located on three different chromosomes and pairwise comparisons of their protein products typically show about 34% amino acid sequence identity, except for some highly conserved domains for which we present consensus mammalian sequences. The data indicate that the novel PHC3 and Phc3 proteins are significantly more closely related to PHC2/Phc2 than either is to PHC1/Phc1 and reveal two hitherto unknown but highly conserved N-terminal domains that are shared by the PHC2/Phc2 and PHC3/Phc3 proteins but that are poorly conserved or absent in other polyhomeotic family members.


Age-related changes in P2-purinergic receptors on vascular smooth muscle and endothelium.
The present study examined age-related changes in the vascular relaxation response to adenine nucleotides in hypertensive and normotensive rats. Aortic ring segments from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), age 4-6, 9-10, and 13-14 weeks, were examined for relaxation to adenosine 5'-triphosphate (ATP). The extent of ATP-induced relaxation in aortic ring segments with intact endothelium was unchanged with advancing age. Rubbed (endothelium-denuded) ring preparations at the age of 4-6 weeks showed a dose-dependent relaxation similar to that of the unrubbed rings. With advancing age, the ATP-induced relaxation in the rubbed rings decreased and was abolished. The relaxation response did not differ between the SHR and WKY animals at any age, whether the preparations were rubbed or unrubbed. The stable ATP analogue beta,r-methylene ATP induced a relaxation response similar to ATP in rubbed rings at 4-6 weeks of age. In addition, treatment with 8-phenyltheophylline did not diminish the relaxation induced by ATP. ATP-induced relaxation may be manifested via the direct action on the vascular smooth muscle in young rats and may be altered through the response mediated by endothelium with advancing age. This suggests that the vascular smooth muscle of young rats has a P2-purinergic receptor leading to relaxation and that this receptor activity declines with advancing age. In contrast, a P2-purinergic receptor leading to the generation of endothelium-derived relaxing factor may be activated in endothelial cells with advancing age. The alterations with age of P2-purinergic receptor in the vascular smooth muscle and endothelial cell are not affected by genetic hypertension.


GTP binding by class II transactivator: role in nuclear import.
Class II transactivator (CIITA) is a global transcriptional coactivator of human leukocyte antigen-D (HLA-D) genes. CIITA contains motifs similar to guanosine triphosphate (GTP)-binding proteins. This report shows that CIITA binds GTP, and mutations in these motifs decrease its GTP-binding and transactivation activity. Substitution of these motifs with analogous sequences from Ras restores CIITA function. CIITA exhibits little GTPase activity, yet mutations in CIITA that confer GTPase activity reduce transcriptional activity. GTP binding by CIITA correlates with nuclear import. Thus, unlike other GTP-binding proteins, CIITA is involved in transcriptional activation that uses GTP binding to facilitate its own nuclear import.


DNA damage alters DNA polymerase delta to a form that exhibits increased discrimination against modified template bases and mismatched primers.
Human DNA polymerase delta (Pol delta4), a key enzyme in chromosomal replication, is a heterotetramer composed of the p125, p50, p68 and p12 subunits. Genotoxic agents such as UV and alkylating chemicals trigger a DNA damage response in which Pol delta4 is converted to a trimer (Pol delta3) by degradation of p12. We show that Pol delta3 has altered enzymatic properties: it is less able to perform translesion synthesis on templates containing base lesions (O(6)-MeG, 8-oxoG, an abasic site or a thymine-thymine dimer); a greater proofreading activity; an increased exonuclease/polymerase activity ratio; a decreased tendency for the insertion of wrong nucleotides, and for the extension of mismatched primers. Overall, our findings indicate that Pol delta3 exhibits an enhanced ability for the detection of errors in both primers and templates over its parent enzyme. These alterations in Pol delta3 show that p12 plays a major role in Pol delta4 catalytic functions, and provides significant insights into the rationale for the conversion of Pol delta4 to Pol delta3 in the cellular response to DNA damage.


