Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.
In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.


Cost-effectiveness of adult spinal deformity surgery in a military healthcare system.
OBJECTIVEAdult spinal deformity surgery is an effective way of treating pain and disability, but little research has been done to evaluate the costs associated with changes in health outcome measures. This study determined the change in quality-adjusted life years (QALYs) and the cost per QALY in patients undergoing spinal deformity surgery in the unique environment of a military healthcare system (MHS).METHODSPatients were enrolled between 2011 and 2017. Patients were eligible to participate if they were undergoing a thoracolumbar spinal fusion spanning more than 6 levels to treat an underlying deformity. Patients completed the 36-Item Short Form Health Survey (SF-36) prior to surgery and 6 and 12 months after surgery. The authors used paired t-tests to compare SF-36 Physical Component Summary (PCS) scores between baseline and postsurgery. To estimate the cost per QALY of complex spine surgery in this population, the authors extended the change in health-related quality of life (HRQOL) between baseline and follow-up over 5 years. Data on the cost of surgery were obtained from the MHS and include all facility and physician costs.RESULTSHRQOL and surgical data were available for 49 of 91 eligible patients. Thirty-one patients met additional criteria allowing for cost-effectiveness analysis. Over 12 months, patients demonstrated significant improvement (p < 0.01) in SF-36 PCS scores. A majority of patients met the minimum clinically important difference (MCID; 83.7%) and substantive clinical benefit threshold (SCBT; 83.7%). The average change in QALY was an increase of 0.08. Extended across 5 years, including the 3.5% discounting per year, study participants increased their QALYs by 0.39, resulting in an average cost per QALY of $181,649.20. Nineteen percent of patients met the < $100,000/QALY threshold with half of the patients meeting the < $100,000/QALY mark by 10 years. A sensitivity analysis showed that patients who scored below 60 on their preoperative SF-36 PCS had an average increase in QALYs of 0.10 per year or 0.47 over 5 years.CONCLUSIONSWith a 5-year extended analysis, patients who receive spinal deformity surgery in the MHS increased their QALYs by 0.39, with 19% of patients meeting the $100,000/QALY threshold. The majority of patients met the threshold for MCID and SCBT at 1 year postoperatively. Consideration of preoperative functional status (SF-36 PCS score < 60) may be an important factor in determining which patients benefit the most from spinal deformity surgery.


Creatine Supplementation Increases Total Body Water Without Altering Fluid Distribution.
OBJECTIVE: To examine the effects of oral creatine (Cr) monohydrate supplementation on muscle Cr concentration, body mass, and total body water (TBW), extracellular water (ECW), and intracellular water (ICW) volumes. DESIGN AND SETTING: After an overnight fast, urinary Cr and creatinine concentrations, muscle Cr concentration, body mass, TBW, ECW, and ICW were measured, and subjects were randomly assigned to either a Cr or a placebo (P) group. The Cr group ingested 25 g/d of Cr for 7 days (loading phase) and 5 g/d for the remaining 21 days (maintenance phase), whereas the P group ingested a sucrose P using the same protocol. All the measures were reassessed immediately after the loading and maintenance phases. SUBJECTS: Sixteen men (age = 22.8 +/- 3.01 years, height = 179.8 +/- 7.1 cm, body mass = 84.8 +/- 11.2 kg) and 16 women (age = 21.8 +/- 2.51 years, height = 163.4 +/- 5.9 cm, body mass = 63.6 +/- 14.0 kg) involved in resistance training volunteered to participate in this study. MEASUREMENTS: Muscle Cr concentration was determined from the vastus lateralis muscle using a percutaneous needle-biopsy technique. Total body water, ECW, and ICW volumes were assessed using deuterium oxide and sodium bromide dilution analyses. RESULTS: The Cr group experienced a significant increase in muscle Cr concentration, body mass, and TBW. The P group experienced a small but significant increase in TBW only. CONCLUSIONS: The Cr supplementation protocol was effective for increasing muscle Cr concentrations, body mass, and TBW; however, fluid distribution was not changed.


Acetabular labral tear complicating idiopathic osteonecrosis of the femoral head treated by labral repair with hip arthroscopy: a case report.
It has been well documented that labral tear is frequently associated with femoroacetabular impingement and dysplasia of the hip; however, there have been few reported cases of labral tear associated with idiopathic osteonecrosis of the hip. Here we report the case of a patient with labral tear associated with idiopathic osteonecrosis of the femoral head who was treated by hip arthroscopy, with a favorable short-term outcome. Under the diagnosis of systemic lupus erythematosus, a 28-year-old Japanese woman was treated with the oral administration of steroid in 2007. A year after the treatment, she developed right hip joint pain and was diagnosed with idiopathic osteonecrosis of the femoral head at our institution. In November of 2011, she revisited our hospital when her right hip joint pain exacerbated and she became unable to walk. On the visit, the anterior impingement sign and Patrick test were positive. Radiography and magnetic resonance imaging in 2011 demonstrated neither spreading of the osteonecrosis area nor collapse of the femoral head in the right joint; however, magnetic resonance imaging showed a high-intensity area in the articular labrum in a T2-weighted image, leading to a diagnosis of labral tear. She underwent labral repair with hip arthroscopy in August of 2012. Now, 1 year after surgery, she does not feel any pain during walking and her modified Harris hip score has improved from 20 prior to surgery to 85. The case indicated that it is important to be aware of the possibility of labral tear in patients with idiopathic osteonecrosis of the femoral head, when spreading of the osteonecrosis area or collapse of the femoral head has not been seen on magnetic resonance imaging.


Properties of the dorsalizing signal in gastrulae of Xenopus laevis.
According to the 'three signal model', the regional specification of tissue type within the mesoderm of Xenopus laevis occurs in a process called 'dorsalization'. We have studied the timing and transmission characteristics of this signal, and assessed the dorsalizing activity of the lithium ion and a panel of cytokines.The marginal zone has been fate mapped during gastrulation by colloidal gold labelling and it is shown that the ventral tissue undergoes substantial circumferential expansion. The fate map information is used to provide tissues of constant cellular composition for experiments conducted at different stages.The stage at which dorsalization can occur has been investigated by means of heterochronic dorsal-ventral combinations. The results indicate that the interaction occurs during gastrulation, with a decline in both signal strength and competence of the ventral marginal zone to respond as gastrulation proceeds.The signal is capable of passing through arrangements of membranes that exclude the possibility of cytoplasmic contact, implying that it can be carried by a diffusible morphogen.The effect on the ventral marginal zone of lithium and a number of cytokines has also been studied. While none appears to function as a dorsalizing signal, lithium acts during blastula stages to alter the response to the mesoderm-inducing signal such that the inductions are of a more dorsal character.These data confirm that the dorsalizing signal is independent of and operates later than the signal(s) from the vegetal hemisphere that induce mesoderm during the blastula stages.


Reversible water activation driven by contraction and expansion of a 12-vertex-closo-12-vertex-nido biscarborane cluster.
The activation of O-H bonds of water at room temperature driven by the cage-opening rearrangement of a biscarborane-based cluster is reported. The reaction of the 12-vertex-closo-12-vertex-nido biscarborane cluster with water led to the quantitative and selective two-vertex decapitation of a carborane cluster and formation of the pendent boronic acid hydride B(H)(OH) group. Remarkably, this transformation can be quantitatively reversed with the release of water and re-formation of the starting biscarborane cage. The flexibility of cage decapitation/expansion and its influence on the reactivity of an exohedral substituent represent a new approach to cluster-induced organic transformations.


The association between family members' migration and cognitive function among people left behind in China.
While internal migration is widely occurring in countries across the world and older people are more likely to be left behind by family members who out-migrated to other locations, little attention has been paid to the cognitive health of those people who have been left behind (PLB). Understanding how these demographic patterns relate to older persons' cognitive health may inform efforts to reduce the disease burden due to cognitive decline. Data came from the China Health and Nutrition Survey in 1997, 2000 and 2004. Participants aged 55 to 93 who participated in a cognitive function screening test (score range: 0-31) in two or more waves and provided information on family members' migration (n = 1,267) were included in the analysis. A mixed linear model was used to investigate the association between being left behind by any members who had not resided in the household for at least 6 months at baseline and cognitive function. Approximately 10% of the participants had been left behind by family members who migrated out of their communities. A significant interaction was observed in relation to cognitive function between being left behind and the number of years from the first test. Specifically, there was a less steep decline in cognitive function of PLB compared to people not left behind. This longitudinal study showed that PLB tended to have a higher cognitive function compared to those not left behind due to their relatively stable transition in cognitive function during the study period.


MetaPath Online: a web server implementation of the network expansion algorithm.
We designed a web server for the analysis of biosynthetic capacities of metabolic networks. The implementation is based on the network expansion algorithm and the concept of scopes. For a given network and predefined external resources, called the seed metabolites, the scope is defined as the set of products which the network is in principle able to produce. Through the web interface the user can select a variety of metabolic networks or provide his or her own list of reactions. The information on the organism-specific networks has been extracted from the KEGG database. By choosing an arbitrary set of seed compounds, the user can obtain the corresponding scopes. With our web server application we provide an easy to use interface to perform a variety of structural and functional network analyses. Problems that can be addressed using the web server include the calculation of synthesizing capacities, the visualization of synthesis pathways, functional analysis of mutant networks or comparative analysis of related species. The web server is accessible through http://scopes.biologie.hu-berlin.de.


