The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma.
The optimal treatment strategy with the use of hematopoietic stem cell transplantation (HSCT) for relapsed and refractory Hodgkin lymphoma (HL) remains unclear. We performed a retrospective analysis using registry data from the Japanese Society for Hematopoietic Cell Transplantation. Adult patients with HL who underwent a first autologous or a first allogeneic HSCT between 2002 and 2009 were included. Patients who underwent HSCT in first complete remission (CR) were excluded. Autologous and allogeneic HSCT were performed in 298 and 122 patients, respectively. For autologous HSCT, overall survival at 3 years (3yOS) was 70%, and sex, age, disease status, and performance status (PS) at HSCT were prognostic factors. OS was favorable even in patients who underwent autologous HSCT in disease status other than CR. For allogeneic HSCT, 3yOS was 43%, and sex and PS at HSCT were prognostic factors. Disease status at HSCT, previous autologous HSCT, and conditioning intensity did not affect OS. Moreover, graft-versus-host disease did not affect progression-free survival or relapse/progression rate. A first allogeneic HSCT without a previous autologous HSCT was performed in 40 patients. 3yOS was 45%, and was significantly inferior to that in patients who underwent their first autologous HSCT. This result was retained after the correction by the different patient characteristics according to the type of HSCT. In conclusion, autologous HSCT is effective in prolonging survival in patients with relapsed and refractory HL. Allogeneic HSCT might be beneficial even to relapsed HL after autologous HSCT, although establishing the role of allogeneic HSCT remains a challenge.


A new implant designed to maximize contact with trabecular bone: survival to 18 months.
A roughened, commercially pure titanium (CP-Ti) implant design has been developed that features a different length and pitch for each screw thread to direct functional stresses away from cortical bone and to the more resilient trabecular bone. Abutment-implant connection is made using a conical taper to provide a seal against invasion by microorganisms. To assess short-term (18 months) clinical performance of this innovative implant design. A total of 1,419 implants were placed in 313 patients to support 419 prostheses in a multidisciplinary, multicentered, prospective clinical study conducted by the Ankylos Implant Clinical Research Group (AICRG). More than 100 dentists at 32 centers in the United States, 1 in Korea, and 1 in Taiwan are involved in the study. Failure was defined as implant removal for any reason. The influence of mobility at placement, implant length and diameter, incision type, augmentation, crestal bone reduction, bone density, and the use of the operating room or dental clinic on survival were evaluated over 18 months. Crestal bone loss between placement and uncovering was also determined. Crestal bone loss ranged from 0.2 to 0.5 mm. The overall success rate from placement to 18 months was 96.6%. Implants mobile at placement failed more frequently (16.9%) compared with stable implants (3.1%). Wide-diameter implants and longer implants exhibited higher survival rates. Incision design and surgery location did not influence survival. Bone density was important to clinical survival.


Advance Care Planning Engagement Among Muslim Community-Dwelling Adults Living in the United States.
Advance care planning (ACP) is a cornerstone of self-determination for the type of care provided at the end of life. Despite many national efforts to improve American adults' engagement in ACP, statistics indicate low engagement. Low engagement, especially among racial and ethnic minority populations, immigrants, people with lower socioeconomic status, young adults, rural residents, or non-English speakers, is common. Advance care planning engagement among Muslims living in the United States has been minimally studied. The purpose of this study was to explore Muslims' engagement in ACP. A cross-sectional descriptive design was used. Participants were recruited from Islamic organizations through convenience and snowball sampling. Engagement in ACP was measured by the Advance Care Planning Engagement Survey. A sample of 148 Muslims (18-79 years of age) participated in the study. The average engagement scores ranged from 1.97 to 2.09, with about two-thirds in the precontemplation stage. Significant differences in engagement scores were found according to health condition and end of life experiences. Results suggest a need for further collaborative efforts by health care providers, policymakers, and researchers to mitigate the disparities in ACP engagement in the American Muslim community.


Hippocampal negative event-related potential recorded in humans during a simple sensorimotor task occurs independently of motor execution.
A hippocampal-prominent event-related potential (ERP) with a peak latency at around 450 ms is consistently observed as a correlate of hippocampal activity during various cognitive tasks. Some intracranial EEG studies demonstrated that the amplitude of this hippocampal potential was greater in response to stimuli requiring an overt motor response, in comparison with stimuli for which no motor response is required. These findings could indicate that hippocampal-evoked activity is related to movement execution as well as stimulus evaluation and associated memory processes. The aim of the present study was to investigate the temporal relationship between the hippocampal negative potential latency and motor responses. We analyzed ERPs recorded with 22 depth electrodes implanted into the hippocampi of 11 epileptic patients. Subjects were instructed to press a button after the presentation of a tone. All investigated hippocampi generated a prominent negative ERP peaking at ~420 ms. In 16 from 22 cases, we found that the ERP latency did not correlate with the reaction time; in different subjects, this potential could either precede or follow the motor response. Our results indicate that the hippocampal negative ERP occurs independently of motor execution. We suggest that hippocampal-evoked activity, recorded in a simple sensorimotor task, is related to the evaluation of stimulus meaning within the context of situation.


Does self-monitoring reduce blood pressure? Meta-analysis with meta-regression of randomized controlled trials.
Self-monitoring of blood pressure (BP) is an increasingly common part of hypertension management. The objectives of this systematic review were to evaluate the systolic and diastolic BP reduction, and achievement of target BP, associated with self-monitoring. MEDLINE, Embase, Cochrane database of systematic reviews, database of abstracts of clinical effectiveness, the health technology assessment database, the NHS economic evaluation database, and the TRIP database were searched for studies where the intervention included self-monitoring of BP and the outcome was change in office/ambulatory BP or proportion with controlled BP. Two reviewers independently extracted data. Meta-analysis using a random effects model was combined with meta-regression to investigate heterogeneity in effect sizes. A total of 25 eligible randomized controlled trials (RCTs) (27 comparisons) were identified. Office systolic BP (20 RCTs, 21 comparisons, 5,898 patients) and diastolic BP (23 RCTs, 25 comparisons, 6,038 patients) were significantly reduced in those who self-monitored compared to usual care (weighted mean difference (WMD) systolic -3.82 mmHg (95% confidence interval -5.61 to -2.03), diastolic -1.45 mmHg (-1.95 to -0.94)). Self-monitoring increased the chance of meeting office BP targets (12 RCTs, 13 comparisons, 2,260 patients, relative risk = 1.09 (1.02 to 1.16)). There was significant heterogeneity between studies for all three comparisons, which could be partially accounted for by the use of additional co-interventions. Self-monitoring reduces blood pressure by a small but significant amount. Meta-regression could only account for part of the observed heterogeneity.


The Androgenic Alopecia Protective Effects of Forsythiaside-A and the Molecular Regulation in a Mouse Model.
This study examined the inhibitory effect of forsythiaside-A, a natural substance derived from Forsythia suspensa (F. suspensa), on entry into catagen induced by dihydrotestosterone (DHT) in an androgenic alopecia mouse model. In vitro experiment comparing finasteride with forsythiaside-A showed that forsythiaside-A treatment resulted in a 30% greater inhibition of DHT-induced apoptosis in human hair dermal papilla cell (HHDPCs) and human keratinocytes (HaCaTs). In vivo experiment showed that mouse hair density and thickness were increased by 50% and 30%, respectively, in the forsythiaside-A-treated group when compared to a DHT group. Tissue histological results revealed that the forsythiaside-A-treated group had an increase in size and shape of the hair follicles and a 1.5 times increase in the follicle anagen/telogen ratio when compared to the finasteride group. Western blot examination of TGF-β2 expression related to apoptosis signaling in mouse skin verified that forsythiaside-A reduced the expression of TGF-β2 by 75% and suppressed apoptosis by reducing the expression of caspase-9 by 40%, and caspase-3 by 53%, which play an roles up-regulator in the apoptosis signal. The forsythiaside-A group also showed a 60% increase in the Bcl-2/Bax ratio, which is a factor related to mitochondrial apoptosis. Our results indicated that forsythiaside-A prevents apoptosis by similar mechanism with finasteride, but forsythiaside-A is more effective than finasteride. In summary, forsythiaside-A controlled the apoptosis of hair cells and retarded the entry into the catagen phase and therefore represents a natural product with much potential for use as a treatment for androgenic alopecia.


Firm foundations: strength-based approaches to adolescent chronic disease.
Chronic disease management is an increasingly important aspect of caring for adolescents. Strength-based approaches hold tremendous promise in the face of current challenges. Recent clinical innovations and research findings that provide evidence of the efficacy of strength-based approaches and represent a fundamental evolution in the clinical approach to adolescent care are reviewed. Resilience and positive youth development are important conceptual frameworks in adolescent health, which have recently been brought into the clinic setting in the form of the strength-based approach to care. In parallel, studies of motivational interviewing, a strength-based technique with known efficacy in behavioral change, have begun to demonstrate clinical efficacy in various adolescent chronic disease applications. The coupling of a strength-based approach with motivational interviewing holds promise for not only modifying end behaviors but also helping teens to develop strengths and assets to promote general well-being and healthy development. This distinction in goals might be described as the difference between being transiently problem-free and durably problem-resistant. Strength-based approaches, including motivational interviewing, hold tremendous potential for equipping providers to address the rapidly increasing burden of chronic disease in adolescents.


Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma.
Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1 ) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, cancer tissues. Remarkably, we and others have previously showed that genetic inactivation of the Nupr1 gene antagonizes the growth of pancreatic cancer as well as several other tumors. With the use of a multidisciplinary strategy by combining biophysical, biochemical, bioinformatic, and biological approaches, a trifluoperazine-derived compound, named ZZW-115, has been identified as an inhibitor of the NUPR1 functions. The anticancer activity of the ZZW-115 was first validated on a large panel of cancer cells. Furthermore, ZZW-115 produced a dose-dependent tumor regression of the tumor size in xenografted mice. Mechanistically, we have demonstrated that NUPR1 binds to several importins. Because ZZW-115 binds NUPR1 through the region around the amino acid Thr68, which is located into the nuclear location signal (NLS) region of the protein, we demonstrated that treatment with ZZW-115 inhibits completely the translocation of NUPR1 from the cytoplasm to the nucleus by competing with importins.


Global perspective of herbicide-resistant weeds.
Two hundred and twenty weed species have evolved resistance to one or more herbicides, and there are now 404 unique cases (species × site of action) of herbicide-resistant weeds globally. ALS inhibitor-resistant weeds account for about a third of all cases (133/404) and are particularly troublesome in rice and cereals. Although 71 weed species have been identified with triazine resistance, their importance has dwindled with the shift towards Roundup Ready® crops in the USA and the reduction of triazine usage in Europe. Forty-three grasses have evolved resistance to ACCase inhibitors, with the most serious cases being Avena spp., Lolium spp., Phalaris spp., Setaria spp. and Alopecurus myosuroides, infesting more than 25 million hectares of cereal production globally. Of the 24 weed species with glyphosate resistance, 16 have been found in Roundup Ready® cropping systems. Although Conyza canadensis is the most widespread glyphosate-resistant weed, Amaranthus palmeri and Amaranthus tuberculartus are the two most economically important glyphosate-resistant weeds because of the area they infest and the fact that these species have evolved resistance to numerous other herbicide sites of action, leaving growers with few herbicidal options for their control. The agricultural chemical industry has not brought any new herbicides with novel sites of action to market in over 30 years, making growers reliant on using existing herbicides in new ways. In addition, tougher registration and environmental regulations on herbicides have resulted in a loss of some herbicides, particularly in Europe. The lack of novel herbicide chemistries being brought to market combined with the rapid increase in multiple resistance in weeds threatens crop production worldwide.


Photosynthesis under drought and salt stress: regulation mechanisms from whole plant to cell.
Plants are often subjected to periods of soil and atmospheric water deficits during their life cycle as well as, in many areas of the globe, to high soil salinity. Understanding how plants respond to drought, salt and co-occurring stresses can play a major role in stabilizing crop performance under drought and saline conditions and in the protection of natural vegetation. Photosynthesis, together with cell growth, is among the primary processes to be affected by water or salt stress. The effects of drought and salt stresses on photosynthesis are either direct (as the diffusion limitations through the stomata and the mesophyll and the alterations in photosynthetic metabolism) or secondary, such as the oxidative stress arising from the superimposition of multiple stresses. The carbon balance of a plant during a period of salt/water stress and recovery may depend as much on the velocity and degree of photosynthetic recovery, as it depends on the degree and velocity of photosynthesis decline during water depletion. Current knowledge about physiological limitations to photosynthetic recovery after different intensities of water and salt stress is still scarce. From the large amount of data available on transcript-profiling studies in plants subjected to drought and salt it is becoming apparent that plants perceive and respond to these stresses by quickly altering gene expression in parallel with physiological and biochemical alterations; this occurs even under mild to moderate stress conditions. From a recent comprehensive study that compared salt and drought stress it is apparent that both stresses led to down-regulation of some photosynthetic genes, with most of the changes being small (ratio threshold lower than 1) possibly reflecting the mild stress imposed. When compared with drought, salt stress affected more genes and more intensely, possibly reflecting the combined effects of dehydration and osmotic stress in salt-stressed plants.


Experimental use of free gastric flaps for the repair of pharyngoesophageal defects.
The repair of large pharyngoesophageal defects was accomplished experimentally in 16 dogs with revascularized free flaps from the greater curvature of the stomach. These flaps were based on the gastroepiploic vessels, and they were anastomosed to the carotid artery and external jugular vein in the neck. The procedure had a low mortality and did not lead to peptic ulceration or hyperchlorhydria in these animals.


Mathematical Modeling of Hepatitis C Prevalence Reduction with Antiviral Treatment Scale-Up in Persons Who Inject Drugs in Metropolitan Chicago.
New direct-acting antivirals (DAAs) provide an opportunity to combat hepatitis C virus (HCV) infection in persons who inject drugs (PWID). Here we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago. To estimate the HCV antibody and HCV-RNA (chronic infection) prevalence among the metropolitan Chicago PWID population, we used empirical data from three large epidemiological studies. Cost of DAAs is assumed $50,000 per person. Approximately 32,000 PWID reside in metropolitan Chicago with an estimated HCV-RNA prevalence of 47% or 15,040 cases. Approximately 22,000 PWID (69% of the total PWID population) attend harm reduction (HR) programs, such as syringe exchange programs, and have an estimated HCV-RNA prevalence of 30%. There are about 11,000 young PWID (<30 years old) with an estimated HCV-RNA prevalence of 10% (PWID in these two subpopulations overlap). The model suggests that the following treatment scale-up is needed to reduce the baseline HCV-RNA prevalence by one-half over 10 years of treatment [cost per year, min-max in millions]: 35 per 1,000 [$50-$77] in the overall PWID population, 19 per 1,000 [$20-$26] for persons in HR programs, and 5 per 1,000 [$3-$4] for young PWID. Treatment scale-up could dramatically reduce the prevalence of chronic HCV infection among PWID in Chicago, who are the main reservoir for on-going HCV transmission. Focusing treatment on PWID attending HR programs and/or young PWID could have a significant impact on HCV prevalence in these subpopulations at an attainable cost.


Relations between morphology, buoyancy and energetics of requiem sharks.
Sharks have a distinctive shape that remained practically unchanged through hundreds of millions of years of evolution. Nonetheless, there are variations of this shape that vary between and within species. We attempt to explain these variations by examining the partial derivatives of the cost of transport of a generic shark with respect to buoyancy, span and chord of its pectoral fins, length, girth and body temperature. Our analysis predicts an intricate relation between these parameters, suggesting that ectothermic species residing in cooler temperatures must either have longer pectoral fins and/or be more buoyant in order to maintain swimming performance. It also suggests that, in general, the buoyancy must increase with size, and therefore, there must be ontogenetic changes within a species, with individuals getting more buoyant as they grow. Pelagic species seem to have near optimally sized fins (which minimize the cost of transport), but the majority of reef sharks could have reduced the cost of transport by increasing the size of their fins. The fact that they do not implies negative selection, probably owing to decreased manoeuvrability in confined spaces (e.g. foraging on a reef).


How are we going to live with Alzheimer's disease?
Alzheimer's disease confronts us with an ethical challenge: How do we live with dignity and quality of life in the face of progressive disability and, ultimately, death? Patients' cognitive and decision-making impairments often make them unable to answer this question, and when professionals who provide services for older adults fail to recognize and accommodate these impairments, patients suffer. Patients and their caregivers need a health care system that fosters caregiving so that each will live with dignity and well-being. Another way to answer this question is to discover treatments that prevent disabling cognitive impairments, but this strategy will require expanding the Alzheimer's label to include people who do not have dementia or who are even cognitively normal. Controversies are likely to occur over how best to describe the Alzheimer's problem, measure the value of early diagnosis and treatment, and live with a brain at risk.


In-gantry MRI guided prostate biopsy diagnosis of prostatitis and its relationship with PIRADS V.2 based score.
The recent literature has focussed predominantly on prostate cancer detection which has been revolutionized by multiparametric magnetic resonance imaging (mpMRI). Due to an overlap of features, prostatitis may mimic prostate cancer on MRI, especially in patients with chronic prostatitis. We retrospectively analysed our in-gantry MRI-guided biopsy (MRGB) results to determine incidental detection rate of prostatitis in Prostate Imaging Reporting and Data System (PIRADS) 3, 4 and 5 foci reported on diagnostic MRI of the prostate. About 137 patients underwent in-gantry MRGB for lesions with PIRADS score of 3 or above. All the biopsies were performed utilizing the dynaTRIM™ system (Invio Inc, Germany) on a three-tesla MRI scanner (Ingenia 3.0T, Philips, Netherlands) by a Radiologist and a Urologist. We biopsied 228 lesions in 137 patients. There were 55 lesions that returned positive for prostate cancer with a Gleason Score of 3 + 3 = 6 or above. There were 62 lesions that showed inflammation. The distribution of these lesions was 3 (5%) in the central zone, 32 (52%) in the transitional zone and 27 (43%) in the peripheral zone. Inflammation was found in 36 (58%) PIRADS 3 lesions, 24 (39%) PIRADS 4 lesions and 2 (3%) PIRADS 5 lesions on pre biopsy MRI evaluation. In our series, biopsies which showed inflammation had a radiological appearance on mpMRI more likely of a PIRADS 3 or 4 lesions with only 3% of PIRADS 5 biopsies showing inflammation. This would suggest that a higher PIRADS score can more reliably differentiate between prostate cancer and prostatitis.