Gigantic Phonon-Scattering Cross Section To Enhance Thermoelectric Performance in Bulk Crystals.
In thermoelectric energy conversions, thermal conductivity reduction is essential for enhancing thermoelectric performance while maintaining a high power factor. Herein, we propose an approach based on coated-grain structures to effectively reduce the thermal conductivity to a much greater degree when compared to that done by conventional nanodot nanocomposite. By incorporating CdTe coated layers on the surface of SnTe grains, the thermal conductivity is as low as 1.16 W/m-K at 929 K, resulting in a thermoelectric figure of merit, i.e., zT, of 1.90. According to our developed theory, phonons scatter coherently due to the phase lag between phonons passing through and around the coated grain. Such scattering is induced by the acoustic impedance mismatch between the coated layer and the grain, resulting in a gigantic phonon-scattering cross section. The phonon-scattering cross section of the coated grains is several orders of magnitude larger than that of the nanodots with the same impurity concentration. The power factor was also slightly increased by the energy filtering effect at the coated surface and additional minority carrier blocking by the heterointerfaces. This scheme can be utilized for various bulk crystals, meaning a broad range of materials can be considered for thermoelectric applications.


Abortion: knowledge and perceptions of adolescents in two districts in Kenya.
Pregnancy among adolescents is unplanned in many instances. Although some pregnant adolescents carry the pregnancy to term, abortion, in many instances unsafely induced, is a commonly sought solution in Kenya. To determine adolescents' perceptions of induced abortion. A cross-sectional descriptive study carried out between July 1995 and June 1996. An urban and a rural district in Kenya. Adolescents aged 10-19 years in schools in Nairobi and Kiambu districts, and a group of immediate post-abortion adolescent girls in some health facilities in Nairobi. The number of health programmes formulated and put into use, which are adolescent-friendly and providing information, education and communication on abortion issues. One thousand eight hundred and twenty adolescents were subjected to a self-administered questionnaire that collected demographic and health data as well as perceptions of induced abortion. Focus group discussions on perceptions of abortion were held with 12 groups of adolescents in schools and the information obtained recorded on paper and in a tape-recorder. One thousand nine hundred and fifty two adolescents, comprising of 1048 school girls (SG), 580 boys (SB), 192 post-abortion girls (PA) and 132 adolescents in the focus group discussions, formed the study sample. More than 90% were aware of induced abortion (IA). Knowledge of IA correlated positively with level of education (P < 0.01). Seventy one per cent of SG, 84% of PA and 40% of SB were aware of abortion-related complications, the most common being infections, death and infertility. Eighty three per cent of PA felt that complications were preventable by seeking care from a qualified doctor compared to one quarter each for the SB and SG. 56% PA, 69% SB and 72% SG felt that abortions were preventable. However, less than 40% proposed abstinence as a primary strategy. The most important source of information on abortion was the media followed by friends and teachers. Adolescents are aware of abortion and the related complications, but there is more variability in their knowledge and preventive measures.


Modulation of the sympathetic response to acute hypoxia by the caudal ventrolateral medulla in rats.
Hypoxia elevates splanchnic sympathetic nerve activity (SNA) with differential effects during inspiration and expiration by unresolved central mechanisms. We examined the hypothesis that cardiovascular-related neurones in the caudal ventrolateral medulla (CVLM) contribute to the complex sympathetic response to hypoxia. In chloralose-anaesthetized, ventilated, vagotomized rats, acute hypoxia (10% O2, 60 s) evoked an increase in SNA (103 +/- 12%) that was characterized by a decrease in activity during early inspiration followed by a prominent rise during expiration. Some recorded baro-activated CVLM neurones (n = 13) were activated by hypoxia, and most of these neurones displayed peak activity during inspiration that was enhanced during hypoxia. In contrast, other baro-activated CVLM neurones were inhibited during hypoxia (n = 6), and most of these neurones showed peak activity during expiration prior to the onset of hypoxia. Microinjection of the glutamate antagonist kynurenate into the CVLM eliminated the respiratory-related fluctuations in SNA during hypoxia and exaggerated the magnitude of the sympathetic response. In contrast, microinjection of a GABA(A) antagonist (bicuculline or gabazine) into the CVLM dramatically attenuated the sympathetic response to hypoxia. These data suggest the response to hypoxia in baro-activated CVLM neurones is related to their basal pattern of respiratory-related activity, and changes in the activity of these neurones is consistent with a contribution to the respiratory-related sympathetic responses to hypoxia. Furthermore, both glutamate and GABA in the CVLM contribute to the complex sympathetic response to acute hypoxia.


