Social status and mating activity in elephant seals.
Individually marked male elephant seals, Mirounga angustirostris, observed on an island off central California participate in a social hierarchy resembling the peck order of domestic chickens. Individuals achieve status by fighting and maintain it by stereotyped threat displays. The higher the status of a male, the more readily he approaches and copulates with females. Four percent of the males inseminated 85 percent of the females.


Aerobic exercise increases brain vessel lumen size and blood flow in young adults with elevated blood pressure. Secondary analysis of the TEPHRA randomized clinical trial.
Cerebrovascular changes are already evident in young adults with hypertension and exercise is recommended to reduce cardiovascular risk. To what extent exercise benefits the cerebrovasculature at an early stage of the disease remains unclear. To investigate whether structured aerobic exercise increases brain vessel lumen diameter or cerebral blood flow (CBF) and whether lumen diameter is associated with CBF. Open, parallel, two-arm superiority randomized controlled (1:1) trial in the TEPHRA study on an intention-to-treat basis. The MRI sub-study was an optional part of the protocol. The outcome assessors remained blinded until the data lock. Single-centre trial in Oxford, UK. Participants were physically inactive (<150 min/week moderate to vigorous physical activity), 18 to 35 years old, 24-hour ambulatory blood pressure 115/75 mmHg-159/99 mmHg, body mass index below 35 kg/m2 and never been on prescribed hypertension medications. Out of 203 randomized participants, 135 participated in the MRI sub-study. Randomisation was stratified for sex, age (<24, 24-29, 30-35 years) and gestational age at birth (<32, 32-37, >37 weeks). Study participants were randomised to a 16 week aerobic exercise intervention targeting 3×60 min sessions per week at 60 to 80 % peak heart rate. cerebral blood flow (CBF) maps from ASL MRI scans, internal carotid artery (ICA), middle cerebral artery (MCA) M1 and M2 segments, anterior cerebral artery (ACA), basilar artery (BA), and posterior cerebral artery (PCA) diameters extracted from TOF MRI scans. Of the 135 randomized participants (median age 28 years, 58 % women) who had high quality baseline MRI data available, 93 participants also had high quality follow-up data available. The exercise group showed an increase in ICA (0.1 cm, 95 % CI 0.01 to 0.18, p =.03) and MCA M1 (0.05 cm, 95 % CI 0.01 to 0.10, p =.03) vessel diameter compared to the control group. Differences in the MCA M2 (0.03 cm, 95 % CI 0.0 to 0.06, p =.08), ACA (0.04 cm, 95 % CI 0.0 to 0.08, p =.06), BA (0.02 cm, 95 % CI -0.04 to 0.09, p =.48), and PCA (0.03 cm, 95 % CI -0.01 to 0.06, p =.17) diameters or CBF were not statistically significant. The increase in ICA vessel diameter in the exercise group was associated with local increases in CBF. Aerobic exercise induces positive cerebrovascular remodelling in young people with early hypertension, independent of blood pressure. The long-term benefit of these changes requires further study. Clinicaltrials.gov NCT02723552, 30 March 2016.


Methods of milk expression for lactating women.
This is an update of a 2008 Cochrane review. Breastfeeding is important. However, not all infants can feed at the breast and methods of expressing milk need evaluation. To assess acceptability, effectiveness, safety, effect on milk composition, contamination and cost implications of methods of milk expression. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2014), CINAHL (1982 to March 2014), conference proceedings, secondary references and contacted researchers. Randomised and quasi-randomised trials comparing methods at any time after birth. Three authors independently assessed trials, extracted data and assessed risk of bias. This updated review includes 34 studies involving 1998 participants, with 17 trials involving 961 participants providing data for analysis. Eight studies compared one or more types of pump versus hand expression and 14 studies compared one type of pump versus another type of pump, with three of these studies comparing both hand expression and multiple pump types. Fifteen studies compared a specific protocol or adjunct behaviour including sequential versus simultaneous pumping protocols (five studies), pumping > 4 times per day versus < 3 times per day (one study), provision of a milk expression education and support intervention to mothers of preterm infants versus no provision (one study), provision of audio/visual relaxation to mothers of preterm infants versus no specific relaxation (two studies), commencing pumping within one hour of delivery versus between one to six hours (one study), breast massage before or during pumping versus no massage (two studies, of which one also tested a second behaviour), therapeutic touch versus none (one study), warming breasts before pumping versus not warming breasts (one study), combining hand expression with pumping versus pumping alone (one study) and a breast cleansing protocol versus no protocol (one study).There were insufficient comparable data on outcomes to undertake meta-analysis and data reported relates to evidence from single studies.Only one of the 17 studies examining maternal satisfaction/acceptability provided data in a way that could be analysed, reporting that mothers assigned to the pumping group had more agreement with the statement 'I don't want anyone to see me pumping' than mothers in the hand expression group and the statement 'I don't want anyone to see me hand expressing' (n = 68, mean difference (MD) -0.70, 95% confidence interval (CI) -1.25 to -0.15, P = 0.01), and that mothers found instructions for hand expression were clearer than for pumping (n = 68, MD 0.40, 95% CI 0.05 to 0.75, P = 0.02). No evidence of a difference was found between methods related to adverse effects of milk contamination (one study, n = 28, risk ratio (RR) 0.89, 95% CI 0.62 to 1.27, P = 0.51), (one study, n = 142 milk samples, MD 0.20, 95% CI -0.18 to 0.58, P = 0.30), (one study, n = 123 milk samples, MD 0.10, 95% CI -0.29 to 0.49, P = 0.61), (one study, n = 141 milk samples, MD -0.10, 95% CI -0.46 to 0.26, P = 0.59 ); or level of maternal breast or nipple pain or damage (one study, n = 68, MD 0.02, 95% CI -0.67 to 0.71, P = 0.96).For the secondary outcomes, greater volume was obtained when mothers with infants in a neonatal unit were provided with a relaxation tape or music-listening interventions to use while pumping, when the breasts was warmed before pumping or massaged while pumping.Initiation of milk pumping within 60 minutes of birth of a very low birthweight infant obtained higher mean milk quantity in the first week than the group who initiated pumping later. No evidence of difference in volume was found with simultaneous or sequential pumping or between pumps studied. Differences between methods was found for sodium, potassium, protein and fat constituents; no evidence of difference was found for energy content.No consistent effect was found related to prolactin change or effect on oxytocin release with pump type or method. Economic aspects were not reported.Most studies were classified as unclear or low risk of bias. Most studies did not provide any information regarding blinding of outcome assessment. Fifteen of the 25 studies that evaluated pumps or products had support from the manufacturers. The most suitable method for milk expression may depend on the time since birth, purpose of expression and the individual mother and infant. Low-cost interventions including early initiation when not feeding at the breast, listening to relaxation music, massage and warming of the breasts, hand expression and lower cost pumps may be as effective, or more effective, than large electric pumps for some outcomes. Small sample sizes, large standard deviations, and the diversity of the interventions argue caution in applying these results beyond the specific method tested in the specific settings.


Dietary B vitamin and methionine intakes and lung cancer risk among female never smokers in China.
B vitamins and methionine have been postulated to have potential effects on carcinogenesis; however, findings from previous epidemiologic studies on B vitamins, methionine, and lung cancer risk are inconsistent. We investigated associations of dietary intakes of B vitamins (i.e., riboflavin, niacin, vitamin B6, folate, and vitamin B12) and methionine with lung cancer risk among female never smokers. The Shanghai Women's Health Study, a population-based, prospective cohort study, included 74,941 women. During a median follow-up of 11.2 years, 428 incident lung cancer cases accrued among 71,267 women with no history of smoking or cancer at baseline. Baseline dietary intakes were derived from a validated, interviewer-administered food frequency questionnaire. Cancer incidence and vital status were ascertained through annual linkage to the Shanghai Cancer Registry and Shanghai Vital Statistics Registry databases and through biennial in-person follow-ups with participants. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox regression. Dietary riboflavin intake was inversely associated with lung cancer risk (HR = 0.62; 95 % CI = 0.43-0.89; p trend = 0.03 for the highest quartile compared with the lowest). A higher than median intake of methionine was associated with lower risk of lung cancer (HR = 0.78; 95 % CI = 0.60-0.99); however, there was no dose-response relation. Intakes of other B vitamins were not associated with lung cancer risk. Our study suggests that dietary riboflavin intake may be inversely associated with lung cancer risk among female never smokers, which warrants further investigation.


Enhanced maternal and child health nurse care for women experiencing intimate partner/family violence: protocol for MOVE, a cluster randomised trial of screening and referral in primary health care.
Intimate partner violence (IPV) can result in significant harm to women and families and is especially prevalent when women are pregnant or recent mothers. Maternal and child health nurses (MCHN) in Victoria, Australia are community-based nurse/midwives who see over 95% of all mothers with newborns. MCHN are in an ideal position to identify and support women experiencing IPV, or refer them to specialist family violence services. Evidence for IPV screening in primary health care is inconclusive to date. The Victorian government recently required nurses to screen all mothers when babies are four weeks old, offering an opportunity to examine the effectiveness of MCHN IPV screening practices. This protocol describes the development and design of MOVE, a study to examine IPV screening effectiveness and the sustainability of screening practice. MOVE is a cluster randomised trial of a good practice model of MCHN IPV screening involving eight maternal and child health nurse teams in Melbourne, Victoria. Normalisation Process Theory (NPT) was incorporated into the design, implementation and evaluation of the MOVE trial to enhance and evaluate sustainability. Using NPT, the development stage combined participatory action research with intervention nurse teams and a systematic review of nurse IPV studies to develop an intervention model incorporating consensus guidelines, clinical pathway and strategies for individual nurses, their teams and family violence services. Following twelve months' implementation, primary outcomes assessed include IPV inquiry, IPV disclosure by women and referral using data from MCHN routine data collection and a survey to all women giving birth in the previous eight months. IPV will be measured using the Composite Abuse Scale. Process and impact evaluation data (online surveys and key stakeholders interviews) will highlight NPT concepts to enhance sustainability of IPV identification and referral. Data will be collected again in two years. MOVE will be the first randomised trial to determine IPV screening effectiveness in a community based nurse setting and the first to examine sustainability of an IPV screening intervention. It will further inform the debate about the effectiveness of IPV screening and describe IPV prevalence in a community based post-partum and early infant population. ACTRN12609000424202.


