The technical report on sodium intake and cardiovascular disease in low- and middle-income countries by the joint working group of the World Heart Federation, the European Society of Hypertension and the European Public Health Association.
Ingestion of sodium is essential to health, but excess sodium intake is a risk factor for hypertension and cardiovascular disease. Defining an optimal range of sodium intake in populations has been challenging and controversial. Clinical trials evaluating the effect of sodium reduction on blood pressure have shown blood pressure lowering effects down to sodium intake of less than 1.5 g/day. Findings from these blood pressure trials form the basis for current guideline recommendations to reduce sodium intake to less than 2.3 g/day. However, these clinical trials employed interventions that are not feasible for population-wide implementation (i.e. feeding studies or intensive behavioural interventions), particularly in low and middle-income countries. Prospective cohort studies have identified the optimal range of sodium intake to reside in the moderate range (3-5 g/day), where the risk of cardiovascular disease and death is lowest. Therefore, there is consistent evidence from clinical trials and observational studies to support reducing sodium intake to less than 5 g/day in populations, but inconsistent evidence for further reductions below a moderate intake range (3-5 g/day). Unfortunately, there are no large randomized controlled trials comparing low sodium intake (< 3 g/day) to moderate sodium intake (3-5 g/day) in general populations to determine the net clinical effects of low sodium intake. Until such trials are completed, it is likely that controversy about optimal sodium intake range will continue. This working group calls for the completion of large definitive clinical trials to clarify the range of sodium intake for optimal cardiovascular health within the moderate to low intake range. We support interventions to reduce sodium intake in populations who consume high sodium intake (> 5 g/day), which should be embedded within an overall healthy dietary pattern.


Consumption in the G20 nations causes particulate air pollution resulting in two million premature deaths annually.
Worldwide exposure to ambient PM2.5 causes over 4 million premature deaths annually. As most of these deaths are in developing countries, without internationally coordinated efforts this polarized situation will continue. As yet, however, no studies have quantified nation-to-nation consumer responsibility for global mortality due to both primary and secondary PM2.5 particles. Here we quantify the global footprint of PM2.5-driven premature deaths for the 19 G20 nations in a position to lead such efforts. G20 consumption in 2010 was responsible for 1.983 [95% Confidence Interval: 1.685-2.285] million premature deaths, at an average age of 67, including 78.6 [71.5-84.8] thousand infant deaths, implying that the G20 lifetime consumption of about 28 [24-33] people claims one life. Our results indicate that G20 nations should take responsibility for their footprint rather than focusing solely on transboundary air pollution, as this would expand opportunities for reducing PM2.5-driven premature mortality. Given the infant mortality footprint identified, it would moreover contribute to ensuring infant lives are not unfairly left behind in countries like South Africa, which have a weak relationship with G20 nations.


Mass spectrometry based identification of galectin-3 interacting proteins potentially involved in lung melanoma metastasis.
Adhesive interactions between molecules on tumor cells and those on target organs play a key role in organ specific metastasis. Poly-N-acetyl-lactosamine (polyLacNAc) substituted N-oligosaccharides on melanoma cell surface glycoproteins promote lung specific metastasis via galectin-3 by facilitating their arrest and extravasation. This study reports the identification and characterization of galectin-3 interacting proteins using a combination of galectin-3 sepharose affinity and leucoagglutinating phytohemagglutinin (L-PHA) columns. A total of 83 proteins were identified as galectin-3 interacting glycoproteins, of which 35 were constituents of the L-PHA bound fraction, suggesting that these proteins carry polyLacNAc substituted β1,6 branched N-glycans. The identities of some of these proteins, like LAMP-1, LAMP-3, basigin, embigin, and α5 and β1 Integrin, have been confirmed by western blotting, and functional relevance with respect to metastatic properties has been established.


Structure of H/ACA RNP protein Nhp2p reveals cis/trans isomerization of a conserved proline at the RNA and Nop10 binding interface.
H/ACA small nucleolar and Cajal body ribonucleoproteins (RNPs) function in site-specific pseudouridylation of eukaryotic rRNA and snRNA, rRNA processing, and vertebrate telomerase biogenesis. Nhp2, one of four essential protein components of eukaryotic H/ACA RNPs, forms a core trimer with the pseudouridylase Cbf5 and Nop10 that binds to H/ACA RNAs specifically. Crystal structures of archaeal H/ACA RNPs have revealed how the protein components interact with each other and with the H/ACA RNA. However, in place of Nhp2p, archaeal H/ACA RNPs contain L7Ae, which binds specifically to an RNA K-loop motif absent from eukaryotic H/ACA RNPs, while Nhp2 binds a broader range of RNA structures. We report solution NMR studies of Saccharomyces cerevisiae Nhp2 (Nhp2p), which reveal that Nhp2p exhibits two major conformations in solution due to cis/trans isomerization of the evolutionarily conserved Pro83. The equivalent proline is in the cis conformation in all reported structures of L7Ae and other homologous proteins. Nhp2p has the expected α-β-α fold, but the solution structures of the major conformation of Nhp2p with trans Pro83 and of Nhp2p-S82W with cis Pro83 reveal that Pro83 cis/trans isomerization affects the positions of numerous residues at the Nop10 and RNA binding interface. An S82W substitution, which stabilizes the cis conformation, also stabilizes the association of Nhp2p with H/ACA snoRNPs expressed in vivo. We propose that Pro83 plays a key role in the assembly of the eukaryotic H/ACA RNP, with the cis conformation locking in a stable Cbf5-Nop10-Nhp2 ternary complex and positioning the protein backbone to interact with the H/ACA RNA.


Abrupt climate change and collapse of deep-sea ecosystems.
We investigated the deep-sea fossil record of benthic ostracodes during periods of rapid climate and oceanographic change over the past 20,000 years in a core from intermediate depth in the northwestern Atlantic. Results show that deep-sea benthic community "collapses" occur with faunal turnover of up to 50% during major climatically driven oceanographic changes. Species diversity as measured by the Shannon-Wiener index falls from 3 to as low as 1.6 during these events. Major disruptions in the benthic communities commenced with Heinrich Event 1, the Inter-Allerød Cold Period (IACP: 13.1 ka), the Younger Dryas (YD: 12.9-11.5 ka), and several Holocene Bond events when changes in deep-water circulation occurred. The largest collapse is associated with the YD/IACP and is characterized by an abrupt two-step decrease in both the upper North Atlantic Deep Water assemblage and species diversity at 13.1 ka and at 12.2 ka. The ostracode fauna at this site did not fully recover until approximately 8 ka, with the establishment of Labrador Sea Water ventilation. Ecologically opportunistic slope species prospered during this community collapse. Other abrupt community collapses during the past 20 ka generally correspond to millennial climate events. These results indicate that deep-sea ecosystems are not immune to the effects of rapid climate changes occurring over centuries or less.


A randomized trial of Internet-delivered treatment for social anxiety disorder in high school students.
Internet-based cognitive behavior therapy (CBT) has been shown effective for university students with social anxiety disorder (SAD) and public speaking fears. The aim of this study was to investigate whether the promising results can be transferred to high school students suffering from this condition. A total of 19 speech-anxious high school students with SAD were randomized either into 9 weeks of Internet-delivered CBT or to a wait-list control group. Significant improvements were found on measures of social anxiety, general anxiety, and depression. Effects were maintained at 1-year follow-up. The average within- and between-group effect sizes (Cohen's d) for the primary social anxiety scales at posttest were 0.98 and 1.38, respectively. However, the average number of completed modules in the CBT program was low. Although compliance can be improved, the results suggest that Internet-based guided self-help is effective in the treatment of high school students with SAD.


Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells.
Elucidating mechanisms of cell cycle control in normally quiescent human pancreatic β-cells has the potential to impact regeneration strategies for diabetes. Previously we demonstrated that Id3, a repressor of basic Helix-Loop-Helix (bHLH) proteins, was sufficient to induce cell cycle entry in pancreatic duct cells, which are closely related to β-cells developmentally. We hypothesized that Id3 might similarly induce cell cycle entry in primary human β-cells. To test this directly, adult human β-cells were transduced with adenovirus expressing Id3. Consistent with a replicative response, β-cells exhibited BrdU incorporation. Further, Id3 potently repressed expression of the cyclin dependent kinase inhibitor p57 (Kip2 ) , a gene which is also silenced in a rare β-cell hyperproliferative disorder in infants. Surprisingly however, BrdU positive β-cells did not express the proliferation markers Ki67 and pHH3. Instead, BrdU uptake reflected a DNA damage response, as manifested by hydroxyurea incorporation, γH2AX expression, and 53BP1 subcellular relocalization. The uncoupling of BrdU uptake from replication raises a cautionary note about interpreting studies relying solely upon BrdU incorporation as evidence of β-cell proliferation. The data also establish that loss of p57 (Kip2) is not sufficient to induce cell cycle entry in adult β-cells. Moreover, the differential responses to Id3 between duct and β-cells reveal that β-cells possess intrinsic resistance to cell cycle entry not common to all quiescent epithelial cells in the adult human pancreas. The data provide a much needed comparative model for investigating the molecular basis for this resistance in order to develop a strategy for improving replication competence in β-cells.