Effects of social support and resilient coping on violent behavior in military veterans.
Violence toward others has been identified as a serious postdeployment adjustment problem in a subset of Iraq- and Afghanistan-era veterans. In the current study, we examined the intricate links between posttraumatic stress disorder (PTSD), commonly cited psychosocial risk and protective factors, and violent behavior using a national randomly selected longitudinal sample of Iraq- and Afghanistan-era United States veterans. A total of 1,090 veterans from the 50 United States and all United States military branches completed 2 waves of self-report survey-data collection 1 year apart (retention rate = 79%). History of severe violent behavior at Wave 1 was the most substantial predictor of subsequent violence. In bivariate analyses, high correlations were observed among risk and protective factors, and between risk and protective factors and severe violence at both time points. In multivariate analyses, baseline violence (OR = 12.43, p < .001), baseline alcohol misuse (OR = 1.06, p < .05), increases in PTSD symptoms between Waves 1 and 2 (OR = 1.01, p < .05), and decreases in social support between Waves 1 and 2 (OR = .83, p < .05) were associated with increased risk for violence at Wave 2. Our findings suggest that rather than focusing specifically on PTSD symptoms, alcohol use, resilience, or social support in isolation, it may be more useful to consider how these risk and protective factors work in combination to convey how military personnel and veterans are managing the transition from wartime military service to civilian life, and at what point it might be most effective to intervene. (PsycINFO Database Record


The contribution of recess to children's school-day physical activity.
Recess is an important component of a Comprehensive School Physical Activity Program, providing approximately 1268 and 914 steps for boys and girls, respectively, within a 15-minute time period. The purpose of this study was to determine the contribution of unstructured recess on children's school-day physical activity levels and to examine if recess and school-day physical activity levels varied by BMI, gender, and grade level. One-hundred sixty third- to fifth-grade students from 2 elementary schools wore pedometers during 4 recess periods. Recess accounted for 17% to 44% of school-day step counts. There was a significant main effect for grade level, but not for BMI or gender, on the percentage of school-day steps accumulated during recess. A 15-minute recess makes a valuable contribution to children's school-day physical activity, especially for the least active children. More research is warranted to determine environmental influences on children's recess physical activity.


Insertion of Provox2 voice prosthesis using the anterograde technique immediately after the secondary tracheoesophageal puncture.
Insertion of a voice prosthesis through the tracheoesophageal puncture (TEP) is one way to restore the voice after total laryngectomy. The second generation Provox voice prosthesis is presently one of the most popular devices. Although TEP can be done primarily, there are many centres that prefer it to be done at a second stage for various reasons. However, secondary TEP for retrograde replacement of prosthesis can be difficult and general anaesthesia is very often necessary. Moreover, the presence of neck stiffness and fibrosis from the surgery or previous radiotherapy could affect the neck extension for proper positioning of the trocar. Similarly, it is difficult to insert the prosthesis if there is stenosis at the pharyngoesophageal segment. We describe a technique in which creation of secondary TEP and insertion of Provox2 is done with local anaesthesia under the same setting. The procedure is well tolerated and can be safely performed on an out-patient basis.


Characteristics of being hospitalized as a child with a new diagnosis of type 1 diabetes: a phenomenological study of children's past and present experiences.
Our understanding of children and childhood has changed over the last few decades, which may have an impact on children's conditions in hospitals. Children's rights have been strengthened by the "Convention on the Rights of the Child" and ward regulations. The aim of this Norwegian study was to identify potential characteristics of children's lived experience of being hospitalized diagnosed with type 1 diabetes today and from a retrospective view in the period 1950-1980, despite the many obvious external changes. This study presents a further analysis of data from two previous phenomenological studies. The first had a retrospective perspective, and the second assumed a contemporary perspective. Twelve adults and nine children who had been hospitalized for newly diagnosed type 1 diabetes at the age of approximately 6-12 years old participated. The adults relayed narratives from their childhood memories through interviews, and the study with the children was designed as a combination of observations, in-depth interviews, and photographs. A hermeneutic phenomenological method was used in the analysis. The analysis revealed a meaning structure that described a tension between vulnerability and agency in the experiences of being hospitalized as a child, both past and present. The experiences may further be characterized as alienation versus recognition and as passivity versus activity, relating to both the hospital environment and the illness. To a greater extent than ever, children today tend to experience themselves as active and competent individuals who can manage their own illness. Previously, children seemed to experience themselves as more vulnerable and less competent in relationship to their environment and illness. Presently, as before, children appear to desire involvement in their illness; however, at the same time, they prefer to share responsibility with or hand over responsibility to adults. However, living with diabetes was and remains demanding, and it affects children's lifeworld. Balancing the children's vulnerability and agency seems to be the best way to care for children in hospitals. In this article, we thus argue for a lifeworld-led approach when caring for hospitalized children, paying attention to both their vulnerability and agency.


Construction of an Acid-Tolerant Rhizobium leguminosarum Biovar Trifolii Strain with Enhanced Capacity for Nitrogen Fixation.
Strain ANU1173 is an acid-tolerant Rhizobium leguminosarum biovar trifolii strain that is able to nodulate subterranean clover plants growing in agar culture at pH 4.4 At pH 6.5, its symbiotic effectiveness in association with Trifolium subterraneum cv. Mt. Barker was 80% relative to that of strain ANU794, a Sm derivative of the commercial inoculant R. leguminosarum bv. trifolii TA1. Strain ANU1173 contained four indigenous megaplasmids, the smallest of these being the symbiotic (Sym) plasmid. The critical pH requirement for growth of strain ANU1173 in laboratory media was shown not to be associated with this plasmid. When the Sym plasmid of strain ANU1173(pSym-1173) was mobilized into a Nod strain of R. leguminosarum bv. viciae, the plasmid conferred to the transconjugant a level of symbiotic effectiveness in association with T. subterraneum that was similar to that observed with ANU1173. The symbiotic effectiveness of strain ANU1173 was improved by first curing pSym-1173 (generating strain ANU1184) and replacing it with another R. leguminosarum bv. trifolii Sym plasmid, pBR1AN. Subterranean clover plants inoculated with strain ANU1184 (pBR1AN) exhibited a 35 or 53% increase in acetylene reduction activity and a 20 or 17% increase in dry weight when grown at pH 6.5 and pH 4.4, respectively, compared with plants inoculated with strain ANU1173 and grown under the same pH conditions. It was further shown that pBR1AN was stably maintained in strain ANU1184 under free-living and symbiotic conditions. These results indicate that it is possible to construct an acid-tolerant strain of R. leguminosarum bv. trifolii with an enhanced capacity for nitrogen fixation.


25-Hydroxy-Vitamin D Concentration Is Not Affected by Severe or Non-Severe Pneumonia, or Inflammation, in Young Children.
Poor vitamin D status has been associated with increased risk and severity of respiratory tract infections. Whether or not inflammation and infection affects 25-hydroxy vitamin D (25(OH)D) concentration is controversial and is important in the interpretation of observational studies using plasma-25(OH)D as a biomarker for status. Our objectives were to measure whether 25(OH)D concentration was altered by an episode of acute lower respiratory tract infection and whether markers of inflammation predicted the 25(OH)D concentration. Children aged 2-35 months with severe (n = 43) and non-severe (n = 387) community-acquired, WHO-defined pneumonia were included. 25(OH)D concentration and inflammatory markers (cytokines, chemokines, and growth factors) were measured in plasma during the acute phase and 14, 45, and 90 days later. Predictors for 25(OH)D concentrations were identified in multiple linear regression models. Mean 25(OH)D concentration during the acute phase and after recovery (14, 45, and 90 days) was 84.4 nmol/L ± 33.6, and 80.6 ± 35.4, respectively. None of the inflammatory markers predicted 25(OH)D concentration in the multiple regression models. Age was the most important predictor for 25(OH)D concentration, and there were no differences in 25(OH)D concentrations during illness and after 14, 45, and 90 days when adjusting for age. Infection and inflammation did not alter the 25(OH)D concentration in young children with acute lower respiratory tract infections.


The Insulin-Like Growth Factor System in the Long-Lived Naked Mole-Rat.
Naked mole-rats (Heterocephalus glaber) (NMRs) are the longest living rodents known. They show negligible senescence, and are resistant to cancers and certain damaging effects associated with aging. The insulin-like growth factors (IGFs) have pluripotent actions, influencing growth processes in virtually every system of the body. They are established contributors to the aging process, confirmed by the demonstration that decreased IGF signaling results in life-extending effects in a variety of species. The IGFs are likewise involved in progression of cancers by mediating survival signals in malignant cells. This report presents a full characterization of the IGF system in the NMR: ligands, receptors, IGF binding proteins (IGFBPs), and IGFBP proteases. A particular emphasis was placed on the IGFBP protease, pregnancy-associated plasma protein-A (PAPP-A), shown to be an important lifespan modulator in mice. Comparisons of IGF-related genes in the NMR with human and murine sequences indicated no major differences in essential parts of the IGF system, including PAPP-A. The protease was shown to possess an intact active site despite the report of a contradictory genome sequence. Furthermore, PAPP-A was expressed and translated in NMRs cells and retained IGF-dependent proteolytic activity towards IGFBP-4 and IGF-independent activity towards IGFBP-5. However, experimental data suggest differential regulatory mechanisms for PAPP-A expression in NMRs than those described in humans and mice. This overall description of the IGF system in the NMR represents an initial step towards elucidating the complex molecular mechanisms underlying longevity, and how these animals have evolved to ensure a delayed and healthy aging process.