The impact of risk management practice upon the implementation of recovery-oriented care in community mental health services: a qualitative investigation.
Recovery-oriented care has become guiding principle for mental health policies and practice in the UK and elsewhere. However, a pre-existing culture of risk management practice may impact upon the provision of recovery-oriented mental health services. To explore how risk management practice impacts upon the implementation of recovery-oriented care within community mental health services. Semi-structured interviews using vignettes were conducted with eight mental health worker and service user dyads. Grounded theory techniques were used to develop explanatory themes. Four themes arose: (1) recovery and positive risk taking; (2) competing frameworks of practice; (3) a hybrid of risk and recovery; (4) real-life recovery in the context of risk. In abstract responses to the vignettes, mental health workers described how they would use a positive-risk taking approach in support of recovery. In practice, this was restricted by a risk-averse culture embedded within services. Mental health workers set conditions with which service users complied to gain some responsibility for recovery. A lack of strategic guidance at policy level and lack of support and guidance at practice level may result in resistance to implementing ROC in the context of RMP. Recommendations are made for policy, training and future research.


The relationship between direct predation and antipredator responses: a test with multiple predators and multiple prey.
Most species adjust their behavior to reduce the likelihood of predation. Many experiments have shown that antipredator responses carry energetic costs that can affect growth, survival, and reproduction, so that the total cost of predation depends on a trade-off between direct predation and risk effects. Despite these patterns, few field studies have examined the relationship between direct predation and the strength of antipredator responses, particularly for complete guilds of predators and prey. We used scan sampling in 344 observation periods over a four-year field study to examine behavioral responses to the immediate presence of predators for a complete antelope guild (dominated by wildebeest, zebra, and oribi) in Liuwa Plains National Park, Zambia, testing for differences in response to all large carnivores in the ecosystem (lions, spotted hyenas, cheetahs, and African wild dogs). We quantified the proportion that each prey species contributed to the kills made by each predator (516 total kills), used distance sampling on systematic line transects to determine the abundance of each prey species, and combined these data to quantify the per-capita risk of direct predation for each predator-prey pair. On average, antelopes increased their vigilance by a factor of 2.4 when predators were present. Vigilance varied strongly among prey species, but weakly in response to different predators. Increased vigilance was correlated with reduced foraging in a similar manner for all prey species. The strength of antipredator response was not detectably related to patterns of direct predation (n = 15 predator-prey combinations with sufficient data). This lack of correlation has implications for our understanding of the role of risk effects as part of the limiting effect of predators on prey.


Viral RNA trafficking is inhibited in replicase-mediated resistant transgenic tobacco plants.
Transgenic tobacco (Nicotiana tabacum cv. Turkish Samsun NN) plants expressing a truncated replicase gene sequence from RNA-2 of strain Fny of cucumber mosaic virus (CMV) are resistant to systemic CMV disease. This is due to suppression of virus replication and cell-to-cell movement in the inoculated leaves of these plants. In this study, microinjection protocols were used to directly examine cell-to-cell trafficking of CMV viral RNA in these resistant plants. CMV RNA fluorescently labeled with the nucleotide-specific TOTO-1 iodide dye, when coinjected with unlabeled CMV 3a movement protein (MP), moved rapidly into the surrounding mesophyll cells in mature tobacco leaves of vector control and untransformed plants. Such trafficking required the presence of functional CMV 3a MP. In contrast, coinjection of CMV 3a MP and CMV TOTO-RNA failed to move in transgenic resistant plants expressing the CMV truncated replicase gene. Furthermore, coinjection of 9.4-kDa fluorescein-conjugated dextran (F-dextran) along with unlabeled CMV 3a MP resulted in cell-to-cell movement of the F-dextran in control plants, but not in the transgenic plants. Similar results were obtained with viral RNA when the 30-kDa MP of tobacco mosaic virus (TMV) was coinjected with TMV TOTO-RNA into replicase-resistant transgenic tobacco expressing the 54-kDa gene sequence of TMV. However, in these transgenic plants, the TMV-MP was still capable of mediating cell-to-cell movement of itself and the 9.4-kDa F-dextran. These results indicate that an inhibition of cell-to-cell viral RNA trafficking is correlated with replicase-mediated resistance. This raises the possibility that the RNA-2 product is potentially involved in the regulation of cell-to-cell movement of viral infectious material during CMV replication.


Interspecific resource partitioning in sympatric ursids.
The fundamental niche of a species is rarely if ever realized because the presence of other species restricts it to a narrower range of ecological conditions. The effects of this narrower range of conditions define how resources are partitioned. Resource partitioning has been inferred but not demonstrated previously for sympatric ursids. We estimated assimilated diet in relation to body condition (body fat and lean and total body mass) and reproduction for sympatric brown bears (Ursus arctos) and American black bears (U. americanus) in south-central Alaska, 1998-2000. Based on isotopic analysis of blood and keratin in claws, salmon (Oncorhynchus spp.) predominated in brown bear diets (> 53% annually) whereas black bears assimilated 0-25% salmon annually. Black bears did not exploit salmon during a year with below average spawning numbers, probably because brown bears deterred black bear access to salmon. Proportion of salmon in assimilated diet was consistent across years for brown bears and represented the major portion of their diet. Body size of brown bears in the study area approached mean body size of several coastal brown bear populations, demonstrating the importance of salmon availability to body condition. Black bears occurred at a comparable density (mass:mass), but body condition varied and was related directly to the amount of salmon assimilated in their diet. Both species gained most lean body mass during spring and all body fat during summer when salmon were present. Improved body condition (i.e., increased percentage body fat) from salmon consumption reduced catabolism of lean body mass during hibernation, resulting in better body condition the following spring. Further, black bear reproduction was directly related to body condition; reproductive rates were reduced when body condition was lower. High body fat content across years for brown bears was reflected in consistently high reproductive levels. We suggest that the fundamental niche of black bears was constrained by brown bears through partitioning of food resources, which varied among years. Reduced exploitation of salmon caused black bears to rely more extensively on less reliable or nutritious food sources (e.g., moose [Alces alces], berries) resulting in lowered body condition and subsequent reproduction.


An assessment of printed oral cancer materials from local health departments in Illinois.
Local health departments can be resources for the public and health professionals to access educational materials on a variety of topics. Though the dental office is ideal, it should not be the only venue for obtaining oral cancer educational materials. As part of a cancer prevention and early detection project, this pilot study solicited printed educational materials concerning oral cancer from all local health departments (LHDs) in Illinois. Sixty of the 94 health departments responded, for a response rate of 63.8%. Only 32 had printed oral cancer educational materials for public and professional distribution, and most focused on tobacco. Forty-eight different samples were received. At least one risk factor was identified in all materials. The most common was tobacco usage, present in 100% of the materials. Twenty-nine (61%) identified tobacco use as the only risk factor. Alcohol consumption, the second most frequently identified risk factor, was mentioned in only 12 (26%) of the materials. Few materials comprehensively covered areas such as signs and symptoms, risk factors, and the importance of examinations for early detection. Only five materials (11%) acknowledged that early lesions are often asymptomatic. Local health departments are in an influential position to disseminate educational materials to the public and health professionals. Dental hygienists have the knowledge and expertise required to identify quality materials. They should be proactive in assisting LHDs with acquisition of appropriate printed materials and partner with them to advocate for prevention and early detection of oral cancer. In collaboration, the two can ensure that all LHDs have current and comprehensive printed materials about oral cancer to distribute to the public and other health professionals.


Attention-deficit hyperactivity disorder.
Attention-deficit hyperactivity disorder (ADHD) affects between 1.4% and 6% of children. The importance of the role of primary care in the recognition and joint management of this disorder is being increasingly highlighted. Despite a wealth of research, the diagnosis and management of ADHD have attracted a good deal of controversy. In this discussion paper, we focus on the empirical basis for some of the more controversial aspects of ADHD, such as diagnosis (discussing both under- and overdiagnosis), aetiology, outcomes, and the role of psychosocial factors in this disorder. We conclude that, provided the diagnosis of ADHD is made accurately and systematically, there are no good scientific grounds for dismissing the concept of ADHD or for failing to intervene.


Paralog dispensability shapes homozygous deletion patterns in tumor genomes.
Genomic instability is a hallmark of cancer, resulting in tumor genomes having large numbers of genetic aberrations, including homozygous deletions of protein coding genes. That tumor cells remain viable in the presence of such gene loss suggests high robustness to genetic perturbation. In model organisms and cancer cell lines, paralogs have been shown to contribute substantially to genetic robustness-they are generally more dispensable for growth than singletons. Here, by analyzing copy number profiles of > 10,000 tumors, we test the hypothesis that the increased dispensability of paralogs shapes tumor genome evolution. We find that genes with paralogs are more likely to be homozygously deleted and that this cannot be explained by other factors known to influence copy number variation. Furthermore, features that influence paralog dispensability in cancer cell lines correlate with paralog deletion frequency in tumors. Finally, paralogs that are broadly essential in cancer cell lines are less frequently deleted in tumors than non-essential paralogs. Overall, our results suggest that homozygous deletions of paralogs are more frequently observed in tumor genomes because paralogs are more dispensable.