Oxypnictide SmFeAs(O,F) superconductor: a candidate for high-field magnet applications.
The recently discovered oxypnictide superconductor SmFeAs(O,F) is the most attractive material among the Fe-based superconductors due to its highest transition temperature of 56 K and potential for high-field performance. In order to exploit this new material for superconducting applications, the knowledge and understanding of its electro-magnetic properties are needed. Recent success in fabricating epitaxial SmFeAs(O,F) thin films opens a great opportunity to explore their transport properties. Here we report on a high critical current density of over 10(5) A/cm(2) at 45 T and 4.2 K for both main field orientations, feature favourable for high-field magnet applications. Additionally, by investigating the pinning properties, we observed a dimensional crossover between the superconducting coherence length and the FeAs interlayer distance at 30-40 K, indicative of a possible intrinsic Josephson junction in SmFeAs(O,F) at low temperatures that can be employed in electronics applications such as a terahertz radiation source and a superconducting Qubit.


Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications.
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, studies over the past decades have demonstrated that epigenetic regulation also participates in the development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are a group of enzymes which catalyze the removal of the acetyl groups of both histones and non-histone proteins. HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors are being investigated to act as cancer chemotherapeutics. The primary purpose of this paper is to summarize recent studies of the links between HDACs and cancer, and further discuss the underlying mechanisms of anti-tumor activities of HDAC inhibitors and clinical implications.


Unusual course of congenital hypothyroidism and route of the L-thyroxine treatment in a preterm newborn.
Congenital hypothyroidism (CH) is the most common endocrine pathology in neonates. Inappropriate treatment of CH is complicated by irreversible brain damage or low IQ score. Hormone replacement therapy with L-thyroxine (L-T4) is sufficient for a very large proportion of patients. However, during treatment, the patient needs to be carefully monitored for presence of factors which might affect the absorption or bio-availability of the drug as well as its dose. Herein, we report a preterm newborn with CH who presented with gastrointestinal problems mimicking necrotizing enterocolitis. The clinical course was also complicated by cholestasis. The L-T4 replacement treatment was switched from oral route to parenteral. After resolution of the cholestasis, L-T4 treatment was continued successfully by the oral route.


US cost burden of ischemic stroke: a systematic literature review.
Stroke is an expensive disease from a patient, caregiver, and societal perspective. In spite of the high cost burden, only limited numbers of recent studies have focused on stroke-related costs in the United States. To conduct a systematic literature review to determine current US costs of stroke and to assess if a gap in available information exists. A literature search was conducted using the PubMed/MEDLINE and Ovid/EMBASE databases, within the date range of January 1995 to July 2008. The search, screening, application of eligibility criteria, appraisal, data extraction, and synthesis were completed by one investigator and then independently confirmed by a second. The literature review revealed that the majority of cost-related analyses focused on short-term in-hospital care and early critical care as the key drivers of acute ischemic stroke hospitalization costs. Moreover, long-term medical expenses resulting from nursing home and ambulatory care as well as indirect expenditure from lost earnings and informal care represent the most significant burden on lifetime costs of stroke. Further studies that focus on these long-term and indirect expenditures are essential to assess the impact of new treatments on total stroke costs. Overall, the high costs associated with stroke clearly indicate there is an imperative need for effective preventive therapy, early critical care, and rehabilitation, which in turn will reduce the national expenditure for stroke-related healthcare services and improve productivity.


Approximations to ideal-observer performance on signal-detection tasks.
The ideal-observer performance, as measured by the area under the receiver's operating characteristic curve, is computed for six examples of signal-detection tasks. Exact values for this quantity, as well as approximations based on the signal-to-noise ratio of the log likelihood and the likelihood-generating function, are found. The noise models considered are normal, exponential, Poisson, and two-sided exponential. The signal may affect the mean or the variance in each case. It is found that the approximation from the likelihood-generating function tracks well with the exact area, whereas the log-likelihood signal-to-noise approximation can fail badly. The signal-to-noise ratio of the likelihood ratio itself is also computed for each example to demonstrate that it is not a good measure of ideal-observer performance.


Active mechanics and dynamics of cell spreading on elastic substrates.
The spreading area of cells has been shown to play a central role in the determination of cell fate and tissue morphogenesis; however, a clear understanding of how spread cell area is determined is still lacking. The observation that cell area and force generally increase with substrate rigidity suggests that cell area is dictated mechanically, by means of a force-balance between the cell and the substrate. A simple mechanical model, corroborated by experimental measurements of cell area and force is presented to analyze the temporal force balance between the cell and the substrate during spreading. The cell is modeled as a thin elastic disc that is actively pulled by lamellipodia protrusions at the cell front. The essential molecular mechanisms of the motor activity at the cell front, including, actin polymerization, adhesion kinetics, and the actin retrograde flow, are accounted for and used to predict the dynamics of cell spreading on elastic substrates; simple, closed-form expressions for the evolution of cell size and force are derived. Time-resolved, traction force microscopy, combined with measurements of cell area are performed to investigate the simultaneous variations of cell size and force. We find that cell area and force increase simultaneously during spreading but the force develops with an apparent delay relative to the increase in cell area. We demonstrate that this may reflect the strain-stiffening property of the cytoskeleton. We further demonstrate that the radial cell force is a concave function of spreading speed and that this may reflect the strengthening of cell-substrate adhesions during spreading.


Causes of crises and appropriate interventions: the views of people with dementia, carers and healthcare professionals.
The aims of this study were to identify which factors may lead to crisis for people with dementia and their carers and identify interventions these individuals believe could help in crisis. Qualitative study using focus groups to compare the perspectives of people with dementia, family carers and healthcare professionals on causes of crises and crisis interventions. To help in a crisis, people with dementia were favourable towards support from family and friends, access to mobile phones and home adaptations to reduce risks. Carers were keen on assistive technology and home adaptation. Both carers and staff valued carer training and education, care plans and well-coordinated care. Staff were the only group emphasizing more intensive interventions such as emergency home respite and extended hours services. In terms of causes of crises, people with dementia focused on risks and hazards in their home, whereas family carers emphasized carer stress and their own mental health problems. Staff, in contrast were concerned about problems with service organization and coordination leading to crises. Physical problems were less commonly identified as causes of crises but when they did occur they had a major impact. Practical interventions such as home adaptations, assistive technology, education and training for family carers, and flexible home care services were highly valued by service users and their families during times of crisis and may help prevent hospital admissions. Specialist home care was highly valued by all groups.


Molecular force transfer mechanisms in graphene oxide paper evaluated using atomic force microscopy and in situ synchrotron micro FT-IR spectroscopy.
The mechanical properties of graphene oxide (GO) paper are critically defined both by the mechanical properties of the constituent GO sheets and the interaction between these sheets. Functional carbonyl and carboxyl groups decorating defects, expected to be predominantly sheet edges of the GO, are shown to transfer forces to the in-plane carbon-carbon bonding using a novel technique combining atomic force microscopy (AFM) to mechanically deform discrete volumes of GO materials while synchrotron Fourier-transform infra-red (FTIR) microspectroscopy evaluated molecular level bond deformation mechanisms of the GO. Spectroscopic absorption peaks corresponding to in-plane aromatic C=C bonds from GO sheets were observed to shift during tensile tests. Importantly, FTIR provided information on clear absorption peak shifts from C=O bonds linking along the GO sheet edges, indicating transfer of forces between both C=C and C=O bonds during tensile deformation. Grüneisen parameters were used to quantitatively link the macroscopic FTIR peak shifts to molecular level chemical bond strains, with relatively low bond strains prevalent when applying external forces to the GO paper suggesting probing of hydrogen bonding interactions. We propose a mechanistic description of molecular interactions between GO sheets in the paper from these experiments, which is important in future strategies for further modification and improvement of GO-based materials.


Employee benefits, retirement patterns, and implications for increased work life.
This Issue Brief examines why policymakers are concerned about the trend toward early retirement and how it relates to Social Security, Medicare, and employee health and retirement benefits. It reviews the rationale for the effects of economic incentives on early retirement decisions and includes a summary of empirical literature on the retirement process. It presents data on how employee benefits influence workers' expected retirement patterns. Finally, it examines the implications of public policies to reverse early-retirement trends and raise the eligibility age for Social Security and Medicare. An employee Benefit Research Institute/Gallup survey indicates that there is a direct link between a worker's decision to retire early and the availability of retiree health benefits. In 1993, 61 percent of workers reported that they would not retire before becoming eligible for Medicare if their employer did not provide retiree health benefits. Participation in a pension plan can be an important determinant of retirement. Twenty-one percent of pension plan participants planned to stop working before age 65, compared with 12 percent among nonparticipants. Workers whose primary pension plan was a defined benefit plan were more likely to expect to stop working before age 65 (23 percent) than workers whose primary plan was a defined contribution plan (18 percent). Expected income replacement rates effect retirement patterns, indicating that as the expected replacement increases, the probability of expecting to stop working before age 65 increases. Twenty-two percent of workers with an expected income replacement rate below 60 percent expected to stop working before age 65, compared with 29 percent for those in the 60-69 percent replacement range, and 30 percent for those in the 70-79 percent replacement range. Workers expecting to receive retiree health insurance are more likely to expect to stop working before age 65 than workers who do not expect to have retiree health insurance. Twenty-one percent of workers with retiree health insurance expected to stop working before age 65, compared with 12 percent of workers not expecting to receive retiree health insurance. The Social Security Old-Age and Survivors Insurance (OASI) program depends on obtaining sufficient revenue from active workers' payroll taxes to fund the benefits received by retired beneficiaries. Funding the program in the past was in large part effortless because of the relatively large number of workers per retiree. Today, funding the program is a greater challenge because the ratio of workers to retirees has fallen. Policymakers have been able to agree that reform of the program is necessary for its survival; however, the debate over options to reform the program is just beginning, and it is likely to be a long time before a consensus emerges.