Toxoplasma gondii profilin acts primarily to sequester G-actin while formins efficiently nucleate actin filament formation in vitro.
Apicomplexan parasites employ gliding motility that depends on the polymerization of parasite actin filaments for host cell entry. Despite this requirement, parasite actin remains almost entirely unpolymerized at steady state; formation of filaments required for motility relies on a small repertoire of actin-binding proteins. Previous studies have shown that apicomplexan formins and profilin exhibit canonical functions on heterologous actins from higher eukaryotes; however, their biochemical properties on parasite actins are unknown. We therefore analyzed the impact of T. gondii profilin (TgPRF) and FH1-FH2 domains of two formin isoforms in T. gondii (TgFRM1 and TgFRM2) on the polymerization of T. gondii actin (TgACTI). Our findings based on in vitro assays demonstrate that TgFRM1-FH1-FH2 and TgFRM2-FH1-FH2 dramatically enhanced TgACTI polymerization in the absence of profilin, making them the sole protein factors known to initiate polymerization of this normally unstable actin. In addition, T. gondii formin domains were shown to both initiate polymerization and induce bundling of TgACTI filaments; however, they did not rely on TgPRF for these activities. In contrast, TgPRF sequestered TgACTI monomers, thus inhibiting polymerization even in the presence of formins. Collectively, these findings provide insight into the unusual control mechanisms of actin dynamics within the parasite.


A descriptive cross-sectional study of cholera at Kakuma and Kalobeyei refugee camps, Kenya in 2018.
cholera is a significant public health concern among displaced populations. Oral cholera vaccines are safe and can effectively be used as an adjunct to prevent cholera in settings with limited access to water and sanitation. Results from this study can inform future consideration for cholera vaccination at Kakuma and Kalobeyei. a descriptive cross-sectional study of cholera cases at Kakuma refugee camp and Kalobeyei integrated settlement was carried out between May 2017 to May 2018 (one year). Data were extracted from the medical records and line lists at the cholera treatment centres. the results found 125 clinically suspected and confirmed cholera cases and one related death (CFR 0.8%). The cumulative incidence of all cases was 0.67 (95% CI=0.56-0.80) cases/1000 persons. Incidence of cholera was higher in children under the age of five 0.94(95% CI=0.63-1.36) cases/1000 persons. Children aged <5 years showed 51% increased risk of cholera compared to those aged ≥5 years (RR=1.51; 95% CI=1.00-2.31, p=0.051). Individuals from the Democratic Republic of Congo had nearly 9-fold risk of reporting cholera (RR=8.62; 95% CI=2.55-37.11, p<0.001) while individuals from South Sudan reported 7 times risk of cholera case compared to those from Somalia (RR=7.39; 95% CI=2.78-27.73, p<0.001). in addition to the improvement of water, sanitation and hygiene (WaSH), vaccination could be implemented as a short-medium term measure of preventing cholera outbreaks. Age, country of origin and settlement independently predicted the risk of cholera.


[Mortality from contact with poisonous snakes and lizards in Mexico from 1979 to 2003].
To describe the trend of standardized mortality by contact with poisonous snakes and lizards in Mexico from 1979 to 2003. We describe the standardized mortality trend by contact with poisonous snakes and lizards occurring in Mexico from 1979 to 2003, and report the mortality data bases from the INEGI (Instituto Nacional de Estadística, Geografía e Informática). We determined frequencies, percentages, mortality rates, standardized mortality rates and mortality relative risks with 95% confidence intervals. The general trend shows a statistically significant descent of 63.8%. The highest mortality rate within the 2000-2003 period was reported in Quintana Roo (7.47/1,000,000), Oaxaca (4.01/1,000,000), Veracruz (1.56/1,000,000), Chiapas (1.48/1,000,000), Campeche (1.43/1,000,000) and Yucatan (1.29/1,000,000). The groups with the highest risk are those older than 60 years and males. In spite of the detected decrease in mortality, the contact with poisonous snakes and lizards still is a public health problem in Mexico. As timely treatment saves lives, it is necessary to include and offer treatment in all emergency units of the country.


Virus-free transfer of the herpes simplex virus thymidine kinase gene followed by ganciclovir treatment induces tumor cell death.
We report virus-free transfer of a "suicide" gene into tumoral cells. The system can be used in vitro or in vivo to induce tumor cell death. A plasmid carrying the herpes simplex virus thymidine kinase (HSV-TK) gene with its 5'- and 3'-flanking regions was used both alone and in liposomes to transduce B16 cells. In vitro, a 5-day treatment with ganciclovir after transfection with the HSV-TK gene in liposomes induced a significant lysis of B16 melanoma cells as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. The efficacy of transfection was determined using liposomes harboring the beta-galactosidase reporter gene and was around 10%. Thus, the cytotoxicity observed resulted presumably from a large bystander effect. In vivo, direct transfer of the TK DNA into established B16 melanoma tumors in C57B6 mice followed by i.p. ganciclovir treatment induced a 50% reduction of tumor weight after 8 days and an increased necrosis. Despite the use of the nonspecific strong TK promoter, no necrosis was detected in normal tissues surrounding the tumor or elsewhere. Thus, this system of tumor transfection, which does not involve any viral vector, is safe and straightforward and seems to be suitable for testing in clinical trials.


Comparison of blood flow velocities of the extraocular vessels in patients with pseudoexfoliation or primary open-angle glaucoma.
To evaluate orbital blood flow velocities in patients with pseudoexfoliation glaucoma (PXG) or primary open-angle glaucoma (POAG). Blood flow velocities in the ophthalmic, central retinal, and posterior ciliary arteries were evaluated by color Doppler imaging in 26 patients with PXG, 28 patients with POAG and 30 age-matched normal control subjects. The results were compared. Compared to the control subjects, patients with PXG showed statistically significant decreases in the mean peak systolic and end-diastolic velocities and increased mean resistive indices in all vessels except for the ophthalmic artery mean peak systolic velocity (p < 0.05). Patients with POAG, when compared to the control subjects, showed statistically significant decreases in the mean end-diastolic velocities and increased mean resistive indices in all vessels measured (p < 0.05). No statistically significant differences were found in the mean blood flow parameters between POAG and PXG. Blood flow velocities of the retrobulbar vessels are decreased in patients with PXG. Reduced blood flow velocities may be secondary as well as contributory to exfoliative glaucomatous damage. Although there was no significant difference in the mean blood flow parameters between POAG and PXG, alterations of retrobulbar vessels might be associated with different pathogenic mechanisms of PXG.


Streptococcusdentiloxodontae sp. nov., isolated from the oral cavity of elephants.
A Gram-stain-positive, catalase-negative, coccus-shaped organism was isolated from oral cavity samples collected from healthy elephants. The isolated strain, NUM 2404T, was tentatively identified as a streptococcal species based on the results of biochemical tests. Although a comparative 16S rRNA gene sequence analysis suggested the classification of this organism into the genus Streptococcus, it did not correspond to any recognized species of the genus. Strain NUM 2404T was related most closely to Streptococcus saliviloxodontae NUM 6306T with 95.8 % 16S rRNA gene sequence similarity, but the phylogenetic tree reconstructed based on the 16S rRNA gene sequence showed that NUM 2404T clustered with Streptococcus mutans NCTC 10449T and Streptococcus troglodytae TKU 31T. Comparative sequence analysis based on two housekeeping genes, groEL, which encodes the 60 kDa heat-shock protein, and rpoB, encoding the β subunit of RNA polymerase, of NUM 2404T indicated that it was most closely related to those of Streptococcus orisratti A63T and Streptococcus sobrinus ATCC 33478T with 82.7 and 85.1 % sequence similarities, respectively. On the basis of genotypic and phenotypic differences, it is proposed that the novel isolate be classified in the genus Streptococcus as representative of a novel species, Streptococcus dentiloxodontae sp. nov. The type strain is NUM 2404T (=JCM 19284T=DSM 27381T).


Cardiovascular calcification in Hispanic Americans (HA) with chronic kidney disease (CKD) due to type 2 diabetes.
Cardiovascular calcification (CVC) is common and severe in patients with end-stage renal disease on dialysis. However, the prevalence and severity of CVC is less well documented in patients with chronic kidney disease (CKD) not yet on dialysis. Fifty-eight nondialyzed HA with type 2 diabetes and CKD were enrolled. They comprise 29 patients with stages 1 and 2 CKD (early CKD group) and 26 patients with stages 4 and 5 CKD (advanced CKD group). Coronary artery calcification (CAC) was measured by ultrafast spiral computed tomography, while peripheral artery calcification (PAC) was evaluated by plain x-ray of the chest, pelvis, thighs, and lower extremities. The prevalence of CAC and PAC were significantly higher in the advanced CKD group compared to the early CKD group (73% vs. 38%; P < 0.01 and 85% vs. 35%; P < 0.0001, respectively). The median CAC scores were 18-fold greater in the advanced CKD group (138.9 vs. 7.8, respectively). By linear regression analysis, a strong association was found between the level of renal function and ln total volume of CAC. Our data indicate that CAC and PAC are common and severe in HA diabetic patients with CKD not previously treated with dialysis, calcium-based phosphate binders, or vitamin D analogues. Lower level of renal function is associated with increased burden of vascular calcification in predialysis patients with CKD.


Promotion of murine orthotopic corneal allograft survival by systemic administration of anti-CD4 monoclonal antibody.
A mouse model of orthotopic corneal allograft rejection was used to examine the efficacy of anti-CD4 and anti-CD8 monoclonal antibodies in preventing immunologic rejection of corneal allografts. Although it is believed by many that corneal graft rejection is mediated, at least in part, by CD8-positive cytotoxic T-lymphocytes, systemic administration of anti-CD8 antibody did not reduce the rejection rate of corneal allografts that differed from the host at the entire major histocompatibility complex. By contrast, systemic administration of anti-CD4 monoclonal antibody reduced the rejection rate from 83% (untreated controls) to 33%. Fluorocytometric analysis of residual lymphoid populations showed that neither monoclonal antibody eliminated the inappropriate subset of T-cells in antibody-treated animals. In vitro cell-mediated cytotoxicity assays showed that both antibodies eliminated allospecific cytotoxic T-lymphocyte populations; however, only anti-CD4 antibody promoted graft survival. Thus, these results indicate that anti-CD4 monoclonal antibody is a powerful immunosuppressive agent for promoting corneal graft survival and that CD8-positive T-cells alone do not cause rejection of corneal allografts.


