Writing treatment for aphasia: a texting approach.
Treatment studies have documented the therapeutic and functional value of lexical writing treatment for individuals with severe aphasia. The purpose of this study was to determine whether such retraining could be accomplished using the typing feature of a cellular telephone, with the ultimate goal of using text messaging for communication. A 31-year-old man with persistent Broca's aphasia, severe apraxia of speech, global dysgraphia, and right hemiparesis participated in this study. Using a multiple baseline design, relearning and maintenance of single-word spellings (and oral naming) of targeted items were examined in response to traditional Copy and Recall Treatment (CART) for handwriting and a new paradigm using 1-handed typing on a cell phone keyboard (i.e., a texting version of CART referred to as T-CART). Marked improvements were documented in spelling and spoken naming trained in either modality, with stronger maintenance for handwriting than cell phone typing. Training resulted in functional use of texting that continued for 2 years after treatment. These results suggest that orthographic retraining using a cell phone keyboard has the potential to improve spelling knowledge and provide a means to improve functional communication skills. Combined training with both handwriting and cell phone typing should be considered in order to maximize the durability of treatment effects.


Comparison of the effects of a high- and normal-casein breakfast on satiety, 'satiety' hormones, plasma amino acids and subsequent energy intake.
The present study compared the effects of a high- and normal-casein-protein breakfast on satiety, 'satiety' hormones, plasma amino acid responses and subsequent energy intake. Twenty-five healthy subjects (BMI 23.9 (SEM 0.3) kg/m2; age 22 (SEM 1) years) received a subject-specific standardised breakfast (20% of daily energy requirements): a custard with casein as the single protein source with either 10, 55 and 35 (normal-casein breakfast) or 25, 55 and 20 (high-casein breakfast) % of energy (En%) from protein, carbohydrate and fat respectively in a randomised, single-blind design. Appetite profile (visual analogue scale; VAS), plasma glucose, insulin, glucagon-like peptide 1, ghrelin and amino acid concentrations were determined for 4 h; here the sensitive moment in time for lunch was determined. Subjects came for a second set of experiments and received the same custards for breakfast, and an ad libitum lunch was offered at 180 min after breakfast; energy intake was assessed. There were increased scores of fullness and satiety after the 25 En% casein-custard compared with the 10 En% casein-custard, particularly at 180 min (26 (SEM 4) v. 11 (SEM 5) mm VAS; P<0.01) and 240 min (13 (SEM 5) v. -1 (SEM 5) mm VAS; P<0.01). This coincided with prolonged elevated plasma amino acid concentrations; total amino acids and branched-chain amino acids were higher after the 25 En% casein-custard compared with the 10 En% casein-custard at 180 and 240 min (P<0.001). There was no difference in energy intake (3080 (SEM 229) v. 3133 (SEM 226) kJ for 25 En% and 10 En% respectively; NS) from the ad libitum lunch. In conclusion, a breakfast with 25% of energy from casein is rated as being more satiating than a breakfast with 10% of energy from casein at 3 and 4 h after breakfast, coinciding with prolonged elevated concentrations of plasma amino acids, but does not reduce subsequent energy intake.


Amine dehydrogenases: efficient biocatalysts for the reductive amination of carbonyl compounds.
Amines constitute the major targets for the production of a plethora of chemical compounds that have applications in the pharmaceutical, agrochemical and bulk chemical industries. However, the asymmetric synthesis of α-chiral amines with elevated catalytic efficiency and atom economy is still a very challenging synthetic problem. Here, we investigated the biocatalytic reductive amination of carbonyl compounds employing a rising class of enzymes for amine synthesis: amine dehydrogenases (AmDHs). The three AmDHs from this study - operating in tandem with a formate dehydrogenase from Candida boidinii (Cb-FDH) for the recycling of the nicotinamide coenzyme - performed the efficient amination of a range of diverse aromatic and aliphatic ketones and aldehydes with up to quantitative conversion and elevated turnover numbers (TONs). Moreover, the reductive amination of prochiral ketones proceeded with perfect stereoselectivity, always affording the (R)-configured amines with more than 99% enantiomeric excess. The most suitable amine dehydrogenase, the optimised catalyst loading and the required reaction time were determined for each substrate. The biocatalytic reductive amination with this dual-enzyme system (AmDH-Cb-FDH) possesses elevated atom efficiency as it utilizes the ammonium formate buffer as the source of both nitrogen and reducing equivalents. Inorganic carbonate is the sole by-product.