Effect of microstimulation of the superior colliculus on visual space attention.
We investigated the effect of microstimulation of the superficial layers of the superior colliculus (SC) on the performance of animals in a peripheral detection paradigm while maintaining fixation. In a matching-to-sample paradigm, a sample stimulus was presented at one location followed by a brief test stimulus at that (relevant) location and a distractor at another (irrelevant) location. While maintaining fixation, the monkey indicated whether the sample and the test stimulus matched, ignoring the distractor. The relevant and irrelevant locations were switched from trial to trial. Cells in the superficial layers of SC gave enhanced responses when the attended test stimulus was inside the receptive field compared with when the (physically identical) distractor was inside the field. These effects were found only in an "automatic" attentional cueing paradigm, in which a peripheral stimulus explicitly cued the animal as to the relevant location in the receptive field. No attentional effects were found with block of trials. The transient enhancement to the attended stimulus was observed at the onset and not at the offset of the stimulus. Electrical stimulation at the site corresponding to the irrelevant distractor location in the SC causes it to gain control over attention, causing impaired performance of the task at the relevant location. Stimulation at unattended sites without the presence of a distractor stimulus causes little or no impairment in performance. The effect of stimulation decays with successive stimulations. The animals learn to ignore the stimulation unless the parameters of the task are varied.


The influence of friendship and merit on children's resource allocation in three societies.
Recent work has suggested that principles of fairness that seem like natural laws to the Western mind, such as sharing more of the spoils with those who contributed more, can in fact vary significantly across populations. To build a better understanding of the developmental roots of population differences with respect to fairness, we investigated whether 7-year-old children (N = 432) from three cultural backgrounds-Kenya, China, and Germany-consider friendship and merit in their distribution of resources and how they resolve conflicts between the two. We found that friendship had considerable and consistent influence as a cross-culturally recurrent motivation: children in all three cultures preferentially shared with a friend rather than with a neutral familiar peer. On the other hand, the role of merit in distribution seemed to differ cross-culturally: children in China and Germany, but not in Kenya, selectively distributed resources to individuals who worked more. When we pitted friendship against merit, there was an approximately even split in all three cultures between children who favored the undeserving friend and children who shared with the hard-working neutral individual. These results demonstrate commonalities and variability in fairness perceptions across distinct cultures and speak to the importance of cross-cultural research in understanding the development of the human mind.


Honesty-humility in contemporary students: manipulations of self-image by inflated IQ estimations.
The HEXACO model offers a complement to the Big Five model, including a sixth factor, Honesty-Humility, and its four facets (Sincerity, Fairness, Greed-avoidance, and Modesty). The four facets of Honesty-Humility and three indicators of intelligence (one performance-based cognitive ability test, one self-estimated academic potential, and one self-report of previous IQ test results) were assessed in students entering higher education (N = 187). A significant negative correlation was observed between Honesty-Humility and self-reported intelligence (r = -.37), most evident in the Modesty facet. These results may be interpreted as tendencies of exaggeration, using a theoretical frame of psychological image-management, concluding that the Honesty-Humility trait captures students' self-ambitions, particularly within the context of an individualistic, competitive culture such as Sweden.


An association study of polymorphisms in JAK3 gene with lung cancer in the Korean population.
The genetic alteration of the janus kinases (JAKs), non-receptor tyrosine kinase, is related to the development of human cancers. However, little is known about how the sequence variation of JAK3 contributes to the development of lung cancer. This study investigated whether polymorphisms at the promoter region of the JAK3 gene are associated with the risk of lung cancer in the Korean population. A total of 819 subjects, including 409 lung cancer patients and 410 healthy controls were recruited. The SNaPshot assay and polymerase chain reaction-restriction fragment length polymorphism analysis were used, and logistic regression analyses were performed to characterize the association between polymorphisms of JAK3 and lung cancer risk. Three polymorphisms (-672 G>A, +64 A>G and +227 G>A) of JAK3 were analyzed for large-scale genotyping (n=819). Statistical analyses revealed that polymorphisms and haplotypes in the JAK3 gene were not significantly associated with lung cancer. JAK3 gene was not significantly associated with the risk of lung cancer in the Korean population.


Confusion and inconsistency in diagnosis of Asperger syndrome: a review of studies from 1981 to 2010.
This paper presents a review of past and current research on the diagnosis of Asperger syndrome (AS) in children. It is suggested that the widely used criteria for diagnosing AS in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV are insufficient and invalid for a reliable diagnosis of AS. In addition, when these diagnostic criteria are applied, there is the potential bias of receiving a diagnosis towards the high-functioning end of the autism spectrum. Through a critical review of 69 research studies carried out between 1981 and 2010, this paper shows that six possible criteria for diagnosing AS (specifically, the age at which signs and symptoms related to autism become apparent, language and social communication abilities, intellectual abilities, motor or movement skills, repetitive patterns of behaviour and the nature of social interaction) overlap with the criteria for diagnosing autism. However, there is a possibility that some finer differences exist in the nature of social interaction, motor skills and speech patterns between groups with a diagnosis of AS and autism. These findings are proposed to be of relevance for designing intervention studies aimed at the treatment of specific symptoms in people with an autism spectrum disorder.


Impact of postoperative pancreatic fistula on surgical outcome--the need for a classification-driven risk management.
The International Study Group of Pancreatic Fistula (ISGPF) classification allows comparison of incidence and severity of postoperative pancreatic fistula (POPF). Its post hoc character, however, does not provide a guideline for the treatment of POPF in individual patient. We therefore studied the association of POPF type A-C on secondary surgical morbidity and mortality in patients undergoing pancreatic resection. Between 3/2001-12/2007, 483 patients underwent pancreatic resections. POPF were classified according to the ISGPF classification. All patient data were entered in a clinical data management system prospectively. Patients who developed POPF had significantly more vascular but not other surgical complications than patients without POPF. Patients with POPF A had no vascular or surgical complications. Twenty one of the 29 patients with POPF C had surgical complications (17 vascular complications). Mortality attributed to surgical complications after POPF C was 5/29. A soft pancreatic consistency (OR 8.5; p < 0.008) and a high drain lipase activity on postoperative day 3 (OR 4.4; p = 0,065) were predictors for the development of POPF C. POPF C is associated with vascular complications like erosion bleeding and other surgical complications like delayed gastric emptying or pleural effusions. A soft pancreatic consistency and a high drain lipase activity on postoperative day 3 are early predictors for the development of POPF C.


The Canadian general internist: education and future role.
Available manpower data indicate that for the forseeable future there will be a continuing requirement in Canada for specialists in general internal medicine. While these specialists will be located predominantly in community hospitals, they will also be needed in university medical centres. The major roles of the general internist will be (a) to provide consultative service to primary care physicians and to other specialists, (b) to provide continuing care to patients with complex serious illness and (c) to participate in intensive care, particularly in community hospitals. Therefore training programs in this specialty must provide adequate experience in consultative medicine in both university and community hospitals, an opportunity to follow up patients with chronic serious illness over long periods, and experience in a variety of intensive care settings including surgical intensive care units. In some university departments the organization and supervision of training programs in this discipline have been carried out by a division of internal medicine that has equal status with other specialty divisions within the department. This seems to have been a salutory development.


Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma.
Recently, S-1, a novel 5-fluorouracil (5-FU)-based agent containing the strong dihydropyrimidine dehydrogenase (DPD) inhibitor, 5-chloro-2,4-dihydropyrimidine (CDHP) has been clinically used to treat various non-urothelial carcinomas (UC). High levels of thymidylate synthase (TS), the target enzyme of 5-FU and DPD which degrades the majority of 5-FU, are associated with poor prognosis in some cancers. However, only a few reports have dealt with this in UC. The aim of this study was to investigate the clinical significance of TS and DPD in upper tract urothelial carcinoma (UTUC) and evaluate the role of TS and DPD on the sensitivity of 5-FU in UC cell lines and the anti-tumor effect of S-1 in UC xenograft model. Firstly, we evaluated the immunohistochemical expression of TS and DPD in 176 patients with UTUC to determine their prognostic significance. Secondly, the levels of TS and DPD in UC cell lines were measured by ELISA and real-time PCR. Furthermore, the association between their levels and the sensitivity to 5-FU was examined using the small interfering RNA (siRNA) specific for TS and DPD. Thirdly, the anti-tumor effect of S-1 was evaluated in UC xenograft model. Immunohistochemical evaluation of TS and DPD in UTUC human samples revealed that TS expression was significantly associated with stage, grade, and lymphovascular invasion and DPD expression was significantly associated with grade. Multivariate analysis revealed that high TS expression was an independent predictor of disease-specific survival in them. In in vitro study using UC cell lines, high levels of TS and DPD were associated with low response to 5-FU and these associations were confirmed with siRNA specific for TS and DPD. In in vivo study using UC xenograft model, S-1 treatment dramatically inhibited tumor growth compared to controls, tegafur, or UFT in UC tumor with a high level of DPD. TS plays an important role in the prognosis of UTUC and S-1 may be a key agent for UC tumor, especially with a high level of DPD.