A comparison of nanoparticle and fine particle uptake by Daphnia magna.
The use of nanoparticles in various applications is steadily on the rise, with use in a range of applications, including printer toner, sunscreen, medical imaging, and enhanced drug delivery. While research on human effects via, for example, inhalation is relatively well developed, the environmental assessment of nanoparticles is in its infancy. In the present study, we assessed the uptake and quantitative accumulation, as well as the depuration, of a model nanoparticle, a 20-nm fluorescent carboxylated polystyrene bead, in the aquatic invertebrate Daphnia magna and compared it to a larger, 1,000-nm particle. Using confocal microscopy, rapid accumulation in the gastrointestinal tract was observed within an hour of exposure to both particle sizes in both adults and neonates. Fluorescence could also be observed in the oil storage droplets, suggesting that both particle sizes have crossed the gut's epithelial barrier. Quantification of fluorescence of both sizes of particles showed that although uptake of the 20-nm particles was lower in terms of mass it was equal to or greater than 1000-nm particle uptake when expressed as surface area or particle number. Depuration was relatively rapid for the 1000-nm beads, decreasing by more than 90% over 4 h. In contrast, depuration of the 20-nm beads was less extensive, reaching 40% over 4 h. Transmission electron microscopy confirmed uptake of 1,000-nm beads, but uptake of 20-nm beads was inconclusive since similar-sized inclusions could be observed in control treatments.


A systematic review on the effectiveness of the Nucleoplasty procedure for discogenic pain.
Nucleoplasty is a minimally invasive procedure for treating pain caused by symptomatic disc herniation that is refractory to conservative therapy. Observational studies have reported differing outcomes for this procedure and thus its effectiveness is yet to be determined. A systematic review of the efficacy of the nucleoplasty procedure. To assess the clinical efficacy of the nucleoplasty procedure for treating back pain from symptomatic, contained disc herniation and to evaluate the methodological quality of the included studies. The relevant literature for nucleoplasty was identified through a search of the following databases: Pubmed, Ovid Medline, and the Cochrane library, and by a review of the bibliographies of the included studies. A review of the literature of the effectiveness of the nucleoplasty procedure for managing discogenic pain was performed according to the criteria for observational studies using a "Quality Index" scale to determine the methodological quality of the literature. The level of evidence was classified as Level I, II, or III based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF) for therapeutic interventions. Recommendations were based on the criteria developed by Guyatt et al. The main outcome measures evaluated were the percentage of pain relief based on visual analogue scale (VAS) or numeric rating scale (NRS), percentage of patients with more than 50% reduction in pain, percentage of patients meeting one or more success criteria after nucleoplasty, and improvement in patient function. Secondary measures noted were reports of complications and the Quality Index scores of each study that was evaluated. The quality of evidence for improvement in pain or function after a nucleoplasty procedure is Level II-3. The recommendation is 1C/strong for the nucleoplasty procedure based on the quality of evidence available. The median Quality Index score was 16 (range 12 - 19), indicating adequate methodological quality of the available literature. None of the studies reported major complications related to nucleoplasty. Observational studies suggest that nucleoplasty is a potentially effective minimally invasive treatment for patients with symptomatic disc herniations who are refractory to conservative therapy. The recommendation is a level 1C, strongly supporting the therapeutic efficacy of this procedure. However, prospective randomized controlled trials with higher quality of evidence are necessary to confirm efficacy and risks, and to determine ideal patient selection for this procedure.


Systematic review of barriers to surgical care in low-income and middle-income countries.
There is increasing evidence that lack of facilities, equipment, and expertise in district hospitals across many low- and middle-income countries constitutes a major barrier to accessing surgical care. However, what is less clear, is the extent to which people perceive barriers when trying to access surgical care. PubMed and EMBASE were searched using key words ("access" and "surgery," "barrier" and "surgery," "barrier" and "access"), MeSH headings ("health services availability," "developing countries," "rural population"), and the subject heading "health care access." Articles were included if they were qualitative and applied to illnesses where the treatment is primarily surgical. Key barriers included difficulty accessing surgical services due to distance, poor roads, and lack of suitable transport; lack of local resources and expertise; direct and indirect costs related to surgical care; and fear of undergoing surgery and anesthesia. The significance of cultural, financial, and structural barriers pertinent to surgery and their role in wider health care issues are discussed. Immediate action to improve financial and geographic accessibility along with investment in district hospitals is likely to make a significant impact on overcoming access and barrier issues. Further research is needed to identify issues that need to be addressed to close the gap between the care needed and that provided.