Functional characterization of the Mycobacterium tuberculosis serine/threonine kinase PknJ.
Eukaryotic-like Ser/Thr protein kinases (STPKs) are present in many bacterial species, where they control various physiological and virulence processes by enabling microbial adaptation to specific environmental signals. PknJ is the only member of the 11 STPKs identified in Mycobacterium tuberculosis that still awaits characterization. Here we report that PknJ is a functional kinase that forms dimers in vitro, and contains a single transmembrane domain. Using a high-density peptide-chip-based technology, multiple potential mycobacterial targets were identified for PknJ. We confirmed PknJ-dependent phosphorylation of four of these targets: PknJ itself, which autophosphorylates at Thr(168), Thr(171) and Thr(173) residues; the transcriptional regulator EmbR; the methyltransferase MmaA4/Hma involved in mycolic acid biosynthesis; and the dipeptidase PepE, whose encoding gene is located next to pknJ in the mycobacterial genome. Our results provide a number of candidate phospho-targets for PknJ and possibly other mycobacterial STPKs that could be studied to investigate the role of STPKs in M. tuberculosis physiology and virulence.


Morphometric variations in the grasshopper, Chromacris speciosa from two localities of Pernambuco in northeastern Brazil.
Abstract The present study describes morphometric variations in the grasshopper, Chromacris speciosa (Thunberg, 1824) (Orthoptera: Acridoidea: Romaleidae) from two locations in the state of Pernambuco, Brazil. The distance between the sites chosen for collections (Recife and São Lourenço da Mata) is approximately 16 km. The investigation was based on a comparative study of external morphological characteristics of the grasshoppers. Morphometric measurements took into account the different body parts and appendages. Statistical analysis of the measurements revealed significant differences in the size of the specimens between the two locations. Homogeneity tests of the covariance and equality matrices between mean vectors of the results revealed that the grasshopper populations in Recife and São Lourenço da Mata are distinctly different. These findings provide morphological evidence for intraspecific variation in morphological characteristics of the C. speciosa populations from the two locations.


Perceiving expressions of emotion: What evidence could bear on questions about perceptual experience of mental states?
What evidence could bear on questions about whether humans ever perceptually experience any of another's mental states, and how might those questions be made precise enough to test experimentally? This paper focusses on emotions and their expression. It is proposed that research on perceptual experiences of physical properties provides one model for thinking about what evidence concerning expressions of emotion might reveal about perceptual experiences of others' mental states. This proposal motivates consideration of the hypothesis that categorical perception of expressions of emotion occurs, can be facilitated by information about agents' emotions, and gives rise to phenomenal expectations. It is argued that the truth of this hypothesis would support a modest version of the claim that humans sometimes perceptually experience some of another's mental states. Much available evidence is consistent with, but insufficient to establish, the truth of the hypothesis. We are probably not yet in a position to know whether humans ever perceptually experience others' mental states.


Green tea protection of hypoxia/reoxygenation injury in cultured cardiac cells.
Antioxidant-rich diets exert a protective effect in diseases involving oxidative damage. Among dietary components, green tea is an excellent source of antioxidants. In this study, cultured neonatal rat cardiomyocytes were used to clarify the protective effect of a green tea extract on cell damage and lipid peroxidation induced by different periods of hypoxia followed by reoxigenation. Cultures of neonatal rat cardiomyocytes were exposed to 2--8 hr hypoxia, eventually followed by reoxygenation, in the absence or presence of alpha-tocopherol or green tea. LDH release and the production of conjugated diene lipids were measured, and appeared linearly related to the duration of hypoxia. During hypoxia, both LDH release and conjugated diene production were reduced by alpha-tocopherol and, in a dose dependent manner, by green tea, the 50 &mgr;g/ml being the most effective dose. Reoxygenation caused no further increase in LDH leakage, while it caused a significant increase in conjugate dienes, which absolute value was lower in antioxidant supplemented cells. Anyway, the ratio between conjugated diene production after hypoxia and after reoxygenation was similar in all groups, indicating that the severity of free radical-induced reoxygenation injury is proportional to the severity of previous hypoxic injury. Since hypoxic damage is reduced by alpha-tocopherol and green tea, our data suggest that any nutritional intervention to attenuate reoxygenation injury must be directed toward the attenuation of the hypoxic injury. Therefore, recommendations about a high dietary intake of antioxidants may be useful not only in the prevention, but also in the reduction of cardiac injury following ischemia.