Effect of hydroxyurea on physical fitness indices in children with sickle cell anemia.
The current studies aimed at determining physical fitness indices and anthropometrics profiles of children with sickle cell anemia (SCA) after the use of hydroxyurea (HU). Ninety-three male schoolchildren--who participated previously in a similar study before the introduction of HU--comprising 2 groups participated in the studies. Group 1 was 41 children who were suffering from sickle cell disease (SCD) and were on HU for a minimum of 2 years, whereas group 2 was 50 normal healthy controls. Anthropometrics measurement and parameters of physical fitness were assessed in all subjects. All children were also subjected to a minimum of 6-minute running exercise test on a flat motorized treadmill at speed corresponding to 5 km/h. Throughout the test heart rate was monitored and recorded during exercise and for 10 minutes during recovery. Blood hemoglobin (Hb) and HbF% were measured after the use of HU. The mean values of weight, height, and lean body mass were still lower in the SCD children (P < .05) compared with the healthy subjects. However, they had significant decrease in the mean heart rate values and they spent longer time on the treadmill before they got tired compared to their previous performance and were just below the normal controls. Hydroxyurea treatment improved the aerobic exercise tolerance and most of the physical fitness parameters in children with SCD.


Transcriptional components of anteroposterior positional information during zebrafish fin regeneration.
Many fish and salamander species regenerate amputated fins or limbs, restoring the size and shape of the original appendage. Regeneration requires that spared cells retain or recall information encoding pattern, a phenomenon termed positional memory. Few factors have been implicated in positional memory during vertebrate appendage regeneration. Here, we investigated potential regulators of anteroposterior (AP) pattern during fin regeneration in adult zebrafish. Sequence-based profiling from tissues along the AP axis of uninjured pectoral fins identified many genes with region-specific expression, several of which encoded transcription factors with known AP-specific expression or function in developing embryonic pectoral appendages. Transgenic reporter strains revealed that regulatory sequences of the transcription factor gene alx4a activated expression in fibroblasts and osteoblasts within anterior fin rays, whereas hand2 regulatory sequences activated expression in these same cell types within posterior rays. Transgenic overexpression of hand2 in all pectoral fin rays did not affect formation of the proliferative regeneration blastema, yet modified the lengths and widths of regenerating bones. Hand2 influenced the character of regenerated rays in part by elevation of the vitamin D-inactivating enzyme encoded by cyp24a1, contributing to region-specific regulation of bone metabolism. Systemic administration of vitamin D during regeneration partially rescued bone defects resulting from hand2 overexpression. Thus, bone-forming cells in a regenerating appendage maintain expression throughout life of transcription factor genes that can influence AP pattern, and differ across the AP axis in their expression signatures of these and other genes. These findings have implications for mechanisms of positional memory in vertebrate tissues.


Thinking small: research designs appropriate for clinical practice.
Even though some treatments have been shown to be efficacious in clinical trials, there is no guarantee that they are effective with a specific patient. This article outlines some of the methods clinicians can use to evaluate the effectiveness of therapy with individual patients. These methods include 1) the before-after design, 2) the reversal design, 3) interrupted time series, and 4) multiple baselines. This paper recommends that patients who are being treated, whether privately or in hospital, be seen as experiments with a sample size of 1 and that their progress be monitored using 1 of these methods.


Current status of pharmacogenomics testing for anti-tumor drug therapies: approaches to non-melanoma skin cancer.
Skin cancer is one of the most commonly occurring cancer types, with substantial social, physical, and financial burdens on both individuals and societies. Although the role of UV light in initiating skin cancer development has been well characterized, genetic studies continue to show that predisposing factors can influence an individual's susceptibility to skin cancer and response to treatment. In the future, it is hoped that genetic profiles, comprising a number of genetic markers collectively involved in skin cancer susceptibility and response to treatment or prognosis, will aid in more accurately informing practitioners' choices of treatment. Individualized treatment based on these profiles has the potential to increase the efficacy of treatments, saving both time and money for the patient by avoiding the need for extensive or repeated treatment. Increased treatment responses may in turn prevent recurrence of skin cancers, reducing the burden of this disease on society. Currently existing pharmacogenomic tests, such as those that assess variation in the metabolism of the anticancer drug fluorouracil, have the potential to reduce the toxic effects of anti-tumor drugs used in the treatment of non-melanoma skin cancer (NMSC) by determining individualized appropriate dosage. If the savings generated by reducing adverse events negate the costs of developing these tests, pharmacogenomic testing may increasingly inform personalized NMSC treatment.


Health resort medicine in non-musculoskeletal disorders: is there evidence of its effectiveness?
Health resort medicine (HRM; in German: Kurortmedizin) is a field of medicine with long-lasting tradition in several European countries. A number of systematic reviews have shown the effectiveness of HRM in musculoskeletal conditions. Reviews focusing on the effectiveness of HRM in non-musculoskeletal disorders are rare. This systematic review aims to provide an overview about all types of health resort treatments applied in non-musculoskeletal conditions, to summarize evidence for its effectiveness and to assess the quality of published studies. MEDLINE, Web of Knowledge and Embase were searched for articles published between January 2002 and December 2013. We used a broad search strategy in order to find studies investigating the effects of HRM in non-musculoskeletal disorders. Two authors independently extracted data and assessed quality using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies (EPHPP-QAT). Forty-one studies (19 of them with control group) from eight countries examining the efficacy of various forms of spa treatment for 12 disease groups were included. The studies are markedly heterogeneous regarding study design, population and treatment. HRM treatment is associated with clinical improvement in diseases of the skin, respiratory, circulatory, digestive and nervous system among others. However, small samples, the lack of control groups and an insufficient follow-up often limit the generated evidence. The scientific literature of the last decade has shown that a number of non-musculoskeletal disorders are treated with different kinds of HRM. The challenge for the future will be to carry out thoroughly designed studies in larger patient populations to corroborate the impact of HRM treatment on non-musculoskeletal disorders.


The effect of two different electronic health record user interfaces on intensive care provider task load, errors of cognition, and performance.
The care of critically ill patients generates large quantities of data. Increasingly, these data are presented to the provider within an electronic medical record. The manner in which data are organized and presented can impact on the ability of users to synthesis that data into meaningful information. The objective of this study was to test the hypothesis that novel user interfaces, which prioritize the display of high-value data to providers within system-based packages, reduce task load, and result in fewer errors of cognition compared with established user interfaces that do not. Randomized crossover study. Academic tertiary referral center. Attending, resident and fellow critical care physicians. Novel health care record user interface. Subjects randomly assigned to either a standard electronic medical record or a novel user interface, were asked to perform a structured task. The task required the subjects to use the assigned electronic environment to review the medical record of an intensive care unit patient said to be actively bleeding for data that formed the basis of answers to clinical questions posed in the form of a structured questionnaire. The primary outcome was task load, measured using the paper version of the NASA-task load index. Secondary outcome measures included time to task completion, number of errors of cognition measured by comparison of subject to post hoc gold standard questionnaire responses, and the quantity of information presented to subjects by each environment. Twenty subjects completed the task on eight patients, resulting in 160 patient-provider encounters (80 in each group). The standard electronic medical record contained a much larger data volume with a median (interquartile range) number of data points per patient of 1008 (895-1183) compared with 102 (77-112) contained within the novel user interface. The median (interquartile range) NASA-task load index values were 38.8 (32-45) and 58 (45-65) for the novel user interface compared with the standard electronic medical record (p < .001). The median (interquartile range) times in seconds taken to complete the task for four consecutive patients were 93 (57-132), 60 (48-71), 68 (48-80), and 54 (42-64) for the novel user interface compared with 145 (109-201), 125 (113-162), 129 (100-145), and 112 (92-123) for the standard interface (p < .0001), respectively. The median (interquartile range) number of errors per provider was 0.5 (0-1) and two (0.25-3) for the novel user interface and standard electronic medical record interface, respectively (p = .007). A novel user interface was designed based on the information needs of intensive care unit providers with a specific goal of development being the reduction of task load and errors of cognition associated with filtering, extracting, and using medical data contained within a comprehensive electronic medical record. The results of this simulated clinical experiment suggest that the configuration of the intensive care unit user interface contributes significantly to the task load, time to task completion, and number of errors of cognition associated with the identification, and subsequent use, of relevant patient data. Task-specific user interfaces, developed from an understanding of provider information requirements, offer advantages over interfaces currently available within a standard electronic medical record.


The onset of turbulence in pipe flow.
Shear flows undergo a sudden transition from laminar to turbulent motion as the velocity increases, and the onset of turbulence radically changes transport efficiency and mixing properties. Even for the well-studied case of pipe flow, it has not been possible to determine at what Reynolds number the motion will be either persistently turbulent or ultimately laminar. We show that in pipes, turbulence that is transient at low Reynolds numbers becomes sustained at a distinct critical point. Through extensive experiments and computer simulations, we were able to identify and characterize the processes ultimately responsible for sustaining turbulence. In contrast to the classical Landau-Ruelle-Takens view that turbulence arises from an increase in the temporal complexity of fluid motion, here, spatial proliferation of chaotic domains is the decisive process and intrinsic to the nature of fluid turbulence.


