Assessment of muscle fatigue after an ultra-endurance triathlon using tensiomyography (TMG).
In this study, we used tensiomyography (TMG) to assess muscle status immediately after an ultra-endurance triathlon. Maximal radial displacement or deformation of the muscle belly, contraction time, delay time, sustain time, and relaxation time were measured for both legs, and dependent t-tests were used to compare means between the beginning and end of the race. The 19 men assessed (age 37.9 ± 7.1 years; height 177.5 ± 4.6 cm; weight: 73.6 ± 6.5 kg) participated in the 2009 edition of the Lanzarote Ironman. Deterioration in the neural response was observed for contraction time (P = 0.008) and relaxation time (P = 0.011), with a moderate decrease in the response time (sustain time) and a loss in muscle stiffness (deformation of the muscle belly). The effect of muscle fatigue on the rectus femoris and biceps femoris was different. Barely any changes in contraction time, relaxation time, sustain time, and deformation of the muscle belly were observed, while only the contraction response time decreased to a significant extent (reduction in delay time; P = 0.003). The considerable loss in contractile capacity induced by a long-distance race was reflected in changes in the neuromuscular response and fluctuations in the contractile capacity of the muscle. These modifications, derived from a prolonged, exhausting effort, can be assessed in a simple, non-aggressive, non-invasive way using tensiomyography.


Outcomes and change processes of an established family education program for carers of adults diagnosed with a serious mental health condition.
Family education programs (FEPs) target caregiving-related psychological distress for carers of relatives/friends diagnosed with serious mental health conditions. While FEPs are efficacious in reducing distress, the mechanisms are not fully known. Peer group support and greater mental health knowledge are proposed to reduce carers' psychological distress by reducing stigmatising attitudes and self-blame, and strengthening carers' relationship with their relative. Adult carers (n = 1016) who participated in Wellways Australia's FEP from 2009 to 2016 completed self-report questionnaires at the core program's start and end, during the consolidation period, and at a 6-month follow-up. Those who enrolled early completed questionnaires prior to a wait-list period. We used linear mixed-effects modelling to assess the program's effectiveness using a naturalistic wait-list control longitudinal design, and multivariate latent growth modelling to test a theory-based process change model. While there was no significant change over the wait-list period, psychological distress, self-blame and stigmatising attitudes significantly decreased, and communication and relationship quality/feelings increased from the core program's start to its end. Changes were maintained throughout the consolidation period and follow-up. Peer group support significantly predicted the declining trajectory of distress. Peer group support and greater knowledge significantly predicted declining levels of self-blame and stigmatising attitudes, and increasing levels of communication. This is the first study to quantitatively validate the mechanisms underlying the effect of FEPs on carers' psychological distress. Peer group support is key in modifying carers' appraisals of their friend/relatives' condition. Continued implementation of FEPs within mental health service systems is warranted.


Asymmetrical interhemispheric fiber tracts in patients with hemimegalencephaly on diffusion tensor magnetic resonance imaging.
The internal structures of cerebral white matter in patients with hemimegalencephaly have not yet been investigated except for one, which evaluated aberrant fibers. We examined interhemispheric fiber tracts (FT) passing through the corpus callosum using magnetic resonance (MR) diffusion tensor imaging (DTI). MR studies, including DTI, were performed in nine consecutive patients with hemimegalencephaly and in 11 patients with West syndrome as disease controls. The interhemispheric FT passing through the corpus callosum were evaluated in six regional geometric subdivisions in every hemimegalencephaly and West syndrome patient (54 and 66 subregions, respectively), and the distribution and volume differences between affected and unaffected hemispheres were all compared. In patients with hemimegalencephaly, interhemispheric FT were symmetrically distributed in 27 (50%) of the 54 corpus callosum subregions. However, the FT were distributed to different areas in the same lobes in 22 (40%) subregions, and to different lobes in five (9%) subregions. FT volumes were symmetrical in 35 (65%) subregions, while FT volumes on the affected side were greater, but less than those on the unaffected side, in 14 (26%) and five (9%) subregions, respectively. In contrast, in the West syndrome patients, interhemispheric FT showed symmetrical distributions and volumes in all regions. Asymmetrical interhemispheric FT are often observed in patients with hemimegalencephaly, and DTI was a useful means of elucidating the internal structures of white matter.


Patient Participation in Chronic Pain Management Through Social Media: A Clinical Study.
Chronic pain places a significant burden on individuals as well as health services. Long wait lists to access public clinical pain management services can result, and health outcomes deteriorate. Innovative technologies, such as social media provide opportunities to support self-management within the participatory health framework. This paper aims to investigate patients' perceptions towards using social media while waiting for clinic access, with a particular focus on therapeutic affordances. Seventeen wait-listed patients underwent intervention using various social media resources as part of self-management. Thematic content analysis of semi-structured interviews examined patients' perceptions about social media use and participation. Three therapeutic affordances were most evident in the qualitative data: exploration, connection and narration. Barriers to participation were also identified, such as 'specificity of the resources'. Findings suggest social media are perceived positively. However, there is also the need to balance a desire to deliver evidence-based practice with patient-preferences in shared-decision making about social media use.


[Manipulation of the human genome: ethics and law].
The molecular biology has provided the basic tool for geneticists deepening in the molecular mechanisms that influence different diseases. It should be noted the scientific and moral responsibility of the researchers, because the scientists should imagine the moral consequences of the commercial application of genetic tests, since this fact involves not only the individual and their families, but the entire population. Besides being also necessary to make a reflection on how this information from the human genome will be used, for good or bad. The objective of this review was to bring the light of knowledge, data on characteristics of the ethical application of molecular biology, linking it with the rights of human beings. After studying literature, it might be observed that the Human Genome Project has generated several possibilities, such as the identification of genes associated with diseases with synergistic properties, but sometimes modifying behavior to genetically intervene in humans, bringing benefits or social harm. The big challenge is to decide what humanity wants on this giant leap.


Turkish dental students' and dentists' ability to assess gingival health status with DAAGS software.
The aim of this study was to compare the ability of final-year Turkish dental students and dentists to assess the level of gingival health status by using the Development of Ability to Assess Gingival Status (DAAGS) computer program. Forty-eight students in their final year of dental education and 240 dentists participated in DAAGS tests in which they judged twenty-four photos. The participants were organized into one group of students and five groups of dentists: those who graduated in the last five years, in the last six to ten years, in the last eleven to fifteen years, in the last sixteen to twenty years, and twenty and/or more years ago. A gold standard of each photo was shown to participants after they completed test 1; then, test 2 was conducted immediately. Participants were asked to evaluate the DAAGS by written survey. There were significant differences between the parameters of two tests for all groups. Significance levels differed for each group and both tests considering correct answers, reproducibility, irrelevant answers, and overall ability. The findings from this study indicated that the DAAGS software is easier for more recently graduated dentists to use.


Association of ground hardness with injuries in rugby union.
Ground hardness is considered one of the possible risk factors associated with rugby injuries. To examine the contribution of ground hardness, rainfall and evapotranspiration to the incidence of injury, and to investigate seasonal injury bias throughout one full season of rugby union. A prospective epidemiological study of rugby injuries was performed on 271 players from rugby union teams involved in the premier grade rugby competition in Dunedin, New Zealand. Ground hardness was measured before each match over 20 rounds with an industrial penetrometer, and local weather information was collected through the National Institute of Weather and Atmospheric Research and the Otago Regional Council. Poisson mixed models were used to describe injury incidence as a function of ground hardness throughout the season. The overall injury incidence during the season was 52 injuries per 1000 match player-hours (95% CI 42 to 65). Although injury incidence decreased gradually by round with a rate ratio of 0.98 (95% CI 0.96 to 0.99) (p = 0.036), and the hardness of match grounds decreased significantly over the season (0.16 MPa/round, 95% CI 0.12 to 0.21, p<0.001), a non-significant association was demonstrated between injury incidence and ground hardness. Injury incidence was not associated with a combination of ground hardness, rainfall and evapotranspiration on the day of the match or cumulative rainfall and evapotranspiration before each match. Seasonal change in ground hardness and an early-season bias of injuries was demonstrated. Although the contribution of ground hardness to injury incidence was not statistically significant, match round and injury incidence were highly correlated, confirming a seasonal bias, which may confound the relationship of injury to ground condition.


Increased automatic spreading activation in healthy subjects with elevated scores in a scale assessing schizophrenic language disturbances.
Previous studies on semantic priming have suggested that schizophrenic patients with language disturbances demonstrate enhanced semantic and indirect semantic priming effects relative to controls. However, the interpretation of semantic priming studies in schizophrenic patients is obscured by methological problems and several artefacts (such as length of illness). We, therefore, used a psychometric high-risk approach to test whether healthy subjects reporting language disturbances resembling those of schizophrenics (as measured by the Frankfurt Complaint Questionnaire subscale 'language') display increased priming effects. In addition, the Schizotypal Personality Questionnaire was used to cover symptoms of schizotypal personality. Enhanced priming was expected to occur under conditions favouring automatic processes. One hundred and sixty healthy subjects performed a lexical decision semantic priming task containing two different stimulus onset asynchronicities (200 ms and 700 ms) with two experimental conditions (semantic priming and indirect semantic priming) each. Analyses of variance revealed that the Frankfurt Complaint Questionnaire-' language' high scorers significantly differed from low scorers in three of the four priming conditions indicating increased automatic spreading activation. No significant results were obtained for the Schizotypal Personality Questionnaire total and subscales scores. In line with Maher and Spitzer it is suggested that increased automatic spreading activation underlies schizophrenia-typical language disturbances which in our study cannot be attributed to confounding variables such as different reaction time baselines, medication or length of illness. Finally, results confirm that the psychometric high-risk approach is an important tool for investigating issues relevant to schizophrenia.