Fluid resuscitation in acute medicine: what is the current situation?
The administration of intravenous fluids for resuscitation is the most common intervention in acute medicine. There is increasing evidence that the type of fluid may directly affect patient-centred outcomes. There is a lack of evidence that colloids confer clinical benefit over crystalloids and they may be associated with harm. Hydroxyethyl starch preparations are associated with increased mortality and use of renal replacement therapy in critically ill patients, particularly those with sepsis; albumin is associated with increased mortality in patients with severe traumatic brain injury. Crystalloids, such as saline or balanced salt solutions, are increasingly recommended as first-line resuscitation fluids for the majority of patients with hypovolaemia. There is emerging evidence that saline may be associated with adverse outcomes due to the development of hyperchloraemic metabolic acidosis, although the safety of balanced salt solutions has not been established. Fluid requirements vary over the course of critical illness. The excessive use of fluids during the resuscitative period is associated with increased cumulative fluid balance and adverse outcomes in critically ill patients. The selection of fluid depends on the clinical context in which it is administered and requires careful consideration of the dose and potential for toxicity. There is an urgent need to conduct further high-quality randomized controlled trials of currently available fluid therapy in patients with critical illness.


Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study.
Epilepsy is associated with high rates of premature mortality, but the contribution of psychiatric comorbidity is uncertain. We assessed the prevalence and risks of premature mortality from external causes such as suicide, accidents, and assaults in people with epilepsy with and without psychiatric comorbidity. We studied all individuals born in Sweden between 1954 and 2009 with inpatient and outpatient diagnoses of epilepsy (n=69,995) for risks and causes of premature mortality. Patients were compared with age-matched and sex-matched general population controls (n=660,869) and unaffected siblings (n=81,396). Sensitivity analyses were done to investigate whether these odds differed by sex, age, seizure types, comorbid psychiatric diagnosis, and different time periods after epilepsy diagnosis. 6155 (8.8%) people with epilepsy died during follow-up, at a median age of 34·5 (IQR 21·0-44·0) years with substantially elevated odds of premature mortality (adjusted odds ratio [aOR] of 11·1 [95% CI 10·6-11·6] compared with general population controls, and 11·4 [10·4-12·5] compared with unaffected siblings). Of those deaths, 15·8% (n=972) were from external causes, with high odds for non-vehicle accidents (aOR 5·5, 95 % CI 4·7-6·5) and suicide (3·7, 3·3-4·2). Of those who died from external causes, 75·2% had comorbid psychiatric disorders, with strong associations in individuals with co-occurring depression (13·0, 10·3-16·6) and substance misuse (22·4, 18·3-27·3), compared with patients with no epilepsy and no psychiatric comorbidity. Reducing premature mortality from external causes of death should be a priority in epilepsy management. Psychiatric comorbidity plays an important part in the premature mortality seen in epilepsy. The ability of health services and public health measures to prevent such deaths requires review. Wellcome Trust, the Swedish Prison and Probation Service, and the Swedish Research Council.


CyberKnife radiosurgery for trigeminal neuralgia: unanticipated iatrogenic effect following successful treatment.
This case report of 74-year-old man with trigeminal neuralgia is presented to underscore the importance of evaluating the entire treatment plan, especially when delivering large doses where even a low percentage of the prescription dose can contribute a substantial dose to an unintended target. The patient was treated using the CyberKnife stereotactic radiosurgery system utilizing a nonisocentric beam treatment plan with a 5-mm fixed collimator generating 111 beams to deliver 6000 cGy to the 79% isodose line with a maximum dose of 7594 cGy to the target. Two weeks after treatment the patient's trigeminal neuralgia symptoms resolved; however, the patient developed oral mucositis due to the treatment. This case report reviews the cause of mucositis and makes recommendations on how to prevent unintended targets from receiving treatment.


Functionalisation of Detonation Nanodiamond for Monodispersed, Soluble DNA-Nanodiamond Conjugates Using Mixed Silane Bead-Assisted Sonication Disintegration.
Nanodiamonds have many attractive properties that make them suitable for a range of biological applications, but their practical use has been limited because nanodiamond conjugates tend to aggregate in solution during or after functionalisation. Here we demonstrate the production of DNA-detonation nanodiamond (DNA-DND) conjugates with high dispersion and solubility using an ultrasonic, mixed-silanization chemistry protocol based on the in situ Bead-Assisted Sonication Disintegration (BASD) silanization method. We use two silanes to achieve these properties: (1) 3-(trihydroxysilyl)propyl methylphosphonate (THPMP); a negatively charged silane that imparts high zeta potential and solubility in solution; and (2) (3-aminopropyl)triethoxysilane (APTES); a commonly used functional silane that contributes an amino group for subsequent bioconjugation. We target these amino groups for covalent conjugation to thiolated, single-stranded DNA oligomers using the heterobifunctional crosslinker sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (Sulfo-SMCC). The resulting DNA-DND conjugates are the smallest reported to date, as determined by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). The functionalisation method we describe is versatile and can be used to produce a wide variety of soluble DND-biomolecule conjugates.


Narrative review of women's health in Iran: challenges and successes.
In each society, the health of women in different periods may be endangered by an unequal distribution of resources, facilities, and gender prejudices. The present study evaluated the time trend of Iranian women's health between 1990 and 2013. This narrative review includes an integration and descriptive summary of the existing evidence on trends and criteria of different aspects of women's health from social determinant point of view. The evidence was drawn from peer-reviewed, cross-national or large-scale studies, official sources of the Ministry of Health, reviews, and online scientific databases published between 1990 and 2013. The average life expectancy of Iranian women has increased from 44.15 years in 1960 to 75.75 years in 2012; in most deprived provinces of Iran, however, this criterion is about 67.3 years, and in the capital it is 75.8 years. In 2011, 43.37 % of DALYS, 36.21 % of YLL, and 1.92 % of YLD were dedicated to women; these figures were 3.63 % lower than they were in 2003. Although a significant reduction has occurred in maternal mortality rate, which dropped from 83 to 23 per 100,000 between 1990 and 2013, there is no equal distribution in maternal mortality across the country as manifested by the unfavorable conditions of border provinces (SD = 19.2). The prevalence of HIV/AIDS is an alarming health problem among Iranian females, increasing approximately 546 % between 2007 and 2015. As for mental health, depression in women was ranked first among diseases in 2011 compared to a second place ranking in 2003. As regards social health, the delinquency of women has increased in recent years compared to men with women committing more crimes related to drugs and actions against virtue. The annual report of the United Nations for the gender gap index in 2013 ranked Iran as 130 among 136 countries (from 0.622 in 2000 to 0.584 in 2013). Generally, over the last three decades, the health indices of Iranian women have grown in aspects of physical, mental, and social health. Remarkable differences can be seen among female health indices based on geographic location and in comparison with men. To promote an improved health status for Iranian women, the root causes of the discrepancies must be identified and a comprehensive national plan must be established.


TAp73 depletion accelerates aging through metabolic dysregulation.
Aging is associated with impaired scavenging of reactive oxygen species (ROS). Here, we show that TAp73, a p53 family member, protects against aging by regulating mitochondrial activity and preventing ROS accumulation. TAp73-null mice show more pronounced aging with increased oxidative damage and senescence. TAp73 deletion reduces cellular ATP levels, oxygen consumption, and mitochondrial complex IV activity, with increased ROS production and oxidative stress sensitivity. We show that the mitochondrial complex IV subunit cytochrome C oxidase subunit 4 (Cox4i1) is a direct TAp73 target and that Cox4i1 knockdown phenocopies the cellular senescence of TAp73-null cells. Results indicate that TAp73 affects mitochondrial respiration and ROS homeostasis, thus regulating aging.


Common nonsynonymous variants in PCSK1 confer risk of obesity.
Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.


Atypical transcriptional regulation and role of a new toxin-antitoxin-like module and its effect on the lipid composition of Bradyrhizobium japonicum.
A toxin-antitoxin (TA)-like system (designated as bat/bto genes) was identified in Bradyrhizobium japonicum, based on sequence homology and similarities in organization and size to known TA systems. Deletion of the bat/bto module resulted in pleiotropic alterations in cell morphology and metabolism. The generation time of the mutant was considerably decreased in rich media. Atomic force microscopy revealed the modified shape (shorter and wider) and softness of mutant cells. The synthesis of phosphatidylcholine was completely blocked in the mutant bacteria, and vaccenic acid, the predominant fatty acid of membranes of the wild-type cell, was replaced by palmitic acid in the mutant membranes. The mutant bacteria synthesized incomplete lipopolysaccharide molecules. Remarkable changes in the membrane lipid composition may explain the observed morphological alterations and growth properties of the mutant bacteria. The overlapping promoter region of bat/bto and glpD (coding for the aerobic sn-glycerol-3-phosphate dehydrogenase) genes suggests a complex regulation and the involvement of bat/bto in the control of main metabolic pathways and an important role in the maintenance of a normal physiological state of B. japonicum. These data reveal new aspects of the role of TA systems in bacteria.


Human pluripotent stem cell-derived cardiomyocytes align under cyclic strain when guided by cardiac fibroblasts.
The myocardium is a mechanically active tissue typified by anisotropy of the resident cells [cardiomyocytes (CMs) and cardiac fibroblasts (cFBs)] and the extracellular matrix (ECM). Upon ischemic injury, the anisotropic tissue is replaced by disorganized scar tissue, resulting in loss of coordinated contraction. Efforts to re-establish tissue anisotropy in the injured myocardium are hampered by a lack of understanding of how CM and/or cFB structural organization is affected by the two major physical cues inherent in the myocardium: ECM organization and cyclic mechanical strain. Herein, we investigate the singular and combined effect of ECM (dis)organization and cyclic strain in a two-dimensional human in vitro co-culture model of the myocardial microenvironment. We show that (an)isotropic ECM protein patterning can guide the orientation of CMs and cFBs, both in mono- and co-culture. Subsequent application of uniaxial cyclic strain-mimicking the local anisotropic deformation of beating myocardium-causes no effect when applied parallel to the anisotropic ECM. However, when cultured on isotropic substrates, cFBs, but not CMs, orient away from the direction of cyclic uniaxial strain (strain avoidance). In contrast, CMs show strain avoidance via active remodeling of their sarcomeres only when co-cultured with at least 30% cFBs. Paracrine signaling or N-cadherin-mediated communication between CMs and cFBs was no contributing factor. Our findings suggest that the mechanoresponsive cFBs provide structural guidance for CM orientation and elongation. Our study, therefore, highlights a synergistic mechanobiological interplay between CMs and cFBs in shaping tissue organization, which is of relevance for regenerating functionally organized myocardium.