Rapid recovery from major depression using magnesium treatment.
Major depression is a mood disorder characterized by a sense of inadequacy, despondency, decreased activity, pessimism, anhedonia and sadness where these symptoms severely disrupt and adversely affect the person's life, sometimes to such an extent that suicide is attempted or results. Antidepressant drugs are not always effective and some have been accused of causing an increased number of suicides particularly in young people. Magnesium deficiency is well known to produce neuropathologies. Only 16% of the magnesium found in whole wheat remains in refined flour, and magnesium has been removed from most drinking water supplies, setting a stage for human magnesium deficiency. Magnesium ions regulate calcium ion flow in neuronal calcium channels, helping to regulate neuronal nitric oxide production. In magnesium deficiency, neuronal requirements for magnesium may not be met, causing neuronal damage which could manifest as depression. Magnesium treatment is hypothesized to be effective in treating major depression resulting from intraneuronal magnesium deficits. These magnesium ion neuronal deficits may be induced by stress hormones, excessive dietary calcium as well as dietary deficiencies of magnesium. Case histories are presented showing rapid recovery (less than 7 days) from major depression using 125-300 mg of magnesium (as glycinate and taurinate) with each meal and at bedtime. Magnesium was found usually effective for treatment of depression in general use. Related and accompanying mental illnesses in these case histories including traumatic brain injury, headache, suicidal ideation, anxiety, irritability, insomnia, postpartum depression, cocaine, alcohol and tobacco abuse, hypersensitivity to calcium, short-term memory loss and IQ loss were also benefited. Dietary deficiencies of magnesium, coupled with excess calcium and stress may cause many cases of other related symptoms including agitation, anxiety, irritability, confusion, asthenia, sleeplessness, headache, delirium, hallucinations and hyperexcitability, with each of these having been previously documented. The possibility that magnesium deficiency is the cause of most major depression and related mental health problems including IQ loss and addiction is enormously important to public health and is recommended for immediate further study. Fortifying refined grain and drinking water with biologically available magnesium to pre-twentieth century levels is recommended.


[Gender and sexuality: fragments of male identity in the Aids era]
This paper focuses on specific aspects of male sexuality and how this sexual identity is built in the Aids era, based on conversations with low-income youth, ages 14-21 years, living in Greater Metropolitan Rio de Janeiro. We examine how Aids is perceived and investigate sexuality in this epidemic context. The goal is to provide concrete data to support a prevention campaign and contribute to preventive policies in Brazilian society. The proposal is based on the sexual identity of this gender/age group, comparing their reports on sexual practice. We used a partially open-ended interview protocol. We focus on the way young males choose their sexual identity under the premise that this is how men can become the channel for Aids transmission. Our research was thus based on gender and sexual identity as categories. Our results indicate that for a young man, 'being a man' means having an active sexual life, thus creating a stereotype placing them at risk for HIV transmission.


Development of a Complex Intervention for the Maintenance of Postpartum Smoking Abstinence: Process for Defining Evidence-Based Intervention.
Relapse to tobacco smoking for pregnant women who quit is a major public health problem. Evidence-based approaches to intervention are urgently required. This study aimed to develop an intervention to be integrated into existing healthcare. A mixed methods approach included a theory-driven systematic review identifying promising behaviour change techniques for targeting smoking relapse prevention, and qualitative focus groups and interviews with women (ex-smokers who had remained quit and those who had relapsed), their partners and healthcare professionals (N = 74). A final stage recruited ten women to refine and initially test a prototype intervention. Our qualitative analysis suggests a lack, but need for, relapse prevention support. This should be initiated by a trusted 'credible source'. For many women this would be a midwife or a health visitor. Support needs to be tailored to individual needs, including positive praise/reward, novel digital and electronic support and partner or social support. Advice and support to use e cigarettes or nicotine replacement therapy for relapse prevention was important for some women, but others remained cautious. The resulting prototype complex intervention includes face-to-face support reiterated throughout the postpartum period, tailored digital and self-help support and novel elements such as gifts and nicotine replacement therapy (NRT).


Spectral-domain optical coherence tomography study on dynamic changes of human tears after instillation of artificial tears.
To analyze in vivo the dynamic changes induced by different artificial tears (ATs) in the precorneal tear film (PCTF) and lower tear meniscus (LTM) by using spectral-domain (SD) anterior segment optical coherence tomography (OCT). We prospectively examined 42 normal human eyes by using SD-OCT imaging. On the day before OCT imaging, all enrolled subjects were evaluated for abnormalities of ocular surface. All tear film images were obtained before and after instillation of three different types of ATs (mucomimetic, lipid-based, and saline) in five serial scans: immediately (within 30 seconds), at the first, fifth, 10th, and 20th minute. Subjects received a drop of 35 μL in one randomly selected eye. All examinations were conducted in the same conditions of temperature, brightness, humidity, and time of day. Changes in the morphological pattern of both LTM and PCTF were associated with the type of artificial tear instilled on the ocular surface. Similarly, the radius of curvature (rc), the height (h), and the depth (d) showed dynamic variations depending on treatment. Although by the 20th minute, both h and d returned to baseline values in all groups, a significant difference in rc (compared with baseline) was detected for mucomimetic ATs (P = 0.04) and lipid ATs (P = 0.02). Spectral-domain OCT imaging has preliminarily proved to be a noninvasive tool to evaluate, in real time, the different changes induced by ATs instillation. An important stride in understanding the clinical response to various tear substitutes can be achieved by this objective and quantitative approach.


Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin.
Although multivalent binding to surfaces is an important tool in nanotechnology, quantitative information about the residual valency and orientation of surface-bound molecules is missing. To address these questions, we study streptavidin (SAv) binding to commonly used biotinylated surfaces such as supported lipid bilayers (SLBs) and self-assembled monolayers (SAMs). Stability and kinetics of SAv binding are characterized by quartz crystal microbalance with dissipation monitoring, while the residual valency of immobilized SAv is quantified using spectroscopic ellipsometry by monitoring binding of biotinylated probes. Purpose-designed SAv constructs having controlled valencies (mono-, di-, trivalent in terms of biotin-binding sites) are studied to rationalize the results obtained on regular (tetravalent) SAv. We find that divalent interaction of SAv with biotinylated surfaces is a strict requirement for stable immobilization, while monovalent attachment is reversible and, in the case of SLBs, leads to the extraction of biotinylated lipids from the bilayer. The surface density and lateral mobility of biotin, and the SAv surface coverage are all found to influence the average orientation and residual valency of SAv on a biotinylated surface. We demonstrate how the residual valency can be adjusted to one or two biotin binding sites per immobilized SAv by choosing appropriate surface chemistry. The obtained results provide means for the rational design of surface-confined supramolecular architectures involving specific biointeractions at tunable valency. This knowledge can be used for the development of well-defined bioactive coatings, biosensors and biomimetic model systems.


Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients.
Advances in DNA sequencing have made genetic testing fast and affordable, but limitations of testing processes are impeding realisation of patient benefits. Ovarian cancer exemplifies the potential value of genetic testing and the shortcomings of current pathways to access testing. Approximately 15% of ovarian cancer patients have a germline BRCA1 or BRCA2 mutation which has substantial implications for their personal management and that of their relatives. Unfortunately, in most countries, routine implementation of BRCA testing for ovarian cancer patients has been inconsistent and largely unsuccessful. We developed a rapid, robust, mainstream genetic testing pathway in which testing is undertaken by the trained cancer team with cascade testing to relatives performed by the genetics team. 207 women with ovarian cancer were offered testing through the mainstream pathway. All accepted. 33 (16%) had a BRCA mutation. The result informed management of 79% (121/154) women with active disease. Patient and clinician feedback was very positive. The pathway offers a 4-fold reduction in time and 13-fold reduction in resource requirement compared to the conventional testing pathway. The mainstream genetic testing pathway we present is effective, efficient and patient-centred. It can deliver rapid, robust, large-scale, cost-effective genetic testing of BRCA1 and BRCA2 and may serve as an exemplar for other genes and other diseases.


Perturbed Calcineurin-NFAT Signaling Is Associated with the Development of Alzheimer's Disease.
Down syndrome (DS), the most common genetic disorder, is caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor. However, it is unclear whether the calcineurin-NFAT signaling pathway is involved in AD pathology in DS patients. Here, we investigated the association between the calcineurin-NFAT signaling pathway and AD using neuronal cells. Short-term pharmacological stimulation decreased gene expression of tau and neprilysin, and long-term inhibition of the signaling pathway decreased that of amyloid precursor protein. Moreover, a calcineurin inhibitor, cyclosporine A, also decreased neprilysin activity, leading to increases in amyloid-β peptide levels. Taken together, our results suggest that a dysregulation in calcineurin-NFAT signaling may contribute to the early onset of AD in people with DS.