Clinicians' fidelity to a manual-based family treatment as a predictor of the one-year course of bipolar disorder.
This study assessed whether therapist adherence to the family focused treatment model for patients with bipolar disorder and their relatives was associated with patient outcomes at one year after treatment entry. A total of 78 videotaped sessions of FFT consisting of 26 families with a member with bipolar disorder (3 sessions/family) were rated on fidelity using the Therapist Competence/Adherence Scale (TCAS; see Endnote 1, p. 130). Patients' outcomes (relapse status) were assessed using the Brief Psychiatric Rating Scale (BPRS) and selected items from the Schedule of Affective Disorders and the Schizophrenia-Change (SADS-C) scale (measured at 3-month intervals for 12 months). Contrary to expectations, therapist fidelity was not related to overall outcome as assessed by the BPRS and the SADS-C. Among patients who did relapse, higher levels of cooperation among therapists predicted a later date for relapse than did lower levels of cooperation. Surprisingly, and in opposition to the study's hypotheses, patients who were hospitalized because of relapses had therapists who were rated as more competent in their ability to conduct the problem-solving module of FFT. Study implications are discussed.


Community cluster of meningococcal disease by Neisseria meningitidis serogroup C in Andalusia, Spain, March to May 2011.
Between March and May of 2011, a cluster of three fatal cases of meningococcal sepsis occurred in Andalusia, Spain, in a municipality with a population of around 20,000 inhabitants. The cases were in their mid-teens to early thirties and were notified to the epidemiological surveillance system of Andalusia (Sistema de Vigilancia Epidemiológica de Andalucía, SVEA) during a 68-day period from March through May 2011. All three were infected with the same strain of Neisseria meningitidis serogroup C genosubtype VR1:5-1;VR2:10-8. None of the cases had been previously vaccinated against N. meningitidis serogroup C. Antibiotic post-exposure chemoprophylaxis was administered to close contacts of every diagnosed case. Once the cluster was confirmed, the local population was informed through the media about the control measures taken by the health authorities. The vaccination history against N. meningitidis serogroup C of the population under 25 years-old in the municipality was checked. Vaccination was offered to unimmunised individuals younger than 25 years of age and an additional dose of vaccine was offered to those who had been vaccinated between 2000 and 2006 with a vaccination schedule of three doses before the first year of age. No further cases occurred since the beginning of these actions.


Factors shaping workplace segregation between natives and immigrants.
Research on segregation of immigrant groups is increasingly turning its attention from residential areas toward other important places, such as the workplace, where immigrants can meet and interact with members of the native population. This article examines workplace segregation of immigrants. We use longitudinal, georeferenced Swedish population register data, which enables us to observe all immigrants in Sweden for the period 1990-2005 on an annual basis. We compare estimates from ordinary least squares with fixed-effects regressions to quantify the extent of immigrants' self-selection into specific workplaces, neighborhoods, and partnerships, which may bias more naïve ordinary least squares results. In line with previous research, we find lower levels of workplace segregation than residential segregation. The main finding is that low levels of residential segregation reduce workplace segregation, even after we take into account intermarriage with natives as well as unobserved characteristics of immigrants' such as willingness and ability to integrate into the host society. Being intermarried with a native reduces workplace segregation for immigrant men but not for immigrant women.


Analysis of the Pioneer-Venus Lyman-agr Image of the Hydrogen Coma of Comet P/Halley.
Comet Halley passed within 0.27 astronomical unit of Venus on 4 February 1986, 5 days before perihelion. This provided a unique opportunity to observe the comet's coma with the ultraviolet spectrometer orbiting the planet aboard the Pioneer Venus Orbiter spacecraft when the coma was otherwise obscured from Earth's view by the sun's glare. More than 9000 data points acquired systematically over the 5-day period from 2 to 6 February were combined to construct an excellent Lyman-alpha image of the hydrogen coma. The Lyman-alpha image was successfully reproduced with a comprehensive physical model, thereby verifying and documenting the underlying chemical kinetics and dynamics of the hydrogen coma.


Methane, microbes and models: fundamental understanding of the soil methane cycle for future predictions.
Methane is an important greenhouse gas and microbes in the environment play major roles in both global methane emissions and terrestrial sinks. However, a full mechanistic understanding of the response of the methane cycle to global change is lacking. Recent studies suggest that a number of biological and environmental processes can influence the net flux of methane from soils to the atmosphere but the magnitude and direction of their impact are still debated. Here, we synthesize recent knowledge on soil microbial and biogeochemical process and the impacts of climate change factors on the soil methane cycle. We focus on (i) identification of the source and magnitude of methane flux and the global factors that may change the flux rate and magnitude in the future, (ii) the microbial communities responsible for methane production and terrestrial sinks, and (iii) how they will respond to future climatic scenarios and the consequences for feedback responses at a global scale. We also identify the research gaps in each of the topics identified above, provide evidence which can be used to demonstrate microbial regulation of methane cycle and suggest that incorporation of microbial data from emerging -omic technologies could be harnessed to increase the predictive power of simulation models.


Radiology reports for incidental thyroid nodules on CT and MRI: high variability across subspecialties.
Variability in radiologists' reporting styles and recommendations for incidental thyroid nodules can lead to confusion among clinicians and may contribute to inconsistent patient care. Our aim was to describe reporting practices of radiologists for incidental thyroid nodules seen on CT and MR imaging and to determine factors that influence reporting styles. This is a retrospective study of patients with incidental thyroid nodules reported on CT and MR imaging between January and December 2011, identified by text search for "thyroid nodule" in all CT and MR imaging reports. The studies included CT and MR imaging scans of the neck, spine, and chest. Radiology reports were divided into those that mentioned the incidental thyroid nodules only in the "Findings" section versus those that reported the incidental thyroid nodules in the "Impression" section as well, because this latter reporting style gives more emphasis to the finding. Univariate and multivariate analyses were performed to identify radiologist, patient, and nodule characteristics that influenced reporting styles. Three hundred seventy-five patients met the criterion of having incidental thyroid nodules. One hundred thirty-eight (37%) patients had incidental thyroid nodules reported in the "Impression" section. On multivariate analysis, only radiologists' divisions and nodule size were associated with reporting in "Impression." Chest radiologists and neuroradiologists were more likely to report incidental thyroid nodules in the "Impression" section than their abdominal imaging colleagues, and larger incidental thyroid nodules were more likely to be reported in "Impression" (P ≤ .03). Seventy-three percent of patients with incidental thyroid nodules of ≥20 mm were reported in the "Impression" section, but higher variability in reporting was seen for incidental thyroid nodules measuring 10-14 mm and 15-19 mm, which were reported in "Impression" for 61% and 50% of patients, respectively. Reporting practices for incidental thyroid nodules detected on CT and MR imaging are predominantly influenced by nodule size and the radiologist's subspecialty. Reporting was highly variable for nodules measuring 10-19 mm; this finding can be partially attributed to different reporting styles among radiology subspecialty divisions. The variability demonstrated in this study further underscores the need to develop CT and MR imaging practice guidelines with the goal of standardizing reporting of incidental thyroid nodules and thereby potentially improving the consistency and quality of patient care.


Reproducible quantification of cancer-associated proteins in body fluids using targeted proteomics.
The rigorous testing of hypotheses on suitable sample cohorts is a major limitation in translational research. This is particularly the case for the validation of protein biomarkers; the lack of accurate, reproducible, and sensitive assays for most proteins has precluded the systematic assessment of hundreds of potential marker proteins described in the literature. Here, we describe a high-throughput method for the development and refinement of selected reaction monitoring (SRM) assays for human proteins. The method was applied to generate such assays for more than 1000 cancer-associated proteins, which are functionally related to candidate cancer driver mutations. We used the assays to determine the detectability of the target proteins in two clinically relevant samples: plasma and urine. One hundred eighty-two proteins were detected in depleted plasma, spanning five orders of magnitude in abundance and reaching below a concentration of 10 ng/ml. The narrower concentration range of proteins in urine allowed the detection of 408 proteins. Moreover, we demonstrate that these SRM assays allow reproducible quantification by monitoring 34 biomarker candidates across 83 patient plasma samples. Through public access to the entire assay library, researchers will be able to target their cancer-associated proteins of interest in any sample type using the detectability information in plasma and urine as a guide. The generated expandable reference map of SRM assays for cancer-associated proteins will be a valuable resource for accelerating and planning biomarker verification studies.


Best Practices for Quantification of Uncertainty and Sampling Quality in Molecular Simulations [Article v1.0].
The quantitative assessment of uncertainty and sampling quality is essential in molecular simulation. Many systems of interest are highly complex, often at the edge of current computational capabilities. Modelers must therefore analyze and communicate statistical uncertainties so that "consumers" of simulated data understand its significance and limitations. This article covers key analyses appropriate for trajectory data generated by conventional simulation methods such as molecular dynamics and (single Markov chain) Monte Carlo. It also provides guidance for analyzing some 'enhanced' sampling approaches. We do not discuss systematic errors arising, e.g., from inaccuracy in the chosen model or force field.


Public health preparedness in Alberta: a systems-level study.
Recent international and national events have brought critical attention to the Canadian public health system and how prepared the system is to respond to various types of contemporary public health threats. This article describes the study design and methods being used to conduct a systems-level analysis of public health preparedness in the province of Alberta, Canada. The project is being funded under the Health Research Fund, Alberta Heritage Foundation for Medical Research. We use an embedded, multiple-case study design, integrating qualitative and quantitative methods to measure empirically the degree of inter-organizational coordination existing among public health agencies in Alberta, Canada. We situate our measures of inter-organizational network ties within a systems-level framework to assess the relative influence of inter-organizational ties, individual organizational attributes, and institutional environmental features on public health preparedness. The relative contribution of each component is examined for two potential public health threats: pandemic influenza and West Nile virus. The organizational dimensions of public health preparedness depend on a complex mix of individual organizational characteristics, inter-agency relationships, and institutional environmental factors. Our study is designed to discriminate among these different system components and assess the independent influence of each on the other, as well as the overall level of public health preparedness in Alberta. While all agree that competent organizations and functioning networks are important components of public health preparedness, this study is one of the first to use formal network analysis to study the role of inter-agency networks in the development of prepared public health systems.