The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma.
Colony-stimulating factor 1 (CSF-1) is a homodimeric growth factor that humorally regulates the growth and differentiation of mononuclear phagocytes, and locally regulates maternal-fetal interactions during pregnancy. It exerts these actions through a transmembrane tyrosine kinase receptor, colony-stimulating factor 1 receptor (CSF-1R), the product of the c-fms proto-oncogene. Recent studies have demonstrated overexpression of CSF-1 and its receptor in breast, ovarian, and endometrial adenocarcinomas. To further investigate the possible role of CSF-1 and its receptor in the pathogenesis of endometrial adenocarcinoma, a prospective study was undertaken to study CSF-1 expression in benign and neoplastic endometrial epithelium and to compare serum CSF-1 levels in endometrial adenocarcinoma patients with healthy perimenopausal women. The mean serum levels of CSF-1 in 71 patients with endometrial cancer (4.9 +/- 1.8 microgram/liter) were significantly elevated compared with levels found in the 32 controls (3.5 +/- 1.1 microgram/liter). Within the endometrial adenocarcinoma group, circulating CSF-1 levels were significantly elevated in patients with large tumor volume, high grade, myometrial invasion, residual disease, and circulating CA-125 levels. High serum levels of serum CSF-1 were associated with elevated serum CA19-9 and CA-125 levels. Immunohistochemistry results revealed in tumor epithelium intense staining for CSF-1R (27 of 54 cases, 50%) and elevated staining for CSF-1 (41 of 54 cases, 75.9%), with intense staining of CSF-1 in 16 of 54 cases (29.6%). Staining was significantly greater in intensity and number of cells involved in malignant compared with benign epithelium for CSF-1R and CSF-1 (P = 0.05 and <0.0001, respectively). A positive correlation between amount and intensity of CSF-1 and CSF-1R staining in endometrial adenocarcinoma tissue was also demonstrated (P = 0.007). CSF-1 and CSF-1R mRNA was also detected in the tumor samples, confirming the expression of the protein in these tissues. Reverse transcription-PCR demonstrated the presence of mRNA for both the transmembrane and secreted forms of CSF-1 in all tumors analyzed. These results therefore support the hypotheses that CSF-1 and CSF-1R are overexpressed in endometrial adenocarcinoma, that levels of expression significantly correlate with clinicopathological risk factors for poor outcome, and that CSF-1 in association with its receptor via autocrine, juxtacrine, and/or paracrine interactions has a causal role in endometrial adenocarcinoma development and proliferation.


Speaking out of turn: a role for silent synapses in pain.
Severe tissue or nerve injury can result in a chronic and inappropriate sensation of pain, mediated in part by the sensitization of spinal dorsal horn neurons to input from primary afferent fibers. Synaptic transmission at primary afferent synapses is mainly glutamatergic. Although a functioning excitatory synapse contains both alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the postsynaptic membrane, recent evidence suggests that dorsal horn neurons contain some "silent" synapses, which exhibit purely NMDA receptor-mediated evoked postsynaptic currents and do not conduct signals at resting membrane potential. Serotonin, which is released onto dorsal horn neurons by descending fibers from the rostroventral medulla, potentiates sensory transmission by activating silent synapses on those neurons, i.e., by recruiting functional AMPA receptors to the postsynaptic membrane. This phenomenon may contribute to the hyperexcitability of dorsal horn neurons seen in chronic pain conditions.


Low current and nadir CD4+ T-cell counts are associated with higher hepatitis C virus RNA levels in the Swiss HIV cohort study.
The aim of this study was to evaluate the effect of CD4+ T-cell counts and other characteristics of HIV-infected individuals on hepatitis C virus (HCV) RNA levels. All HIV-HCV-coinfected Swiss HIV Cohort Study participants with available HCV RNA levels and concurrent CD4+ T-cell counts before starting HCV therapy were included. Potential predictors of HCV RNA levels were assessed by multivariate censored linear regression models that adjust for censored values. The study included 1,031 individuals. Low current and nadir CD4+ T-cell counts were significantly associated with higher HCV RNA levels (P = 0.004 and 0.001, respectively). In individuals with current CD4+ T-cell counts < 200/microl, median HCV RNA levels (6.22 log10 IU/ml) were +0.14 and +0.24 log10 IU/ml higher than those with CD4+ T-cell counts of 200-500/microl and > 500/microl. Based on nadir CD4+ T-cell counts, median HCV RNA levels (6.12 log10 IU/ml) in individuals with < 200/microl CD4+ T-cells were +0.06 and +0.44 log10 IU/ml higher than those with nadir T-cell counts of 200-500/microl and > 500/microl. Median HCV RNA levels were also significantly associated with HCV genotype: lower values were associated with genotype 4 and higher values with genotype 2, as compared with genotype 1. Additional significant predictors of lower HCV RNA levels were female gender and HIV transmission through male homosexual contacts. In multivariate analyses, only CD4+ T-cell counts and HCV genotype remained significant predictors of HCV RNA levels. Higher HCV RNA levels were associated with CD4+ T-cell depletion. This finding is in line with the crucial role of CD4+ T-cells in the control of HCV infection.


Youth Perspectives on the Mental Health Treatment Process: What Helps, What Hinders?
In this study we explored adolescent perceptions of what was most helpful and most challenging about mental health treatment for mood and/or anxiety disorders. Youth seeking treatment at the First Episode Mood and Anxiety Program were recruited to participate in a follow-up survey about their experiences of mental health care services. Responses to two open-ended questions were analyzed for emerging themes and differences between age groups and gender. Males were more likely to report therapy as being helpful than females, 16-18 year olds were more likely to report medication as a challenge to treatment and 19-26 year olds were more likely to report accessing services as a challenge to treatment. Understanding what helps and what hinders treatment-seeking youth can guide both clinical treatment and service delivery models for this population.


Positional information, positional error, and readout precision in morphogenesis: a mathematical framework.
The concept of positional information is central to our understanding of how cells determine their location in a multicellular structure and thereby their developmental fates. Nevertheless, positional information has neither been defined mathematically nor quantified in a principled way. Here we provide an information-theoretic definition in the context of developmental gene expression patterns and examine the features of expression patterns that affect positional information quantitatively. We connect positional information with the concept of positional error and develop tools to directly measure information and error from experimental data. We illustrate our framework for the case of gap gene expression patterns in the early Drosophila embryo and show how information that is distributed among only four genes is sufficient to determine developmental fates with nearly single-cell resolution. Our approach can be generalized to a variety of different model systems; procedures and examples are discussed in detail.


The use of static stretching in warm-up for training and competition.
Static stretching (SS) is widely used in warm-ups before training and competition. A growing amount of research, however, has demonstrated that SS can impair muscle performance, leading to a reevaluation of optimal warm-up protocols. This commentary discusses many of the methodological issues that can influence conclusions about the acute effects of SS on performance. One difficulty in interpreting the literature is the lack of control or communication about the volume and intensity of the various stretching treatments used. Another major issue is the failure of many researchers to evaluate SS as it is used in practice, particularly the interaction with the other general and sport-specific components of the warm-up. Acute warm-up effects on performance should be considered in conjunction with potential effects on injury prevention. Future directions in research include optimizing general and sport-specific warm-ups, time course of physiological and performance effects, and individualization of warm-ups according to fitness and skill level.


Haemodynamic response to endotracheal intubation in coronary artery disease: Direct versus video laryngoscopy.
Endotracheal intubation involving conventional laryngoscopy elicits a haemodynamic response associated with increased heart and blood pressure. The study was aimed to see if video laryngoscopy and endotracheal intubation has any advantages over conventional laryngoscopy and endotracheal intubation in patients with coronary artery disease. Thirty patients suffering from coronary artery disease scheduled for elective coronary artery bypass grafting (CABG) were studied. The patients were randomly allocated to undergo either conventional laryngoscopy (group A) or video laryngoscopy (group B). The time taken to perform endotracheal intubation and haemodynamic changes associated with intubation were noted in both the groups at different time points. The duration of laryngoscopy and intubation was significantly longer in group B (video laryngoscopy) when compared to group A patients. However, haemodynamic changes were no different between the groups. There were no events of myocardial ischaemia as monitored by surface electrocardiography during the study period in either of the groups. In conclusion, video laryngoscopy did not provide any benefit in terms of haemodynamic response to laryngoscopy and intubation in patients undergoing primary CABG with a Mallampatti grade of <2.


Soil microbial species loss affects plant biomass and survival of an introduced bacterial strain, but not inducible plant defences.
Plant growth-promoting rhizobacteria (PGPR) strains can influence plant-insect interactions. However, little is known about the effect of changes in the soil bacterial community in general and especially the loss of rare soil microbes on these interactions. Here, the influence of rare soil microbe reduction on induced systemic resistance (ISR) in a wild ecotype of Arabidopsis thaliana against the aphid Myzus persicae was investigated. To create a gradient of microbial abundances, soil was inoculated with a serial dilution of a microbial community and responses of Arabidopsis plants that originated from the same site as the soil microbes were tested. Plant biomass, transcription of genes involved in plant defences, and insect performance were measured. In addition, the effects of the PGPR strain Pseudomonas fluorescens SS101 on plant and insect performance were tested under the influence of the various soil dilution treatments. Plant biomass showed a hump-shaped relationship with soil microbial community dilution, independent of aphid or Pseudomonas treatments. Both aphid infestation and inoculation with Pseudomonas reduced plant biomass, and led to downregulation of PR1 (salicylic acid-responsive gene) and CYP79B3 (involved in synthesis of glucosinolates). Aphid performance and gene transcription were unaffected by soil dilution. Neither the loss of rare microbial species, as caused by soil dilution, nor Pseudomonas affect the resistance of A. thaliana against M. persicae. However, both Pseudomonas survival and plant biomass respond to rare species loss. Thus, loss of rare soil microbial species can have a significant impact on both above- and below-ground organisms.