A new lipophilic amino alcohol, chemically similar to compound FTY720, attenuates the pathogenesis of experimental autoimmune encephalomyelitis by PI3K/Akt pathway inhibition.
Experimental autoimmune encephalomyelitis (EAE) is one of the main animal models used for the study of Multiple Sclerosis (MS). Long-chain lipophilic amino alcohols with immunoregulatory activities have already been studied in some models of inflammatory diseases, but the action of these compounds in EAE and MS is still unknown. In this study, we investigated whether the lipophilic amino alcohol 4b would act to improve the clinical signs of EAE and reduce the demyelination process and the neuroinflammatory parameters in the spinal cord, as well as the inflammatory process in the inguinal lymph nodes, of C57Bl/6 mice induced with EAE after stimulation with MOG35-55 and pertussis toxin. The 4b treatment (1.0 mg/kg/day) was orally administered, starting on the day of onset of clinical signs of the disease (10th) and ending on the 20th day after immunization. This treatment was able to reduce the cell count on the inguinal lymph nodes, the migration of inflammatory cells into the central nervous system (CNS), as well as the processes of microgliosis, astrogliosis, and the production of chemokines and pro-inflammatory cytokines, thus increasing the IL-10 anti-inflammatory cytokine levels in EAE mice. The inhibition of Akt phosphorylation in the CNS of EAE mice after treatment with 4b indicates that the immunoregulatory action of 4b is related to the PI3K/Akt signaling pathway. Our results indicate the immunoregulatory efficacy of the new compound 4b in the control of some inflammatory parameters and in the glial proliferation. In addition, 4b was able to reduce the demyelination of neurons and the worsening of clinical signs of EAE as effectively as the compound FTY720, the first oral drug approved by the FDA for the treatment of MS.


Evaluation of bacterial contamination in raw milk, ultra-high temperature milk and infant formula using single molecule, real-time sequencing technology.
The Pacific Biosciences (Menlo Park, CA) single molecule, real-time sequencing technology (SMRT) was reported to have some advantages in analyzing the bacterial profile of environmental samples. In this study, the presence of bacterial contaminants in raw milk, UHT milk, and infant formula was determined by SMRT sequencing of the full length 16S rRNA gene. The bacterial profiles obtained at different taxonomic levels revealed clear differences in bacterial community structure across the 16 analyzed dairy samples. No indicative pathogenic bacteria were found in any of these tested samples. However, some of the detected bacterial species (e.g., Bacillus cereus, Enterococcus casseliflavus, and Enterococcus gallinarum) might potentially relate with product quality defects and bacterial antibiotic gene transfer. Although only a limited number of dairy samples were analyzed here, our data have demonstrated for the first time the feasibility of using the SMRT sequencing platform in detecting bacterial contamination. Our paper also provides interesting reference information for future development of new precautionary strategies for controlling the dairy safety in large-scale industrialized production lines.


The effect of various dietary fibres on tissue concentration and chemical form of mercury after methylmercury exposure in mice.
The whole-body retention of mercury after exposure of BALB/c mice to methylmercury was measured in animals fed fibre-free, 5% pectin, 5% cellulose or 5, 15 or 30% wheat bran diets. The rate of elimination of mercury was dependent on the diet fed, with dietary bran increasing the rate of elimination. The incorporation of 15 or 30% bran in the diet of the mice decreased the total mercury concentration in the brain, blood and small intestine, although the effects were significant only in those animals on 30% bran diet. The fibres had little effect on mercury levels in other tissues. The proportion of mercury found in the mercuric form was significantly greater in liver, kidneys and gut of mice fed bran. The results suggest that dietary bran may reduce the levels of mercury in the brain after methylmercury exposure and may therefore reduce the neurotoxic effects of the organomercurial. We suggest that wheat bran exerts its effects on mercury retention and brain level via a modification of the metabolic activity of the gut microflora.


[Zinc is the most important trace element].
Zinc is one of the most important trace elements. Zinc deficiency is a major health problem worldwide. Causes of zinc deficiency can be nutritional, iatrogenic, genetic or a result of diseases. Severe zinc deficiency results in symptoms like pustular dermatitis, alopecia, weight loss, diarrhoea, infections secondary to immune dysfunction, hypogonadism and problems in ulcer healing. Zinc supplementation is necessary in cases of zinc deficiency, but high doses zinc supplementation through a long time can result in copper deficiency or anaemia. Thus a rational use of zinc supplementation in the required time is necessary.


Pest categorisation of Leptinotarsa decemlineata.
The EFSA Panel on Plant Health performed a pest categorisation of the Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae) for the EU. L. decemlineata is primarily known as a major defoliator of potatoes (Solanum tuberosum); feeding damage can result in significant yield loss. Field grown tomatoes and eggplants can be attacked and wild solanaceous species are also hosts. Having first established in Europe from North America in the early 20th century, L. decemlineata is now distributed in 21 EU Member States and is regulated in the EU by Commission Implementing Regulation 2019/2072, (Annex III) with protected zones in place for Cyprus, Ireland, Malta, Northern Ireland, parts of Spain (Ibiza and Menorca) and Portugal (Azores and Madeira), seven districts of Finland and five counties in Sweden. Adults occasionally enter some protected zones due to wind currents that carry flying adults; pathways are also provided by plant produce moved in trade. The availability of hosts and suitable climate make establishment of the pest possible in protected zones in the EU, especially in the southern EU. Spread within the protected zones could occur via adult flight and via leafy vegetables moved in trade. Impacts on potato yields would be expected within the protected zones; outdoor grown tomatoes and eggplants could be impacted in the protected zones of southern Member States too. Previous incursions into the current protected zones have been eradicated. L. decemlineata satisfies all of the criteria that are within the remit of EFSA to assess, to conclude that it is a potential protected zone quarantine pest. L. decemlineata does not satisfy all of the criteria that are within the remit of EFSA to assess with respect to regulated non-quarantine pest status, specifically plants for planting are not the main means of spread.


Morphology of the nervous system of monogonont rotifer Epiphanes senta with a focus on sexual dimorphism between feeding females and dwarf males.
Monogononta is a large clade of rotifers comprised of diverse morphological forms found in a wide range of ecological habitats. Most monogonont species display cyclical parthenogenesis, where generations of asexually reproducing females are interspaced by mixis events when sexual reproduction occurs between mictic females and dwarf, haploid males. The morphology of monogonont feeding females is relatively well described, however data on male anatomy are very limited. Thus far, male musculature of only two species has been described with confocal laser scanning microscopy (CLSM) and it remains unknown how dwarfism influences the neuroanatomy of males on detailed level. Here, we provide a CLSM-based description of the nervous system of both sexes of Epiphanes senta, a freshwater monogonont rotifer. The general nervous system architecture is similar between males and females and shows a similar level of complexity. However, the nervous system in males is more compact and lacks a stomatogastric part. Comparison of the neuroanatomy between male and normal-sized feeding females provides a better understanding of the nature of male dwarfism in Monogononta. We propose that dwarfism of monogonont non-feeding males is the result of a specific case of heterochrony, called "proportional dwarfism" as they, due to their inability to feed, retain a juvenile body size, but still develop a complex neural architecture comparable to adult females. Reduction of the stomatogastric nervous system in the males correlates with the loss of the entire digestive tract and associated morphological structures.


Association between Perioperative Blood Transfusion and Oncologic Outcomes after Curative Surgery for Renal Cell Carcinoma.
We aimed to elucidate the association between perioperative blood transfusion (PBT) and the prognosis of patients undergoing curative surgery for renal cell carcinoma (RCC). In all, 3,832 patients with RCC who had undergone curative surgery were included in this study from a multicenter database. PBT was defined as the transfusion of packed red blood cells within seven days before surgery, during surgery, or within the postoperative hospitalization period. The association of PBT with oncologic outcomes was evaluated using univariate and multivariate Cox regression analyses, and regression adjustment with propensity score matching. Overall, 11.7% (447/3,832) of patients received PBT. Patients receiving PBT were significantly older at diagnosis, and had lower BMI, higher comorbidities, worse ECOG performance status, and more initial symptoms. Moreover, higher pathologic TNM stage, larger mass size, higher nuclear grade, more sarcomatoid differentiation, and more tumor necrosis were all observed more frequently in patients who received PBT. In univariate analysis, relapse-free survival, cancer-specific survival, and overall survival rates were worse in patients who received PBT; however, these factors became insignificant in the matched pairs after propensity score matching. On multivariate Cox regression analysis and regression adjustment with propensity score matching, significant prognostic effects of PBT on disease relapse, cancer-specific mortality, and all-cause mortality were not observed. This multicenter database analysis demonstrates no significant prognostic association between PBT and oncologic outcomes in patients with RCC.


Prognostic correlates of combined coronary flow reserve assessment on left anterior descending and right coronary artery in patients with negative stress echocardiography by wall motion criteria.
To assess the prognostic correlates of Doppler echocardiographically derived coronary flow reserve (CFR) on two coronaries in patients with negative stress echo. Vasodilator stress echocardiography allows dual imaging of regional wall motion and CFR both on left anterior descending (LAD) and right coronary artery (RCA). The study group comprised 460 patients with known or suspected coronary artery disease and negative stress echo by wall motion criteria. All underwent dipyridamole (up to 0.84 mg/kg over 6 minutes) stress echo with CFR evaluation of either LAD or RCA by Doppler, and were followed up for a median of 32 months. A CFR value of < or =2.0 was taken as abnormal. CFR was abnormal in 174 patients (38%) (57 in LAD only, 48 in RCA only, and 69 in both LAD and RCA) and normal in 286 patients (62%). During follow-up, there were 77 cardiac events: 5 deaths, 44 acute coronary syndromes (6 STEMI, and 38 NSTEMI) and 28 late (>6 months from stress echo) revascularisations. CFR of < or =2.0 on LAD was the strongest multivariable predictor of either definite (death, acute coronary syndrome) and major (death, acute coronary syndrome, late revascularisation) events, followed by diabetes mellitus. Anti-ischaemic therapy at the time of testing and resting wall motion abnormality were also independently associated with major events. Preserved CFR in both LAD and RCA was associated with better (p<0.0001) definite and major event-free survival compared to abnormal CFR in one or both coronary vessels. CFR evaluation of either LAD or RCA allows the identification of distinct prognostic patterns. In particular, preserved CFR in both coronary vessels is highly predictive of a very favourable outcome, while reduced CFR in either coronary vessel, and especially on LAD, is a strong predictor of future cardiac events.