Full-length mRNA sequencing uncovers a widespread coupling between transcription initiation and mRNA processing.
The multifaceted control of gene expression requires tight coordination of regulatory mechanisms at transcriptional and post-transcriptional level. Here, we studied the interdependence of transcription initiation, splicing and polyadenylation events on single mRNA molecules by full-length mRNA sequencing. In MCF-7 breast cancer cells, we find 2700 genes with interdependent alternative transcription initiation, splicing and polyadenylation events, both in proximal and distant parts of mRNA molecules, including examples of coupling between transcription start sites and polyadenylation sites. The analysis of three human primary tissues (brain, heart and liver) reveals similar patterns of interdependency between transcription initiation and mRNA processing events. We predict thousands of novel open reading frames from full-length mRNA sequences and obtained evidence for their translation by shotgun proteomics. The mapping database rescues 358 previously unassigned peptides and improves the assignment of others. By recognizing sample-specific amino-acid changes and novel splicing patterns, full-length mRNA sequencing improves proteogenomics analysis of MCF-7 cells. Our findings demonstrate that our understanding of transcriptome complexity is far from complete and provides a basis to reveal largely unresolved mechanisms that coordinate transcription initiation and mRNA processing.


The dynamics of memory for United States presidents in younger and older adults.
ABSTRACTSerial position effects are often observed within the free recall of unassociated words but also when recalling items from a semantic category like U.S. presidents. We investigated the dynamics of recall for U.S. presidents in younger and older adults to examine potential age-related differences in the organisation of retrieval from semantic long-term memory. Older adults recalled more presidents than younger adults and also demonstrated dual serial position effects such that, in addition to overall serial position effects, primacy (e.g., Eisenhower) and recency presidents (e.g., Obama) within older adults' lifetime were better recalled than presidents from the middle of their lives (e.g., Ford). Additionally, participants initiated recall with the most distinct presidents (highly familiar or memorable presidents like Washington, Obama, Trump), and conditional-response probabilities revealed that presidents from similar eras were recalled in close proximity, indicating that the retrieval of distinct presidents can facilitate memory for presidents from a similar era. Collectively, we demonstrate the potential interplay of the mechanisms that influence the organisation of retrieval such that distinctiveness and temporal contiguity effects may simultaneously impact recall. Specifically, semantic and temporal-contextual associations can drive semantic autobiographical memory and people likely organise retrieval from long-term memory according to familiarity and distinctiveness.


Viral factors reveal a role for REF/Aly in nuclear RNA stability.
TREX is a conserved multiprotein complex that is necessary for efficient mRNA export to the cytoplasm. In Saccharomyces cerevisiae, the TREX complex is additionally implicated in RNA quality control pathways, but it is unclear whether this function is conserved in mammalian cells. The Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein binds and recruits the TREX component REF/Aly to viral mRNAs. Here, we demonstrate that REF/Aly is recruited to the KSHV noncoding polyadenylated nuclear (PAN) RNA by ORF57. This recruitment correlates with ORF57-mediated stabilization of PAN RNA, suggesting that REF/Aly promotes nuclear RNA stability. Further supporting this idea, tethering REF/Aly to PAN RNA is sufficient to increase the nuclear abundance and half-life of PAN RNA but is not sufficient to promote its export. Interestingly, REF/Aly appears to protect the poly(A) tail from deadenylation, and REF/Aly-stabilized transcripts are further adenylated over time, consistent with previous reports linking poly(A) tail length with nuclear RNA surveillance. These studies show that REF/Aly can stabilize nuclear RNAs independently of their export and support a broader conservation of RNA quality control mechanisms from yeast to humans.


Evaluation of factors affecting gastrointestinal absorption of a novel anticoagulant FX-93 for development of oral formulation.
To find out factors causing the low bioavailability of FX-93, a novel anticoagulant, its solubility, membrane permeability, and the effect of bile salt on the absorption of FX-93 were investigated. The solubility of FX-93 under physiological conditions ranged from 0.3 to 18.3 mg/mL and the dose number was calculated to be 0.02-0.27, suggesting that the intrinsic solubility of FX-93 should not be a limiting factor for oral absorption. Apparent permeability of FX-93 across Caco-2 cell monolayer suggested that its fraction of dose absorbed would range between 30% and 40% in humans. Furthermore, FX-93 was substantially absorbed from each segment of rat intestine. However, the decrease in the gastrointestinal transit rate significantly decreased maximum plasma concentration and area under the plasma concentration-time curve of FX-93 after oral dosing in dogs, suggesting that FX-93 absorption would be suppressed by some components in the small intestinal lumen. An in situ rat administration study indicated that bile significantly decreased the intestinal absorption of FX-93 by two-thirds, which could be attributed to the decrease in FX-93 solubility by the interaction with bile or bile acid. Nuclear magnetic resonance spectroscopy analysis suggested that FX-93 would interact with bile salt between the naphthalene ring of FX-93 and steroidal backbone of bile salt.


Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein.
Lipid rafts are regions of the plasma membrane that are enriched in cholesterol, glycosphingolipids and acylated proteins, and which have been proposed as sites for the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Lipid rafts can be isolated on the basis of their insolubility in Triton X-100 at 4 degrees C, with the resulting low-density, detergent-insoluble glycolipid-enriched fraction (DIG) being isolated by flotation through a sucrose density gradient. The detergent-insolubility of APP in mouse cerebral cortex relative to a variety of DIG marker proteins (alkaline phosphatase, flotillin, F3 protein and prion protein) and non-DIG proteins (alkaline phosphodiesterase I, aminopeptidase A and clathrin) has been examined. Alkaline phosphatase, flotillin, F3 protein and the prion protein were present exclusively in the DIG region of the sucrose gradient over a range of protein/detergent ratios used to solubilize the membranes and displayed a characteristic enrichment in the low-density fraction as the protein/detergent ratio was decreased. In contrast, most of the APP, alkaline phosphodiesterase I, aminopeptidase A and clathrin was effectively solubilized at all of the protein/detergent ratios examined. However, a minor proportion of these latter proteins was detected in DIGs at levels which remained constant irrespective of the protein/detergent ratio. When DIGs were isolated from the sucrose gradients and treated with excess Triton X-100, both the DIG marker proteins and APP, alkaline phosphodiesterase I and clathrin were predominantly resistant to detergent extraction at 37 degrees C. These results show that, although a minor proportion of APP is present in DIGs, where it is detergent-insoluble even at 37 degrees C, it behaves as an atypical lipid raft protein and raises questions as to whether lipid rafts are a site for its proteolytic processing.


IMU-based ambulatory walking speed estimation in constrained treadmill and overground walking.
This study evaluated the performance of a walking speed estimation system based on using an inertial measurement unit (IMU), a combination of accelerometers and gyroscopes. The walking speed estimation algorithm segments the walking sequence into individual stride cycles (two steps) based on the inverted pendulum-like behaviour of the stance leg during walking and it integrates the angular velocity and linear accelerations of the shank to determine the displacement of each stride. The evaluation was performed in both treadmill and overground walking experiments with various constraints on walking speed, step length and step frequency to provide a relatively comprehensive assessment of the system. Promising results were obtained in providing accurate and consistent walking speed/step length estimation in different walking conditions. An overall percentage root mean squared error (%RMSE) of 4.2 and 4.0% was achieved in treadmill and overground walking experiments, respectively. With an increasing interest in understanding human walking biomechanics, the IMU-based ambulatory system could provide a useful walking speed/step length measurement/control tool for constrained walking studies.


Differential colocalization of profilin with microfilaments in PtK2 cells.
Profilins are thought to be involved in the control of actin dynamics in eukaryotic cells. In accordance with this concept, profilin was found to be colocalized with the cortical microfilament webs in leading lamellae of locomoting and spreading fibroblasts. However, so far, there is little information on the distribution of profilin in other cell types. In this study, we report on the colocalization of profilin with various microfilament suprastructures in the epithelial cell line PtK2. This cell line, which is derived from rat kangaroo, contains a profilin sharing an N-terminal epitope with bovine and human profilin I, as seen by immunoblotting with monoclonal antibodies. By using immunofluorescence in conjunction with conventional fluorescence microscopy and confocal laser-scanning microscopy, we found profilin in ruffling areas of the peripheral lamellae and nascent stress fibers of spreading cells, whereas the peripheral belts of stationary cells growing in epithelioid sheets lacked profilin staining. In these cells, profilin was primarily distributed in a fine reticular or vesicular network that was not related to the microfilament system. Conspicuously low levels of profilins was not related to the contractile ring of mitotic cells. This was found for different fixation protocols and antibodies of the IgG and IgM type, respectively, indicating that lack of staining of the cleavage furrow was not due to antibody penetration problems. Depending on the fixation protocol, the nuclear matrix appeared strongly positive or negative for profilin. Cells microinjected with birch pollen profilin and labeled with a birch profilin-specific monoclonal antibody corroborated the results obtained with the endogeneous protein: The injected profilin was targeted to the cortical web and to nascent stress fibers of spreading cells but not to the cleavage ring of mitotic cells. These results suggest that high concentrations of a profilin I homologue are preferentially located with those microfilament suprastructures in PtK2 cells that are subject to rapid modulation by external signals.