Hydrogen-rich saline ameliorates renal injury induced by unilateral ureteral obstruction in rats.
Hydrogen has been demonstrated to have effective protection against tissue injuries caused by oxidative stress, inflammation, and apoptosis. This study investigated the efficacy of hydrogen-rich saline (HS) on the prevention of renal injury induced by unilateral ureteric obstruction (UUO) in rats. Male Sprague-Dawley rats were divided randomly into 4 groups: sham group, UUO group, UUO+saline group, and UUO+HS group. UUO was induced by ligation of the left ureter. 5ml/kg HRSS or saline was administered beginning 1day after UUO and for 10days thereafter. Rats were killed at 10days after UUO. Left kidneys were excised immediately for the tissue histologic examinations and biochemical assays. Renal injury scores in the UUO group and the UUO+saline group were significantly higher compared with those in the sham group. However, administration of HS significantly reduced the injury score. Apoptosis index was significantly increased in UUO group and the UUO+saline group. HS treatment also reduced the apoptosis index. Interstitial fibrosis and macrophage infiltration were obvious in UUO kidneys. However, HS treatment significantly reduced the fibrosis and infiltration of macrophage in UUO kidneys. Significant increase in the MDA level and decrease in the SOD activity were observed in UUO group and the UUO+saline group. MDA level of UUO+HS group was significantly reduced. In addition, SOD activity of was significantly improved after treatment of HS. The data provide a biochemical and histologic basis for HS acting as a novel therapeutic strategy for preventing the renal injury induced by UUO.


Postatrophic hyperplasia of the prostate. A histologic mimic of prostatic adenocarcinoma.
Clusters of atrophic prostatic acini that display proliferative epithelial changes are referred to as postatrophic hyperplasia (PAH). PAH is histologically similar to adenocarcinoma and may cause diagnostic confusion. Despite the importance of distinguishing PAH from carcinoma, the last systematic study of this lesion was reported > 40 years ago, and many contemporary pathologists are unfamiliar with this lesion. We reviewed 100 consecutive whole-mount radical prostatectomy specimens removed for carcinoma to determine the incidence of PAH. In addition, 11 prostatic needle biopsy specimens with PAH were evaluated to further characterize the lesion in limited specimens. PAH was identified in 18 radical prostatectomies (18%), including 10 unicentric and eight multicentric cases. It was found exclusively in the peripheral zone in all but two cases, which had additional involvement of the transition zone. PAH consisted of a microscopic lobular cluster of small acini with irregular atrophic-appearing contours lined by cuboidal cells with mild nucleomegaly and micronucleoli; mildly enlarged nucleoli were focally present in 39% of cases. Within the small acinar cluster, a larger dilated acinus was usually present centrally, which was lined by flattened to cuboidal epithelial cells. The basal cell layer at the periphery of each acinus was invariably present but often inconspicuous. Immunohistochemical staining for high-molecular-weight keratin (antibody 34 beta E12) showed the presence of an intact basal cell layer in seven of 10 cases and a focally fragmented basal cell layer in three other cases. PAH was associated with patchy chronic inflammation in 16 of 18 prostatectomy cases; stromal changes were present in all cases, ranging from smooth atrophy to dense sclerosis with compression of acini. No intraluminal basophilic mucin was identified, but two needle biopsies showed PAH with focal mucinous metaplasia. Crystalloids were not seen in any case. Focal partial acinar involvement by high-grade prostatic intraepithelial neoplasia was present in adjacent acini in two cases. Adjacent acini also invariably showed typical changes of atrophy. In the needle biopsy specimens, PAH showed the same features as those in prostatectomies, but often only a portion of the lesion was sampled. PAH is distinguished from carcinoma by its characteristic architecture, intact or fragmented basal cell layer, inconspicuous or mildly enlarged nucleoli, and adjacent acinar atrophy with stromal fibrosis or smooth muscle atrophy. Distinguishing PAH from carcinoma is most difficult in needle biopsy specimens in which only a portion of the lesion is sampled, and awareness of this entity assists in this distinction.


Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts.
Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension-generating capacity. We demonstrated that cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts with contractile dysfunction. We employed a transgenic murine model of DCM caused by the D230N-tropomyosin (Tm) mutation and designed a sarcomere-based intervention specifically targeting the twitch tension-time integral of D230N-Tm hearts using multiscale computational models of intramolecular and intermolecular interactions in the thin filament and cell-level contractile simulations. Our models predicted that increasing the calcium sensitivity of thin filament activation using the cardiac troponin C (cTnC) variant L48Q can sufficiently augment twitch tension-time integrals of D230N-Tm hearts. Indeed, cardiac muscle isolated from double-transgenic hearts expressing D230N-Tm and L48Q cTnC had increased calcium sensitivity of tension development and increased twitch tension-time integrals compared with preparations from hearts with D230N-Tm alone. Longitudinal echocardiographic measurements revealed that DTG hearts retained normal cardiac morphology and function, whereas D230N-Tm hearts developed progressive DCM. We present a computational and experimental framework for targeting molecular mechanisms governing the twitch tension of cardiomyopathic hearts to counteract putative mechanical drivers of adverse remodeling and open possibilities for tension-based treatments of genetic cardiomyopathies.


Understanding Nepali widows' experiences for the adaptation of an instrument to assess Prolonged Grief Disorder.
The experience of grief varies across different cultures and contexts. Women in Nepal who lose their husbands confront discrimination, social isolation, and abuse that influence their experience of grief. Through eight focus group discussions with Nepali widows, we elicited socially sanctioned grief reactions and local idioms used to describe common cognitive, behavioral, and emotional symptoms of grief. Accordingly, modifications to an existing instrument for Prolonged Grief Disorder, the PG-13, are suggested to capture grief symptoms as experienced by Nepali widows. Items in the PG-13 were translated to colloquial Nepali and adapted to maintain comprehensibility, acceptability, relevance, and completeness. Based on the grief-related issues reported in the focus group discussions, the addition of five new items and a new criterion to capture symptoms related to social discrimination are proposed. Widows perceived elevated symptoms one year after the loss to be problematic. It is thus recommended that the duration criterion in the original PG-13 be adjusted from at least six months to at least one year after the loss. These proposed modifications to the instrument should be validated through future psychometric testing.


A three-dimensional breast software phantom for mammography simulation.
This paper presents a methodology for three-dimensional (3D) computer modelling of the breast, using a combination of 3D geometrical primitives and voxel matrices that can be further subjected to simulated x-ray imaging, to produce synthetic mammograms. The breast phantom is a composite model of the breast and includes the breast surface, the duct system and terminal ductal lobular units. Cooper's ligaments, the pectoral muscle, the 3D mammographic background and breast abnormalities. A second analytical x-ray matter interaction modelling module is used to generate synthetic images from monoenergetic fan beams. Mammographic images of various synthesized breast models differing in size, shape and composition were produced. A preliminary qualitative assessment performed by three radiologists and a quantitative evaluation study using fractal and grey-level histogram analysis were conducted. A comparative study of extracted features with published data has also been performed. The evaluation results indicated good correlation of characteristics between synthetic and actual radiographs. Applications foreseen are not only in the area of breast imaging experimentation but also in education and training.


Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma. An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed. There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype. The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.


Putative role of dietary trace elements in coronary heart disease and cancer.
Relatively little attention has been given to the role of dietary trace elements in oxidative processes or in the aetiologies of chronic disease processes. Iron and copper are pro-oxidants in vitro, but there is now compelling evidence that adequate body copper status is required to maintain antioxidant defences in vivo. Epidemiological evidence linking measures of high iron nutritional status with both coronary heart disease (CHD) and cancer is accumulating, although there are few mechanisms implicating iron in these disease processes apart from acting as a pro-oxidant. In contrast, low copper nutritional status may produce pro-oxidant effects and experimental evidence, especially from animal models of CHD, suggests that copper has an involvement in disease mechanisms which is much wider than simply an involvement in maintaining oxidant/antioxidant balance. Zinc is considered to have antioxidant effects in vivo but the role of zinc as an antioxidant, or in CHD and cancer processes, is presently unclear. Although selenium has for some time been recognised as an antioxidant nutrient, epidemiological data gathered to date linking this trace element with either CHD or cancer are inconsistent.


Using remote sensing to map the risk of human monkeypox virus in the Congo Basin.
Although the incidence of human monkeypox has greatly increased in Central Africa over the last decade, resources for surveillance remain extremely limited. We conducted a geospatial analysis using existing data to better inform future surveillance efforts. Using active surveillance data collected between 2005 and 2007, we identified locations in Sankuru district, Democratic Republic of Congo (DRC) where there have been one or more cases of human monkeypox. To assess what taxa constitute the main reservoirs of monkeypox, we tested whether human cases were associated with (i) rope squirrels (Funisciurus sp.), which were implicated in monkeypox outbreaks elsewhere in the DRC in the 1980s, or (ii) terrestrial rodents in the genera Cricetomys and Graphiurus, which are believed to be monkeypox reservoirs in West Africa. Results suggest that the best predictors of human monkeypox cases are proximity to dense forests and associated habitat preferred by rope squirrels. The risk of contracting monkeypox is significantly greater near sites predicted to be habitable for squirrels (OR = 1.32; 95% CI 1.08-1.63). We recommend that semi-deciduous rainforests with oil-palm, the rope squirrel's main food source, be prioritized for monitoring.