Initial construction and validation of the Pathological Narcissism Inventory.
The construct of narcissism is inconsistently defined across clinical theory, social-personality psychology, and psychiatric diagnosis. Two problems were identified that impede integration of research and clinical findings regarding narcissistic personality pathology: (a) ambiguity regarding the assessment of pathological narcissism vs. normal narcissism and (b) insufficient scope of existing narcissism measures. Four studies are presented documenting the initial derivation and validation of the Pathological Narcissism Inventory (PNI). The PNI is a 52-item self-report measure assessing 7 dimensions of pathological narcissism spanning problems with narcissistic grandiosity (Entitlement Rage, Exploitativeness, Grandiose Fantasy, Self-sacrificing Self-enhancement) and narcissistic vulnerability (Contingent Self-esteem, Hiding the Self, Devaluing). The PNI structure was validated via confirmatory factor analysis. The PNI correlated negatively with self-esteem and empathy, and positively with shame, interpersonal distress, aggression, and borderline personality organization. Grandiose PNI scales were associated with vindictive, domineering, intrusive, and overly-nurturant interpersonal problems, and vulnerable PNI scales were associated with cold, socially avoidant, and exploitable interpersonal problems. In a small clinical sample, PNI scales exhibited significant associations with parasuicidal behavior, suicide attempts, homicidal ideation, and several aspects of psychotherapy utilization.


Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway.
Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of chordoma. In view of the reported association of chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.


Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice.
Syndecan-1 is a cell-surface, heparan-sulphate proteoglycan (HSPG) predominantly expressed by epithelial cells. It binds specifically to many proteins, including oncoproteins. For example, it induces the assembly of a signalling complex between FGF ligands and their cognate receptors. But so far there has been no direct evidence that this proteoglycan contributes to tumorigenesis. Here we have examined the role of syndecan-1 (encoded by Sdc1) during mammary tumour formation in response to the ectopic expression of the proto-oncogene Wnt1. We crossed syndecan-1-deficient mice with transgenic mice that express Wnt1 in mammary gland (TgN(Wnt-1)1Hev; ref. 2). Ectopic Wnt-1 expression induces generalized mammary hyperplasia, followed by the development of solitary tumours (median time 22 weeks). We show that in Sdc1-/- mice, Wnt-1-induced hyperplasia in virgin mammary gland was reduced by 70%, indicating that the Wnt-1 signalling pathway was inhibited. Of the 39 tumours that developed in a test cohort of mice, only 1 evolved in the Sdc1-/- background. In addition, we show that soluble syndecan-1 ectodomain purified from mouse mammary epithelial cells stimulates the activity of a Wnt-1 homologue in a tissue culture assay. Our results provide both genetic and biochemical evidence that syndecan-1 can modulate Wnt signalling, and is critical for Wnt-1-induced tumorigenesis of the mouse mammary gland.


A multistate epidemic outbreak of Salmonella Goldcoast infection in humans, June 2009 to March 2010: the investigation in Italy.
After an urgent inquiry into a suspected international outbreak of Salmonella Goldcoast infection was launched by Hungary in October 2009 a nationwide multidisciplinary investigation was carried out in Italy. The aims were to verify whether the higher than expected number of cases of S. Goldcoast infection that had occurred in Italy in the previous months were linked to the outbreak in Hungary and to determine their origin. Between June 2009 and March 2010, 79 confirmed cases of S. Goldcoast infection were identified. Of these, 17 were part of three different point-source outbreaks probably associated with the consumption of salami. Eating salami was also reported by 20 of the 39 sporadic cases that could be interviewed. Fifteen strains of S. Goldcoast isolated from the cases were typed by pulsed-field gel electrophoresis. They shared more than 90% homology with the Hungarian epidemic strain and were also highly similar to S. Goldcoast strains that had been isolated in Italy from pigs and pork-containing food items in 2009 and 2010. Although the origin of the outbreak and the common source linking the Hungarian and the Italian cases could not be definitively identified, our results suggest a possible zoonotic connection of the outbreak cases with the pork production chain.