Patients with sequelae of poliomyelitis. Does the anesthetic technique impose risks?
Several questions arise before performing neuro-axis block in patients with sequelae of poliomyelitis. Reports in the literature are scarce. The objective of this study was to describe the anesthetic techniques used in patients undergoing surgeries and possible complications. We undertook a retrospective study of patients with sequelae of poliomyelitis who underwent surgeries during a five-year period. Demographic data, physical status (ASA), onset of the disease, body part affected, diagnosis of post-poliomyelitis syndrome, surgeries and type anesthesia used, postoperative analgesia, intra- and postoperative complications, outpatient follow-up, and development of neurological changes were evaluated. One-hundred and twenty-three patients who underwent 162 surgical procedures were evaluated. Most patients (n = 82; 66.6%) had neurological sequela in a lower limb. Patients developed acute poliomyelitis at approximately 28 months of age. Orthopedic surgery was performed in 87.7% of patients. Neuro-axis block was used in 64.1% of the cases; epidural block was more frequent. Intraoperative complications reported included: accidental puncture of the dura-mater (n = 1; 0.61%), bradycardia (n = 1; 0.61%), hypotension (n = 2; 1.23%), and apnea and thoracic rigidity (n = 1; 0.61%). Postoperative complications included: vomiting (n = 2; 1.23%), urinary retention (n = 4; 2.64%), and complex regional pain syndrome type 1 (n = 2; 1.23%). Patients were followed for 22 months and worsening of the neurological disorder was not observed. Patients with sequelae of poliomyelitis who underwent neuro-axis block did not develop any postoperative complications or worsening of their neurological status that could be attributed to the anesthetic technique used.


Evaluating Hedgehog Acyltransferase Activity and Inhibition Using the Acylation-coupled Lipophilic Induction of Polarization (Acyl-cLIP) Assay.
Palmitoylation of the Hedgehog family of proteins is a critical step in the Hedgehog signaling pathway and is performed by the membrane-bound O-acyltransferase enzyme Hedgehog acyltransferase (HHAT). Measurement of HHAT activity has traditionally relied on radiolabeled fatty acid substrates, which imposes considerable constraints on throughput, cost, and safety, consequently hindering the efficient identification and development of small-molecule HHAT inhibitors. The Acylation-coupled Lipophilic Induction of Polarisation (Acyl-cLIP) assay was recently developed in our lab as a novel platform to evaluate lipidation of peptides in real time and high throughput. In this chapter, we describe the isolation of active HHAT from HEK293a cells and application of the Acyl-cLIP assay to characterize HHAT inhibitors. Our methodology uses standard chemical biology lab equipment and yields high-quality kinetic data from minimal sample volumes. The assay uses standard 384-well plates and is easily adapted to medium- or high-throughput screening formats.


VEGF signaling has distinct spatiotemporal roles during heart valve development.
Heart valve malformations are one of the most common types of birth defects, illustrating the complex nature of valve development. Vascular endothelial growth factor (VEGF) signaling is one pathway implicated in valve formation, however its specific spatial and temporal roles remain poorly defined. To decipher these contributions, we use two inducible dominant negative approaches in mice to disrupt VEGF signaling at different stages of embryogenesis. At an early step in valve development, VEGF signals are required for the full transformation of endocardial cells to mesenchymal cells (EMT) at the outflow tract (OFT) but not atrioventricular canal (AVC) endocardial cushions. This role likely involves signaling mediated by VEGF receptor 1 (VEGFR1), which is highly expressed in early cushion endocardium before becoming downregulated after EMT. In contrast, VEGFR2 does not exhibit robust cushion endocardium expression until after EMT is complete. At this point, VEGF signaling acts through VEGFR2 to direct the morphogenesis of the AVC cushions into mature, elongated valve leaflets. This latter role of VEGF requires the VEGF-modulating microRNA, miR-126. Thus, VEGF roles in the developing valves are dynamic, transitioning from a differentiation role directed by VEGFR1 in the OFT to a morphogenetic role through VEGFR2 primarily in the AVC-derived valves.


Insulin-like growth factor binding protein 5 and apoptosis in mammary epithelial cells.
Insulin-like growth factors (IGFs) are important survival signals that can protect a range of cell types from apoptosis. Although IGF bioavailability is modulated by high affinity interactions with IGF-binding proteins (IGFBPs), there is currently no experimental evidence that IGFBPs regulate the survival function of IGFs in the mammary gland. We have examined IGFBP expression during mammary gland development and studied the effects of IGFBPs on IGF-mediated survival and signalling in mammary epithelial cells in culture. IGFBP-5 protein was greatly increased during days 1-3 of mammary gland involution, when levels of apoptosis are dramatically elevated to remodel the gland after lactation. Primary cultures of mammary epithelial cells (MECs) expressed IGFBP-5 from their basal surface suggesting that IGFBP-5 is suitably located to inhibit IGF signalling. Addition of exogenous IGFBP-5 and IGFBP-3 to MECs suppressed IGF-I-mediated survival, resulting in threefold greater apoptosis in cells incubated with IGF-I and IGFBP-5 compared with IGF-I alone. Examination of signalling pathways involved in apoptosis revealed that phosphorylation of PKB and the forkhead transcription factor, FKHRL1, was induced by IGFs, but that phosphorylation was blocked by IGFBP-5 and IGFBP-3. This study provides evidence that IGFBP-5 plays an important role in the regulation of apoptosis in the mammary gland.


Lipid metabolism during bacterial growth, sporulation, and germination: an obligate nutritional requirement in Bacillus thuringiensis for compounds that stimulate fatty acid synthesis.
The regulation of fatty acid biosynthesis by compounds that are required for growth of Bacillus thuringiensis was investigated using an vivo assay developed to measure fatty acid synthesis in germinating spores. A minimal glucose-ammonium-salts medium does not support growth even though previous radiorespirometric studies have shown B. thuringiensis to possess intact tricarboxylic acid and Embden-Meyerhof-Parnas pathways. Abundant growth does occur, however, when this medium is supplemented with either glutamate, aspartate, citrate, thiosulfate, cystine, or ethylenediaminetetraacetic acid. Cells held under nongrowing conditions incorporate acetate into fatty acids; fatty acid synthesis is stimulated by the compounds that permit growth. These alternate nutritional requirements are not manifestations of a vitamin or trace metal deficiency and do not reflect a chelation phenomenon. These results indicate a direct correlation between the capacity of these compounds to promote growth and to stimulate formation of fatty acids.


Tetracycline-resistant coliforms in the effluent of the main sewage treatment plant in Hamilton, Ontario - do they have a common ancestral strain?
Sewage, a major source of bacterial contamination of the environment, can be an important health hazard. The presence of antibiotic-resistant bacteria in sewage can exacerbate this problem. The sources of antibiotic-resistant bacteria in sewage are, for this reason, worth identifying and addressing. The bacterial flora in the effluent of the Woodward Avenue Wastewater Treatment Plant (WAWTP) in Hamilton, Ontario, Canada, contains many antibiotic-resistant coliforms. Here we ask, are the antibiotic resistance genes in the coliforms in the effluent of WAWTP descended from a recent common ancestor strain? If so, the source could be identified and eliminated. If, on the other hand, the antibiotic resistance genes in the bacterial flora of the WAWTP have more than one origin, identification and elimination of the source(s) could be difficult. There was considerable diversity of antibiotic resistance patterns and antibiotic resistance genes among the effluent and influent coliform isolates of the WAWTP, suggesting multiple genetic ancestry. The patterns of horizontal transmissibility and sequence differences in the genes tetA and tetE among these coliform isolates also suggest that they have no one predominant ancestral strain. Using the same logic, the evidence presented here is not compatible with a single ancestral origin of the antibiotic resistance genes in the isolates described herein.


Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort.
Although clinics for the evaluation of cognitive dysfunction have typically emphasized the detection and treatment of the reversible causes of dementia, it remains unclear whether the treatment of such causes results in reversal of the dementia. Therefore, the appropriate work-up for dementia is in dispute. A chart review was performed with records from an urban tertiary care referral-based memory clinic. The records for 196 patients with dementia or suspected dementia, seen between October 1991 and December 1993, were examined to determine the prevalence of potentially reversible dementias and whether the cognitive dysfunction improved or resolved after treatment. Data abstracted from the medical charts included demographic information, medication use, presence of depression, and results of neuropsychological tests, blood work and neuroimaging. The clinical diagnosis, the response to treatment, if applicable, and the outcome (mean follow-up period 16 months) were analysed. The recommendations of the 1989 Canadian Consensus Conference on the Assessment of Dementia (CCCAD) on the use of CT were retrospectively applied in each case. Of the 196 patients, 45 (23.0%) had a potentially reversible condition identified by history, physical examination, blood testing or CT; in only 7 (3.6% of the total) did treatment result in improvement or resolution of the dementia. These 7 patients had higher results for the Mini-Mental State examination (mean result 26) and exhibited only mild cognitive deficits. Potentially reversible lesions were found in the CT scans of 6 (3.1%) patients: 4 had normal-pressure hydrocephalus and 2 had a brain tumour. If the CCCAD recommendations had been followed, CT would have been performed in 76 (38.8%) of the patients, and 1 of the 6 patients with a lesion would have been missed. Both potential and actual reversibility of dementia was low in these memory clinic patients. The patients whose condition improved with intervention had early and milder cognitive deficits, which suggests that thorough evaluation of early memory loss is warranted.