Endogenous GFAP-positive neural stem/progenitor cells in the postnatal mouse cortex are activated following traumatic brain injury.
Interest in promoting regeneration of the injured nervous system has recently turned toward the use of endogenous stem cells. Elucidating cues involved in driving these precursor cells out of quiescence following injury, and the signals that drive them toward neuronal and glial lineages, will help to harness these cells for repair. Using a biomechanically validated in vitro organotypic stretch injury model, cortico-hippocampal slices from postnatal mice were cultured and a stretch injury equivalent to a severe traumatic brain injury (TBI) applied. In uninjured cortex, proliferative potential under in vitro conditions is virtually absent in older slices (equivalent postnatal day 15 compared to 8). However, following a severe stretch injury, this potential is restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human glial fibrillary acidic protein (GFAP) promoter, we show that GFAP+ cells account for the majority of proliferating neurospheres formed, and that these cells are likely to arise from the cortical parenchyma and not from the subventricular zone. Moreover, we provide evidence for a correlation between upregulation of sonic hedgehog signaling, a pathway known to regulate stem cell proliferation, and this restoration of regenerative potential following TBI. Our results indicate that a source of quiescent endogenous stem cells residing in the cortex and subcortical tissue proliferate in vitro following TBI. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. This raises the possibility of using this endogenous source of stem cells for repair following TBI.


A number no greater than the sum of its parts: the use and abuse of heritability.
Though widely used in quantitative genetics, in the study of human variation perhaps no statistic is more easily misinterpreted than heritability. While the contribution of genetic heritage to complex biological and behavioral phenotypes cannot be lightly dismissed, nonetheless we remain profoundly ignorant of how that legacy plays out in any environmental context. To be sure, it is not reducible to a single number. Nor does the preference among anthropologists for analyzing biological rather than behavioral phenotypes improve what heritability can reasonably say about the sources of human variation. This paper discusses the meaning of heritability, the methods for its estimation, the fallacies underlying its misuse, and its utility for inquiries in evolutionary anthropology and epidemiology. Progress in anthropological genetics will be realized through greater sophistication in study designs, including the measurement of environmental (physical and sociocultural) variation and the judicious choice of phenotypes for study. Elucidating the ontogenetic processes underlying adaptive plasticity is particularly critical to understanding the evolution of human biological variation. Such advancements will also shed light on the feasibility of genotype-targeted biomedical treatments. Failure to appreciate the limits of such approaches can divert resources from demonstrably effective environmentally based health interventions that benefit entire populations. Simplistic notions of genetic determinism should be challenged for the sake of our theories and the well-being of larger communities. As exemplified by the work of Frank B. Livingstone, anthropological genetics is at its best when incorporating anthropology into the study of human phenotypic variation.


Utilization of third molars in the orthodontic treatment of skeletal class III subjects with severe lateral deviation: case report.
This clinical report discusses the importance and use of third molars in the adult patient by presenting a case in which their use during orthodontic treatment allowed occlusal improvement. SUBJECT AND TREATMENT PLAN: The patient was a Japanese adolescent boy who had a skeletal Class III malocclusion with severe lateral deviation of the mandible, significant loss of posterior occlusal vertical dimension, due to premature loss of the maxillary and mandibular left first molars, and furthermore, both first molars had advanced carious lesions that had resulted in reduced crown heights and bilateral chewing surfaces. The mandible had shifted to the left, with a bilateral chewing pattern and a lack of posterior vertical alveolar height, which in turn had produced an abnormal occlusal plane and curve of Spee. The maxillary arch was expanded, the maxilla was moved downward and forward, and the mandible was moved slightly backward and rotated open to increase posterior vertical alveolar and crown height. The reconstruction of a functional occlusal plane was achieved by uprighting the posterior teeth to correct asymmetric posterior vertical alveolar and crown height, using a full multibracket system incorporating four third molars and closing the space from the missing first molars and extraction of the questionable first molars. A normal overbite and overjet and adequate posterior support and anterior guidance were established, achieving a better intercuspation of the posterior teeth. A favorable perioral environment was created, with widened tongue space to produce an adequate airway. A well-balanced lip profile and almost symmetric face were achieved using the four wisdom teeth without extraction of the four premolars. Subsequent mandibular growth, with development of posterior vertical alveolar height and temporomandibular joint adaptation, has resulted in an almost symmetric posterior vertical height and joint structure between right and left sides. These factors have contributed to the occlusal stability maintained for more than 5 years. In the growing patient, with missing and/or early advanced caries of the first molars, it may be more beneficial to plan occlusal improvement through extraction of the questionable first molar rather than premolar extraction. This method of treatment can equalize posterior vertical dimension and does not restrict tongue space. In addition, this treatment method addresses the clinician's concern about postorthopedic relapse due to tongue habits and eruption of the third molars.