Differential growth factor content of uterine luminal fluids from large white and prolific Meishan pigs during the estrous cycle and early pregnancy.
Uterine luminal fluids (ULF) from Large White (LW) and prolific Chinese Meishan (MS) gilts were compared with respect to their peptide growth factor content during an estrous cycle and early pregnancy. Insulin-like growth factor-I (IGF-I) was quantitated by RIA; in vitro growth promoting properties of uterine luminal fluid mitogen (ULFM) were measured by [3H]thymidine incorporation into DNA of quiescent AKR-2B fibroblastic cells in culture. Peak concentrations (pg/microgram ULF protein) of IGF-I in ULF of Large White and Meishan gilts, respectively, were: estrous cycle, 9.8 +/- 1.4 (on d 10) and 39.7 +/- 7.8 (on d 12); gestation, 13.1 +/- 3.2 (on d 8 and 10) and 11.9 +/- 2.1 (on d 12), with differences among days (except d 10, P greater than .5) being affected by breed (P less than .10). For both breeds, there was a rapid decline in IGF-I concentrations by d 14 of the cycle and of pregnancy. Uterine luminal fluid mitogen activity was greater (P less than .01) for LW than for MS gilts on d 10 to 14 of an estrous cycle and gestation and diminished in a time-dependent manner in both breeds. No correlation was observed between IGF-I concentrations and uterine weights for either breed. In contrast, a negative correlation between uterine weight and ULFM activity was detected for cyclic (MS: r = -.855, P less than .10; LW: r = -.834, P less than .05) and pregnant (MS: r = -.806, P less than .10; LW: r = -.928, P less than .05) gilts.(ABSTRACT TRUNCATED AT 250 WORDS)


Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII, and XIV with l- and d-histidine and crystallographic analysis of their adducts with isoform II: engineering proton-transfer processes within the active site of an enzyme.
Activation of six human carbonic anhydrases (CA, EC 188.8.131.52), that is, hCA I, II, IV, VA, VII, and XIV, with l- and d-histidine was investigated through kinetics and by X-ray crystallography. l-His was a potent activator of isozymes I, VA, VII, and XIV, and a weaker activator of hCA II and IV. d-His showed good hCA I, VA, and VII activation properties, being a moderate activator of hCA XIV and a weak activator of hCA II and IV. The structures as determined by X-ray crystallography of the hCA II-l-His/d-His adducts showed the activators to be anchored at the entrance of the active site, contributing to extended networks of hydrogen bonds with amino acid residues/water molecules present in the cavity, explaining their different potency and interaction patterns with various isozymes. The residues involved in l-His recognition were His64, Asn67, Gln92, whereas three water molecules connected the activator to the zinc-bound hydroxide. Only the imidazole moiety of l-His interacted with these amino acids. For the d-His adduct, the residues involved in recognition of the activator were Trp5, His64, and Pro201, whereas two water molecules connected the zinc-bound water to the activator. Only the COOH and NH(2) moieties of d-His participated in hydrogen bonds with these residues. This is the first study showing different binding modes of stereoisomeric activators within the hCA II active site, with consequences for overall proton-transfer processes (rate-determining for the catalytic cycle). The study also points out differences of activation efficiency between various isozymes with structurally related activators, convenient for designing alternative proton-transfer pathways, useful both for a better understanding of the catalytic mechanism and for obtaining pharmacologically useful derivatives, for example, for the management of Alzheimer's disease.


Modulation of cytolytic T cell function by lectins.
Human thymocytes cultured for 5 days in interleukin 2 containing supernatants (IL 2 Sup) virtually become a population of mature T cells (T3+, HTA-) that acquires strong cytotoxic activity against NK-sensitive and NK-resistant target cells. The addition of different lectins to the cultures abrogated the expression of the cytotoxic activity and enhanced thymocyte proliferation. The modulation of this cytotoxic activity by lectins has the following properties: a) inhibition of cytotoxicity is related to the concentration of lectins added, but does not correlate with their mitogenic properties, because either strong mitogens such as PHA or weak mitogens such as wheat germ agglutinin (WGA) are both able to strongly decrease cytotoxicity; b) lectin presence is not required at the onset of the culture but is required during the last 24 hr of the 5-day incubation period; c) reversion of inhibition with full expression of cytotoxic activity can be obtained after removal of the lectin and subsequent culture in lectin-free conditions for at least an 18 to 24 hr period; d) lack of cytotoxicity is observed regardless of target cell specificities and cannot be overcome in a lectin-dependent cytotoxicity assay (LDCC); and e) abrogation of cytotoxicity is not restricted to thymocyte cultures because it can also be observed in peripheral lymphocytes. These results cannot be explained by a simple steric blockade, the overgrowth of a distinctive noncytotoxic lymphocyte population, autologous killing, or a failure in the recognition phase of the lytic event. Modulation by lectins of function-associated cell surface structures implicated in cytolysis is discussed as an alternative hypothesis that might account for the observed phenomenon.


Knowledge, attitudes, representations and declared practices of nurses and physicians about obesity in a university hospital: training is essential.
In the context of a worldwide obesity epidemic, healthcare providers play a key role in obesity management. Knowledge of current guidelines and attitudes to prevent stigmatization are especially important. This study aimed to assess knowledge, attitudes, beliefs, perception of opportunity for intervention, declared practices and need for training and material of nurses and physicians about obesity in a Swiss University Hospital. A total of 834 physicians and nurses filled an online survey. The questionnaire was based on literature, exploratory interviews and expert committee review. It was pre-tested with 15 physicians and nurses. Participants declared a low level of negative attitudes towards individuals living with obesity. However, the results highlighted a lack of knowledge to diagnose obesity in adults and children, as well as confidence and training to care of patients with obesity. One-third of providers did not know how to calculate body mass index. Half of providers felt it was part of their role to take care of patients with obesity, even if 55% of them had the feeling that they did not have adequate training. Nurses and physicians working in a university hospital showed a low level of negative attitudes but a lack of knowledge and skills on obesity management. Training should be improved in this population to insure adequate and coherent messages and equal access to evidence-based treatment for patients living with obesity.


Crossovers in the dynamics of supercooled liquids probed by an amorphous wall.
We study the relaxation dynamics of a binary Lennard-Jones liquid in the presence of an amorphous wall generated from equilibrium particle configurations. In qualitative agreement with the results presented by Kob et al. [Nat. Phys. 8, 164 (2012).] for a liquid of harmonic spheres, we find that our binary mixture shows a saturation of the dynamical length scale close to the mode-coupling temperature T(c). Furthermore we show that, due to the broken symmetry imposed by the wall, signatures of an additional change in dynamics become apparent at a temperature well above T(c). We provide evidence that this modification in the relaxation dynamics occurs at a recently proposed dynamical crossover temperature T(s) > T(c), which is related to the breakdown of the Stokes-Einstein relation. We find that this dynamical crossover at T(s) is also observed for the harmonic spheres as well as a WCA liquid, showing that it may be a general feature of glass-forming systems.


High energy phosphate stores and lactate levels in different layers of the canine left ventricle during reactive hyperemia.
To study postischemic recovery of myocardial energy metabolism in relation to the reactive hyperemic response, the tissue levels of creatine phosphate (CP), adenosine triphosphate (ATP), and lactate were estimated in the outer, middle, and inner layers of the left ventricle before, during, and at several times after a 20-second bilateral coronary arterial occlusion in the open-chest dog. The reactive hyperemic response was characterized by monitoring blood flow in the cannulated coronary sinus in a separate group of dogs. Substantial changes in myocardial CP and lactate, but not ATP, were produced by the occlusion and reciprocal transmural gradients in CP and lactate occurred such that CP was lowest and lactate was highest in the inner layer. Recovery of high energy phosphate stores (CP + ATP) occurred long before blood flow returned to the preocclusion level, this being achieved in two of the three layers after completion of only 29% of the reactive hyperemic response when the blood flow debt repayment was 151%. Lactate returned to control levels during the response, but recovery times in the different layers were delayed compared to those for the high energy phosphate stores. A transmural lactate gradient was maintained as the regional levels declined, and recovery times were different for each of the three layers, being longest in the inner layer. The results suggest that during the reactive hyperemic response (1) kinetically different processes are involved in the repletion of energy stores and the removal of anaerobically produced metabolites, and (2) metabolic vasodilation of coronary vessels probably is more pronounced and sustained longer in the inner than in the outer ventricular layer.


Psychometric Properties of the Korean Version of the PsyMate Scale Using a Smartphone App: Ecological Momentary Assessment Study.
Ecological momentary assessment (EMA) is a method for capturing the changes in the variables in daily life with increased accuracy and decreased recall bias. The PsyMate scale assesses momentary moods in daily life and can be used in various settings. The aim of this study was to develop a Korean version of the PsyMate (K-PsyMate) scale and evaluate its psychometric properties by using the EMA method in patients with moyamoya disease (MMD) in South Korea. Patients with MMD aged over 18 years were recruited from July 2018 to January 2019 at the inpatient and outpatient departments of a university hospital in South Korea. The K-PsyMate scale comprising 13 items was developed following a translation/back translation approach of the English version and loaded onto a mobile app. Participants were instructed to enter their moods 4 times a day for 7 consecutive days. Content validity index, factor analysis, and Pearson's correlation were performed for validity analysis. For reliability, intraclass correlation coefficients between the first and last measurements were estimated by mean rating, absolute agreement, and a 2-way mixed-effects model. Usability was analyzed through a descriptive analysis, 2-tailed t test, and analysis of variance, and the results were confirmed by Mann-Whitney U test and the Kruskal-Wallis test, as the dependent variable was not normally distributed. In total, 1929 assessments from 93 patients were analyzed. The mean age of the participants was 40.59 (SD 10.06) years, and 66 (71%) of the 93 participants were women. Content validity was excellent as content validity index was 0.99, and 2 factors, negative affect and positive affect, were derived by an exploratory factor analysis. The correlations between the subdomains of the K-PsyMate scale and Hospital Anxiety and Depression Scale were significant (P<.001). The agreement between the first and last measurements was poor to moderate according to the obtained intraclass correlation coefficient values. Usability was evaluated by 67 (72%) out of the 93 participants. The participants rated the accuracy of assessing their momentary moods on the app at 4.13 (SD 0.97), easiness in understanding questions, operating, and inputting answers at 4.12 (SD 0.88), and interruption by the survey alarms at 2.48 (SD 1.02) out of 5. The K-PsyMate scale has good validity but poor to moderate agreement, which reflects the characteristics of the EMA data collected in real and natural living environments without control. The findings of our study show that the K-PsyMate scale uploaded in a mobile app can be a valid and reliable tool for evaluating the momentary mood of patients with MMD because using a mobile app is convenient and patients are familiar with their own smartphones, which they use in their daily lives.