Effects of vitamin D in skeletal muscle: falls, strength, athletic performance and insulin sensitivity.
Accompanying the high rates of vitamin D deficiency observed in many countries, there is increasing interest in the physiological functions of vitamin D. Vitamin D is recognized to exert extra-skeletal actions in addition to its classic roles in bone and mineral homeostasis. Here, we review the evidence for vitamin D's actions in muscle on the basis of observational studies, clinical trials and basic research. Numerous observational studies link vitamin D deficiency with muscle weakness and sarcopaenia. Randomized trials predominantly support an effect of vitamin D supplementation and the prevention of falls in older or institutionalized patients. Studies have also examined the effect of vitamin D in athletic performance, both inferentially by UV radiation and directly by vitamin D supplementation. Effects of vitamin D in muscle metabolic function, specifically insulin sensitivity, are also addressed in this review. At a mechanistic level, animal studies have evaluated the roles of vitamin D and associated minerals, calcium and phosphate, in muscle function. In vitro studies have identified molecular pathways by which vitamin D regulates muscle cell signalling and gene expression. This review evaluates evidence for the various roles of vitamin D in skeletal muscle and discusses controversies that have made this a dynamic field of research.


Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.
We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.


Distribution of plant-parasitic nematodes on sugarcane in louisiana and efficacy of nematicides.
A survey conducted from May 1995 through August 1998 revealed diverse nematode communities in Louisiana sugarcane fields. High populations of Mesocriconema, Paratrichodorus, Pratylenchus, and Tylenchorhynchus were widespread in nine sugarcane production parishes. Comparisons of plant cane and ratoon sugarcane crops indicated that nematode community levels increase significantly in successive ratoon crops. Nematicide trials evaluated the efficacy of aldicarb, ethoprop, and phorate against indigenous nematode populations. Aldicarb consistently increased the number of millable stalks, cane tonnage, and yield of sucrose in soils with a high sand content. Yield increases were concomitant with reductions in the density of the nematode community shortly after planting and at harvest. In soils with a higher clay content, the chemicals were less effective in controlling nematode populations and, as a result, yield increases were minimal.


A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.
Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.


Effect of oral dioctyl sodium sulfosuccinate on intake-output studies of human small and large intestine.
Dioctyl sodium sulfosuccinate (DSS) is an anionic detergent that is used widely as a laxative and promoted as a stool softener. Although many anecdotal reports attest to the laxative and stool softening efficacy of DSS, no controlled trials have been performed to document the effect of DSS on small or large bowel function in humans. We have compared, therefore, the effects of 100 mg of DSS three times daily (the maximum recommended dose) with placebo in a randomized, single blind, crossover study in two groups of subjects. First, 6 healthy ileostomates were studied while they ate a constant diet for 8 days. Dioctyl sodium sulfosuccinate administered for 4 days did not increase the daily ileal output of carbohydrate, total fatty acids, bile acids, nitrogen, or water. Cholesterol excretion was decreased while taking DSS (p less than 0.05). Second, 6 healthy volunteers were studied while eating a constant diet of 20 g of fiber plus 30 radiopaque markers daily so that mean daily transit time could be measured. After equilibration, a 7-day collection of stool was weighed and lyophylized to measure fecal water. Dioctyl sodium sulfosuccinate had no effect on stool weight, stool frequency, stool water, or mean transit time. We conclude that 300 mg/day of DSS does not increase ileal or colonic output of solids or water in healthy human subjects.


Dissecting Phaseolus vulgaris innate immune system against Colletotrichum lindemuthianum infection.
The genus Colletotrichum is one of the most economically important plant pathogens, causing anthracnose on a wide range of crops including common beans (Phaseolus vulgaris L.). Crop yield can be dramatically decreased depending on the plant cultivar used and the environmental conditions. This study aimed to identify potential genetic components of the bean immune system to provide environmentally friendly control measures against this fungus. As the common bean is not amenable to reverse genetics to explore functionality and its genome is not fully curated, we used putative Arabidopsis orthologs of bean expressed sequence tag (EST) to perform bioinformatic analysis and experimental validation of gene expression to identify common bean genes regulated during the incompatible interaction with C. lindemuthianum. Similar to model pathosystems, Gene Ontology (GO) analysis indicated that hormone biosynthesis and signaling in common beans seem to be modulated by fungus infection. For instance, cytokinin and ethylene responses were up-regulated and jasmonic acid, gibberellin, and abscisic acid responses were down-regulated, indicating that these hormones may play a central role in this pathosystem. Importantly, we have identified putative bean gene orthologs of Arabidopsis genes involved in the plant immune system. Based on experimental validation of gene expression, we propose that hypersensitive reaction as part of effector-triggered immunity may operate, at least in part, by down-regulating genes, such as FLS2-like and MKK5-like, putative orthologs of the Arabidopsis genes involved in pathogen perception and downstream signaling. We have identified specific bean genes and uncovered metabolic processes and pathways that may be involved in the immune response against pathogens. Our transcriptome database is a rich resource for mining novel defense-related genes, which enabled us to develop a model of the molecular components of the bean innate immune system regulated upon pathogen attack.


"Men are Better Than Women!" The Positive Effect of a Negative Stereotype Toward Women on a Self-Paced Cycling Exercise.
Previous research on the stereotype threat phenomenon has shown that inducing a negative stereotype toward a group debilitates motor performance despite the increase in motivation. Most of the studies focused on tasks requiring technical skills. However, what happens when the task does not require technical skills but focuses on energy expenditure? To examine this question, 34 male and female participants were assigned to a negative stereotype toward women and a nullified-stereotype condition and performed 20 min of self-paced cycling exercise. The authors hypothesized better performances when participants were assigned to the negative stereotype toward women condition than when assigned to the nullified-stereotype condition. As predicted, men and women increased their performances, accompanied by increases in heart rate. Concerning women, this result provides support for the notion that the effect of inducing a negative stereotype is task dependent, but further research is needed to more deeply investigate the mechanisms involved.


You can run, you can hide: The epidemiology and statistical mechanics of zombies.
We use a popular fictional disease, zombies, in order to introduce techniques used in modern epidemiology modeling, and ideas and techniques used in the numerical study of critical phenomena. We consider variants of zombie models, from fully connected continuous time dynamics to a full scale exact stochastic dynamic simulation of a zombie outbreak on the continental United States. Along the way, we offer a closed form analytical expression for the fully connected differential equation, and demonstrate that the single person per site two dimensional square lattice version of zombies lies in the percolation universality class. We end with a quantitative study of the full scale US outbreak, including the average susceptibility of different geographical regions.


Vitamin D in health and disease.
Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D(3)) is substantially more potent than ergocalciferol (vitamin D(2)) and that the safe upper intake level for vitamin D(3) is 10,000 IU/d.


Cortical processing of breathing perceptions in the athletic brain.
Athletes regularly endure large increases in ventilation and accompanying perceptions of breathlessness. Whilst breathing perceptions often correlate poorly with objective measures of lung function in both healthy and clinical populations, we have previously demonstrated closer matching between subjective breathlessness and changes in ventilation in endurance athletes, suggesting that athletes may be more accurate during respiratory interoception. To better understand the link between exercise and breathlessness, we sought to identify the mechanisms by which the brain processing of respiratory perception might be optimised in athletes. Twenty endurance athletes and twenty sedentary controls underwent 7 T functional magnetic resonance imaging. Inspiratory resistive loading induced conscious breathing perceptions (breathlessness), and a delay-conditioning paradigm was employed to evoke preceding periods of breathlessness-anticipation. Athletes demonstrated anticipatory brain activity that positively correlated with resulting breathing perceptions within key interoceptive areas, such as the thalamus, insula and primary sensorimotor cortices, which was negatively correlated in sedentary controls. Athletes also exhibited altered connectivity between interoceptive attention networks and primary sensorimotor cortex. These functional differences in athletic brains suggest that exercise may alter anticipatory representations of respiratory sensations. Future work may probe whether these brain mechanisms are harnessed when exercise is employed to treat breathlessness within chronic respiratory disease.


Impairment of host immune response against strongyloides stercoralis by human T cell lymphotropic virus type 1 infection.
A large-scale study was undertaken to clarify the prevalence rate of strongyloidiasis in Okinawa, Japan and to evaluate the relationship between strongyloidiasis and infection with human T cell lymphotropic virus type 1 (HTLV-1). The prevalence rate of Strongyloides stercoralis and HTLV-1 infection were 6.3% and 14.0%, respectively. Among 2,185 patients more than 50 years of age, the rate of S. stercoralis infection was significantly higher in patients with HTLV-1 infection compared with patients without HTLV-1 infection. In 252 patients treated with ivermectin, serum IgE levels and peripheral eosinophil counts were significantly lower in HTLV-1 co-infected patients compared with patients without HTLV-1 infection. In addition, the anthelmintic effect was significantly lower in patients with HTLV-1 infection compared with patients without HTLV-1 infection. Our prospective study demonstrated a prevalence rate for strongyloidiasis and HTLV-1 infections, and clearly demonstrated that co-infection with HTLV-1 impaired the immune response against S. stercoralis.


Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents.
Concern is growing about nonalcoholic fatty liver disease, not only because it is a common liver disorder but also because it is one of the leading causes of chronic liver disease. Unexplained elevations in aminotransferase concentrations have been strongly associated with adiposity and thus may represent nonalcoholic fatty liver disease. We investigated the relation between nonviral or nonalcoholic elevations in alanine aminotransferase (ALT) and the metabolic syndrome in Korean adolescents. Data were obtained from 1594 subjects aged 10-19 y from the Korean National Health and Nutrition Examination Survey 1998, a cross-sectional health survey of a nationally representative sample of noninstitutionalized civilian South Koreans. Body mass index, waist circumference, blood pressure, fasting glucose, lipid profiles, and serum ALT were measured. The prevalence of elevated ALT (> 40 U/L) was 3.6% in boys and 2.8% in girls. The prevalence of metabolic syndrome was 3.3% in both boys and girls. The components of the metabolic syndrome were significantly worse in the group with elevated ALT concentrations than in the group with normal ALT concentrations. The odds ratios (95% CIs) for elevated ALT were 6.6 (3.7, 11.8), 2.3 (1.2, 4.6), and 3.0 (1.6, 5.8) in the adolescents with abdominal obesity, high triacylglycerol concentrations, and low HDL-cholesterol concentrations, respectively. The odds ratios for elevated ALT were 1.5 (0.7, 3.1), 2.6 (1.1, 6.2), and 6.2 (2.3, 16.8) in the adolescents with 1, 2, and > or = 3 risk factors (metabolic syndrome), respectively. The metabolic syndrome was strongly associated with elevated ALT concentrations in Korean adolescents, and this association existed in a graded fashion across the number of metabolic components.


Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication.
The six main minichromosome maintenance proteins (Mcm2-7), which presumably constitute the core of the replicative DNA helicase, are present in chromatin in large excess relative to the number of active replication forks. To evaluate the relevance of this apparent surplus of Mcm2-7 complexes in human cells, their levels were down-regulated by using RNA interference. Interestingly, cells continued to proliferate for several days after the acute (>90%) reduction of Mcm2-7 concentration. However, they became hypersensitive to DNA replication stress, accumulated DNA lesions, and eventually activated a checkpoint response that prevented mitotic division. When this checkpoint was abrogated by the addition of caffeine, cells quickly lost viability, and their karyotypes revealed striking chromosomal aberrations. Single-molecule analyses revealed that cells with a reduced concentration of Mcm2-7 complexes display normal fork progression but have lost the potential to activate "dormant" origins that serve a backup function during DNA replication. Our data show that the chromatin-bound "excess" Mcm2-7 complexes play an important role in maintaining genomic integrity under conditions of replicative stress.


The influence of host-plant connectivity on fungal assemblages in the root microbiota of Brachypodium pinnatum.
Dispersal limitation may drive the structure of fungal microbiota of plant roots at small spatial scales. Fungal root microorganisms disperse through the plant rooting systems from hosts to hosts. Due to a pronounced host-preference effect, the composition of endophytic root microbiota may follow plant distribution. A given plant community may hence include a matrix of host-plant species that represent various habitat permeabilities to fungal dispersal in the floristic landscape. We experimentally tested the effect of host-plant isolation on endophytic fungal assemblages (Ascomycota, Basidiomycota, Glomeromycotina) inhabiting Brachypodium pinnatum roots. We calculated host-plant isolation using Euclidean distance (distance-based dispersal limitation) and resistance distance (functional-based dispersal limitation), based on host presences. All fungal groups were more influenced by the resistance distance between B. pinnatum than by the Euclidean distance. Fungal dispersal was hence strongly related to the spatial distribution of the host plants. The fungal groups displayed however different responses (in richness, abundance, and composition) to host isolation. Additionally, fungal assemblages were more strongly controlled by the degree of connectivity between host plants during the prior year than by current connectivity. This discrepancy may be due to changes in plant species coverage in a year and/or to the delay of dispersal response of fungi. This study it the first to demonstrate how small-scale host-plant distributions mediate connectivity in microorganisms. The consequences of plant distributions for the permeability of the floristic landscape to fungi dispersal appear to control fungal assemblages, but with possibly different mechanisms for the different fungal groups.


Recombination within a nucleotide-binding-site/leucine-rich-repeat gene cluster produces new variants conditioning resistance to soybean mosaic virus in soybeans.
The soybean Rsv1 gene for resistance to soybean mosaic virus (SMV; Potyvirus) has previously been described as a single-locus multi-allelic gene mapping to molecular linkage group (MLG) F. Various Rsv1 alleles condition different responses to the seven (G1-G7) described strains of SMV, including extreme resistance, localized and systemic necrosis, and mosaic symptoms. We describe the cloning of a cluster of NBS-LRR resistance gene candidates from MLG F of the virus-resistant soybean line PI96983 and demonstrate that multiple genes within this cluster interact to condition unique responses to SMV strains. In addition to cloning 3gG2, a strong candidate for the major Rsv1 resistance gene from PI96983, we describe various unique resistant and necrotic reactions coincident with the presence or absence of other members of this gene cluster. Responses of recombinant lines from a high-resolution mapping population of PI96983 (resistant) x Lee 68 (susceptible) demonstrate that more than one gene in this region of the PI96983 chromosome conditions resistance and/or necrosis to SMV. In addition, the soybean cultivars Marshall and Ogden, which carry other previously described Rsv1 alleles, are shown to possess the 3gG2 gene in a NBS-LRR gene cluster background distinct from PI96983. These observations suggest that two or more related non-TIR-NBS-LRR gene products are likely involved in the allelic response of several Rsv1-containing lines to SMV.


Conservation and elaboration of Hox gene regulation during evolution of the vertebrate head.
The comparison of Hox genes between vertebrates and their closest invertebrate relatives (amphioxus and ascidia) highlights two derived features of Hox genes in vertebrates: duplication of the Hox gene cluster, and an elaboration of Hox expression patterns and roles compared with non-vertebrate chordates. We have investigated how new expression domains and their associated developmental functions evolved, by testing the cis-regulatory activity of genomic DNA fragments from the cephalochordate amphioxus Hox cluster in transgenic mouse and chick embryos. Here we present evidence for the conservation of cis-regulatory mechanisms controlling gene expression in the neural tube for half a billion years of evolution, including a dependence on retinoic acid signalling. We also identify amphioxus Hox gene regulatory elements that drive spatially localized expression in vertebrate neural crest cells, in derivatives of neurogenic placodes and in branchial arches, despite the fact that cephalochordates lack both neural crest and neurogenic placodes. This implies an elaboration of cis-regulatory elements in the Hox gene cluster of vertebrate ancestors during the evolution of craniofacial patterning.


Perceptions of Parents With Preterm Infants Hospitalized in Singaporean Neonatal Intensive Care Unit.
Perceptions of parents with preterm infants who were hospitalized in a Singapore-based neonatal intensive care unit were observed. Convenience sampling method was used to recruit 8 parents of preterm infants. Semistructured face-to-face in-depth interviews were used to collect data between November 2013 and February 2014. Data were analyzed using thematic analysis. Four themes were identified: "negative emotions versus positive emotions," "finding ways forward," "nature of support received from various sources," and "need more informational and professional support." Parents of preterm infants experienced a multitude of emotions that varied from shock and sadness to excitement and anticipation through their babies' birth, hospitalization, and impending discharge. These parents adopted several strategies to cope with their birth and subsequent infant hospitalization. While their neonatal intensive care unit (NICU) experience was perceived as positive for most parents, some suggestions were made to improve on the information provided and professional care. This study provides evidence to health care professionals in addressing parents' negative emotions and coping abilities in practice. Emotional and informational support for parents is important for them to be more competent in coping with the hospitalization of their newborn in the NICU.


Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation.
Sympathetic neurons depend on target-derived neurotrophic cues to control their survival and growth. However, whether sympathetic innervation contributes reciprocally to the development of target tissues is less clear. Here, we report that sympathetic innervation is necessary for the formation of the pancreatic islets of Langerhans and for their functional maturation. Genetic or pharmacological ablation of sympathetic innervation during development resulted in altered islet architecture, reduced insulin secretion, and impaired glucose tolerance in mice. Similar defects were observed with pharmacological blockade of β-adrenergic signaling. Conversely, the administration of a β-adrenergic agonist restored islet morphology and glucose tolerance in deinnervated animals. Furthermore, in neuron-islet cocultures, sympathetic neurons promoted islet cell migration in a β-adrenergic-dependent manner. This study reveals that islet architecture requires extrinsic inductive cues from neighboring tissues such as sympathetic nerves and suggests that early perturbations in sympathetic innervation might underlie metabolic disorders.


Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.
A20 is a negative regulator of NF-κB, and mutational loss of A20 expression is involved in the pathogenesis of autoimmune diseases and B-cell lymphomas. To clarify the role of A20 in adult hematopoiesis, we generated conditional A20 knockout mice (A20(flox/flox) ) and crossed them with Mx-1Cre (MxCre (+)) and ERT2Cre (ERT2Cre (+)) transgenic mice in which Cre is inducibly activated by endogenous interferon and exogenous tamoxifen, respectively. A20(flox/flox) MxCre (+) (A20Mx) mice spontaneously exhibited myeloid proliferation, B cell apoptosis, and anemia with overproduction of pro-inflammatory cytokines. Bone marrow transplantation demonstrated that these changes were caused by hematopoietic cells. NF-κB was constitutively activated in A20Mx hematopoietic stem cells (HSCs), which caused enhanced cell cycle entry and impaired repopulating ability. Tamoxifen stimulation of A20(flox/flox) ERT2Cre (+) (A20ERT2) mice induced fulminant apoptosis and subsequent myeloproliferation, lymphocytopenia, and progressive anemia with excessive production of pro-inflammatory cytokines, as observed in A20Mx mice. These results demonstrate that A20 plays essential roles in the homeostasis of adult hematopoiesis by preventing apoptosis and inflammation. Our findings provide insights into the mechanism underlying A20 dysfunction and human diseases in which A20 expression is impaired.


Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.
Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. European Community's Seventh Framework Programme.