Chest wall distortion and discharge of pulmonary slowly adapting receptors.
We assessed the effects of chest wall distortion, changes in lung volume, and abolition of airway smooth muscle tone on the discharge patterns of 92 pulmonary slowly adapting receptors (SAR) in decerebrate, spontaneously breathing cats. Distortion resulted from their inspiratory efforts against an occluded airway at functional residual capacity and at increased end-expiratory lung volumes. Approximately 40% of SAR increased discharge frequencies during occlusions. Modulation of SAR discharge during occlusions persisted after administration of atropine to eliminate airway smooth muscle tone. Phasic modulation of SAR discharge was eliminated during no-inflation tests after paralyzing the cats and ventilating them on a cycle-triggered pump. We conclude 1) parasympathetic modulation of airway smooth muscle tone makes no obvious contribution to SAR discharge in spontaneously breathing cats; 2) the no-inflation test (withholding of lung inflation during neural inspiration) in paralyzed and ventilated cats is a valid test for the presence of projections from SAR to medullary respiratory neurons; and 3) in the absence of tidal volume changes, distortion stimulates some SAR. Sensory feedback from receptors in the lung, not just those in the chest wall, may therefore provide information about abnormal chest wall configurations.


Evidence for adaptive introgression of exons across a hybrid swarm in deer.
Secondary contact between closely related lineages can result in a variety of outcomes, including hybridization, depending upon the strength of reproductive barriers. By examining the extent to which different parts of the genome introgress, it is possible to infer the strength of selection and gain insight into the evolutionary trajectory of lineages. Following secondary contact approximately 8000 years ago in the Pacific Northwest, mule deer (Odocoileus hemionus hemionus) and black-tailed deer (O. h. columbianus) formed a hybrid swarm along the Cascade mountain range despite substantial differences in body size (up to two times) and habitat preference. In this study, we examined genetic population structure, extent of introgression, and selection pressures in freely interbreeding populations of mule deer and black-tailed deer using mitochondrial DNA sequences, 9 microsatellite loci, and 95 SNPs from protein-coding genes. We observed bi-directional hybridization and classified approximately one third of the 172 individuals as hybrids, almost all of which were beyond the F1 generation. High genetic differentiation between black-tailed deer and mule deer at protein-coding genes suggests that there is positive divergent selection, though selection on these loci is relatively weak. Contrary to predictions, there was not greater selection on protein-coding genes thought to be associated with immune function and mate choice. Geographic cline analyses were consistent across genetic markers, suggesting long-term stability (over hundreds of generations), and indicated that the center of the hybrid swarm is 20-30 km to the east of the Cascades ridgeline, where there is a steep ecological transition from wet, forested habitat to dry, scrub habitat. Our data are consistent with a genetic boundary between mule deer and black-tailed deer that is porous but maintained by many loci under weak selection having a substantial cumulative effect. The absence of clear reproductive barriers and the consistent centering of geographic clines at a sharp ecotone suggests that ecology is a driver of hybrid swarm dynamics. Adaptive introgression in this study (and others) promotes gene flow and provides valuable insight into selection strength on specific genes and the evolutionary trajectory of hybridizing taxa.


Within-patient right-left blinded comparison of diode (810 nm) laser therapy and intense pulsed light therapy for hair removal.
Excessive facial hair in women can cause significant psychological distress. A variety of treatment methods are available, including lasers and, more recently, intense pulsed light (IPL) sources. There are very few studies comparing laser and IPL devices. The purpose of our study was to compare a laser diode device with an IPL, using a within-patient, right-left, assessor-blinded, controlled, study design. Hair counts were made, using coded close-up photographs. Treatments were carried out on three occasions at 6-week intervals, and a final assessment was made 6 weeks following the third treatment. Patient self-assessment was also included. Nine women were recruited, and seven completed the study. Average hair counts in a 16 cm(2) area before and after treatment were, respectively, 42.4 and 10.4 (laser), 38.1 and 20.4 (IPL), 45.3 and 44.7 (control). Both laser and IPL reduced the hair count substantially; laser vs control was significant at P=0.028, but IPL vs control had P=0.13, suggesting that more subjects or more treatments were required if statistical significance were to be achieved. Despite subjecting the patients to higher pain scores and more inflammation, laser was preferred by five patients; two preferred IPL and one had no preference.


Haze, public health and mitigation measures in China: A review of the current evidence for further policy response.
With rapid economic development, China has been plagued by choking air pollution in recent years, and the frequent occurrence of haze episodes has caused widespread public concern. The purpose of this study is to describe the sources and formation of haze, summarize the mitigation measures in force, review the relationship between haze pollution and public health, and to discuss the challenges, potential research directions and policy options. Haze pollution has both natural and man-made causes, though it is anthropogenic sources that are the major contributors. Accumulation of air pollutants, secondary formation of aerosols, stagnant meteorological conditions, and trans-boundary transportation of pollutants are the principal causes driving the formation and evolution of haze. In China, haze includes gaseous pollutants and fine particles, of which PM2.5 is the dominant component. Short and long-term exposure to haze pollution are associated with a range of negative health outcomes, including respiratory diseases, cardiovascular and cerebrovascular diseases, mental health problems, lung cancer and premature death. China has paid increasing attention to the improvement of air quality, and has introduced action plans and policies to tackle pollution, but many interventions have only temporary effects. There may be fierce resistance from industry groups and some government agencies, and often it is challenging to enforce relevant control measures and laws. We discuss the potential policy options for prevention, the need for wider public dialogue and the implications for scientific research.


[Quality of life and perception of illness among individuals with high blood pressure].
This study aimed to investigate quality of life in individuals with arterial hypertension and to associate the results with the patients' perceived severity of illness. The sample included 113 patients with arterial hypertension followed up in a clinic in Fortaleza, Ceará State, Brazil, from May to August 2002, using an international scale for assessing quality of life, the SF-36. Of the entire sample of patients, 77% were women, a large proportion were over 50 years of age, living with family, and with some kind of occupation. Assessment with the SF-36 showed compromised quality of life in different domains, although patients viewed their illness as not serious, and curable. These circumstances can interfere in follow-up of their illness over time, which can in turn jeopardize their quality of life. In conclusion, use of the SF-36 to assess individuals with arterial hypertension produced significant results, indicating generally compromised quality of life. According to these results, hypertension jeopardizes the patients' social and physical dimensions, but this situation can be changed by the provision of qualified services.


Pain perception during inferior alveolar injection administered with the Wand or conventional syringe.
This study compared a computerised device (the Wand) with a conventional syringe in terms of the pain of needle insertion and injection during inferior alveolar nerve (IAN) block injection. The subjects were 40 patients between the ages of 18 and 30 years requiring local anaesthesia for dental restoration in the mandible. Before anaesthetic administration, the patients' anxiety levels were determined. Contralateral IAN injections were administrated at two separate appointments with random use of either the Wand or a conventional syringe. Following the injection, the patients used both the pain rating score (PRS) and a visual analogue scale (VAS) to assess the intensity of pain. When pain was measured after the injection, the Wand was found to be less painful than the syringe for the pain of both needle insertion and injection (p <0.05). The Wand technique resulted in significantly lower pain scores during the IAN block injections. Most of the patients preferred the IAN injection with the Wand for future dental injections.


Nutrition content of food and beverage products on Web sites popular with children.
We assessed the nutritional quality of branded food and beverage products advertised on 28 Web sites popular with children. Of the 77 advertised products for which nutritional information was available, 49 met Institute of Medicine criteria for foods to avoid, 23 met criteria for foods to neither avoid nor encourage, and 5 met criteria for foods to encourage. There is a need for further research on the nature and extent of food and beverage advertising online to aid policymakers as they assess the impact of this marketing on children.


Collision-induced time shift of a dispersion-managed soliton and its minimization in wavelength-division-multiplexed transmission.
The formula for the time shift of a dispersion-managed soliton that results from its collision with other solitons in different channels consists of two terms, one related to the frequency shift during collision, and the other related to the residual frequency shift after collision. It is found that an optimal relative delay exists between pulses in adjacent channels after each dispersion-managed span that balances the contributions from the two terms and minimizes the overall time shift, leading to a substantial improvement in transmission performance.


Manipulation of caloric content but not diet composition, attenuates the deficit in learning and memory of senescence-accelerated mouse strain P8.
Calorie restriction (CR) is an experimental intervention in laboratory animals that attenuates age-associated increases in morbidity, mortality, and functional impairment. It is characterized by mild ketosis, hypoinsulinemia and hypoglycemia. In this study, we examined whether metabolic simulation of CR by a diet of isocaloric ketogenic or hypoinsulinemic diets ameliorated the learning and memory deficit in a strain of senescence-accelerated prone mice (SAMP8), a mouse model of age-dependent impairments in learning and memory. Male SAMP8 mice were fed high carbohydrate (CHO), high fat (FAT), or high protein (PRO) diets after weaning, and calorie intake was adjusted to 95% (sub ad libitum, sAL) or 70% (CR) of the mean calorie intake of control mice. At 28 weeks of age, we found CR ameliorated the performance defects of SAMP8 mice in a passive avoidance task. Neither FAT nor PRO diets affected performance of the task when fed sAL level, although a diet of these compositions partially mimicked the serum parameters of CR mice. These results suggest restriction of calorie intake is important for the prevention of learning and memory deficits, and that the simulation of serum changes induced by CR is not sufficient to prevent the cognitive defects of SAMP8 mice.


Cranial anatomy of oreopithecus.
Reexamination of the 1958 skull of the late Miocene Oreopithecus bambolii revealed a cranial anatomy different from that widely accepted for this taxon. There is a sagittal crest, a high nuchal crest, a large gonial angle, and alpha high, rather vertical, occiput. This catarrhine was not a very large brained primate compared to known advanced hominoids.