Genetically based low oxygen affinities of felid hemoglobins: lack of biochemical adaptation to high-altitude hypoxia in the snow leopard.
Genetically based modifications of hemoglobin (Hb) function that increase blood-O2 affinity are hallmarks of hypoxia adaptation in vertebrates. Among mammals, felid Hbs are unusual in that they have low intrinsic O2 affinities and reduced sensitivities to the allosteric cofactor 2,3-diphosphoglycerate (DPG). This combination of features compromises the acclimatization capacity of blood-O2 affinity and has led to the hypothesis that felids have a restricted physiological niche breadth relative to other mammals. In seeming defiance of this conjecture, the snow leopard (Panthera uncia) has an extraordinarily broad elevational distribution and occurs at elevations above 6000 m in the Himalayas. Here, we characterized structural and functional variation of big cat Hbs and investigated molecular mechanisms of Hb adaptation and allosteric regulation that may contribute to the extreme hypoxia tolerance of the snow leopard. Experiments revealed that purified Hbs from snow leopard and African lion exhibited equally low O2 affinities and DPG sensitivities. Both properties are primarily attributable to a single amino acid substitution, β2His→Phe, which occurred in the common ancestor of Felidae. Given the low O2 affinity and reduced regulatory capacity of feline Hbs, the extreme hypoxia tolerance of snow leopards must be attributable to compensatory modifications of other steps in the O2-transport pathway.


Suppressor analysis of temperature-sensitive mutations of the largest subunit of RNA polymerase I in Saccharomyces cerevisiae: a suppressor gene encodes the second-largest subunit of RNA polymerase I.
The SRP3-1 mutation is an allele-specific suppressor of temperature-sensitive mutations in the largest subunit (A190) of RNA polymerase I from Saccharomyces cerevisiae. Two mutations known to be suppressed by SRP3-1 are in the putative zinc-binding domain of A190. We have cloned the SRP3 gene by using its suppressor activity and determined its complete nucleotide sequence. We conclude from the following evidence that the SRP3 gene encodes the second-largest subunit (A135) of RNA polymerase I. First, the deduced amino acid sequence of the gene product contains several regions with high homology to the corresponding regions of the second-largest subunits of RNA polymerases of various origins, including those of RNA polymerase II and III from S. cerevisiae. Second, the deduced amino acid sequence contains known amino acid sequences of two tryptic peptides from the A135 subunit of RNA polymerase I purified from S. cerevisiae. Finally, a strain was constructed in which transcription of the SRP3 gene was controlled by the inducible GAL7 promoter. When this strain, which can grow on galactose but not on glucose, was shifted from galactose medium to glucose medium, a large decrease in the cellular concentration of A135 was observed by Western blot analysis. We have also identified the specific amino acid alteration responsible for suppression by SRP3-1 and found that it is located within the putative zinc-binding domain conserved among the second-largest subunits of eucaryotic RNA polymerases. From these results, it is suggested that this putative zinc-binding domain is in physical proximity to and interacts with the putative zinc-binding domain of the A190 subunit.


Integrated telehealth care for chronic illness and depression in geriatric home care patients: the Integrated Telehealth Education and Activation of Mood (I-TEAM) study.
To evaluate an integrated telehealth intervention (Integrated Telehealth Education and Activation of Mood (I-TEAM)) to improve chronic illness (congestive heart failure, chronic obstructive pulmonary disease) and comorbid depression in the home healthcare setting. Randomized controlled trial. Hospital-affiliated home healthcare setting. Medically frail older homebound individuals (N = 102). The 3-month intervention consisted of integrated telehealth chronic illness and depression care, with a telehealth nurse conducting daily telemonitoring of symptoms, body weight, and medication use; providing eight weekly sessions of problem-solving treatment for depression; and providing for communication with participants' primary care physicians, who also prescribed antidepressants. Control participants were allocated to usual care with in-home nursing plus psychoeducation (UC+P). The two groups were compared at baseline and 3 and 6 months after baseline on clinical measures (depression, health, problem-solving) and 12 months after baseline on health utilization (readmission, episodes of care, and emergency department (ED) visits). Depression scores were 50% lower in the I-TEAM group than in the UC+P group at 3 and 6 months. Those who received the I-TEAM intervention significantly improved their problem-solving skills and self-efficacy in managing their medical condition. The I-TEAM group had significantly fewer ED visits (P = .01) but did not have significantly fewer days in the hospital at 12 months after baseline. Integrated telehealth care for older adults with chronic illness and comorbid depression can reduce symptoms and postdischarge ED use in home health settings.


"It is not an easy decision on HIV, especially in Zambia": opting for silence, limited disclosure and implicit understanding to retain a wider identity.
As universal testing moves onto the HIV agenda, there is a need for more understanding of the relatively low uptake of HIV testing and the dynamics of disclosure in Sub-Saharan Africa. Despite the expanding provision of anti-retroviral therapy in Zambia since 2004, disclosure of HIV status - beyond a closed network - remains limited. Drawing on 20 years of living and working in a high HIV prevalence country, research on HIV-related stigma and existing literature on disclosure, this paper explores the reasons that lie behind limited disclosure. Unravelling why HIV disclosure remains "a navigation in a moral field", the pattern of silence around HIV and the routine and often subtle presence of HIV in daily life reveals two key dynamics. The first dynamic is shifting public/private boundaries and retaining a wider identity. People living with HIV juggle the pragmatic advantages of disclosing to a limited circle with the importance of maintaining not only their moral integrity, status and (for some) professional and group identity but also of maintaining their privacy. A more public disclosure ("speaking it" more widely) shifts private-public boundaries and can be threatening, dangerous and can fix identity. Furthermore, disclosure carries obligations which, given high levels of poverty, can be hard to meet. The second dynamic is a pattern of implicit understanding. It can be easier in a context of high HIV prevalence to opt for silence, in its various forms, with the presence of HIV implicitly understood but not often explicitly spoken about. Although this gives more room for manoeuvre and for respect, silence too can be dangerous and certain situations dictate that it is better to breach the silence. More aggressive promotion of HIV testing needs to both respect and consider how to work within these existing dynamics to facilitate safe disclosure.


A framework for evidence evaluation and methodological issues in implantable device studies.
Implantable medical devices (IMD) are frequently used in interventional medicine. There are a host of complex methodological issues to consider in conducting device studies. A general conceptual framework for evidence evaluation is needed to help investigators conduct comparative studies in this setting. It is known that clinical trials of implants require study design planning and creative execution that are quite different from those in pharmaceutical setting. Important study design issues such as randomization, masking and allocation concealment require unique approaches for each device. In addition, device comparative studies must cope with sources of variability different from pharmaceutical studies. These include operator learning curve effects, hospital-operator-patient interactions, and issues related to device technical characteristics. Observational studies of IMDs are particularly challenging. Selection of comparison groups, adjusting for confounding and addressing learning curve issues needs careful planning. We propose a general framework for IMD evaluation and provide an outline of the methodological issues that require further discussion. We hope this article will inspire and help to inform those interested in advancing comparative safety and effectiveness of IMDs and to plan and pursue future methodological work in this area.


Is sexuality a problem? A follow-up of patients with severe burns 6 months to 7 years after injury.
This is the first study investigating sexuality from 6 months up to 7 years after burn. The aim was to examine sexuality in females and males by using the BSHS-B sexuality subscale and to examine possible contributing factors with regard to sociodemographics, burn characteristics, personality traits, and previous psychiatric disorders. A cohort of 107 patients consecutively admitted to a Swedish national burn center was followed up at 6, 12, and 24 months after burn, and 67 individuals were followed up at 2-7 years after burn. The present study utilized the BSHS-B sexuality subscale, and multiple regression analyses were used to examine possible contributing factors. Women were less satisfied than men, and sexuality mean scores improved over time, even up to 7 years after-burn, in both men and women. The strongest contributing factors for worse outcome regarding sexuality were a history of psychiatric morbidity, neuroticism and burn severity. As some patients experience sexual problems after burns, even many years later, it is important to identify these individuals. The BSHS-B sexuality subscale may be used as a screening tool, but more in-depth assessment might be needed to address all aspects of sexuality.