The N-glycosidase activity of the ribosome-inactivating protein ME1 targets single-stranded regions of nucleic acids independent of sequence or structural motifs.
ME(1), a type I ribosome-inactivating protein (RIP), belongs to a family of enzymes long believed to possess rRNA N-glycosidase activity directed solely at the universally conserved residue A4324 in the sarcin/ricin loop of large eukaryotic and prokaryotic rRNAs. We have investigated the effect of modifying the structure of nonribosomal RNA substrates on their interaction with ME(1) and other RIPs. ME(1) was shown to depurinate a variety of partially denatured nucleic acids, randomly removing adenine residues from single-stranded regions and, to a lesser extent, guanine residues from wobble base-pairs in hairpin stems. A defined sequence motif was not required for recognition of non-paired adenosines and cleavage of the N-glycosidic bond. Substrate recognition and ME(1) activity appeared to depend on the physical availability of nucleotides, and denaturation of nucleic acid substrates increased their interaction with ME(1). Pretreatment of mRNA at 75 degrees C rather than 60 degrees C, for example, lowered the apparent K(D) from 87.1 to 73.9 nm, making it more vulnerable to depurination by RIPs. Exposure to ME(1) in vitro completely abolished the infectivity of partially denatured RNA transcripts of the potato spindle tuber viroid, suggesting that RIPs may target invading nucleic acids before they reach host ribosomes in vivo. Our data suggest that the extensive folding of many potential substrates interferes with their ability to interact with RIPs, thereby blocking their inactivation by ME(1) (or other RIPs).


Development of a fully automated, web-based, tailored intervention promoting regular physical activity among insufficiently active adults with type 2 diabetes: integrating the I-change model, self-determination theory, and motivational interviewing components.
Type 2 diabetes is a major challenge for Canadian public health authorities, and regular physical activity is a key factor in the management of this disease. Given that fewer than half of people with type 2 diabetes in Canada are sufficiently active to meet the recommendations, effective programs targeting the adoption of regular physical activity (PA) are in demand for this population. Many researchers argue that Web-based, tailored interventions targeting PA are a promising and effective avenue for sedentary populations like Canadians with type 2 diabetes, but few have described the detailed development of this kind of intervention. This paper aims to describe the systematic development of the Web-based, tailored intervention, Diabète en Forme, promoting regular aerobic PA among adult Canadian francophones with type 2 diabetes. This paper can be used as a reference for health professionals interested in developing similar interventions. We also explored the integration of theoretical components derived from the I-Change Model, Self-Determination Theory, and Motivational Interviewing, which is a potential path for enhancing the effectiveness of tailored interventions on PA adoption and maintenance. The intervention development was based on the program-planning model for tailored interventions of Kreuter et al. An additional step was added to the model to evaluate the intervention's usability prior to the implementation phase. An 8-week intervention was developed. The key components of the intervention include a self-monitoring tool for PA behavior, a weekly action planning tool, and eight tailored motivational sessions based on attitude, self-efficacy, intention, type of motivation, PA behavior, and other constructs and techniques. Usability evaluation, a step added to the program-planning model, helped to make several improvements to the intervention prior to the implementation phase. The intervention development cost was about CDN $59,700 and took approximately 54 full-time weeks. The intervention officially started on September 29, 2014. Out of 2300 potential participants targeted for the tailored intervention, approximately 530 people visited the website, 170 people completed the registration process, and 83 corresponded to the selection criteria and were enrolled in the intervention. Usability evaluation is an essential step in the development of a Web-based tailored intervention in order to make pre-implementation improvements. The effectiveness and relevance of the theoretical framework used for the intervention will be analyzed following the process and impact evaluation. Implications for future research are discussed.


Clinical aspects of myasthenia explained.
Myasthenia gravis and myasthenic syndromes are diseases of the neuromuscular junction. Autoantibodies and toxins to or mutations in one of the synaptic proteins are the main causes of dysfunction. Myasthenic phenotypes can be classified according to the basic aetiological mechanisms or divided depending on the clinical phenotype.


Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia.
It is not possible to identify all pregnancies at risk of neonatal hypoxic-ischemic encephalopathy (HIE). Many women use some form of analgesia during childbirth and some anesthetic agents have been shown to be neuroprotective when used as analgesics at subanesthetic concentrations. In this study we sought to understand the effects of two anesthetic agents with presumptive analgesic activity and known preconditioning-neuroprotective properties (sevoflurane or xenon), in reducing hypoxia-induced brain damage in a model of intrauterine perinatal asphyxia. The analgesic and neuroprotective effects at subanesthetic levels of sevoflurane (0.35%) or xenon (35%) were tested in a rat model of intrauterine perinatal asphyxia. Analgesic effects were measured by assessing maternal behavior and spinal cord dorsal horn neuronal activation using c-Fos. In separate experiments, intrauterine fetal asphyxia was induced four hours after gas exposure; on post-insult day 3 apoptotic cell death was measured by caspase-3 immunostaining in hippocampal neurons and correlated with the number of viable neurons on postnatal day (PND) 7. A separate cohort of pups was nurtured by a surrogate mother for 50 days when cognitive testing with Morris water maze was performed. Both anesthetic agents provided analgesia as reflected by a reduction in the number of stretching movements and decreased c-Fos expression in the dorsal horn of the spinal cord. Both agents also reduced the number of caspase-3 positive (apoptotic) neurons and increased cell viability in the hippocampus at PND7. These acute histological changes were mirrored by improved cognitive function measured remotely after birth on PND 50 compared to control group. Subanesthetic doses of sevoflurane or xenon provided both analgesia and neuroprotection in this model of intrauterine perinatal asphyxia. These data suggest that anesthetic agents with neuroprotective properties may be effective in preventing HIE and should be tested in clinical trials in the future.


Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts.
Following the recent demonstration of increased mitochondrial DNA mutations in lymphocytes of POAG patients, the authors sought to characterize mitochondrial function in a separate cohort of POAG. Using similar methodology to that previous applied to Leber's hereditary optic neuropathy (LHON) patients, maximal adenosine triphosphate (ATP) synthesis and cellular respiration rates, as well as cell growth rates in glucose and galactose media, were assessed in transformed lymphocytes from POAG patients (n = 15) and a group of age- and sex-matched controls (n = 15). POAG lymphoblasts had significantly lower rates of complex-I-driven ATP synthesis, with preserved complex-II-driven ATP synthesis. Complex-I driven maximal respiration was also significantly decreased in patient cells. Growth in galactose media, where cells are forced to rely on mitochondrial ATP production, revealed no significant differences between the control and POAG cohort. POAG lymphoblasts in the study cohort exhibited a defect in complex-I of the oxidative phosphorylation pathway, leading to decreased rates of respiration and ATP production. Studies in LHON and other diseases have established that lymphocyte oxidative phosphorylation measurement is a reliable indicator of systemic dysfunction of this pathway. While these defects did not impact lymphoblast growth when the cells were forced to rely on oxidative ATP supply, the authors suggest that in the presence of a multitude of cellular stressors as seen in the early stages of POAG, these defects may lead to a bioenergetic crisis in retinal ganglion cells and an increased susceptibility to cell death.


Clinical practice and the UK Human Rights Act 1998: protecting individual rights in the interest of the wider community.
Health professionals have expressed concern that the UK Human Rights Act 1988, which came into force in 2000, may threaten their autonomy in clinical practice/decision-making and resource allocation by health authorities. Although healthcare-related cases have so far been slow to emerge under the Act, it seems clear that in clinical practice the transition from duty to legal obligation will involve a degree of change for health professionals, in attitude if not in behaviour. With regard to resource allocation, it appears that the UK courts are likely to consider challenges to health authorities' decisions in a way that takes into account the need to set priorities, so long as these decisions do not discriminate unfairly and can be shown to have been made in the best interest of the wider community.


Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors.
The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively.


FCSS: Fully Convolutional Self-Similarity for Dense Semantic Correspondence.
We present a descriptor, called fully convolutional self-similarity (FCSS), for dense semantic correspondence. Unlike traditional dense correspondence approaches for estimating depth or optical flow, semantic correspondence estimation poses additional challenges due to intra-class appearance and shape variations among different instances within the same object or scene category. To robustly match points across semantically similar images, we formulate FCSS using local self-similarity (LSS), which is inherently insensitive to intra-class appearance variations. LSS is incorporated through a proposed convolutional self-similarity (CSS) layer, where the sampling patterns and the self-similarity measure are jointly learned in an end-to-end and multi-scale manner. Furthermore, to address shape variations among different object instances, we propose a convolutional affine transformer (CAT) layer that estimates explicit affine transformation fields at each pixel to transform the sampling patterns and corresponding receptive fields. As training data for semantic correspondence is rather limited, we propose to leverage object candidate priors provided in most existing datasets and also correspondence consistency between object pairs to enable weakly-supervised learning. Experiments demonstrate that FCSS significantly outperforms conventional handcrafted descriptors and CNN-based descriptors on various benchmarks.