Coastal freshening drives acidification state in Greenland fjords.
Greenland's fjords and coastal waters are highly productive and sustain important fisheries. However, retreating glaciers and increasing meltwater are changing fjord circulation and biogeochemistry, which may threaten future productivity. The freshening of Greenland fjords caused by unprecedented melting of the Greenland Ice Sheet may alter carbonate chemistry in coastal waters, influencing CO2 uptake and causing biological consequences from acidification. However, few studies to date explore the current acidification state in Greenland coastal waters. Here we present the first-ever large-scale measurements of carbonate system parameters in 16 Greenlandic fjords and seek to identify the drivers of acidification state in these freshening ecosystems. Aragonite saturation state (Ω), a proxy for ocean acidification, was calculated from dissolved inorganic carbon (DIC) and total alkalinity from fjords along the east and west coast of Greenland spanning 68-75°N. Aragonite saturation was primarily >1 in the surface mixed layer. However, undersaturated-or corrosive--conditions (Ω < 1) were observed on both coasts (west: Ω = 0.28-3.11, east: Ω = 0.70-3.07), albeit at different depths. West Greenland fjords were largely corrosive at depth while undersaturation in East Greenland fjords was only observed in surface waters. This reflects a difference in the coastal boundary conditions and mechanisms driving acidification state. We suggest that advection of Sub Polar Mode Water and accumulation of DIC from organic matter decomposition drive corrosive conditions in the West, while freshwater alkalinity dilution drives acidification in the East. The presence of marine terminating glaciers also impacted local acidification states by influencing fjord circulation: upwelling driven by subglacial discharge brought corrosive bottom waters to shallower depths. Meanwhile, discharge from land terminating glaciers strengthened stratification and diluted alkalinity. Regardless of the drivers in each system, increasing freshwater discharge will likely lower carbonate saturation states and impact biotic and abiotic carbon uptake in the future.


Unprepared human colon does not discriminate between solids and liquids.
In five healthy male volunteers, we compared solid and liquid transit though the unprepared colon. 99mTc-diethylenetriaminepentaacetic acid in 10 ml saline was injected into the cecum through an orocecal tube at 1 ml/min immediately after a methacrylate-coated medication capsule was seen to deliver 111In-labeled Amberlite IR-120PLUS pellets (avg diam, 1.0 mm) into the cecum. Segmental transits through the ascending, transverse, descending, and rectosigmoid regions were determined using a dual gamma camera system and a variable region of interest program. There was no difference between solid [half time, 247 +/- 60 (SE) min] and liquid (312 +/- 88 min) emptying from the ascending colon. Colonic transit of solids and liquids was further compared by regional counts and stool outputs at 12 and 24 h. There were no significant differences between solids and liquids (P greater than 0.05). Our data suggest that transit through the unprepared human colon is not different for solids and small volumes of liquids, when these are delivered together to the ascending colon.


Mate fidelity in a polygamous shorebird, the snowy plover (Charadrius nivosus).
Social monogamy has evolved multiple times and is particularly common in birds. However, it is not well understood why some species live in long-lasting monogamous partnerships while others change mates between breeding attempts. Here, we investigate mate fidelity in a sequential polygamous shorebird, the snowy plover (Charadrius nivosus), a species in which both males and females may have several breeding attempts within a breeding season with the same or different mates. Using 6 years of data from a well-monitored population in Bahía de Ceuta, Mexico, we investigated predictors and fitness implications of mate fidelity both within and between years. We show that in order to maximize reproductive success within a season, individuals divorce after successful nesting and re-mate with the same partner after nest failure. Therefore, divorced plovers, counterintuitively, achieve higher reproductive success than individuals that retain their mate. We also show that different mating decisions between sexes predict different breeding dispersal patterns. Taken together, our findings imply that divorce is an adaptive strategy to improve reproductive success in a stochastic environment. Understanding mate fidelity is important for the evolution of monogamy and polygamy, and these mating behaviors have implications for reproductive success and population productivity.


Neuroimaging of pain mechanisms.
Functional neuroimaging has made a huge impact scientifically, not least within the field of pain research. The noninvasive identification of pain mechanisms that underpin chronicity, such as central sensitization and other amplification processes related to the cognitive or emotional state of the patient, is of considerable interest to the clinical pain community and pharmaceutical industry. Relating data to a person's specific pain report or measure of pain relief provide a clearer understanding of the mechanisms driving and maintaining this complex experience. It is timely, therefore, to review the advances in neuroimaging applications to pain. New data have emerged to further support the descending modulatory system's critical role in chronic pain. The neural correlates that underpin tonic, ongoing and spontaneous pain in patients are being identified. Additionally, the prefrontal cortex is emerging as a critical brain region for pain processing, especially in patients. Finally, data from structural and molecular imaging studies are highlighting the extent of damage the brain sustains when patients live with their chronicity unrelieved. Neuroimaging tools have advanced our understanding of central pain mechanisms in normals and patients, forcing us to reconsider issues related to diagnosis and provision of treatment.


Fluorescence pharmacokinetics of Lutetium Texaphyrin (PCI-0123, Lu-Tex) in the skin and in healthy and tumoral hamster cheek-pouch mucosa.
We have investigated the pharmacokinetics (PK) of Lutetium Texaphyrin (Lu-Tex), a second-generation photosensitizer, in the Syrian hamster cheek pouch early cancer model. Ten male hamsters, five with chemically induced early squamous cell cancer of the left cheek pouch, received an intracardiac injection of a 10 mg/ml Lu-Tex solution, resulting in a dose of 12 mg Lu-Tex per kg of bodyweight. The PK of the dye have been measured during the 24 h following the injection with an optical-fiber-based spectrofluorometer on the ventral skin, the healthy and the tumoral cheek-pouch mucosa. The Lu-Tex fluorescence is excited at 460 nm and detected around 740 nm. All the measurements yield very similar pharmacokinetic curves. The fluorescence intensity reaches a maximum between two and three hours after the injection and, at its maximum, it is consistently higher (up to 1.5 times) on the tumor than on the healthy mucosa. It remains smaller on the skin than on cheek-pouch mucosa. After 24 h, the Lu-Tex fluorescence is no longer detectable either on the skin, on the lesion or on the healthy mucosa. Moreover, Lu-Tex clearly displays a significant fluorescence selectivity between early carcinoma and healthy mucosa in this model. Furthermore, the inter-animal fluctuations of the fluorescence signal are small (+/-16% on the tumor-bearing mucosa). Eight-minute-long skin-irradiation tests have been performed 24 h after the injection of the Lu-Tex on the ventral skin of 16 additional animals with a solar simulator. No reaction is observed, either macroscopically or microscopically, which further demonstrates, as suggested by the fluorescence measurements, that this photosensitizer is significantly cleared from the skin after 24 h.


The complement regulator CD46 is bactericidal to Helicobacter pylori and blocks urease activity.
CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer. Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses. H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice. CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection.


Encoding of a homolog of the IFN-gamma receptor by myxoma virus.
Many poxvirus-encoded virulence factors have been identified as proteins that are secreted from infected cells. The major secreted protein (37 kilodaltons) from cells infected with myxoma virus is encoded by the M-T7 open reading frame. This protein has significant sequence similarity to the human and mouse receptors for interferon-gamma (IFN-gamma). Furthermore, the myxoma M-T7 protein specifically binds rabbit IFN-gamma and inhibits the biological activity of extracellular IFN-gamma, one of the key regulatory cytokines in the host immune response against viral infections.


Self-filling microwell arrays (SFMAs) for tumor spheroid formation.
Tumor spheroid formation in microwell arrays is a promising approach for high-throughput screening of chemotherapeutic agents. This method offers the advantage of better mimicking the complexities of tumors as compared to conventional monolayer culture systems. However, using these technologies to their full potential is hindered by the inability to seed the cells within the wells uniformly and with high yield and reproducibility. Moreover, standard manufacturing approaches for fabrication of microwell arrays rely on lithography and etching techniques, which are costly, labor-intensive, and time-consuming. Herein, we report on the development of self-filling microwell arrays (SFMAs) in which cells are directed from a loading chamber to microwells using inclined guiding channels. The SFMAs are fabricated by replica molding of three-dimensionally (3D) printed molds in agarose. We characterize the fabrication process, demonstrate the ability to culture breast adenocarcinoma MCF-7 and glioma U87 in SFMAs and perform drug toxicity studies. We envision that the proposed innovative approach opens avenues of opportunities for high-throughput three-dimensional cell culture for drug screening and disease modeling.


Insulin-like growth factor-I mRNA and peptide in the human anterior pituitary.
The pituitary is the central organ regulating virtually all endocrine processes, and pathologies of the pituitary cause manifold adverse effects. Because insulin-like growth factor (IGF)-I appears to be involved in tumour pathogenesis, progression, and persistence, and only few data exist on the cellular synthesis sites of IGF-I, the present study aims to create a basis for further research on pituitary adenomas by investigating the presence of IGF-I in the human pituitary using reverse transcriptase-polymerase chain reaction, in situ hybridisation, immunohistochemistry and immunocytochemistry. IGF-I was expressed in the pituitary, and gene sequence analysis revealed a sequence identical to that found in human liver. The distribution pattern of IGF-I mRNA found by in situ hybridisation corresponded to that of IGF-I peptide in immunohistochemistry. In all pituitary samples investigated, IGF-I-immunoreactivity occurred in almost all adrenocorticotrophic hormone (ACTH)-immunoreactive cells. Occasionally, an interindividually varying number of growth hormone (GH) and, infrequently, follicle-stimulating hormone and luteinising hormone cells contained IGF-I-immunoreactivity but none was detected in supporting cells. At the ultrastructural level, IGF-I-immunoreactivity was confined to secretory granules in coexistence with ACTH- or GH-immunoreactivity, respectively, indicating a concomitant release of the hormones. Thus, in humans, IGF-I appears to be a constituent in ACTH cells whereas its production in GH-producing and gonadotrophic cells may depend on the physiological status (e.g. serum IGF-I level, age or reproductive phase). It is assumed that locally produced IGF-I plays a crucial role in the regulation of endocrine cells by autocrine/paracrine mechanisms in addition to the endocrine route.