Spikelets in pyramidal neurons: generating mechanisms, distinguishing properties, and functional implications.
Spikelets are small spike-like depolarizations that are found in somatic recordings of many neuron types. Spikelets have been assigned important functions, ranging from neuronal synchronization to the regulation of synaptic plasticity, which are specific to the particular mechanism of spikelet generation. As spikelets reflect spiking activity in neuronal compartments that are electrotonically distinct from the soma, four modes of spikelet generation can be envisaged: (1) dendritic spikes or (2) axonal action potentials occurring in a single cell as well as action potentials transmitted via (3) gap junctions or (4) ephaptic coupling in pairs of neurons. In one of the best studied neuron type, cortical pyramidal neurons, the origins and functions of spikelets are still unresolved; all four potential mechanisms have been proposed, but the experimental evidence remains ambiguous. Here we attempt to reconcile the scattered experimental findings in a coherent theoretical framework. We review in detail the various mechanisms that can give rise to spikelets. For each mechanism, we present the biophysical underpinnings as well as the resulting properties of spikelets and compare these predictions to experimental data from pyramidal neurons. We also discuss the functional implications of each mechanism. On the example of pyramidal neurons, we illustrate that several independent spikelet-generating mechanisms fulfilling vastly different functions might be operating in a single cell.


Mutational analysis of an autoantibody: differential binding and pathogenicity.
We have used site-directed mutagenesis to change amino acid residues in the heavy chain of the pathogenic R4A anti-double-stranded DNA (dsDNA) antibody and have looked for resultant alterations in DNA binding and in pathogenicity. The data demonstrate that single amino acid substitutions in both complementarity determining and framework regions alter antigen binding. Changes in only a few amino acids entirely ablate DNA specificity or cause a 10-fold increase in relative binding. In vivo studies in mice of the pathogenicity of the mutated antibodies show that a single amino acid substitution leading to a loss of dsDNA binding leads also to a loss of glomerular sequestration. Amino acid substitutions that increase relative affinity for dsDNA cause a change in localization of immunoglobulin deposition from glomeruli to renal tubules. These studies demonstrate that small numbers of amino acid substitutions can dramatically alter antigen binding and pathogenicity, and that the pathogenicity of anti-DNA antibodies does not strictly correlate with affinity for DNA.


Ordered ferrimagnetic form of ferrihydrite reveals links among structure, composition, and magnetism.
The natural nanomineral ferrihydrite is an important component of many environmental and soil systems and has been implicated as the inorganic core of ferritin in biological systems. Knowledge of its basic structure, composition, and extent of structural disorder is essential for understanding its reactivity, stability, and magnetic behavior, as well as changes in these properties during aging. Here we investigate compositional, structural, and magnetic changes that occur upon aging of "2-line" ferrihydrite in the presence of adsorbed citrate at elevated temperature. Whereas aging under these conditions ultimately results in the formation of hematite, analysis of the atomic pair distribution function and complementary physicochemical and magnetic data indicate formation of an intermediate ferrihydrite phase of larger particle size with few defects, more structural relaxation and electron spin ordering, and pronounced ferrimagnetism relative to its disordered ferrihydrite precursor. Our results represent an important conceptual advance in understanding the nature of structural disorder in ferrihydrite and its relation to the magnetic structure and also serve to validate a controversial, recently proposed structural model for this phase. In addition, the pathway we identify for forming ferrimagnetic ferrihydrite potentially explains the magnetic enhancement that typically precedes formation of hematite in aerobic soil and weathering environments. Such magnetic enhancement has been attributed to the formation of poorly understood, nano-sized ferrimagnets from a ferrihydrite precursor. Whereas elevated temperatures drive the transformation on timescales feasible for laboratory studies, our results also suggest that ferrimagnetic ferrihydrite could form naturally at ambient temperature given sufficient time.


The fern-feeder aphids (Hemiptera: Aphididae) from China: a generic account, descriptions of one new genus, one new species, one new subspecies, and keys.
Fern-feeder aphids (Hemiptera: Aphididae) in China are represented by 13 species in 10 genera, including a new genus, Vietaphis gen nov., a new species, Vietaphis aliquantus sp nov., from Guizhou and Tibet on Plagiogyria japonicum, and a new subspecies, Amphorophora scabripes galba ssp nov., from Guizhou on Pentarhizidium intermedium. Two genera, Amphorophora Buckton and Idiopterus Davis, and four species or subspecies, Amphorophora ampullate ben-galensis Hille Ris Lambers and Basu, Idiopterus nephrelepidis Davis, Micromyzodium polypodii Takahashi, and Myzus filicis Basu, are reported for the first time in China. Apterae and alatae of Myzus filicis are redescribed herein, and with host plant notes. The fern-feeder aphid genus Ne-omacromyzus Lee is considered a junior synonym of Idiopterus. Furthermore, Neomacromyzus cyrtomicola Lee is transferred to the genus Idiopterus, as Idiopterus cyrtomicola (Lee), comb nov., which is herein considered a junior synonym of Idiopterus nephrelepidis Davis. Keys to Chinese fern-feeder species are provided. Morphological figures and biometrical data of Vietaphis aliquantus sp nov., Amphorophora scabripes galba ssp nov., and Myzus filicis are presented.


A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer.
This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients. mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety. Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints. These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging.


DNP NMR spectroscopy of cross-linked organic polymers: rational guidelines towards optimal sample preparation.
Cross-linked polystyrenes (PS) are an important class of polymers, whose properties are strongly dependent on incorporated functionalities, for which detailed understanding of their structure remains a challenge. Here, we develop a rational guideline for dynamic nuclear polarization (DNP) sample formulation for cross-linked PS to interrogate their structure. We show that the DNP enhancement on a series of cross-linked PS bearing alkylammonium groups as prototypical organic polymers correlates with the polymer swelling properties in both apolar and polar formulations (TEKPol/1,1,2,2-tetrachloroethane and AMUPol/dimethyl sulfoxide). This work provides guidelines to easily optimize DNP formulation using a simple swelling test and enables natural abundance 15N NMR to be recorded on a series of PS-supported quaternary alkylammonium salts, allowing a detailed structural analysis.


Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor.
Atrial natriuretic peptide (ANP) is a peptide hormone that in response to atrial stretch is secreted from atrial myocytes into the circulation, where it stimulates vasodilatation and natriuresis. ANP is an important biomarker of heart failure where low plasma concentrations exclude cardiac dysfunction. ANP is a member of the natriuretic peptide (NP) family, which also includes the B-type natriuretic peptide (BNP) and the C-type natriuretic peptide. The proforms of these hormones undergo processing to mature peptides, and for proBNP, this process has previously been demonstrated to be regulated by O-glycosylation. It has been suggested that proANP also may undergo post-translational modifications. Here, we conducted a targeted O-glycoproteomics approach to characterize O-glycans on NPs and demonstrate that all NP members can carry O-glycans. We identified four O-glycosites in proANP in the porcine heart, and surprisingly, two of these were located on the mature bioactive ANP itself. We found that one of these glycans is located within a conserved sequence motif of the receptor-binding region, suggesting that O-glycans may serve a function beyond intracellular processing and maturation. We also identified an O-glycoform of proANP naturally occurring in human circulation. We demonstrated that site-specific O-glycosylation shields bioactive ANP from proteolytic degradation and modifies potency at its cognate receptor in vitro Furthermore, we showed that ANP O-glycosylation attenuates acute renal and cardiovascular ANP actions in vivo The discovery of novel glycosylated ANP proteoforms reported here significantly improves our understanding of cardiac endocrinology and provides important insight into the etiology of heart failure.


Identification and characterization of alternative exon usage linked glioblastoma multiforme survival.
Alternative exon usage (AEU) is an important component of gene regulation. Exon expression platforms allow the detection of associations between AEU and phenotypes such as cancer. Numerous studies have identified associations between gene expression and the brain cancer glioblastoma multiforme (GBM). The few consistent gene expression biomarkers of GBM that have been reported may be due to the limited consideration of AEU and the analytical approaches used. The objectives of this study were to develop a model that accounts for the variations in expression present between the exons within a gene and to identify AEU biomarkers of GBM survival. The expression of exons corresponding to 25,403 genes was related to the survival of 250 individuals diagnosed with GBM in a training data set. Genes exhibiting AEU in the training data set were confirmed in an independent validation data set of 78 patients. A hierarchical mixed model that allows the consideration of covariation between exons within a gene and of the effect of the epidemiological characteristics of the patients was developed to identify associations between exon expression and patient survival. This general model describes all three possible scenarios: multi-exon genes with and without AEU, and single-exon genes. AEU associated with GBM survival was identified on 2477 genes (P-value < 5.0E-04 or FDR-adjusted P-value < 0.05). G-protein coupled receptor 98 (Gpr98) and epidermal growth factor (Egf) were among the genes exhibiting AEU with 30 and 9 exons associated with GBM survival, respectively. Pathways enriched among the AEU genes included focal adhesion, ECM-receptor interaction, ABC transporters and pathways in cancer. In addition, 24 multi-exon genes without AEU and 8 single-exon genes were associated with GBM survival (FDR-adjusted P-value < 0.05). The inferred patterns of AEU were consistent with in silico AS models. The hierarchical model used offered a flexible and simple way to interpret and identify associations between survival that accommodates multi-exon genes with or without AEU and single exon genes. Our results indicate that differential expression of AEU could be used as biomarker for GBM and potentially other cancers.