Variation in very preterm extrauterine growth in a European multicountry cohort.
Extrauterine growth restriction (EUGR) among very preterm infants is related to poor neurodevelopment, but lack of consensus on EUGR measurement constrains international research. Our aim was to compare EUGR prevalence in a European very preterm cohort using commonly used measures. Population-based observational study. 19 regions in 11 European countries. 6792 very preterm infants born before 32 weeks' gestational age (GA) surviving to discharge. We investigated two measures based on discharge-weight percentiles with (1) Fenton and (2) Intergrowth (IG) charts and two based on growth velocity (1) birth weight and discharge-weight Z-score differences using Fenton charts and (2) weight-gain velocity using Patel's model. We estimated country-level relative risks of EUGR adjusting for maternal and neonatal characteristics and associations with population differences in healthy newborn size, measured by mean national birth weight at 40 weeks' GA. About twofold differences in EUGR prevalence were observed between countries for all indicators and these persisted after case-mix adjustment. Discharge weight <10th percentile using Fenton charts varied from 24% (Sweden) to 60% (Portugal) and using IG from 13% (Sweden) to 43% (Portugal), while low weight-gain velocity ranged from 35% (Germany) to 62% (UK). Mean term birth weight strongly correlated with both percentile-based measures (Spearman's rho=-0.90 Fenton, -0.84 IG, p<0.01), but not Patel's weight-gain velocity (rho: -0.38, p=0.25). Very preterm infants have a high prevalence of EUGR, with wide variations between countries in Europe. Variability associated with mean term birth weight when using common postnatal growth charts complicates international benchmarking.


Phase conjugate self-organized coherent beam combination: a passive technique for laser power scaling.
In this Letter, a first (to our knowledge) demonstration of phase conjugate self-organized coherent beam combination is reported. A demonstration involving combination of two self-adaptive gain grating holographic laser resonators is presented. Output powers of up to 27 W, with a combination efficiency of 94%, are demonstrated. This technique coherently combines individual phase conjugate laser modules, which do not have predefined spectral or spatial modes. This removes the problem of finding shared resonator modes, which should allow coherent beam combination of much larger laser arrays than standard self-organized coherent beam combination.


Digital screen use for a road safety campaign message was not associated with road safety awareness of passers-by: A quasi-experimental study.
Recent evidence suggests fatality risks for cyclists may be increasing in Britain. Understanding how to increase levels of cycling while keeping risk low is paramount. Educating drivers about cyclists may help with road safety, and mass-media messaging is a possible avenue, potentially utilizing digital displays screens in public areas. However, no studies have examined the use of these screens for road safety campaigns. A quasi-experiment was conducted to examine if digital screens may be effective to raise awareness of a campaign message and encourage recall of car drivers. A digital campaign image was selected that encouraged car drivers and cyclists to 'look out for each other,' and stated than 80% of cyclists owned a driving license. Views and knowledge on driver priorities around cyclists were examined before (control) and after campaign exposure (intervention), and tested using regression modelling. 364 people were interviewed over five days. Those interviewed on intervention days were more likely to rank 'Look out for cyclists' as being more important compared to those interviewed on control days (OR 1.20), but this was not statistically significant (p = 0.355). Those who said they had seen the image did not rank 'Look out for cyclists' higher than those who said they had not seen it (p = 0.778). The disparity between reported and displayed percentage of cyclists with a driving license did not differ between intervention and control days, but was 8% higher amongst those who claimed to have seen the image (p = 0.026). We did not find strong evidence that use of an image on digital screens increased public awareness or recall of a casualty reduction campaign message. Work is needed to investigate the effects of longer-term exposure to road safety images. Practical Applications: Short-term use of digital signage is not recommended for raising awareness of road safety campaigns.


The genetic architecture of domestication in the chicken: effects of pleiotropy and linkage.
The extent of pleiotropy and epistasis in quantitative traits remains equivocal. In the case of pleiotropy, multiple quantitative trait loci are often taken to be pleiotropic if their confidence intervals overlap, without formal statistical tests being used to ascertain if these overlapping loci are statistically significantly pleiotropic. Additionally, the degree to which the genetic correlations between phenotypic traits are reflected in these pleiotropic quantitative trait loci is often variable, especially in the case of antagonistic pleiotropy. Similarly, the extent of epistasis in various morphological, behavioural and life-history traits is also debated, with a general problem being the sample sizes required to detect such effects. Domestication involves a large number of trade-offs, which are reflected in numerous behavioural, morphological and life-history traits which have evolved as a consequence of adaptation to selective pressures exerted by humans and captivity. The comparison between wild and domestic animals allows the genetic analysis of the traits that differ between these population types, as well as being a general model of evolution. Using a large F(2) intercross between wild and domesticated chickens, in combination with a dense SNP and microsatellite marker map, both pleiotropy and epistasis were analysed. The majority of traits were found to segregate in 11 tight 'blocks' and reflected the trade-offs associated with domestication. These blocks were shown to have a pleiotropic 'core' surrounded by more loosely linked loci. In contrast, epistatic interactions were almost entirely absent, with only six pairs identified over all traits analysed. These results give insights both into the extent of such blocks in evolution and the development of domestication itself.


M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice.
In T-cell-dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell-like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell-dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive.


HAART and medical management: the realities of clinical care. Interview with Keith Henry, M.D. Interview by John S. James.
In many outpatient HIV clinics the medical staff is so poorly funded that over 95% of the cost of patient care goes to drugs and laboratory tests--and less than 5% to physicians, nurses, other staff, clinic overhead, medical records, patient education, adherence monitoring, and other costs of care. This misdirection of resources results in patients not receiving the professional time and attention they need, and drug being taken incorrectly, leading to unnecessary drug failure and other medical problems. Keith Henry, M.D., who recently called for more cautious use of antiretroviral therapy, describes the realities of inadequate funding for medical care, and some needed steps for improvement. Also, we asked him to explain how his clinic has consistently performed leading-edge research without the major funding usually available at research institutions.


Deletion of Crry, the murine ortholog of the sporadic Alzheimer's disease risk gene CR1, impacts tau phosphorylation and brain CFH.
Large-scale genome-wide SNP association studies have identified an association between variants of CR1, the gene encoding complement component receptor 1, and the sporadic form of Alzheimer's disease. The role of CR1 and the complement system in Alzheimer's disease remains far from clear. In rodents the closest ortholog of CR1 is the Crry gene (Cr1-related protein Y). To begin to explore its role in Alzheimer's disease we examined hippocampal lysates from Crry(-/-) mice and age matched controls by immunoblotting. We measured complement factor H, a component of the complement system and biomarker for Alzheimer's disease progression, and tau phosphorylation at the serine 235 site, hyperphosphorylated forms of tau being a defining neuropathological hallmark of the disease. We found that levels of CFH and of tau phosphorylation at serine 235 were strongly and significantly reduced in Crry(-/-) samples. These observations provide a starting point for further attempts to determine the role of CR1 in the neuropathological process driving Alzheimer's disease.


Moxibustion in breech version--a descriptive review.
The management of breech presentation at term remains controversial. It appears logical that maternal and perinatal outcomes would be improved if breech presentation could be avoided. External cephalic version is considered a safe procedure if cases are selected appropriately and anaesthesia avoided. Moxibustion is a traditional Chinese method of treatment, which utilizes the heat generated by burning herbal preparations containing the plant Artemisia vulgaris to stimulate the acupuncture points. It is used for breech version with a reported success rate of 84.6% after 34 weeks gestation. Moxibustion technique is cheap, safe, simple, self-administered, non-invasive, painless and generally well tolerated. Although many studies give encouraging results regarding the use of moxibustion in inducing cephalic version of breech presentation, a definitive conclusion cannot be made as most involve small sample sizes and are not randomised. Moxibustion could be an extra option offered to women with breech presentation along with vaginal delivery, caesarean section and external cephalic version. This article discusses the possible role of moxibustion in correction of breech presentation in the hope that, some interest will be stimulated in what is a very interesting area for future research.


Immunomodulatory effects of honey cannot be distinguished from endotoxin.
In recent years, the use of honey has re-emerged as a remedy for wound treatment. Effects of honey have been related to the presence of an unidentified component that induces release of inflammatory cytokines from monocytic cells. The present study was intended to further characterize the reported in vitro effects of honey. Our results show that natural honeys induce interleukin-6 release from Mono Mac 6 cells as well as release of reactive oxygen species from all-trans retinoic acid (ATRA) differentiated HL-60 cells. The natural honeys contained substantial amounts of endotoxin, and the responses observed in the cell based assays were similar to the responses induced by endotoxin alone. In addition, we determined that the immunomodulatory component present in the natural honeys was retained in the ultra filtrated fraction with a molecular weight greater than 20 kDa. The component was resistant to boiling and its immunomodulatory activity could be abrogated by the addition of polymyxin B. We speculate that the observed in vitro immunomodulatory effects of honey might solely be explained by the endotoxin content in the natural honeys.


Prevalence of Anguillicoloides crassus and growth variation in migrant yellow-phase American eels of the upper Potomac River drainage.
Prevalence of the non-native swim bladder nematode Anguillicoloides crassus has recently increased in American eels from estuaries of the North American Atlantic coast, but little is known about parasite prevalence or conditions of previous infection in upstream migrant eels within upper watersheds. This study is the first to confirm presence of A. crassus in the upper Potomac River watershed. We estimated A. crassus prevalence during 3 time periods: September to October 2006 (5/143 eels, 3.5%), August to October 2007 (0/49 eels), and June 2008 (0/50 eels). All eels were sampled from the Millville Dam eel ladder on the lower Shenandoah River, a Potomac River tributary located approximately 285 km upstream of Chesapeake Bay, USA. Of the 5 infected eels, parasite intensity was 1 for each eel, and mean intensity was also 1.0. A swim bladder degenerative index (SDI) was calculated for the 50 eels from the final sampling period, and 38% of those eels (19 of 50) showed signs of previous infection by A. crassus. We also aged 42 of the 50 eels (mean ± SE = 6.7 ± 0.29 yr, range 4 to 11 yr) from the final sampling period. Based on the range of possible SDI scores (0 to 6), severity of previously infected swim bladders was moderate (SDI = 1 or 2). Previously infected eels, however, had a lower length-at-age than that of uninfected eels. Female yellow-phase eels in upper watersheds develop into large highly fecund silver-phase adults; hence, a parasite-induced effect on growth of yellow-phase eels could ultimately reduce reproductive potential.