Fiber-format CARS spectroscopy by spectral compression of femtosecond pulses from a single laser oscillator.
We demonstrate an approach to coherent anti-Stokes Raman scattering (CARS) spectroscopy/microscopy based on spectral compression of femtosecond pulses emitted by a compact Er-fiber oscillator. Spectral compression is achieved by group-velocity mismatched second-harmonic generation in periodically poled nonlinear crystals, and it allows efficient synthesis of synchronized narrow-bandwidth (less than 10 cm(-1)) pump and Stokes pulses with the frequency difference continuously tunable up to approximately 3000 cm(-1). CARS signal enhancement by up to 3 orders of magnitude is obtained by interferometric superposition with a phase-coherent local oscillator field, also synthesized by spectral compression.


A golden orb-weaver spider (Araneae: Nephilidae: Nephila) from the Middle Jurassic of China.
Nephila are large, conspicuous weavers of orb webs composed of golden silk, in tropical and subtropical regions. Nephilids have a sparse fossil record, the oldest described hitherto being Cretaraneus vilaltae from the Cretaceous of Spain. Five species from Neogene Dominican amber and one from the Eocene of Florissant, CO, USA, have been referred to the extant genus Nephila. Here, we report the largest known fossil spider, Nephila jurassica sp. nov., from Middle Jurassic (approx. 165 Ma) strata of Daohugou, Inner Mongolia, China. The new species extends the fossil record of the family by approximately 35 Ma and of the genus Nephila by approximately 130 Ma, making it the longest ranging spider genus known. Nephilidae originated somewhere on Pangaea, possibly the North China block, followed by dispersal almost worldwide before the break-up of the supercontinent later in the Mesozoic. The find suggests that the palaeoclimate was warm and humid at this time. This giant fossil orb-weaver provides evidence of predation on medium to large insects, well known from the Daohugou beds, and would have played an important role in the evolution of these insects.


Food-web structure in relation to environmental gradients and predator-prey ratios in tank-bromeliad ecosystems.
Little is known of how linkage patterns between species change along environmental gradients. The small, spatially discrete food webs inhabiting tank-bromeliads provide an excellent opportunity to analyse patterns of community diversity and food-web topology (connectance, linkage density, nestedness) in relation to key environmental variables (habitat size, detrital resource, incident radiation) and predators:prey ratios. We sampled 365 bromeliads in a wide range of understorey environments in French Guiana and used gut contents of invertebrates to draw the corresponding 365 connectance webs. At the bromeliad scale, habitat size (water volume) determined the number of species that constitute food-web nodes, the proportion of predators, and food-web topology. The number of species as well as the proportion of predators within bromeliads declined from open to forested habitats, where the volume of water collected by bromeliads was generally lower because of rainfall interception by the canopy. A core group of microorganisms and generalist detritivores remained relatively constant across environments. This suggests that (i) a highly-connected core ensures food-web stability and key ecosystem functions across environments, and (ii) larger deviations in food-web structures can be expected following disturbance if detritivores share traits that determine responses to environmental changes. While linkage density and nestedness were lower in bromeliads in the forest than in open areas, experiments are needed to confirm a trend for lower food-web stability in the understorey of primary forests.


Progression and impact of the first winter wave of the 2009 pandemic H1N1 influenza in New South Wales, Australia.
A range of surveillance systems were used to assess the progression and impact of the first wave of pandemic H1N1 influenza in New South Wales, Australia during the southern hemisphere winter. Surveillance methods included laboratory notifications, near real-time emergency department syndromic surveillance, ambulance despatch surveillance, death certificate surveillance and purpose-built web-based data systems to capture influenza clinic and intensive care unit activity. The epidemic lasted 10 weeks. By 31 August 2009, 1,214 people with pandemic H1N1 influenza infection were hospitalised (17.2 per 100,000 population), 225 were admitted to intensive care (3.2 per 100,000), and 48 died (0.7 per 100,000). Children aged 0-4 years had the highest hospitalisation rates, while adults aged 50-54 had the highest rates of intensive care admission. During the epidemic period, overall presentations to emergency departments were 6% higher than in 2008, while presentations for influenza-like illness were 736% higher. At the peak, confirmed cases of pandemic H1N1 influenza consumed 15% of intensive care capacity. Excess mortality from influenza and pneumonia was lower than in recent influenza seasons. Health services, particularly emergency departments and intensive care units, were substantially affected by the epidemic. Mortality from influenza was comparable with previous seasons.