Electronic fetal monitoring: a Canadian survey.
To determine the current status of electronic fetal monitoring (EFM) in Canadian teaching and nonteaching hospitals, to review the medical and nursing standards of practice for EFM and to determine the availability of EFM educational programs. National survey in 1989. The directors of nursing at the 737 hospitals providing obstetric care were sent a questionnaire and asked to have it completed by the most appropriate staff member. The response rate was 80.5% (593/737); 44 hospitals did not have deliveries in 1988 and were excluded. The remaining hospitals varied in size from 8 to 1800 (mean 162.1) beds and had 1 to 7500 (mean 617.1) births in 1988; 18.8% were teaching hospitals. Of the 549 hospitals 419 (76.3%) reported having at least 1 monitor (range 1 to 30; mean 2.6); the mean number of monitors per hospital was higher in the teaching hospitals than in the nonteaching hospitals (6.2 v. 1.7). Manitoba had the lowest mean number of monitors per hospital (1.1) and Ontario the highest (3.7). In 71.8% of the hospitals with monitors almost all of the obstetric patients were monitored at some point during labour. However, 21.6% of the hospitals with monitors had no policy on EFM practice. The availability of EFM educational programs for physicians and nurses varied according to hospital size, type and region. Most Canadian hospitals providing obstetric services have electronic fetal monitors and use them frequently. Although substantial research has questioned the benefits of EFM, further definitive research is required. In the meantime, a national committee should be established to develop multidisciplinary guidelines for intrapartum fetal assessment.


Surface plasmon-enhanced nanoscopy of intracellular cytoskeletal actin filaments using random nanodot arrays.
The feasibility of super-resolution microscopy has been investigated based on random localization of surface plasmon using blocked random nanodot arrays. The resolution is mainly determined by the size of localized fields in the range of 100-150 nm. The concept was validated by imaging FITC-conjugated phalloidin that binds to cellular actin filaments. The experimental results confirm improved resolution in reconstructed images. Effect of far-field registration on image reconstruction was also analyzed. Correlation between reconstructed images was maintained to be above 81% after registration. Nanodot arrays are synthesized by temperature-annealing without sophisticated lithography and thus can be mass-produced in an extremely large substrate. The results suggest a super-resolution imaging technique that can be accessible and available in large amounts.


In vitro activity of Tedizolid phosphate against multidrug-resistant Streptococcus pneumoniae isolates from Asian countries.
Tedizolid phosphate is a second-generation oxazolidinone prodrug that is potential activity against a wide range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, penicillin-resistant streptococci, and vancomycin-resistant enterococci. The in vitro activity of tedizolid and other comparator agents against multidrug-resistant (MDR) pneumococci from various Asian countries were evaluated. Of the S. pneumoniae clinical pneumonia isolates collected during 2008 and 2009 from 8 Asian countries (Korea, Taiwan, Thailand, Hong Kong, Vietnam, Malaysia, Philippines, and Sri Lanka), 104 isolates of MDR pneumococci were included in this study. Antimicrobial susceptibility testing for 18 antimicrobial agents was performed by broth microdilution method. Tedizolid was highly active against pneumococci. All isolates tested were inhibited at a tedizolid minimum inhibitory concentration (MIC) value of ≤0.25μg/ml (ranged from ≤0.03μg/ml to 0.25μg/ml). The MIC50 and MIC90 of tedizolid against MDR pneumococci were both 0.12μg/ml, while MIC50 and MIC90 of linezolid were 0.5μg/ml and 1μg/ml, respectively. In addition, tedizolid maintained the activity against S. pneumoniae regardless of the extensively drug-resistant (XDR) phenotype of the isolates. The activity of tedizolid was excellent against all types of MDR pneumococci, exhibiting and maintaining at least 4-fold-greater potency compared to linezolid, regardless of resistance phenotypes to other commonly utilized agents. Tedizolid has the potential to be an agent to treat infections caused by MDR pneumococci in the Asia.


Retributive and restorative justice.
The emergence of restorative justice as an alternative model to Western, court-based criminal justice may have important implications for the psychology of justice. It is proposed that two different notions of justice affect responses to rule-breaking: restorative and retributive justice. Retributive justice essentially refers to the repair of justice through unilateral imposition of punishment, whereas restorative justice means the repair of justice through reaffirming a shared value-consensus in a bilateral process. Among the symbolic implications of transgressions, concerns about status and power are primarily related to retributive justice and concerns about shared values are primarily related to restorative justice. At the core of these processes, however, lies the parties' construal of their identity relation, specifically whether or not respondents perceive to share an identity with the offender. The specific case of intergroup transgressions is discussed, as are implications for future research on restoring a sense of justice after rule-breaking.


First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques.
Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders.


Transcriptional response to metal starvation in the emerging pathogen Mycoplasma genitalium is mediated by Fur-dependent and -independent regulatory pathways.
Transition metals participate in numerous enzymatic reactions and they are essential for survival in all living organisms. For this reason, bacterial pathogens have evolved dedicated machineries to effectively compete with their hosts and scavenge metals at the site of infection. In this study, we investigated the mechanisms controlling metal acquisition in the emerging human pathogen Mycoplasma genitalium. We observed a robust transcriptional response to metal starvation, and many genes coding for predicted lipoproteins and ABC-transporters were significantly up-regulated. Transcriptional analysis of a mutant strain lacking a metalloregulator of the Fur family revealed the activation of a full operon encoding a putative metal transporter system and a gene coding for a Histidine-rich lipoprotein (Hrl). We recognized a conserved sequence with dyad symmetry within the promoter region of the Fur-regulated genes. Mutagenesis of the predicted Fur operator within the hrl promoter abrogated Fur- and metal-dependent expression of a reporter gene. Metal starvation still impelled a strong transcriptional response in the fur mutant, demonstrating the existence of Fur-independent regulatory pathways controlling metal homeostasis. Finally, analysis of metal accumulation in the wild-type strain and the fur mutant by ICP-MS revealed an important role of Fur in nickel acquisition.


Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study.
Type 2 diabetes mellitus is a heterogeneous inherited disorder characterized by chronic hyperglycemia resulting from pancreatic beta-cell dysfunction and insulin resistance. Although the pathogenic mechanisms are not fully understood, manifestation of the disease most likely requires interaction between both environmental and genetic factors. In the search for such susceptibility genes, we have performed a genomewide scan in 58 multiplex families (comprising 440 individuals, 229 of whom were affected) from the Botnia region in Finland. Initially, linkage between chromosome 12q24 and impaired insulin secretion had been reported, by Mahtani et al., in a subsample of 26 families. In the present study, we extend the initial genomewide scan to include 32 additional families, update the affectation status, and fine map regions of interest, and we try to replicate the initial stratification analysis. In our analysis of all 58 families, we identified suggestive linkage to one region, chromosome 9p13-q21 (nonparametric linkage [NPL] score 3.9; P<.0002). Regions with nominal P values <.05 include chromosomes 2p11 (NPL score 2.0 [P<.03]), 3p24-p22 (NPL score 2.2 [P<.02]), 4q32-q33 (NPL score 2.5 [P<.01]), 12q24 (NPL score 2.1 [P<.03]), 16p12-11 (NPL score 1.7 [P<.05]), and 17p12-p11 (NPL score 1.9 [P<.03]). When chromosome 12q24 was analyzed in only the 32 additional families, a nominal P value <.04 was observed. Together with data from other published genomewide scans, these findings lend support to the hypothesis that regions on chromosome 9p13-q21 and 12q24 may harbor susceptibility genes for type 2 diabetes.


Early stroke care in Italy--a steep way ahead: an observational study.
To measure the performance of selected Italian emergency medical system (EMS) dispatch centres managing calls for patients suffering from stroke. Data on outcome and on early treatment in the ED were collected. Prospective data collection for a trimester from interventions for a suspected stroke in 13 EMS dispatch centres over five Italian regions. Altogether, 1041 calls for a suspected stroke were analysed. Mean intervals of the sequential phases were 2.3+/-2 minutes between call and ambulance dispatch, 8.4+/-5.5 minutes to reach the patient, 14.5+/-8.5 minutes on the scene, and 40.2+/-16.2 minutes between call and arrival at the ED. Interventions were performed in 56% of cases by a basic life support (BLS) crew, advanced life support (ALS) crews intervened in 28% of cases, and a combination of ALS and BLS in the remaining 16%. Mean diagnostic interval was 99+/-85 minutes between emergency system call and the first CT scan. This was performed 71+/-27 minutes after ED admission. Only 1.6% were admitted to a stroke unit. One month outcome according to GCS was good recovery in 32%, moderate disability in 28%, severe disability in 14%, and death in 25% of the patients. Mean times show a rapid response of the selected EMS dispatch centres to calls for a suspected stroke. Nevertheless, mean times of the ED phase are still unacceptable according to international guidelines such as Brain Attack Coalition and American Stroke Association guidelines. Efforts should be spent to reduce the time between the arrival and the CT scan and more patients should be admitted to a stroke unit.


Factors associated with expressed satisfaction among people with intellectual disability receiving residential supports.
The aim of the present study was to identify factors associated with variations in the levels of expressed satisfaction among adults with intellectual disability (ID) receiving residential supports. Semi-structured interviews were conducted with 96 people with ID. Forty-five subjects lived in village communities and 51 received community-based residential supports. Ratings were made of the participants' expressed levels of satisfaction in seven domains: (1) their home; (2) daytime activities; (3) social and recreational activities; (4) support from services; (5) friendships and relationships; (6) choices available to them; and (7) risks. The data indicated that: (1) interviewees living in village communities expressed greater satisfaction with friendships and relationships than interviewees living in community-based residential supports; (2) in the other six domains of life satisfaction which were investigated, there were no statistically significant differences between groups; (3) interviewees expressed greater satisfaction with their accommodation and day activities than with friendships, risks and support received; and (4) a wide range of variables relating to the personal characteristics of the interviewees and support received were associated with variations in levels of expressed satisfaction. Variation in the levels of expressed satisfaction was reliably associated with variables relating to the personal characteristics of the interviewees and the nature of the support received.