Testing sex-specific pathways from peer victimization to anxiety and depression in early adolescents through a randomized intervention trial.
The aim of this study was to test for sex differences in the role of physical and relational victimization in anxiety and depression development through a randomized prevention trial. 448 seven-year-old boys and girls were randomly assigned to the Good Behavior Game intervention, a two-year universal classroom based intervention aimed at reducing disruptive behavior problems and creating a safe and predictable classroom environment, or to a control condition. Assessments of self-reported physical and relational victimization at age 10 years, and self-reported major depressive disorder, generalized anxiety, social anxiety, and panic/agoraphobia symptoms at age 13 years were available. Reductions in anxiety/depression were mediated by reduced rates of relational victimization in girls, whereas reductions in physical victimization accounted for the reduced anxiety/depression scores among boys. The results support sex-specific pathways of victimization leading to anxiety and depression.


Cloning and characterization of an esophageal-gland-specific chorismate mutase from the phytoparasitic nematode Meloidogyne javanica.
Root-knot nematodes are obligate plant parasites that alter plant cell growth and development by inducing the formation of giant feeder cells. It is thought that nematodes inject secretions from their esophageal glands into plant cells while feeding, and that these secretions cause giant cell formation. To elucidate the mechanisms underlying the formation of giant cells, a strategy was developed to clone esophageal gland genes from the root-knot nematode Meloidogyne javanica. One clone, shown to be expressed in the nematode's esophageal gland, codes for a potentially secreted chorismate mutase (CM). CM is a key branch-point regulatory enzyme in the shikimate pathway and converts chorismate to prephenate, a precursor of phenylalanine and tyrosine. The shikimate pathway is not found in animals, but in plants, where it produces aromatic amino acids and derivative compounds that play critical roles in growth and defense. Therefore, we hypothesize that this CM is involved in allowing nematodes to parasitize plants.


Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice.
Thymic atrophy is an age-associated decline in commitment to the T cell lineage considered to be associated with defective TCR beta-chain rearrangement. Both IL-7 and stem cell factor (SCF) have dominant roles at this stage of triple negative (TN) thymocyte development. Because there is no age-associated decrease in the number of CD44(+)CD25(-)CD3(-)CD4(-)CD8(-) cells, this study investigated whether alterations in apoptosis within the TN pathway accounted for diminishing thymocyte numbers with age. Here we show significant age-associated increases in apoptotic TN thymocytes, specifically within CD44(+)CD25(+) and CD44(-)CD25(+) subpopulations, known to be the location of TCR beta-chain rearrangement. IL-7 added to TN cultures established from old mice significantly both reduces apoptosis and increases the percentage of live cells within CD44(+)CD25(+) and CD44(-)CD25(+) subpopulations after 24 h, with prosurvival effects remaining after 5 days. SCF failed to demonstrate prosurvival effects in old or young cultures, and IL-7 and SCF together did not improve upon IL-7 alone. IL-7R expression did not decline with age, ruling out the possibility that the age-associated increase in apoptosis was attributed to reduced IL-7R expression. Compared with PBS, treatment of old mice with IL-7 produced significant increases in live TN cells. By comparison, treatment with SCF failed to increase live TN numbers, and IL-7 and SCF together failed to significantly improve thymopoiesis above that shown by IL-7 alone. Thus, treatment with IL-7 alone can reverse the age-associated defect in TN thymocyte development revealed by in vitro studies to be located at the stages of TCR beta-chain rearrangement.


Exposed and concealed antigens as vaccine targets for controlling ticks and tick-borne diseases.
Tick vaccines derived from Bm86, a midgut membrane-bound protein of the cattle tick, Boophilus microplus, are currently the only commercially available ectoparasite vaccines. Despite its introduction to the market in 1994, and the recognized need for alternatives to chemical pesticides, progress in developing effective antitick vaccines (and ectoparasite vaccines in general) is slow. The primary rate-limiting step is the identification of suitable antigenic targets for vaccine development. Two sources of candidate vaccine antigens have been identified: 'exposed' antigens that are secreted in tick saliva during attachment and feeding on a host and 'concealed' antigens that are normally hidden from the host. Recently, a third group of antigens has been distinguished that combines the properties of both exposed and concealed antigens. This latter group offers the prospect of a broad-spectrum vaccine effective against both adults and immature stages of a wide variety of tick species. It also shows transmission-blocking and protective activity against a tick-borne pathogen. With the proliferation of molecular techniques and their application to vaccine development, there are high hopes for new and effective antitick vaccines that also control tick-borne diseases.


Characterization of Immune System Cell Subsets in Fixed Tissues from Alpine Chamois (Rupicapra rupicapra).
Immune system cell subsets in lymph nodes and spleen from alpine chamois (Rupicapra rupicapra subspecies rupicapra) living in the Italian Alps were characterized immunohistochemically. Seven primary antibodies (against human CD3, CD79αcy, CD68, or ovine CD4, CD8, CD21 and γδ T-cell receptor [TCR] epitopes) were tested on tissues fixed either in formalin or in zinc salts (ZS) and cross-reactivity with chamois immune cell epitopes was shown. ZS fixation allowed wider identification of immune cells, without the need for antigen retrieval. CD4(+) and CD21(+) cells were labelled only in ZS-fixed tissues. Reagents specific for human CD3, CD79 and CD68 antigens successfully detected chamois immune cells, both in ZS-fixed and formalin-fixed tissues. The reactivity and distribution of immune cells in lymph nodes and spleen were similar to those described in other domestic and wild ruminants. Results from this study may allow future investigation of the immune response and pathogenesis of diseases in the chamois.


Idiopathic hypersomnia. A series of 42 patients.
The features of idiopathic hypersomnia are not well defined. We reviewed clinical and laboratory information on 42 subjects with idiopathic hypersomnia and obtained detailed follow-up evaluations on 28 of them. Only 29% of subjects had 'classic' idiopathic hypersomnia with non-imperative sleepiness, long unrefreshing naps, prolonged night-time sleep, difficult awakening with sleep drunkenness and prominent mood disturbances. Thirty-two percent had clinical features similar to narcolepsy, i.e. irresistible sleepiness, short and refreshing naps, few problems with awakening and good response to stimulants, without cataplexy or any indication of abnormal REM (rapid eye movement) sleep. The other 39% had intermediate clinical characteristics. We found no increase in the frequency of the human leucocyte antigens associated with narcolepsy. Overall, response to stimulants was good in three-quarters of the patients and spontaneous improvement of sleepiness occurred in one-quarter. Possible aetiologies identified in 10 patients included viral illness, head trauma and primary mood disorder. Idiopathic hypersomnia is a rare syndrome in which clinical heterogeneity suggests a variable or multifactoral pathogenesis. Only a minority of cases correspond to classical descriptions. Stimulants are often beneficial and spontaneous improvement appears to be more common than in narcolepsy.


Neonatal Inhibition of DNA Methylation Disrupts Testosterone-Dependent Masculinization of Neurochemical Phenotype.
Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.


Screening of cardiovascular risk factors in patients with schizophrenia and patients treated with antipsychotic drugs: are we equally exhaustive as with the general population?
Many studies have previously shown increased cardiovascular risk factors related to schizophrenia independently from the use of antipsychotic drugs. However, a poorer effort in clinical detection and management of cardiovascular risk in patients with severe mental illness could also explain these results. To test this hypothesis, we analyzed the differences in screening and incidence of cardiovascular risk factors between schizophrenia, non-schizophrenic patients on treatment with antipsychotic drugs (NS-TAD) and the general population. Data from adult subjects assessed by high-quality register general practitioners from 2006 to 2011 were extracted from the Catalonian SIDIAP database. The schizophrenia, NS-TAD, and control groups were compared in terms of measurements and incidence of diabetes, dyslipidemia, obesity, hypertension, and smoking. A total of 4911 patients in the schizophrenia group, 4157 in NS-TAD group, and 98644 in the control group were included. Schizophrenia patients were screened for dyslipidemia and diabetes more frequently than the control group, while for obesity or hypertension, they were screened equal to controls. Also, as compared to the control group, the NS-TAD group was more frequently screened for obesity with no differences in dyslipidemia and diabetes and less frequently for hypertension. Smoking was less frequently screened in both study groups. The incidence of all risk factors studied in both study groups was higher than or equal to the control group, except for hypertension, which had lower incidence. The lack of screening of risk factors does not appear decisive in the increased cardiovascular risk of patients diagnosed with schizophrenia seen in primary care. Studies evaluating the possible under diagnosis of the risk factors are required. Schizophrenia (SZ); Treatment with antipsychotic drugs (TAD); Cardiovascular risk factor/s (CVRF); Without schizophrenia but on therapy with antipsychotic drugs (NS-TAD); Defined Daily Dose (DDD).