Effects of radio frequency magnetic fields on iron release from cage proteins.
Ferritin, the iron cage protein, contains a superparamagnetic ferrihydrite nanoparticle formed from the oxidation and absorption of Fe(2+) ions. This nanoparticle increases its internal energy when exposed to alternating magnetic fields due to magnetization lag. The energy is then dissipated to the surrounding proteic cage, affecting its functioning. In this article we show that the rates of iron chelation with ferrozine, an optical marker, are reduced by up to a factor of 3 in proteins previously exposed to radio frequency magnetic fields of 1 MHz and 30 microT for several hours. The effect is non-thermal and depends on the frequency-amplitude product of the magnetic field.


Visceral Adiposity Index: Simple Tool for Assessing Cardiometabolic Risk in Women with Polycystic Ovary Syndrome.
To study visceral adiposity index (VAI) and its association with cardiometabolic risk in different phenotypes of polycystic ovary syndrome (PCOS). It is a case-control cross-sectional study where 100 reproductive age (18-35 years) women with PCOS were classified in different phenotypes as per Rotterdam criteria and compared with age and Body mass index (BMI) matched 50 eumenorrheic and nonhirsute women. Various anthropometric, clinical, biochemical, and hormonal parameters were measured in both women with PCOS and controls. VAI was calculated using waist circumference (WC), BMI, serum triglyceride, and High density lipoprotein (HDL) cholesterol levels in all the subjects and compared between cases and controls. Subsequently, women with PCOS were assessed for cardiometabolic risk according to androgen excess society statement 2010 as "at risk" and "at high risk." Finally, risk was correlated with VAI for all the phenotypes of PCOS. Mean VAI was significantly higher (P < 0.001) in cases than controls (2.07 vs. 1.27). Mean VAI in phenotype A (O+P+HA), B (O+HA), C (P+HA), and D (O+P) was 2.46, 2.48, 1.47, and 1.70, respectively. A total of 56% of women with PCOS were at risk and 12% at high risk for cardiometabolic disease. Metabolic syndrome was prevalent in 11% of cases and 1% had type 2 diabetes mellitus. Phenotypically, 88% of women with PCOS with phenotype A (O+P+HA), 67% of B (O+HA), 67% of C (P+HA), and 55% of D (O+P) were at increased risk. VAI was found to be positively correlated with WC (r, 0.550), waist to hip ratio (r, 0.295), Homeostasis model assessment of insulin resistance (HOMA IR) (r, 0.455), and cardiometabolic risk (r, 0.399). Also, it was the best factor associated with cardiometabolic risk (area under curve, 0.793). This study concluded that visceral adiposity index can be used as simple and effective tool for assessing the cardiometabolic risk in women with PCOS as higher VAI values were observed in those cases who were at high risk for developing cardiometabolic disorder in future.


Psychological treatments for adults with posttraumatic stress disorder: A systematic review and meta-analysis.
Numerous guidelines have been developed over the past decade regarding treatments for Posttraumatic stress disorder (PTSD). However, given differences in guideline recommendations, some uncertainty exists regarding the selection of effective PTSD therapies. The current manuscript assessed the efficacy, comparative effectiveness, and adverse effects of psychological treatments for adults with PTSD. We searched MEDLINE, Cochrane Library, PILOTS, Embase, CINAHL, PsycINFO, and the Web of Science. Two reviewers independently selected trials. Two reviewers assessed risk of bias and graded strength of evidence (SOE). We included 64 trials; patients generally had severe PTSD. Evidence supports efficacy of exposure therapy (high SOE) including the manualized version Prolonged Exposure (PE); cognitive therapy (CT), cognitive processing therapy (CPT), cognitive behavioral therapy (CBT)-mixed therapies (moderate SOE); eye movement desensitization and reprocessing (EMDR) and narrative exposure therapy (low-moderate SOE). Effect sizes for reducing PTSD symptoms were large (e.g., Cohen's d ~-1.0 or more compared with controls). Numbers needed to treat (NNTs) were <4 to achieve loss of PTSD diagnosis for exposure therapy, CPT, CT, CBT-mixed, and EMDR. Several psychological treatments are effective for adults with PTSD. Head-to-head evidence was insufficient to determine these treatments' comparative effectiveness, and data regarding adverse events was absent from most studies.


Hospital and ED use among Medicare beneficiaries with dementia varies by setting and proximity to death.
Hospitalizations and emergency department (ED) visits for people with Alzheimer's disease and related disorders are of particular concern because many of these patients are physically and mentally frail, and the care delivered in these settings is costly. Using data from the Health and Retirement Study linked with Medicare claims from the period 2000-08, we found that among community-dwelling elderly fee-for-service Medicare beneficiaries, those who had dementia were significantly more likely than those who did not to have a hospitalization (26.7 percent versus 18.7 percent) and an ED visit (34.5 percent versus 25.4 percent) in each year. Comparing nursing home residents who had dementia with those who did not, we found only small differences in hospitalizations (45.8 percent versus 41.9 percent, respectively) and ED use (55.3 percent versus 52.7 percent). As death neared, however, utilization rose sharply across settings and by whether or not beneficiaries had dementia: Nearly 80 percent of community-dwelling decedents were hospitalized, and an equal proportion had at least one ED visit during the last year of life, regardless of dementia. Our research suggests that substantial portions of hospitalizations and ED visits both before and during the last year of life were potentially avoidable.


NKCC1: Newly Found as a Human Disease-Causing Ion Transporter.
Among the electroneutral Na+-dependent chloride transporters, NKCC1 had until now evaded identification as a protein causing human diseases. The closely related SLC12A transporters, NKCC2 and NCC have been identified some 25 years ago as responsible for Bartter and Gitelman syndromes: two renal-dependent salt wasting disorders. Absence of disease was most surprising since the NKCC1 knockout mouse was shown in 1999 to be viable, albeit with a wide range of deleterious phenotypes. Here we summarize the work of the past 5 years that introduced us to clinical cases involving NKCC1. The most striking cases are of 3 children with inherited mutations, who have complete absence of NKCC1 expression. These cases establish that lack of NKCC1 causes deafness; CFTR-like secretory defects with mucus accumulation in lung and intestine; severe xerostomia, hypotonia, dysmorphic facial features, and severe neurodevelopmental disorder. Another intriguing case is of a patient with a dominant deleterious SLC12A2 allele. This de novo mutation introduced a premature stop codon leading to a truncated protein. This mutant transporter seems to exert dominant-negative effect on wild-type transporter only in epithelial cells. The patient who suffers from lung, bladder, intestine, pancreas, and multiple endocrine abnormalities has, however, normal hearing and cognition. Finally, new reports substantiate the haploinsufficiency prediction of the SLC12A2 gene. Cases with single allele mutations in SLC12A2 have been linked to hearing loss and neurodevelopmental disorders.


Common, emerging, vector-borne and infrequent abortogenic virus infections of cattle.
This review deals with the aetiology and the diagnosis of bovine viral abortion. While the abortion rates on beef and dairy cattle farms usually do not exceed 10%, significant economic losses because of abortion storms may be encountered. Determining the cause of abortions is usually a challenge, and it generally remains obscure in more than 50% of the necropsy submitted foetuses. Bovine viral diarrhoea virus and bovine herpesvirus-1 are the most common viruses causally associated with bovine abortions in farmed cattle globally. Rift Valley fever virus and bluetongue virus are important insect-transmitted abortogenic viruses. The geographic distribution of these two viruses is primarily dependent on the distribution of the insect vector, but direct transmission is possible. Recent global warming and subsequent insect vector expansion, coupled with the increase in international trade of animals and animal products, have been important factors in recent geographic advances of those two viruses. Bovine herpesviruses-4 and 5 in cattle, as well as other less frequent vector-borne viruses including epizootic haemorrhagic disease virus, Aino virus, Wesselsbron virus and lumpy skin disease virus, are discussed.


Markers of erectile dysfunction.
With the development and marketing of oral pharmacotherapy that is both noninvasive and successful in treating erectile dysfunction (ED), the quest to identify markers of organic ED lost ground. Indeed, the multi-factorial nature of ED may have led many researchers to conclude that searching for a universal marker of ED was futile. However, the realization that ED is strongly correlated with the overall health of men, and may act as a predictor for the development of cardiovascular disease (CVD) and diabetes, has stimulated interest in identifying genes that can distinguish organic ED. In addition, the potential ability to suggest to the patient that ED is reversible (i.e., psychogenic) with a simple test would be of significance to both the physician and patient, as well as for reimbursement issues for therapy by insurance companies. Such a marker may also act as a non-subjective measure of the degree of ED and the efficacy of treatment. This review discusses the importance of identifying such markers and recent work identifying potential markers in human patients.


Perception of light source distance from shading patterns.
Varying the distance of a light source from an object alters both the intensity and spatial distribution of surface shading patterns. We tested whether observers can use such cues to infer light source distance. Participants viewed stereoscopic renderings of rough objects with diffuse and glossy surfaces, which were illuminated by a point source at a range of distances. In one task, they adjusted the position of a small probe dot in three dimensions to report the apparent location of the light in the scene. In a second task, they adjusted the shading on one object (by moving an invisible light source) until it appeared to be illuminated from the same distance as another object. Participants' responses increased linearly with the true light source distance, suggesting that they have clear intuitions about how light source distance affects shading patterns for a variety of different surfaces. However, there were also systematic errors: Subjects overestimated light source distance in the probe adjustment task, and in both experiments, roughness and glossiness affected responses. We find the pattern of results is predicted surprisingly well by a simplistic model based only on the area of the image that exceeds a certain intensity threshold. Thus, although subjects can report light source distance, they may rely on simple--sometimes erroneous--heuristics to do so.