International issues in abusive head trauma.
In the decades since Dr. John Caffey described a series of children with chronic subdural hematoma and long bone fractures, there has been a substantial increase in the medical recognition of various forms child abuse. In the United States, the term shaken baby syndrome was coined to explain a constellation of injuries assumed to be the result of violent shaking of infants. After improved understanding of the variety of mechanisms that occur when children are abused, abusive head trauma (AHT) has become the recommended terminology. AHT is a more comprehensive term that reflects the brain injuries that children suffer as the result of abuse. AHT continues to include shaking as a mechanism of injury as well as shaking with impact, impact alone, crushing injuries or combinations of several mechanisms. The medical community in the United States has led the way in developing new terminology and research to describe this unique and devastating form of abuse. The globalization of medicine and rapid information transfer has resulted in AHT becoming well-recognized internationally as a form of serious and fatal child abuse. This paper will review the historical basis in the United States for the diagnosis of AHT. We will also review some of the current international issue in epidemiology, diagnosis, legal processes and outcomes in selected countries/regions where child abuse physicians are actively involved in the evaluation of AHT.


Evaluating cardiac symptoms in the athlete: is it safe to play?
Concern regarding the risk of sudden unexpected cardiac death has fueled interest in athletes who experience chest pain, syncope, or palpitations during training and competition. This review examines the etiology and evaluation of these symptoms in young athletes. Previously published reports that have provided a base of expert opinion were examined to define the optimal means of assessment before returning athletes to play. A well-defined differential diagnosis must be considered to rule out heart disease and define noncardiac causes of these symptoms. Athletes who experience symptoms such as chest pain, syncope, and palpitations during competition and training can be safely returned to play only after the evaluation is completed.


[Headache in consideration of gender].
Among headaches sufferers in Japan, especially the number of migraine sufferers in Japan is estimated about 8,400 thousands, and the ratio of men and women is said to be about 1 to 4. The pathophysiology of migraines has been commonly explained by the trigeminovascular theory, and recent studies have suggested that the cause of migraines stems from cortical hypersensitivity. As to prophylactic treatment of migraine, anti-epileptic drugs such as valproic acid for cephalic hypersensitivity symptoms may be effective for reducing intensity and frequency of attacks and first line abortive medicine are triptans, which are widely prescribed. Considering from migraine treatment methods from childhood to elder women, to decreasing hypersensitivity of the brain in each life stage will lead falling into medication over used headache and also suppressing development of dizziness, tinnitus, or cephalic ringing in future, and shows that anti-epileptics are effective for treating this condition.


Relation between hospital surgical volume and outcome for pancreatic resection for neoplasm in a publicly funded health care system.
Recent studies from the United States have shown that institutions with higher numbers of pancreatic resection procedures for neoplasm have lower mortality rates associated with this procedure. However, minimal work has been done to assess whether the results of similar volume-outcome studies within a publicly financed health care system would differ from those obtained in a mixed public-private health care system. A population-based retrospective analysis was used to examine pancreatic resection for neoplasm in Ontario for the period 1988/89 to 1994/95. Outcomes examined included in-hospital case fatality rate and mean length of stay in hospital. For each hospital, total procedure volume for the study period was defined as low (fewer than 22), medium (22-42) or high (more than 42). Regression models were used to measure volume-outcome relations. The likelihood of postoperative death was higher in low-volume and medium-volume centres than in high-volume centres (odds ratio 5.1 and 4.5 respectively; p < 0.01 for both). Mean length of stay was greater in low- and medium-volume centres than in high-volume centres (by 7.7 and 9.2 days respectively, p < 0.01 for both). This study adds to growing evidence that, for pancreatic resection for neoplasm, patients may have better outcomes if they are treated in high-volume hospitals rather than low-volume hospitals.


Structural and spectroscopic properties of Yb³⁺-doped MgAl₂O₄ nanocrystalline spinel.
Magnesium spinel (MgAl2O4) powders doped with Yb(3+) ions have been synthesized by a sol-gel method and heat-treated in the range of 700-1000 °C for 3 h. XRD patterns indicated that the powders have a cubic structure with high crystallite dispersion. Nanoparticles in the range of 10-30 nm are obtained as a function of the dopant concentration and sintering temperature. The main Yb(3+) zero-phonon line is located at 976 nm. The spectroscopic properties of the Yb(3+) ions are characterized by broad absorption spectroscopy and emission spectroscopy. Even at low temperature, the spectra reveal a strong distorted spinel lattice due to the high inversion rate between Mg(2+) tetrahedral sites and Al(3+) octahedral sites. The substitution of Mg(2+) ions by Yb(3+) ions favors the creation of Yb(3+) ion pairs which are observed in the cooperative luminescence spectra at around 500 nm. The luminescence decays are influenced by both the Yb(3+) content, the energy transfer between ions and by the presence of pairs and aggregates. Detailed analysis of the observed structural and spectroscopic measurements has been described in this manuscript.


Predicting quantitative traits from genome and phenome with near perfect accuracy.
In spite of decades of linkage and association studies and its potential impact on human health, reliable prediction of an individual's risk for heritable disease remains difficult. Large numbers of mapped loci do not explain substantial fractions of heritable variation, leaving an open question of whether accurate complex trait predictions can be achieved in practice. Here, we use a genome sequenced population of ∼7,000 yeast strains of high but varying relatedness, and predict growth traits from family information, effects of segregating genetic variants and growth in other environments with an average coefficient of determination R(2) of 0.91. This accuracy exceeds narrow-sense heritability, approaches limits imposed by measurement repeatability and is higher than achieved with a single assay in the laboratory. Our results prove that very accurate prediction of complex traits is possible, and suggest that additional data from families rather than reference cohorts may be more useful for this purpose.


A database of two-dimensional images of footwear outsole impressions.
Footwear outsole images were obtained from 150 pairs of used shoes. The motivation for constructing the database was to enable a statistical analysis of two-dimensional (2D) images of shoe outsoles, to understand within shoe (between replicate images of the same shoe) and between shoe variability, and to develop methods for the evaluation of forensic pattern evidence of shoeprints. Since we scanned the outsole of the used shoes, the images capture not only the outsole pattern design but also the marks that arise from wear and tear and that may help identify the shoe that made the impression. Each shoe in a pair was scanned five times, so that replicate images can be used to estimate within-shoe variability. In total, there are 1500 2D images in the database. The EverOS footwear scanner was used to capture the outsole of each shoe. The scanner detects the weight distribution of the person wearing the shoe when he or she steps on the scanning surface. It images the portions of the outsole that make contact with the scanning surface. The database is a useful resource for forensic scientists or for anybody else with an interest in image comparison. The database we describe, was constructed by researchers in the Center for Statistics and Applications in Forensic Evidence (CSAFE) at Iowa State University.


Amplification of multiple copies of mitochondrial Cytochrome b gene fragments in the Australian freshwater crayfish, Cherax destructor Clark (Parastacidae: Decapoda).
Non-coding copies of fragments of the mitochondrial genome translocated to the nucleus or pseudogenes are being found with increasing frequency in a diversity of organisms. As part of a study to evaluate the utility of a range of mitochondrial gene regions for population genetic and systematic studies of the Australian freshwater crayfish, Cherax destructor (the yabby), we report the first detection of Cytochrome b (Cyt b) pseudogenes in crustaceans. We amplified and sequenced fragments of the mitochondrial Cyt b gene from 14 individuals of C. destructor using polymerase chain reaction (PCR) with primers designed from conserved regions of Penaeus monodon and Drosophila melanogaster mitochondrial genomes. The phylogenetic tree produced from the amplified fragments using these primers showed a very different topology to the trees obtained from sequences from three other mitochondrial genes, suggesting one or more nuclear pseudogenes have been amplified. Supporting this conclusion, two highly divergent sequences were isolated from each of two single individuals, and a 2 base pair (bp) deletion in one sequence was observed. There was no evidence to support inadvertent amplification of parasite DNA or contamination of samples from other sources. These results add to other recent observations of pseudogenes suggesting the frequent transfer of mitochondrial DNA (mtDNA) genes to the nucleus and reinforces the necessity of great care in interpreting PCR-generated Cyt b sequences used in population or evolutionary studies in freshwater crayfish and crustaceans more generally.


Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications.
In eccentric exercise the contracting muscle is forcibly lengthened; in concentric exercise it shortens. While concentric contractions initiate movements, eccentric contractions slow or stop them. A unique feature of eccentric exercise is that untrained subjects become stiff and sore the day afterwards because of damage to muscle fibres. This review considers two possible initial events as responsible for the subsequent damage, damage to the excitation-contraction coupling system and disruption at the level of the sarcomeres. Other changes seen after eccentric exercise, a fall in active tension, shift in optimum length for active tension, and rise in passive tension, are seen, on balance, to favour sarcomere disruption as the starting point for the damage. As well as damage to muscle fibres there is evidence of disturbance of muscle sense organs and of proprioception. A second period of exercise, a week after the first, produces much less damage. This is the result of an adaptation process. One proposed mechanism for the adaptation is an increase in sarcomere number in muscle fibres. This leads to a secondary shift in the muscle's optimum length for active tension. The ability of muscle to rapidly adapt following the damage from eccentric exercise raises the possibility of clinical applications of mild eccentric exercise, such as for protecting a muscle against more major injuries.


Periventricular efferent neurons in the optic tectum of rainbow trout.
The efferent connections and axonal and dendritic morphologies of periventricular neurons were examined in the optic tectum of rainbow trout to classify periventricular efferent neurons in salmonids. Among the target nuclei of tectal efferents, tracer injections to the following four structures labeled periventricular neurons: the area pretectalis pars dorsalis (APd), nucleus pretectalis superficialis pars magnocellularis (PSm), nucleus ventrolateralis of torus semicircularis (TS), and nucleus isthmi (NI). Two types of periventricular neurons were labeled by injections to the APd. One of them had an apical dendrite ramifying at the stratum fibrosum et griseum superficiale (SFGS), with an axon that bifurcated into two branches at the stratum griseum centrale (SGC), and the other had an apical dendrite ramifying at the SGC. Two types of periventricular neurons were labeled after injections to the TS. One of them had an apical dendrite ramifying at the boundary between the stratum opticum (SO) and the SFGS, and the other had dendritic branches restricted to the stratum album centrale or stratum periventriculare. Injections to the PSm and NI labeled periventricular neurons of the same type with an apical dendrite ramifying at the SO and a characteristic axon that split into superficial and deep branches projecting to the PSm and NI, respectively. This cell type also possessed axonal branches that terminated within the tectum. These results indicate that periventricular efferent neurons can be classified into at least five types that possess type-specific axonal and dendritic morphologies. We also describe other tectal neurons labeled by the present injections.


Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer.
Progression of prostate cancer is believed to be dependent on angiogenesis induced by tumor cells. 3,3'-Diindolylmethane (DIM) has been shown to repress neovascularization in a Matrigel plug assay and inhibit cell proliferation, migration, invasion, and capillary tube formation of cultured human umbilical vein endothelial cells. However, the molecular mechanism, by which DIM inhibits angiogenesis and invasion, has not been fully elucidated. Therefore, we sought to explore the molecular mechanism by which DIM inhibits angiogenesis and invasion, specifically by investigating the role of angiogenic factors secreted by prostate cancer cells which control all steps of angiogenesis. We found that BioResponse DIM (B-DIM), a formulated DIM with higher bioavailability, inhibited angiogenesis and invasion by reducing the bioavailability of vascular endothelial growth factor (VEGF) via repressing extracellular matrix-degrading proteases, such as matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA), in human prostate cancer cells and reduced vascularity (angiogenesis) in vivo using Matrigel plug assay. We also found that B-DIM treatment inhibited DNA binding activity of nuclear factor-kappaB (NF-kappaB), which is known to mediate the expression of many NF-kappaB downstream target genes, including VEGF, IL-8, uPA, and MMP-9, all of which are involved in angiogenesis, invasion, and metastasis. Our data suggest that inhibition of NF-kappaB DNA binding activity by B-DIM contributes to the regulated bioavailability of VEGF by MMP-9 and uPA and, in turn, inhibits invasion and angiogenesis, which could be mechanistically linked with the antitumor activity of B-DIM as observed previously by our laboratory in a prostate cancer animal model.


Surface adsorption of sulfonated poly(phenylene sulfone)/C14TAB mixtures and its correlation with foam film stability.
Polyelectrolyte/surfactant mixtures of rigid monosulfonated poly(phenylene sulfone) (sPSO2-220) and tetradecyl trimethylammonium bromide (C14TAB) were investigated by surface tension, surface elasticity and foam film stability measurements. The results were compared to former measurements of polyelectrolyte/surfactant mixtures containing more flexible polyelectrolytes (PAMPS or PSS and C14TAB). For all polyelectrolyte/surfactant mixtures an increased surface adsorption in comparison to the pure surfactant was detected. Moreover, sPSO2-220/C14TAB mixtures showed a much higher surface activity and foam film stability than mixtures with more flexible polyelectrolytes. The results presented give insight into the surface adsorption and foam film formation of rigid polyelectrolyte/surfactant mixtures. Therefore, this study helps to understand the role of polyelectrolyte backbone rigidity in the formation and stabilization of foam films made from polyelectrolyte/surfactant mixtures.


Observation of dermal collagen fiber in wrinkled skin using polarization-resolved second-harmonic-generation microscopy.
Optical probe methods for in vivo assessments of cutaneous photoaging are necessary in fields such as anti-aging dermatology and skin cosmetic development. We investigated the relation between wrinkle direction and collagen orientation in ultraviolet-B-exposed (UVB-exposed) skin using polarization-resolved second-harmonic-generation (SHG) microscopy. A polarization anisotropic image of the SHG light indicated that wrinkle direction in UVB-exposed skin is predominantly parallel to the orientation of dermal collagen fibers. Furthermore, collagen orientation in post-UVB-exposed skin with few wrinkles changed from that of UVB-exposed wrinkled skin to that of no-UVB-exposed skin. The method proposed has the potential to become a powerful non-invasive tool for assessment of cutaneous photoaging.


Synergy between a plasminogen cascade and MMP-9 in autoimmune disease.
Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9-deficient mice to the skin disease. In addition, MMP-3-deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.


Simulations of ion permeation through a potassium channel: molecular dynamics of KcsA in a phospholipid bilayer.
Potassium channels enable K(+) ions to move passively across biological membranes. Multiple nanosecond-duration molecular dynamics simulations (total simulation time 5 ns) of a bacterial potassium channel (KcsA) embedded in a phospholipid bilayer reveal motions of ions, water, and protein. Comparison of simulations with and without K(+) ions indicate that the absence of ions destabilizes the structure of the selectivity filter. Within the selectivity filter, K(+) ions interact with the backbone (carbonyl) oxygens, and with the side-chain oxygen of T75. Concerted single-file motions of water molecules and K(+) ions within the selectivity filter of the channel occur on a 100-ps time scale. In a simulation with three K(+) ions (initially two in the filter and one in the cavity), the ion within the central cavity leaves the channel via its intracellular mouth after approximately 900 ps; within the cavity this ion interacts with the Ogamma atoms of two T107 side chains, revealing a favorable site within the otherwise hydrophobically lined cavity. Exit of this ion from the channel is enabled by a transient increase in the diameter of the intracellular mouth. Such "breathing" motions may form the molecular basis of channel gating.


Routine intra-operative trans-oesophageal echocardiography yields better outcomes in surgical repair of CHD.
Trans-oesophageal echocardiographic imaging is valuable in the pre- and post-operative evaluation of children and adults with CHD; however, the frequency by which trans-oesophageal echocardiography guides the intra-operative course of patients is unknown. We retrospectively reviewed 1748 intra-operative trans-oesophageal echocardiograms performed between 1 October, 2005 and 31 December, 2010, and found 99 cases (5.7%) that required return to bypass, based in part upon the intra-operative echocardiographic findings. The diagnoses most commonly requiring further repair and subsequent imaging were mitral valve disease (20.9%), tricuspid valve disease (16.0%), atrioventricular canal defects (12.0%), and pulmonary valve disease (14.1%). The vast majority of those requiring immediate return to bypass benefited by avoiding subsequent operations and longer lengths of hospital stay. A total of 14 patients (0.8%) who received routine imaging required further surgical repair within 1 week, usually due to disease that developed over ensuing days. Patients who had second post-operative trans-oesophageal echocardiograms in the operating room rarely required re-operations, confirming the benefit of routine intra-operative imaging. This study represents a large single institutional review of intra-operative trans-oesophageal echocardiography, and confirms its applicability in the surgical repair of patients with CHD. Routine imaging accurately identifies patients requiring further intervention, does not confer additional risk of mortality or prolonged length of hospital stay, and prevents subsequent operations and associated sequelae in a substantial subset of patients. This study demonstrates the utility of echocardiography in intra-operative monitoring of surgical repair and highlights patients who are most likely to require return to bypass, as well as the co-morbidities of such manipulations.


Actin cortex architecture regulates cell surface tension.
Animal cell shape is largely determined by the cortex, a thin actin network underlying the plasma membrane in which myosin-driven stresses generate contractile tension. Tension gradients result in local contractions and drive cell deformations. Previous cortical tension regulation studies have focused on myosin motors. Here, we show that cortical actin network architecture is equally important. First, we observe that actin cortex thickness and tension are inversely correlated during cell-cycle progression. We then show that the actin filament length regulators CFL1, CAPZB and DIAPH1 regulate mitotic cortex thickness and find that both increasing and decreasing thickness decreases tension in mitosis. This suggests that the mitotic cortex is poised close to a tension maximum. Finally, using a computational model, we identify a physical mechanism by which maximum tension is achieved at intermediate actin filament lengths. Our results indicate that actin network architecture, alongside myosin activity, is key to cell surface tension regulation.


Transplantation of allogeneic bone marrow without graft-versus-host disease using total lymphoid irradiation.
Bone marrow (BM) and skin allografts from C57BL/Ka (H-2b/b) mice were transplanted to BALB/c (H-2d/d) recipients treated with total lymphoid irradiation (TLI), whole-body irradiation (WBI), or fractionated thymic irradiation TLI prolonged skin allograft survival about five times as long as that in untreated controls, and allowed for permanent engraftment of BM cells in approximately equal to 90% of recipients. None of the BM recipients showed clinical signs of graft-versus-host disease (GVHD) (diarrhea, weight loss, hunched back, etc.). On the other hand, recipients given WBI and allogeneic BM cells developed severe clinical GVHD. The majority of the latter recipients died within 12 days after BM transplantation, and 95% died within 61 days. Although TLI protected BALB/c mice against GVHD induced by BM cells, all recipients given TLI and allogeneic spleen cells developed lethal GVHD. Thymic irradiation alone marginally prolonged skin allograft survival, and did not allow for allogeneic BM engraftment. These results suggest that TLI may be a useful regimen in clinical BM transplantation, since this form of radiotherapy is used extensively in humans and has few severe side effects.


Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean.
Mycobacterium tuberculosis is the principal etiologic agent of human tuberculosis. It has no environmental reservoir and is believed to have co-evolved with its host over millennia. This is supported by skeletal evidence of the disease in early humans, and inferred from M. tuberculosis genomic analysis. Direct examination of ancient human remains for M. tuberculosis biomarkers should aid our understanding of the nature of prehistoric tuberculosis and the host/pathogen relationship. We used conventional PCR to examine bone samples with typical tuberculosis lesions from a woman and infant, who were buried together in the now submerged site of Atlit-Yam in the Eastern Mediterranean, dating from 9,250-8,160 years ago. Rigorous precautions were taken to prevent contamination, and independent centers were used to confirm authenticity of findings. DNA from five M tuberculosis genetic loci was detected and had characteristics consistent with extant genetic lineages. High performance liquid chromatography was used as an independent method of verification and it directly detected mycolic acid lipid biomarkers, specific for the M. tuberculosis complex. Human tuberculosis was confirmed by morphological and molecular methods in a population living in one of the first villages with evidence of agriculture and animal domestication. The widespread use of animals was not a source of infection but may have supported a denser human population that facilitated transmission of the tubercle bacillus. The similarity of the M. tuberculosis genetic signature with those of today gives support to the theory of a long-term co-existence of host and pathogen.