Family-based interventions to increase physical activity in children: a meta-analysis and realist synthesis protocol.
Despite the established relationship between physical activity and health, data suggest that many children are insufficiently active, and that levels decline into adolescence. Engaging the family in interventions may increase and maintain children's physical activity levels at the critical juncture before secondary school. Synthesis of existing evidence will inform future studies, but the heterogeneity in target populations recruited, behaviour change techniques and intervention strategies employed, and measurement conducted, may require a multifaceted review method. The primary objective of this work will therefore be to synthesis evidence from intervention studies that explicitly engage the family unit to increase children's physical activity using an innovative dual meta-analysis and realist approach. Peer-reviewed studies will be independently screened by two authors for inclusion based on (1) including 'healthy' participants aged 5-12 years; (2) having a substantive intervention aim of increasing physical activity, by engaging the family and (3) reporting on physical activity. Duplicate data extraction and quality assessment will be conducted using a specially designed proforma and the Effective Public Health Practice Project Quality Assessment Tool respectively. STATA software will be used to compute effect sizes for meta-analyses, with subgroup analyses conducted to identify moderating characteristics. Realist syntheses will be conducted according to RAMESES quality and publication guidelines, including development of a programme theory and evidence mapping. This review will be the first to use the framework of a traditional review to conduct a dual meta-analysis and realist synthesis, examining interventions that engage the family to increase physical activity in children. The results will be disseminated through peer-reviewed publications, conferences, formal presentations to policy makers and practitioners and informal meetings. Evidence generated from this synthesis will also be used to inform the development of theory-driven, evidence-based interventions aimed at engaging the family to increase physical activity levels in children. International Prospective Register for Systematic Reviews (PROSPERO): number CRD42013005780.


Monte Carlo simulations of spectral albedo for artificial snowpacks composed of spherical and nonspherical particles.
The optical properties of snowpacks composed of spherical and nonspherical particles artificially prepared in a cold laboratory are investigated by measuring spectral albedos. The measured spectral albedo in the spectral region lambda=0.35-2.5 microm is compared with the theoretically calculated albedo, for which a Monte Carlo radiative transfer model is employed for multiple scattering combined with the Mie theory and the ray-tracing technique for single scattering by snow particles. Since the spherical particles are a little aggregate, the effects of a cluster of the spheres on snow albedo are examined using a generalized multiparticle Mie-solution model [Appl. Opt. 34, 4573 (1995); J. Quant. Spectrosc. Radiat. Transf. 79-80, 1121 (2003)]. The snow albedo of a cluster of the spheres can be represented with that of the singe sphere slightly larger than its component of the cluster in case of small grains. The observed albedos for the spherical snow particles agree with the theoretically calculated ones for the snow grain size measured in the snow pit work. The snow albedos for the nonspherical particles, which were dendrites, are influenced by the branch width and the branch length, based on a comparison of the theoretically calculated albedo by using circular cylindrical snow particles and the observed albedo. The snow albedo in the near-infrared region depends on the branch width only when the branch length is sufficiently greater than the branch width. The comparison between the spherical and nonspherical snow particles indicates that the spectral albedo of the nonspherical particles can be represented by using an equal volume-area ratio sphere.


RGS7 and RGS8 differentially accelerate G protein-mediated modulation of K+ currents.
The recently discovered family of RGS (regulators of G protein signaling) proteins acts as GTPase activating proteins which bind to alpha subunits of heterotrimeric G proteins. We previously showed that a brain-specific RGS, RGS8 speeds up the activation and deactivation kinetics of the G protein-coupled inward rectifier K+ channel (GIRK) upon receptor stimulation (Saitoh, O., Kubo, Y., Miyatani, Y., Asano, T., and Nakata, H. (1997) Nature 390, 525-529). Here we report the isolation of a full-length rat cDNA of another brain-specific RGS, RGS7. In situ hybridization study revealed that RGS7 mRNA is predominantly expressed in Golgi cells within granule cell layer of cerebellar cortex. We observed that RGS7 recombinant protein binds preferentially to Galphao, Galphai3, and Galphaz. When co-expressed with GIRK1/2 in Xenopus oocytes, RGS7 and RGS8 differentially accelerate G protein-mediated modulation of GIRK. RGS7 clearly accelerated activation of GIRK current similarly with RGS8 but the acceleration effect of deactivation was significantly weaker than that of RGS8. These acceleration properties of RGS proteins may play important roles in the rapid regulation of neuronal excitability and the cellular responses to short-lived stimulations.


Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial.
Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would augment the muscle response to PRT in healthy women and men aged 65 and older. In a randomized, double-blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT. Although responses to PRT varied, placebo gained more lean body mass (p = .003) and thigh muscle mass (p < .001) than metformin. CT scan showed that increases in thigh muscle area (p = .005) and density (p = .020) were greater in placebo versus metformin. There was a trend for blunted strength gains in metformin that did not reach statistical significance. Analyses of vastus lateralis muscle biopsies showed that metformin did not affect fiber hypertrophy, or increases in satellite cell or macrophage abundance with PRT. However, placebo had decreased type I fiber percentage while metformin did not (p = .007). Metformin led to an increase in AMPK signaling, and a trend for blunted increases in mTORC1 signaling in response to PRT. These results underscore the benefits of PRT in older adults, but metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals. ClinicalTrials.gov Identifier: NCT02308228.


Comparative study of Treponemal and non-Treponemal test for screening of blood donated at a blood center.
The non-Treponemal tests such as Rapid Plasma Reagin test (RPR) or the Venereal Disease Reference Laboratory test are the most commonly used test for screening of syphilis in the blood centers in India. Now, with the availability of Enzyme-linked immunosorbent assay (ELISA) and Immunochromatographic assays in the market, we decided to evaluate these assays in comparison with Treponema pallidum Haemagglutination Assay (TPHA) which was considered as a gold standard for this study. A total of 8 685 samples of voluntary blood donors were tested on Trepolisa 3.0 and then the initially reactive samples were retested in duplicate on the same assay as well as on Omega Pathozyme, RPR, RAPHA (Rapid Anti-Treponema pallidum Assay), and TPHA. Of the 158 initially reactive samples, 104 were repeatedly reactive on the same assay, 85 were reactive with RPR, 77 were reactive with RAPHA, 60 were reactive on Omega, and 53 were confirmed reactive on TPHA. 48 (56.4%) of the results on RPR were biological false positive, while 21.9% of results were false negative on RPR. We evaluated that Omega Pathozyme was quite in agreement with TPHA as compared with Trepolisa 3.0, RAPHA, and RPR. We concluded that Omega Pathozyme (ELISA) can be considered as a suitable test for screening of syphilis in a blood center.


Below the Mesophotic.
Mesophotic coral ecosystems, which occur at depths of ~40 to 150 m, have received recent scientific attention as potential refugia for organisms inhabiting deteriorating shallow reefs. These ecosystems merit research in their own right, as they harbor both depth-generalist species and a distinctive reef-fish fauna. Reef ecosystems just below the mesophotic are globally underexplored, and the scant recent literature that mentions them often suggests that mesophotic ecosystems transition directly into those of the deep sea. Through submersible-based surveys in the Caribbean Sea, we amassed the most extensive database to date on reef-fish diversity between ~40 and 309 m at any single tropical location. Our data reveal a unique reef-fish assemblage living between ~130 and 309 m that, while taxonomically distinct from shallower faunas, shares strong evolutionary affinities with them. Lacking an existing name for this reef-faunal zone immediately below the mesophotic but above the deep aphotic, we propose "rariphotic." Together with the "altiphotic," proposed here for the shallowest reef-faunal zone, and the mesophotic, the rariphotic is part of a depth continuum of discrete faunal zones of tropical reef fishes, and perhaps of reef ecosystems in general, all of which warrant further study in light of global declines of shallow reefs.


C-NAP1 and rootletin restrain DNA damage-induced centriole splitting and facilitate ciliogenesis.
Cilia are found on most human cells and exist as motile cilia or non-motile primary cilia. Primary cilia play sensory roles in transducing various extracellular signals, and defective ciliary functions are involved in a wide range of human diseases. Centrosomes are the principal microtubule-organizing centers of animal cells and contain two centrioles. We observed that DNA damage causes centriole splitting in non-transformed human cells, with isolated centrioles carrying the mother centriole markers CEP170 and ninein but not kizuna or cenexin. Loss of centriole cohesion through siRNA depletion of C-NAP1 or rootletin increased radiation-induced centriole splitting, with C-NAP1-depleted isolated centrioles losing mother markers. As the mother centriole forms the basal body in primary cilia, we tested whether centriole splitting affected ciliogenesis. While irradiated cells formed apparently normal primary cilia, most cilia arose from centriolar clusters, not from isolated centrioles. Furthermore, C-NAP1 or rootletin knockdown reduced primary cilium formation. Therefore, the centriole cohesion apparatus at the proximal end of centrioles may provide a target that can affect primary cilium formation as part of the DNA damage response.