Respiratory dysfunction following cardiopulmonary bypass: verification of a non-invasive technique to measure shunt fraction.
Respiratory dysfunction is a well recognized complication of cardiopulmonary bypass. The size of the pulmonary shunt fraction is the best indicator of respiratory dysfunction but its measurement conventionally requires use of a pulmonary artery catheter to measure mixed venous oxygen content. We compared pulmonary shunt fraction, based on a non-invasive technique using a previously described mathematical model, with shunt fraction measured invasively using a pulmonary artery catheter in 22 patients undergoing elective coronary artery surgery. The mean shunt fraction measured by the invasive technique was 19.6 +/- 2.0 (18.8-20.4)% of cardiac output at 24 h (+/- 1 SD and 90% confidence intervals) and 20.9 +/- 2.9 (19.8-22.0)% of cardiac output at 44 h post-surgery. There was good agreement between the two methods of measurement. The mean difference was 0.21 percentage points with 95% confidence interval -0.01 to 0.43. The limits of agreement (-1.17 to 1.59) are small enough to be confident that the non-invasive method can be used to give the same result as that obtained using a pulmonary artery catheter. The values for shunt fractions obtained by the non-invasive technique were 19.7 +/- 2.3 (18.8-20.6)% of cardiac output at 24 h and 20.7 +/- 2.5 (19.7-21.6)% of cardiac output at 44 h. The non-invasive measurement of the shunt fraction provided us with a simple, practical method for following a further ten patients over an extended period of time where prolonged catheterization is impractical.


Aspiration cytopathology of peripancreatic space: a clinicoradiologic and cytopathologic analyses of 42 cases.
The pancreas is surrounded by soft tissue known as the peripancreatic space (PPS). Pathologic lesions of the PPS are infrequent and have only rarely been reported in the cytopathology literature. A retrospective review of cytopathology files at two large institutions revealed 42 cases of PPS lesions obtained by transabdominal fine needle aspiration (FNA) or endoscopic ultrasound-guided FNA over a 16-year period. Clinicoradiologic findings and follow-up information were also reviewed. Patients ranged in age from 23-83 years (mean, 60 years) with an equal gender distribution. The major clinical presentations included pain, jaundice, nausea/vomiting, and abnormal liver enzymes. Radiographic characteristics included lymphadenopathy and cystic/solid soft tissue masses with a size range of 1.5 to 8 cm. Cytologically, 4 (9.5%) cases were nondiagnostic, 9 (21.5%) were diagnosed as benign, 4 (9.5%) were atypical or suspicious for cancer, and 25 (59.5%) were malignant. Six of 25 (24%) patients had metastasis of a prior known malignancy. FNA of PPS masses is a rare occurrence. The majority of lesions are metastatic carcinomas from a variety of primary sites. Flow cytometry and immunoperoxidase studies are useful adjuncts to determine the tumor origin. The sensitivity of PPS aspiration for a malignant diagnosis is 90% with a positive predictive value of 100%.


Progranulin, a New Adipokine at the Crossroads of Metabolic Syndrome, Diabetes, Dyslipidemia and Hypertension.
Progranulin is a multifunctional regulatory protein with growth-promoting, neuroprotective and antiinflammatory activities. Recent studies indicate that progranulin is one of the adipose tissue hormones (adipokines). Progranulin expression in visceral adipose tissue and circulating progranulin concentration are increased in obesity and hyperprogranulinemia is involved in the pathogenesis of obesity-associated insulin resistance. Progranulin impairs insulin signaling and reduces insulin-induced glucose uptake both in vitro and in vivo whereas progranulin deficiency protects from high fat diet-induced insulin resistance. Several studies, including some prospective ones, have demonstrated the association between high progranulin and type 2 diabetes and its complications such as nephro- and retinopathy as well as non-alcoholic fatty liver disease. It is quite well established that progranulin contributes to insulin resistance and resulting deterioration of carbohydrate metabolism. In addition, progranulin may be associated with the development of diabetic microangiopathy, fatty liver disease and possibly with the increased risk of cancer in subjects with the metabolic syndrome. On the other hand, progranulin augments vasorelaxation, inhibits inflammatory reaction, is neuroprotective and reduces ischemiareperfusion injury. Progranulin has both detrimental and beneficial effects. More clinical studies including prospective ones are needed to clarify the role of progranulin in obesity-associated pathologies such as diabetes, hyperlipidemia, hypertension and atherosclerosis.


Measurement of the WW + WZ production cross section using the lepton + jets final state at CDF II.
We report two complementary measurements of the WW + WZ cross section in the final state consisting of an electron or muon, missing transverse energy, and jets, performed using pp collision data at square root of s = 1.96 TeV collected by the CDF II detector. The first method uses the dijet invariant mass distribution while the second more sensitive method uses matrix-element calculations. The result from the second method has a signal significance of 5.4sigma and is the first observation of WW + WZ production using this signature. Combining the results gives sigma(WW + WZ) = 16.0 +/- 3.3 pb, in agreement with the standard model prediction.


Early Identification of Autism: Early Characteristics, Onset of Symptoms, and Diagnostic Stability.
In the first year of life, infants who later go on to develop autistic spectrum disorders (ASD) may exhibit subtle disruptions in social interest and attention, communication, temperament, and head circumference growth that occur prior to the onset of clinical symptoms. These disruptions may reflect the early course of ASD development and may also contribute to the later development of clinical symptoms through alterations in the child's experience of his or her environment. By age 2, developmental precursors of autism symptoms can be used to diagnose children reliably, and by age 3, the diagnosis is thought to be relatively stable. The downward extension of the autism diagnosis poses important questions for therapists in designing interventions that are applicable for infants who demonstrate early risk factors. We review current knowledge of the early signs of ASD in the infancy period (0-12 months) and the manifestation of symptoms in toddlerhood (12- 36 months), noting the importance of considering the variability in onset and trajectory of ASD. Finally, we consider the implications of this emerging research for those who work or interact with young children, including the importance of early monitoring and the development and evaluation of age-appropriate interventions.


Liver histopathology of the hepatitis A virus infection: a comparison with hepatitis type B and non-a, non-b.
Liver biopsies from 86 patients with serologically established acute hepatitis A were evaluated for quantitative and qualitative light microscopic features together with biopsies from 78 patients with acute hepatitis type B and 76 patients with acute hepatitis type non-A, non-B. Hepatitis A was characterised by more pronounced portal inflammation than hepatitis non-A, non-B (p less than 0.01) but less conspicuous parenchymal changes (focal necrosis, Kupffer cell proliferation, acidophil bodies, ballooning) than found in hepatitis type B (p less than 0.01). Steatosis occurred in 10% of the hepatitis A biopsies compared with 26% (p less 0.01) and 6% (not significant) in the hepatitis non-A, non-B and B groups, respectively. A comparison between the histological findings in women and men revealed that iron deposits occurred in more than half of the men compared to less than 20% of the women (p less than 0.01) irrespective of hepatitis type. Histological and biochemical follow-up was available in 36 patients with hepatitis A. For the majority of these patients the bilirubin concentration reached normal values within one month of the initial biopsy. The activity of serum transaminases showed good correlation with the degree of histological resolution. Non-specific reactive hepatitis with slightly raised serum transaminases were often seen during recovery from hepatitis A. These patients may be misinterpreted as cases of acute non-A, non-B hepatitis.


Risk factors of hospitalization for carpal tunnel syndrome among the general working population.
Objectives Carpal tunnel syndrome (CTS) causes a considerable amount of sick leave and healthcare costs. The etiology of CTS is multifactorial, involving both personal and occupational risk factors. To date, few prospective cohort studies on occupational risk factors of CTS have examined the general working population. Methods The study population consisted of participants from the Northern Finland Birth Cohort of 1966 who attended the 31-year follow-up in 1997 and were working ≥3 days a week in a paid job (N=6326). Information on socio-economic status, weight and height, smoking, exposure to occupational physical factors, and long-term illnesses was collected at baseline in 1997. Data on hospitalizations due to CTS came from the Care Register for Health Care, 1997-2016. Results Between 1997 and 2016, 3.4% of the participants had been hospitalized (attended secondary care) for CTS. After adjusting for confounders, women [hazard ratio (HR) 3.77, 95% confidence interval (CI) 2.70-5.25], overweight/obese participants (HR 1.69, 95% CI 1.29-2.22), smokers (HR 1.48, 95% CI 1.12-1.96), farmers and manual workers (HR 3.02, 95% CI 1.85-4.92 compared with upper clerical workers), lower clerical workers (HR 1.74, 95% CI=1.08-2.80), workers exposed to hand vibration (HR 2.29, 95% CI 1.48-3.54) and participants with physically demanding jobs (HR 1.71, CI 1.06-2.76) were at increased risk of hospitalization for CTS. Physically demanding work increased the risk of hospitalization for CTS for overweight/obese participants at baseline, but not for participants of normal weight. Conclusions Excess body mass and occupational physical factors increase the risk of hospitalization for CTS. Excess body mass potentiates the adverse effects of strenuous work on CTS.