Prospective associations between internalising symptoms and educational achievement in youth: A monozygotic twin differences study.
Educational achievement is an independent predictor of many life outcomes and so it is important to understand its causes and correlates. Internalising symptoms, encompassing anxiety and depression symptoms, are one candidate influence. Using a prospective and genetically-informative design, the present study investigated the associations between internalising symptoms and educational achievement, controlling for IQ at age 7 years and socioeconomic status, among participants of the Twin and Early Development Study (up to N = 10,791). Internalising symptoms were measured by the parent-rated Anxiety Related Behaviours Questionnaire (ages 7, 9, 16 years), and educational attainment were indexed by UK-wide standardized examination results at ages 16 and 18 years, and self-reported transition to university education. Negative affect was the only internalising symptom subtype that was uniquely associated with academic underachievement at all timepoints, from mid-adolescence to early adulthood. The association between negative affect and achievement became non-significant when using MZ twin difference scores, suggesting that the majority of the relationship is accounted for by genetic and shared environmental effects. Limitations include the reliance on parent-reported internalising symptoms. Negative affect in youth may be an important marker of later academic underachievement. Findings suggest that academic underachievement is not simply a consequence of the disruption caused by negative affect symptoms and therefore educational interventions may be required to optimise outcomes.


The Importance of Highly Connected Building Units in Reticular Chemistry: Thoughtful Design of Metal-Organic Frameworks.
The prediction of crystal structures assembled in three dimensions has been considered for a long time, simultaneously as a chemical wasteland and a certain growth point of the chemistry of the future. Less than 30 years after Roald Hoffmann's statement, we can categorically affirm that the elevation of reticular chemistry and the introduction of metal-organic frameworks (MOFs) significantly tackled this tridimensional assembly issue. MOFs result from the assembly of organic polytopic organic ligands bridging metal nodes, clusters, chains, or layers together into mostly three-periodic open frameworks. They can exhibit extremely high porosity and offer great potential as revolutionary catalysts, drug carrier systems, sensors, smart materials, and, of course, separation agents. Overall, the progressive development of reticular chemistry has been a game changer in materials chemistry during the last 25 years.Such diverse properties often result not only from the selected organic and inorganic molecular building blocks (MBBs) but also from their distribution within the framework. Indeed, the size and shape of the porous system, as well as the location of active sites influence the overall properties. Therefore, in the continuity of achieving the crystallization of three-periodic structures, chemists and crystal engineers faced the next challenge, as summarized by John Maddox: "it remains in general impossible to predict the structure of even the simplest crystallographic solids from knowledge of their chemical composition". This is where rational design takes place.In this Account, we detail three specific approaches developed by our group to facilitate the design and assembly of finely tuned MOFs. All are based on careful geometrical consideration and a deep study and understanding of the existing nets and topologies. We recognized that highly connected nets, if possible, edge-transitive, are ideal blueprints because their number is limited in contrast to nets with lower connectivity. Therefore, we embarked on taking advantage of existing highly connected MBBs, or, in parallel, promoting their formation to meet our requirements. This is achieved by utilizing externally decorated metal-organic polyhedra as supermolecular building blocks (SBBs), serving as a net-coding building unit, comprising the requisite connectivity and directional information coding for the chosen nets. The SBB approach allowed the synthesis of several families of SBB-based MOFs, including fcu, rht, and gea-MOFs, that are detailed here.The second strategy is directly inherited from the success of the SBB approach. In seeking highly connected building units, our group naturally expanded its research focus to nets that can be deconstructed into layers, pillared in various ways. In the supermolecular building layer (SBL) approach, the layers have an almost infinite connectivity, and the framework backbone is fixed in two dimensions while the third is free for pillar expansion and functionalization. The cases of trigonal pillaring leading to rtl, eea, and apo MOFs as well as the quadrangular pillaring leading to a family of tbo-MOFs are discussed here, along with recent cases of highly connected pillars in pek and aea-MOFs.Finally, our experience with highly coordinated MBBs led us to develop a novel way to use them as secondary building units of lower connectivity and unlock the possibility of assembling a novel class of zeolite-like MOFs (ZMOFs). The case of the Zr-sod-ZMOFs designed through a cantellation strategy is described as a future leading direction of MOF design.


A randomized comparison of high-charge right unilateral electroconvulsive therapy and bilateral electroconvulsive therapy in older depressed patients who failed to respond to 5 to 8 moderate-charge right unilateral treatments.
Electroconvulsive therapy (ECT) is the treatment of choice in some older patients with severe depression. When compared with younger depressed patients, older patients have been shown to be as likely to respond to ECT but more likely to develop cognitive impairment. This study addresses whether adults aged 50 years and over who have already failed to respond to at least 5 moderate-charge right unilateral (RUL) ECT treatments (150% above seizure threshold) are more likely to benefit from a switch to high-charge RUL ECT (450% above threshold) or to bilateral (BL) ECT. Twenty-four patients who were treated with 5 to 8 moderate-charge RUL ECT treatments and who failed to improve sufficiently were randomly assigned to receive either BL ECT (N = 11) or high-charge RUL ECT (N = 13). Depressive (24-item Hamilton Rating Scale for Depression) and cognitive scores (Mini-Mental State Examination [MMSE]) were compared under double-blind conditions at 3 phases of treatment. Patients in the BL ECT group exhibited significantly greater cognitive impairment (mean MMSE score decrease of 1.13) than those receiving high-charge RUL ECT (mean MMSE increase of 1.71). There were no statistically significant differences in clinical response to BL or high-charge RUL ECT (63.6% and 61.5%, respectively) or in depressive symptom remission (18.1% and 46.2%). These results suggest that older patients who fail to respond to moderate-charge RUL ECT may benefit from a switch to high-charge RUL ECT rather than BL ECT. Larger future studies will be needed to compare clinical response in patients switched from moderate-dose RUL ECT to higher-dose RUL or to BL ECT.


Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of lactate dehydrogenase 5 and pyruvate dehydrogenase.
For a long time now, glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. Recent data nevertheless suggest that other molecules, such as monocarboxylates (lactate and pyruvate mainly) could be suitable substrates. Although monocarboxylates poorly cross the blood brain barrier (BBB), such substrates could replace glucose if produced locally. The two key enzymatiques systems required for the production of these monocarboxylates are lactate dehydrogenase (LDH; EC18.104.22.168) that catalyses the interconversion of lactate and pyruvate and the pyruvate dehydrogenase complex that irreversibly funnels pyruvate towards the mitochondrial TCA and oxydative phosphorylation. In this article, we show, with monoclonal antibodies applied to post-mortem human brain tissues, that the typically glycolytic isoenzyme of lactate dehydrogenase (LDH-5; also called LDHA or LDHM) is selectively present in astrocytes, and not in neurons, whereas pyruvate dehydrogenase (PDH) is mainly detected in neurons and barely in astrocytes. At the regional level, the distribution of the LDH-5 immunoreactive astrocytes is laminar and corresponds to regions of maximal 2-deoxyglucose uptake in the occipital cortex and hippocampus. In hippocampus, we observed that the distribution of the oxidative enzyme PDH was enriched in the neurons of the stratum pyramidale and stratum granulosum of CA1 through CA4, whereas the glycolytic enzyme LDH-5 was enriched in astrocytes of the stratum moleculare, the alveus and the white matter, revealing not only cellular, but also regional, selective distributions. The fact that LDH-5 immunoreactivity was high in astrocytes and occurred in regions where the highest uptake of 2-deoxyglucose was observed suggests that glucose uptake followed by lactate production may principally occur in these regions. These observations reveal a metabolic segregation, not only at the cellular but also at the regional level, that support the notion of metabolic compartmentalization between astrocytes and neurons, whereby lactate produced by astrocytes could be oxidized by neurons.


A streamlined solution for processing, elucidating and quality control of cyclobutane pyrimidine dimer sequencing data.
UV radiation may lead to melanoma and nonmelanoma skin cancers by causing helix-distorting DNA damage such as cyclobutane pyrimidine dimers (CPDs). These DNA lesions, if located in important genes and not repaired promptly, are mutagenic and may eventually result in carcinogenesis. Examining CPD formation and repair processes across the genome can shed light on the mutagenesis mechanisms associated with UV damage in relevant cancers. We recently developed CPD-Seq, a high-throughput and single-nucleotide resolution sequencing technique that can specifically capture UV-induced CPD lesions across the genome. This novel technique has been increasingly used in studies of UV damage and can be adapted to sequence other clinically relevant DNA lesions. Although the library preparation protocol has been established, a systematic protocol to analyze CPD-Seq data has not been described yet. To streamline the various general or specific analysis steps, we developed a protocol named CPDSeqer to assist researchers with CPD-Seq data processing. CPDSeqer can accommodate both a single- and multiple-sample experimental design, and it allows both genome-wide analyses and regional scrutiny (such as of suspected UV damage hotspots). The runtime of CPDSeqer scales with raw data size and takes roughly 4 h per sample with the possibility of acceleration by parallel computing. Various guiding graphics are generated to help diagnose the performance of the experiment and inform regional enrichment of CPD formation. UV damage comparison analyses are set forth in three analysis scenarios, and the resulting HTML pages report damage directional trends and statistical significance. CPDSeqer can be accessed at https://github.com/shengqh/cpdseqer .