A redefinition of somatosensory areas in the lateral sulcus of macaque monkeys.
The present investigation was designed to determine the organization of somatosensory fields in the lateral sulcus of macaque monkeys using standard microelectrode recording techniques. Our results provide evidence for two complete representations of the body surface. We term these fields the second somatosensory area (SII) and the parietal ventral area (PV) because of their similarities in position, internal organization, and relationship to anterior parietal fields, as described for SII and PV in other mammals. Areas SII and PV are mirror-symmetrical representations of the body surface, sharing a common boundary at the representations of the digits of the hand and foot, lips, and mouth. These fields are located adjacent to the face representations of anterior parietal fields (areas 3b, 1, and 2), and are bounded ventrally and caudally by other regions of cortex in which neurons are responsive to somatic or multimodal stimulation. The finding of a double representation of the body surface in the region of cortex traditionally designated as SII may explain conflicting descriptions of SII organization in macaque monkeys. In addition, the present study raises some questions regarding the designation of serial processing pathways in Old World monkeys, by suggesting that fields may have been confused in studies demonstrating such pathways. We propose that SII and PV are components of a common plan of organization, and are present in many eutherian mammals.


Protective Effect Against Toxoplasmosis in BALB/c Mice Vaccinated With Toxoplasma gondii Macrophage Migration Inhibitory Factor.
Toxoplasma gondii is an obligate intracellular parasite responsible for toxoplasmosis, which can cause severe disease in the fetus and immunocompromised individuals. Developing an effective vaccine is crucial to control this disease. Macrophage migration inhibitory factor (MIF) has gained substantial attention as a pivotal upstream cytokine to mediate innate and adaptive immune responses. Homologs of MIF have been discovered in many parasitic species, and one homolog of MIF has been isolated from the parasite Toxoplasma gondii. In this study, the recombinant Toxoplasma gondii MIF (rTgMIF) as a protein vaccine was expressed and evaluated by intramuscular injection in BALB/c mice. We divided the mice into different dose groups of vaccines, and all immunizations with purified rTgMIF protein were performed at 0, 2, and 4 weeks. The protective efficacy of vaccination was analyzed by antibody assays, cytokine measurements and lymphoproliferative assays, respectively. The results obtained indicated that the rTgMIF vaccine elicited strong humoral and cellular immune responses with high levels of IgG antibody and IFN-γ production compared to those of the controls, in addition to slight higher levels of IL-4 production. After vaccination, a stronger lymphoproliferative response was also noted. Additionally, the survival time of mice immunized with rTgMIF was longer than that of the mice in control groups after challenge infection with virulent T. gondii RH tachyzoites. Moreover, the number of brain tissue cysts in vaccinated mice was reduced by 62.26% compared with the control group. These findings demonstrated that recombinant TgMIF protein is a potential candidate for vaccine development against toxoplasmosis.


Novel heavy metal resistance gene clusters are present in the genome of Cupriavidus neocaledonicus STM 6070, a new species of Mimosa pudica microsymbiont isolated from heavy-metal-rich mining site soil.
Cupriavidus strain STM 6070 was isolated from nickel-rich soil collected near Koniambo massif, New Caledonia, using the invasive legume trap host Mimosa pudica. STM 6070 is a heavy metal-tolerant strain that is highly effective at fixing nitrogen with M. pudica. Here we have provided an updated taxonomy for STM 6070 and described salient features of the annotated genome, focusing on heavy metal resistance (HMR) loci and heavy metal efflux (HME) systems. The 6,771,773 bp high-quality-draft genome consists of 107 scaffolds containing 6118 protein-coding genes. ANI values show that STM 6070 is a new species of Cupriavidus. The STM 6070 symbiotic region was syntenic with that of the M. pudica-nodulating Cupriavidus taiwanensis LMG 19424T. In contrast to the nickel and zinc sensitivity of C. taiwanensis strains, STM 6070 grew at high Ni2+ and Zn2+ concentrations. The STM 6070 genome contains 55 genes, located in 12 clusters, that encode HMR structural proteins belonging to the RND, MFS, CHR, ARC3, CDF and P-ATPase protein superfamilies. These HMR molecular determinants are putatively involved in arsenic (ars), chromium (chr), cobalt-zinc-cadmium (czc), copper (cop, cup), nickel (nie and nre), and silver and/or copper (sil) resistance. Seven of these HMR clusters were common to symbiotic and non-symbiotic Cupriavidus species, while four clusters were specific to STM 6070, with three of these being associated with insertion sequences. Within the specific STM 6070 HMR clusters, three novel HME-RND systems (nieIC cep nieBA, czcC2B2A2, and hmxB zneAC zneR hmxS) were identified, which constitute new candidate genes for nickel and zinc resistance. STM 6070 belongs to a new Cupriavidus species, for which we have proposed the name Cupriavidus neocaledonicus sp. nov.. STM6070 harbours a pSym with a high degree of gene conservation to the pSyms of M. pudica-nodulating C. taiwanensis strains, probably as a result of recent horizontal transfer. The presence of specific HMR clusters, associated with transposase genes, suggests that the selection pressure of the New Caledonian ultramafic soils has driven the specific adaptation of STM 6070 to heavy-metal-rich soils via horizontal gene transfer.


Factors Associated with Virological Non-suppression among HIV-Positive Patients on Antiretroviral Therapy in Uganda, August 2014-July 2015.
Despite the growing number of people on antiretroviral therapy (ART), there is limited information about virological non-suppression and its determinants among HIV-positive (HIV+) individuals enrolled in HIV care in many resource-limited settings. We estimated the proportion of virologically non-suppressed patients, and identified the factors associated with virological non-suppression. We conducted a descriptive cross-sectional study using routinely collected program data from viral load (VL) samples collected across the country for testing at the Central Public Health Laboratories (CPHL) in Uganda. Data were generated between August 2014 and July 2015. We extracted data on socio-demographic, clinical and VL testing results. We defined virological non-suppression as having ≥1000 copies of viral RNA/ml of blood for plasma or ≥5000 copies of viral RNA/ml of blood for dry blood spots. We used logistic regression to identify factors associated with virological non-suppression. The study was composed of 100,678 patients; of these, 94,766(94%) were for routine monitoring, 3492(4%) were suspected treatment failures while 1436(1%) were repeat testers after suspected failure. The overall proportion of non-suppression was 11%. Patients on routine monitoring registered the lowest (10%) proportion of non-suppressed patients. Virological non-suppression was higher among suspected treatment failures (29%) and repeat testers after suspected failure (50%). Repeat testers after suspected failure were six times more likely to have virological non-suppression (ORadj = 6.3, 95%CI = 5.5-7.2) when compared with suspected treatment failures (ORadj = 3.3, 95%CI = 3.0-3.6). The odds of virological non-suppression decreased with increasing age, with children aged 0-4 years (ORadj = 5.3, 95%CI = 4.6-6.1) and young adolescents (ORadj = 4.1, 95%CI = 3.7-4.6) registering the highest odds. Poor adherence (ORadj = 3.4, 95%CI = 2.9-3.9) and having active TB (ORadj = 1.9, 95%CI = 1.6-2.4) increased the odds of virological non-suppression. However, being on second/third line regimens (ORadj = 0.86, 95%CI = 0.78-0.95) protected patients against virological non-suppression. Young age, poor adherence and having active TB increased the odds of virological non-suppression while second/third line ART regimens were protective against non-suppression. We recommend close follow up and intensified targeted adherence support for repeat testers after suspected failure, children and adolescents.


Suppression of the renin-angiotensin-aldosterone system in chronic heart failure: choice of agents and clinical impact.
Chronic heart failure (CHF) has taken on epidemic proportions in the United States, with approximately 550,000 new cases annually. With the evolution of pharmacotherapy targeting neurohormonal pathways over the past 2 decades, the annual mortality in subjects with New York Heart Association (NYHA) class IV has dramatically improved from 52% in the seminal CONSENSUS trial to less than 20% in more recent trials in CHF. Suppression of the renin-angiotensin system (RAS) with various angiotensin-converting enzyme (ACE) inhibitors has been proven to save lives in several large-scale trials of CHF, and all of them can be used at doses tested in clinical trials without clear preference of one over another. Angiotensin receptor blockers (ARBs) can be used in place of ACE inhibitors in the case of ACE inhibitor intolerance with comparable results. However, some inconsistencies exist between trials with ARBs, and it is uncertain if the ARBs tested in clinical trials provide comparable clinical benefit whether used in place of or in combination with ACE inhibitors. Once ACE inhibition has been started, beta blockade should follow for all subjects with symptomatic CHF. Triple neurohormonal blockade can then be accomplished with the addition of an aldosterone receptor or ARB. Regardless of the exact agent used or sequence of initiation, the critical importance of careful monitoring of neurohormonal blockade cannot be overstated. Renal failure and hyperkalemia are the most important complications of suppression of the renin-angiotensin-aldosterone system (RAAS), and an increase in hospital admissions and death from hyperkalemia after publication of the RALES trial illustrates the danger of "casual" use of neurohormonal blockers. In light of the tremendous benefits of neurohormonal blockade, the only conclusion from these data is to initiate RAAS-blocking agents following the safety precautions tested in the respective clinical trials.


Central nervous system malignant B-cell lymphoma identified with standardized echography of the optic nerve.
Ocular-central nervous system malignant B-cell lymphoma initially caused diplopia and morning headaches in a 10-year-old boy. After initial diagnosis of pseudotumor cerebri was made, based on normal findings from magnetic resonance imaging and magnetic resonance angiography elsewhere, he was treated with acetazolamide. Standardized echography demonstrated a combination of solid infiltration and fluid within the optic nerve sheaths. Lumbar puncture showed elevated opening pressure and cerebrospinal diagnostic of central nervous system (CNS) B-cell lymphoma, which was confirmed by gene rearrangement. Results of peripheral blood study were negative. Aggressive treatment with chemotherapy and external-beam radiation produced complete resolution of solid optic nerve sheath infiltration in both eyes. This report discusses the clinical and ultrasonographic characteristics of CNS malignant B-cell lymphoma with ocular involvement and its differentiation from pseudotumor cerebri.