[Non-motor symptoms in myasthenia gravis: attributed to T-cell clones from thymoma].
Autoimmune myasthenia gravis (MG) comprises a broad spectrum of non-motor symptoms. Patients with MG sometimes have psychiatric symptoms, such as depression and anxiety, which impair their quality of life. However, these symptoms are not principally immune-mediated. Moreover, some patients with MG have additional autoimmune disorders. The clinical manifestations of these diseases are also considered non-motor symptoms, even though the autoimmune mechanisms underlying the association between MG and these disorders are not fully understood. In this review, we clarify that the non-motor symptoms of autoimmune disorders are attributed to abnormal T-cell clones from thymomas. We review the clinical characteristics of patients with MG and associated thymomas who exhibit non-motor symptoms based on previously reported cases and our multicenter cooperative study. CD8+ T-cell cytotoxicity against hematopoietic precursor cells in the bone marrow and unidentified autoantigens in hair follicles result in the development of pure red cell aplasia, immunodeficiency, and alopecia areata. In contrast, neuromyotonia, limbic encephalitis, myocarditis, and taste disorders are autoantibody-mediated disorders, as is MG. Autoantibodies to several types of voltage-gated potassium channels and related molecules can evoke various neurological and cardiac disorders. Approximately 25% of patients with MG and associated thymomas experience at least one non-motor symptom. Non-motor symptoms affect many target organs and result in a broad disease spectrum, ranging from the impairment of quality of life to lethal conditions.


Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.
HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.


MR and CT of tuberous sclerosis: linear abnormalities in the cerebral white matter.
A review of MR and CT images in five patients, 8 months to 22 years old, diagnosed as having tuberous sclerosis, revealed linear abnormalities in the cerebral white matter. A linear abnormality connecting a subependymal nodule to a subcortical lesion was shown in two patients as an area of hypointensity on T1-weighted MR images and as an area of hyperintensity on T2-weighted images. These appeared as faintly high-density areas on CT images. Seventeen linear abnormalities extending from the ventricle to the cortex with a subependymal nodule or subcortical lesion on each end were visible in all five patients as areas of hyperintensity on the T2-weighted images. On the T1-weighted images, only nine hypointense lines were noted. CT scans did not show these latter lines. Linear abnormalities in cerebral white matter are suggestive of lesions of demyelination, dysmyelination, hypomyelination, or lines of migration disorder. MR imaging, especially T2-weighted, is particularly sensitive in detecting these abnormalities.


Associations between food group intakes and circulating insulin-like growth factor-I in the UK Biobank: a cross-sectional analysis.
Circulating insulin-like growth factor-I (IGF-I) concentrations have been positively associated with risk of several common cancers and inversely associated with risk of bone fractures. Intakes of some foods have been associated with increased circulating IGF-I concentrations; however, evidence remains inconclusive. Our aim was to assess cross-sectional associations of food group intakes with circulating IGF-I concentrations in the UK Biobank. At recruitment, the UK Biobank participants reported their intake of commonly consumed foods. From these questions, intakes of total vegetables, fresh fruit, red meat, processed meat, poultry, oily fish, non-oily fish, and cheese were estimated. Serum IGF-I concentrations were measured in blood samples collected at recruitment. After exclusions, a total of 438,453 participants were included in this study. Multivariable linear regression was used to assess the associations of food group intakes with circulating IGF-I concentrations. Compared to never consumers, participants who reported consuming oily fish or non-oily fish ≥ 2 times/week had 1.25 nmol/L (95% confidence interval:1.19-1.31) and 1.16 nmol/L (1.08-1.24) higher IGF-I concentrations, respectively. Participants who reported consuming poultry ≥ 2 times/week had 0.87 nmol/L (0.80-0.94) higher IGF-I concentrations than those who reported never consuming poultry. There were no strong associations between other food groups and IGF-I concentrations. We found positive associations between oily and non-oily fish intake and circulating IGF-I concentrations. A weaker positive association of IGF-I with poultry intake was also observed. Further research is needed to understand the mechanisms which might explain these associations.