Can general practitioners provide effective cardiovascular disease (CVD) prevention? Dreams and realities of CVD prevention.
This study explores how the New Zealand (NZ) population experiences approaches to cardiovascular disease (CVD) risk management: (1) the Primary Health Organisation (PHO) CVD risk performance indicator programme in Akaroa, Canterbury NZ and (2) consumer use of community services that promote healthier lifestyles. An audit identified patients enrolled at the Akaroa Health Centre eligible for CVD risk assessments and the portion with completed formal assessments. This was compared with the standard PHO performance tool for assessing CVD. An exploratory survey identified awareness of and barriers to use of local lifestyle resources that may directly or indirectly reduce CVD risk, in respondents over the age of 45 years. Distinguishing the eligible population who had not already had their CVD risk calculated required complex database analysis. As of April 2009 11.8% of the eligible population had a CVD risk calculated using the PHO performance tool. However, another 10.1% had had these risks assessed through other tools. The combined total of 21.9% meets the minimum target of 21.7% for the year ending June 30th 2009. The community survey found around a third (36%) of lifestyle promoting resources available were recognised with about half (56.9%) of respondents participating in the activities. Barriers to use included lack of time and perceived need of the service. The current performance indicator approach is not practical, subject to error and may have significant opportunity costs. Furthermore, barriers exist in engaging the population identified as at risk in health-promoting activities.


One-, two-, and three-class resistance among HIV-infected patients on antiretroviral therapy in private care clinics: Mumbai, India.
HIV-infected patients receiving antiretroviral (ARV) therapy (ART) in India are not all adequately virally suppressed. We analyzed ARV drug resistance in adults receiving ART in three private clinics in Mumbai, India. HIV viral load was measured in 200 patients with the Roche AMPLICOR HIV-1 Monitor Test, v1.5. HIV genotyping was performed with the ViroSeq HIV-1 Genotyping System for 61 participants who had HIV-1 RNA >1000 copies/ml. Genotyping results were obtained for 51 samples. The participants with resistance results were on ART for a median of 24 months and were on their current regimen for a median of 12 months (median CD4 cell count: 217 cells/mm(3); median HIV viral load: 28,200 copies/ml). ARV regimens included nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (n = 27), dual nucleoside reverse transcriptase inhibitors (NRTIs, n = 19), protease inhibitor (PI)-based regimens (n = 3), and other regimens (n = 2). Twenty-six participants (51.0%) were on their first ARV regimen and 24 (47%) reported >95% adherence. Forty-nine participants (96.1%) had resistance to at least one ARV drug; 47 (92.2%) had NRTI resistance, 32 (62.7%) had NNRTI resistance, and four (7.8%) had PI resistance. Thirty (58.8%) had two-class resistance and three (5.9%) had three-class resistance. Four (8%) had three or more resistance mutations associated with etravirine resistance and two (4%) had two mutations associated with reduced darunavir susceptibility. Almost all patients with HIV-1 RNA >1000 copies/ml had NRTI resistance and nearly two-thirds had NNRTI resistance; PI resistance was uncommon. Nearly 60% and 6% had two- and three-class resistance, respectively. This emphasizes the need for greater viral load and resistance monitoring, use of optimal ART combinations, and increased availability of second- and third-line agents for patients with ARV resistance.


A 10-year time-series analysis of respiratory and cardiovascular morbidity in Nicosia, Cyprus: the effect of short-term changes in air pollution and dust storms.
To date, a substantial body of research has shown adverse health effects of short-term changes in levels of air pollution. Such associations have not been investigated in smaller size cities in the Eastern Mediterranean. A particular feature in the region is dust blown from the Sahara a few times a year resulting in extreme PM10 concentrations. It is not entirely clear whether such natural phenomena pose the same risks. The effect of changes in daily levels of particulate matter (PM10) and ozone (O3) on hospitalization for all, cardiovascular and respiratory causes in the two hospitals in Nicosia during 1 January 1995 and 30 December 2004 was investigated using generalized additive Poisson models after controlling for long- and short-term patterns as well as for the effect of weather. Meteorological records were reviewed to identify dust-storm days and analyses were repeated to quantify their effect on cardio-respiratory morbidity. For every 10 microg/m3 increase in daily average PM10 concentrations, there was a 0.9% (95%CI: 0.6%, 1.2%) increase in all-cause and 1.2% (95%CI: -0.0%, 2.4%) increase in cardiovascular admissions. With respect to respiratory causes, an effect was observed only in the warm months. No lagged effects with levels of PM10 were observed. In contrast, positive associations with levels of ozone were only observed the two days prior to admission. These appeared stronger for cardiovascular causes and independent of the effect of PM. All-cause and cardiovascular admissions were 4.8% (95%CI: 0.7%, 9.0%) and 10.4% (95%CI: -4.7%, 27.9%) higher on dust storm days respectively. In both cases the magnitude of effect was comparable to that seen on the quartile of non-storm days with the highest levels of PM10. We observed an increased risk of hospitalization at elevated levels of particulate matter and ozone generally consistent with the magnitude seen across several European cities. We also observed an increased risk of hospitalization on dust storm days, particularly for cardiovascular causes. While inference from these associations is limited due to the small number of dust storm days in the study period, it would appear imperative to issue health warnings for these natural events, particularly directed towards vulnerable population groups.


IL-4 is protective against development of toxoplasmic encephalitis.
IFN-gamma is critical for prevention of development of toxoplasmic encephalitis (TE). Since IL-4 down-regulates production of IFN-gamma, we examined its role in the pathogenesis of TE in IL-4-targeted mutant (IL-4-/-) mice. IL-4-/- mice all died from 6 to 20 wk after peroral infection with cysts of the ME49 strain of Toxoplasma gondii; control mice survived. At 4 and 8 wk after infection, significantly greater numbers of T. gondii cysts and foci of acute inflammation, and greater amounts of tachyzoite-specific mRNA (by reverse-transcriptase PCR) were in brains of IL-4-/- mice than controls. Toxoplasma IgG2b and IgG3 Ab levels were slightly but significantly higher in sera of IL-4-/- than control mice, whereas IgM and IgG2a levels did not differ between these mice. Toxoplasma IgG1 and IgE Abs were not detected in sera of either strain. Amounts of IFN-gamma, TNF-alpha, IL-6, and IL-10 mRNA detected by reverse-transcriptase PCR did not differ between brains of infected IL-4-/- and controls, although brains of the former mice had greater numbers of inflammatory mononuclear cell infiltrates. IL-4 mRNA was detected only in infected control mice. Spleen cells of control mice at 8 wk after infection produced significantly greater amounts of IFN-gamma following stimulation in vitro with soluble T. gondii Ags than did those from IL-4-/- mice. These results indicate that IL-4 is protective against development of TE by preventing formation of T. gondii cysts and proliferation of tachyzoites in the brain. The impaired ability of IL-4-/- mice in the late stage of T. gondii infection to produce IFN-gamma most likely contributes to their susceptibility for development of severe TE.


Secretion of IL1 by Dedifferentiated Melanoma Cells Inhibits JAK1-STAT3-Driven Actomyosin Contractility of Lymph Node Fibroblastic Reticular Cells.
Fibroblastic reticular cells (FRC) are immunologically specialized myofibroblasts that control the elasticity of the lymph node, in part through their contractile properties. Swelling of tumor-draining lymph nodes is a hallmark of lymphophilic cancers such as cutaneous melanoma. Melanoma displays high intratumoral heterogeneity with the coexistence of melanoma cells with variable differentiation phenotypes from melanocytic to dedifferentiated states. Factors secreted by melanoma cells promote premetastatic lymph node reprograming and tumor spreading. Elucidating the impact of the melanoma secretome on FRC could help identify approaches to prevent metastasis. Here we show that melanocytic and dedifferentiated melanoma cells differentially impact the FRC contractile phenotype. Factors secreted by dedifferentiated cells, but not by melanocytic cells, strongly inhibited actomyosin-dependent contractile forces of FRC by decreasing the activity of the RHOA-RHO-kinase (ROCK) pathway and the mechano-responsive transcriptional coactivator Yes1 associated transcriptional regulator (YAP). Transcriptional profiling and biochemical analyses indicated that actomyosin cytoskeleton relaxation in FRC is driven by inhibition of the JAK1-STAT3 pathway. This FRC relaxation was associated with increased FRC proliferation and activation and with elevated tumor invasion in vitro. The secretome of dedifferentiated melanoma cells also modulated the biomechanical properties of distant lymph node in premetastatic mouse models. Finally, IL1 produced by dedifferentiated cells was involved in the inhibition of FRC contractility. These data highlight the role of the JAK1-STAT3 and YAP pathways in spontaneous contractility of resting FRC. They also suggest that dedifferentiated melanoma cells specifically target FRC biomechanical properties to favor tumor spreading in the premetastatic lymph node niche. Targeting this remote communication could be an effective strategy to prevent metastatic spread of the disease. Communication between dedifferentiated melanoma cells and lymph node fibroblasts reprograms the biomechanical properties of the premetastatic lymph node niche to promote tumor invasion. See related commentary by Lund, p. 1692.


Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures.
Uncomfortable working and sleeping environments, high operational tempos, sustained operations, and insufficient staffing make fatigue a growing concern. In aviation, where a single mistake can cost millions of dollars, it is essential to optimize operator alertness. Although behavioral and administrative fatigue countermeasures should comprise the "first line" approach for sustaining aircrew performance, pharmacological fatigue countermeasures are often required. Various components of the U.S. military have authorized the use of specific compounds for this purpose. Hypnotics such as temazepam, zolpidem, or zaleplon can mitigate the fatigue associated with insufficient or disturbed sleep. Alertness-enhancing compounds such as caffeine, modafinil, or dextroamphetamine can temporarily bridge the gap between widely spaced sleep periods. Each of these medications has a role in sustaining the safety and effectiveness of military aircrews. The present paper provides a short overview of these compounds as well as factors to be considered before choosing one or more to help manage fatigue.