To Treat or Not to Treat: Anticoagulants as Secondary Preventives to the Oldest Old With Atrial Fibrillation.
Anticoagulant treatment is effective for preventing recurrent ischemic strokes in patients who have atrial fibrillation. This benefit is paid by a small increase of hemorrhages. Anticoagulant-related hemorrhages seem to increase with age, but there are few studies showing whether the benefits of treatment persist in old age. For this observational study, 4 different registers were used, among them Riksstroke, the Swedish Stroke Register. Patients who have had a recent ischemic stroke, were 80 to 100 years of age, and had atrial fibrillation, were included from 2006 through 2013. The patients were stratified into 3 age groups: 80 to 84, 85 to 89, and ≥90 years of age. Information on stroke severity, risk factors, drugs, and comorbidities was gathered from the registers. The patients were followed with respect to ischemic or hemorrhagic stroke, other hemorrhages, or death. Of all 23 356 patients with atrial fibrillation, 6361 (27%) used anticoagulants after an ischemic stroke. Anticoagulant treatment was associated with less recurrent ischemic stroke in all age groups. Hemorrhages increased most in the ≥90-year age group, but this did not offset the overall beneficial effect of the anticoagulant. Apart from age, no other cardiovascular risk factor or comorbidity was identified that influenced the risk of anticoagulant-associated hemorrhage. Drugs other than anticoagulants did not influence the incidence of major hemorrhage. Given the patient characteristics in this study, there is room for more patients to be treated with anticoagulants, without hemorrhages to prevail. In nonagenarians, hemorrhages increased somewhat more, but this did not affect the overall outcome in this age stratum.


Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.
A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability. On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members. Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.


The infected knee arthroplasty. A 6-year follow-up of 357 cases.
The incidence of deep infection after 12,118 primary knee arthroplasties performed in Sweden from October 1, 1975 through 1985 with a median follow-up of 6 years was 1.7 percent for arthrosis and 4.4 percent for rheumatoid arthritis. Risk factors for infection were large prostheses, postoperative wound-healing complications, rheumatoid arthritis, a prior deep infection, and skin infections. We have analyzed the treatment of 357 knee arthroplasties with a deep infection. Systemic antibiotics alone were primarily used in 225 knees, with healing of the infection in 44 knees, 20 of which had a functioning prosthesis at the final follow-up; the treatment did not compromise later revision surgery. Soft-tissue surgery was used in 154 knees--37 healed, 15 of which had a functioning prosthesis. Resection arthroplasty resulted in healing of the infection in 11 of 22 knees. Revision arthroplasty was performed in 107 knees, with eventual healing of the infection in 81 knees, 36 of which had a functioning prosthesis; there were no differences in the outcome of one-stage and two-stage procedures. Arthrodesis was attempted in 135 knees, with eventual healing of the infection in 120 knees and fusion in 105. Twenty-two patients were amputated. Thus, the infection healed in 315 knees (88 percent), but only 71 (20 percent) recovered with a functioning prosthesis, and 8 patients died of the infection. Attention should therefore focus on prophylactic measures directed towards the soft-tissue problems--by avoiding conflicting skin incisions, by gentle handling of the periarticular soft tissues, by avoiding the use of constrained prostheses and oversized compartmental prostheses, by letting wound healing take priority over motion in knees with compromised soft tissues, and by using prophylactic antibiotic treatment for skin ulcers until these have healed.


Ruxolitinib treatment for GvHD in patients with myelofibrosis.
Jak1/2 inhibitor ruxolitinib is a promising agent for treating steroid-refractory GvHD after allogeneic hematopoietic stem cell transplantation (SCT) to produce quick and durable responses. However, optimal dose and tapering schedule of ruxolitinib remain to be determined. Discontinuation of ruxolitinib in myelofibrosis often induces 'withdrawal syndrome' characterized by acute relapse of the disease, but this issue is not well addressed in the treatment of GvHD. Four patients with GvHD (one acute and three chronic) after SCT for myelofibrosis were treated with ruxolitinib. Low-dose ruxolitinib at 5 mg/day was safe and effective, but one of two patients treated at 10 mg/day of ruxolitinib was complicated with severe cytopenia. Withdrawal syndrome developed in one patient, who died of recurrence of GvHD shortly after discontinuation of ruxolitinib. Slow tapering or maintenance with low-dose ruxolitinib inhibited GvHD flare. Our experience calls attention that initiation at low-dose of ruxolitinib may be safe and careful tapering schedule is required to avoid withdrawal syndrome in patients with GvHD after SCT for myelofibrosis.


Interactions of the complement system with endotoxic lipopolysaccharides in immunoglobulin-deficient sera.
Bacterial lipopolysaccharides (LPS) derived from a variety of organisms effectively induced C consumption in humans, bovines, and porcines with developmental agammaglobulinemia; birds with experimental agammaglobulinemia; and humans with agammaglobulinemia syndromes. This interaction proceeded even in precolostral piglet sera which contained less than 2.5 x 10(-6) mg/ml gamma globulin, and led to generation of neutrophil chemotactic factor and anaphylatoxin in these sera. Hence, the LPS-C interaction can proceed in sera markedly deficient in immunoglobulin. The question of whether immunoglobulins can be bypassed in the LPS-C interaction, or whether they are regularly utilized in a way so efficient that their participation is masked, was considered.


Cutaneous T-cell lymphoma in asians.
Cutaneous T-cell lymphoma describes a heterogeneous group of neoplasms of skin homing T cells that vary considerably in clinical presentation, histologic appearance, immunophenotype, and prognosis. This paper addresses the cutaneous T-cell lymphoma in Asians with respect to clinical-epidemiologic and histopathological features. Compared with Western countries, Asia usually has higher rates of cutaneous T-cell lymphomas such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like lymphoma, subcutaneous panniculitis T-cell lymphoma, and adult T-cell leukemia/lymphoma and lower rates of cutaneous B-cell lymphomas. Among many variants of mycosis fungoides, hypopigmented lesions, pityriasis lichenoides-like lesions, and ichthyosiform lesions are more prevalent in Asia than in the West. Adult T-cell leukemia/lymphoma is endemic in southwestern Japan especially in the Kyushu island. The clinicopathologic characteristics of cutaneous lymphoma vary according to geography, and this may be ascribed to genetic and environmental etiologic factors.


Substrate Stiffness Controls Osteoblastic and Chondrocytic Differentiation of Mesenchymal Stem Cells without Exogenous Stimuli.
Stem cell fate has been linked to the mechanical properties of their underlying substrate, affecting mechanoreceptors and ultimately leading to downstream biological response. Studies have used polymers to mimic the stiffness of extracellular matrix as well as of individual tissues and shown mesenchymal stem cells (MSCs) could be directed along specific lineages. In this study, we examined the role of stiffness in MSC differentiation to two closely related cell phenotypes: osteoblast and chondrocyte. We prepared four methyl acrylate/methyl methacrylate (MA/MMA) polymer surfaces with elastic moduli ranging from 0.1 MPa to 310 MPa by altering monomer concentration. MSCs were cultured in media without exogenous growth factors and their biological responses were compared to committed chondrocytes and osteoblasts. Both chondrogenic and osteogenic markers were elevated when MSCs were grown on substrates with stiffness <10 MPa. Like chondrocytes, MSCs on lower stiffness substrates showed elevated expression of ACAN, SOX9, and COL2 and proteoglycan content; COMP was elevated in MSCs but reduced in chondrocytes. Substrate stiffness altered levels of RUNX2 mRNA, alkaline phosphatase specific activity, osteocalcin, and osteoprotegerin in osteoblasts, decreasing levels on the least stiff substrate. Expression of integrin subunits α1, α2, α5, αv, β1, and β3 changed in a stiffness- and cell type-dependent manner. Silencing of integrin subunit beta 1 (ITGB1) in MSCs abolished both osteoblastic and chondrogenic differentiation in response to substrate stiffness. Our results suggest that substrate stiffness is an important mediator of osteoblastic and chondrogenic differentiation, and integrin β1 plays a pivotal role in this process.


Sexual dimorphism and growth hormone induction of murine pheromone-binding proteins.
A number of structurally very similar pheromone-binding proteins (major urinary proteins; MUPs) are synthesized in mouse liver and rapidly excreted in the urine. Male and female inbred mice display different characteristic patterns of MUP expression. Here we present a detailed study of the RNA and protein products corresponding to specific MUP genes previously isolated from genomic DNA of the Balb/c strain. By in vitro transcription of equivalent cDNA clones, translation of the resulting RNA in the reticulocyte lysate system and isoelectric focusing, the protein products of genes BL1, BS1 and BS6 were shown to be MUP 2a, MUP 2b and MUP 4 respectively. MUPs 2a and 2b were shown to be abundant both in Balb/c male urine and among the translation products of total Balb/c male liver mRNA. Two oligodeoxynucleotide probes, oBL1A and oBS1, selective for BL1 and BS1 mRNA respectively, were chemically synthesized. mRNA that hybridized with these probes (oBL1A mRNA and oBS1 mRNA) was present at different characteristic levels in the Balb/c and C57BL/6 inbred strains. In both strains the level of expression was much higher in males than females and the male/female expression ratio of oBS1 RNA was higher than that of oBL1A RNA. Comparison of these mRNA levels with the amounts of different MUP proteins present in urine and the translation products of liver mRNA indicated that proteins other than MUP 2a and MUP 2b are coded for by the C57BL/6 oBL1A and oBS1 mRNAs. C57BL/6 mice homozygous for the lit mutation are GH deficient and transcribe MUP genes at a level much lower than that obtaining in normal mice of either sex, indicating that transcription is induced by GH in both males and females. When lit/lit mice were treated with GH under two different regimes, MUP gene transcription was partially induced to different degrees and the level of oBL1A mRNA was induced more highly than that of oBS1 mRNA. Thus there exists a correlation between the inducibility of these mRNAs and their level of expression in females relative to males; oBL1A mRNA is both more highly expressed in females and more readily induced by GH than oBS1 mRNA. This suggests that the male and female expression patterns are due to differential inducibility of different MUP genes together with a stronger inducing stimulus in males. GH administered continuously by infusion repressed MUP gene expression.(ABSTRACT TRUNCATED AT 400 WORDS)