Perchlorate exposure from infant formula and comparisons with the perchlorate reference dose.
Perchlorate exposure may be higher in infants compared with older persons, due to diet (infant formula) and body weight versus intake considerations. Our primary objective was to quantitatively assess perchlorate concentrations in commercially available powdered infant formulas (PIFs). Secondary objectives were: (1) to estimate exposure in infants under different dosing scenarios and compare them with the perchlorate reference dose (RfD); (2) estimate the perchlorate concentration in water used for preparing PIFs that would result in a dose exceeding the RfD; and (3) estimate iodine intakes from PIFs. We quantified perchlorate levels in three samples (different lot numbers) of reconstituted PIF (using perchlorate-free water) from commercial brands of PIF in each of the following categories: bovine milk-based with lactose, soy-based, bovine milk-based but lactose-free, and elemental (typically consisting of synthetic amino acids). Exposure modeling was conducted to determine whether the RfD might be exceeded in 48 dosing scenarios that were dependent on age, centile energy intake per unit of body weight, body weight percentile, and PIF perchlorate concentration. We obtained three different samples in each of the five brands of bovine- and soy-based PIF, three different samples in each of the three brands of lactose-free PIF, and three different samples in two brands of elemental PIF. The results were as follows: bovine milk-based with lactose (1.72 microg/l, range: 0.68-5.05); soy-based (0.21 microg/l, range: 0.10-0.44); lactose-free (0.27 microg/l, range: 0.03-0.93); and elemental (0.18 microg/l, range: 0.08-0.4). Bovine milk-based PIFs with lactose had a significantly higher concentration of perchlorate (P<0.05) compared with all. Perchlorate was a contaminant of all commercially available PIFs tested. Bovine milk-based PIFs with lactose had a significantly higher perchlorate concentration perchlorate than soy, lactose-free, and elemental PIFs. The perchlorate RfD may be exceeded when certain bovine milk-based PIFs are ingested and/or when PIFs are reconstituted with perchlorate-contaminated water.


Computer determination of contact stress distribution and size of weight bearing area in the human hip joint.
The mathematical models and the corresponding computer program for determination of the hip joint contact force, the contact stress distribution, and the size of the weight bearing area from a standard anteroposterior radiograph are described. The described method can be applied in clinical practice to predict an optimal stress distribution after different operative interventions in the hip joint and to analyze the short and long term outcome of the treatment of various pathological conditions in the hip. A group of dysplastic hips and a group of normal hips were examined, with respect to the peak contact stress normalized by the body weight, and with respect to the functional angle of the weight bearing area. It is shown that both these parameters can be used in the assessment of hip dysplasia.


Zwitterionic chitosan-polyamidoamine dendrimer complex nanoparticles as a pH-sensitive drug carrier.
Polyamidoamine (PAMAM) dendrimers have been widely explored as carriers of therapeutics and imaging agents. However, amine-terminated PAMAM dendrimers are rarely utilized in systemic applications due to their cytotoxicity and risk of opsonization, caused by their cationic charges. Such undesirable effects may be mitigated by shielding the PAMAM dendrimer surface with polymers that reduce the charges. However, this shielding may also interfere with the PAMAM dendrimers' ability to interact with target cells, thus reducing the cellular uptake and overall efficacy of the delivery system. Therefore, we propose to use zwitterionic chitosan (ZWC), a new chitosan derivative, which has a unique pH-sensitive charge profile, as an alternative biomaterial to modify the cationic surface of PAMAM dendrimers. A stable electrostatic complex of ZWC and PAMAM dendrimers was formed at pH 7.4, where the PAMAM dendrimer surface was covered with ZWC, as demonstrated by fluorescence spectroscopy and transmission electron microscopy. The presence of ZWC coating protected red blood cells and fibroblast cells from hemolytic and cytotoxic activities of PAMAM dendrimers, respectively. Confocal microscopy showed that the protective effect of ZWC disappeared at low pH as the complex dissociated due to the charge conversion of ZWC, allowing PAMAM dendrimers to enter cells. These results demonstrate that ZWC is able to provide a surface coverage of PAMAM dendrimers in a pH-dependent manner and, thus, enhance the utility of PAMAM dendrimers as a drug carrier to solid tumors with acidifying microenvironments.


Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations.
The dopamine transporter (DAT) provides major regulation of the synaptic levels of dopamine and is a principal target of psychostimulant drugs. Associations between DAT gene polymorphisms and human disorders with possible links to dopaminergic neurotransmission, including attention-deficit/hyperactivity disorder (ADHD) and consequences of cocaine and alcohol administration, have been reported. We now report approximately 60000 bp of genomic sequence containing the entire DAT gene. This sequence was used to amplify each of the 15 DAT gene exons and several introns and analyze these amplification products by single-stranded sequence conformation (SSCP) and/or direct sequencing. These results define silent allelic single nucleotide sequence variants in DAT gene exons 2, 6, 9 and 15. Rare conservative mutations are identified in amino acids encoded by DAT exons 2 and 8. Analyses of the common nucleotide variants and the previously reported VNTR in the non-coding region of exon 15 define the pattern of linkage disequilibrium across the DAT locus. These comprehensive analyses, however, fail to identify any common protein coding DAT sequence variant in more than 150 unrelated individuals free of neuropsychiatric disease, 109 individuals meeting City of Hope criteria for Tourette's syndrome, 64 individuals with DSM-IV diagnoses of ethanol dependence, or 15 individuals with ADHD. These data are consistent with substantial evolutionary conservation of the DAT protein sequence. They suggest that gene variants that alter levels of DAT expression provide the best current candidate mechanism for reported associations between DAT gene markers, ADHD and other more tentatively associated neuropsychiatric disorders.


Molecular characterisation of methicillin-resistant Staphylococcus aureus (MRSA) from keratitis patients: a microbiological analysis.
In order to diagnose and characterise a major corneal infection, 'keratitis,' which can lead to blindness, molecular studies were conducted to assess the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains in patients suffering from keratitis. The selected culture positive for strains of S aureus were subjected to 18 antimicrobial drugs for their sensitivity behaviour, and the minimum inhibitory concentration (MIC) of oxacillin was determined by the microdilution method as recommended by the National Committee for Clinical Laboratory Standards. Further, S strains were characterised using molecular tools. Among the 202 cases included in the present study, 64 (31.2%) cases were found to be S aureus-positive, of which only six strains were MRSA. The highest resistance was observed for penicillin (65.6%) which was followed by a significant number of bacterial isolates showing resistance to methicillin (9.3%), while all organisms were susceptible to vancomycin. The minimum inhibitory concentrations of oxacillin for MRSA strains ranged between 16 and 128 microg/ml. A multiplex PCR assay for Staphylococcal Cassette Chromosome mec complex (SCCmec) of MRSA strains (N=6) showed that five MRSA strains had a Type III cassette, and one had a Type II cassette. The pulsed field gel electrophoresis of three MRSA strains showed closely related band patterns. The close relatedness among bacterial strains as observed by employing different typing techniques suggests that the clonal characteristics of multiresistant MRSA isolates could be deciphered. The presence of Type II SCCmec in keratitis subjects is probably the first report from India, as it has not been reported earlier.


Parallel game-tree search.
The design issues affecting a parallel implementation of the alpha-beta search algorithm are discussed with emphasis on a tree decomposition scheme that is intended for use on well ordered trees. In particular, the principal variation splitting method has been implemented, and experimental results are presented which show how such refinements as progressive deepening, narrow window searching, and the use of memory tables affect the performance of multiprocessor based chess playing programs. When dealing with parallel processing systems, communication delays are perhaps the greatest source of lost time. Therefore, an implementation of our tree decomposition based algorithm is presented, one that operates with a modest amount of message passing within a network of processors. Since our system has low search overhead, the principal basis for comparison is the communication overhead, which in turn is shown to have two components.


Targeted expression of BikDD eliminates breast cancer with virtually no toxicity in noninvasive imaging models.
Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer. Therefore, novel and more effective treatments are critically needed. Of the current methods, targeted therapy, which not only retains cancer-specific expression but also limits toxicity, is a new strategy for treating cancers. In this study, we found that the human telomerase reverse transcriptase (hTERT; T) promoter also possesses high target specificity in breast cancer. Moreover, we developed a versatile T-based breast cancer-specific promoter VISA (VP16-Gal4-WPRE integrated systemic amplifier) composite (T-VISA) to target transgene expression in breast tumors, which has stronger activity comparable or higher than that of the cytomegalovirus promoter in cancer cells. Thereafter, targeted expression of BikDD (a mutant form of proapoptotic gene Bik) through the T-VISA platform in breast cancer initiated robust antitumor effects and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of breast tumors with virtually no toxicity in intact mice. Thus, these findings show that our T-VISA-BikDD nanoparticles effectively and safely eradicate breast cancer in vitro and in vivo and are worthy of development in clinical trials treating breast cancer.