Primary pneumococcal peritonitis as a presenting feature of HIV infection.
We report a case of primary pneumococcal peritonitis in a 28-year old previously healthy woman. There are no previously reported associations between this rare form of spontaneous peritonitis and HIV infection, and it is usually associated with underlying cirrhosis, ascites or other immune compromise. In this case this was the presenting illness of HIV infection. When atypical infections such as this arise in previously healthy adults the clinician must have a high index of suspicion of HIV or other underlying immunodeficiency.


Rapid affinity chromatographic isolation method for LDL in human plasma by immobilized chondroitin-6-sulfate and anti-apoB-100 antibody monolithic disks in tandem.
Low-density lipoprotein (LDL) is considered the major risk factor for the development of atherosclerotic cardiovascular diseases (ASCVDs). A novel and rapid method for the isolation of LDL from human plasma was developed utilising affinity chromatography with monolithic stationary supports. The isolation method consisted of two polymeric monolithic disk columns, one immobilized with chondroitin-6-sulfate (C6S) and the other with apolipoprotein B-100 monoclonal antibody (anti-apoB-100 mAb). The first disk with C6S was targeted to remove chylomicrons, very-low-density lipoprotein (VLDL) particles, and their remnants including intermediate-density lipoprotein (IDL) particles, thus allowing the remaining major lipoprotein species, i.e. LDL, lipoprotein(a) (Lp(a)), and high-density lipoprotein (HDL) to flow to the anti-apoB-100 disk. The second disk captured LDL particles via the anti-apoB-100 mAb attached on the disk surface in a highly specific manner, permitting the selective LDL isolation. The success of LDL isolation was confirmed by different techniques including quartz crystal microbalance. In addition, the method developed gave comparable results with ultracentrifugation, conventionally used as a standard method. The reliable results achieved together with a short isolation time (less than 30 min) suggest the method to be suitable for clinically relevant LDL functional assays.


Vpx is critical for SIVmne infection of pigtail macaques.
Viral protein X (Vpx) of SIV has been reported to be important for establishing infection in vivo. Vpx has several different activities in vitro, promoting preintegration complex import into the nucleus in quiescent lymphocytes and overcoming a block in reverse transcription in macrophages. Vpx interacts with the DDB1-CUL4-DCAF1 E3 ligase complex, which may or may not be required for the ascribed functions. The goal of the current study was to determine whether these activities of Vpx are important in vivo. An infectious, pathogenic clone of SIVmne was used to examine correlations between Vpx functions in vitro and in vivo. Three previously described HIV-2 Vpx mutants that were shown to be important for nuclear import of the preintegration complex in quiescent lymphocytes were constructed in SIVmne: A vpx-deleted virus, a truncation of Vpx at amino acid 102 that deletes the C-terminal proline-rich domain (X(102)), and a mutant with tyrosines 66, 69, and 71 changed to alanine (X(y-a)). All mutant viruses replicated similarly to wild type SIVmne027 in primary pigtail macaque PBMCs, and were only slightly retarded in CEMx174 cells. However, all the vpx mutant viruses were defective for replication in both human and pigtail monocyte-derived macrophages. PCR assays demonstrated that the efficiency of reverse transcription and the levels of viral integration in macrophages were substantially reduced for the vpx mutant viruses. In vitro, the X(y-a) mutant, but not the X(102) mutant lost interaction with DCAF1. The wild type SIVmne027 and the three vpx mutant SIVs were inoculated by the intra-rectal route into pigtail macaques. Peak levels of plasma viremia of the vpx mutant SIVs were variable, but consistently lower than that observed in macaques infected with wild type SIVmne. In situ hybridization for SIV demonstrated that compared to wild type SIVmne infected macaques five of the six animals inoculated with the vpx mutant SIVs had only low levels of SIV-expressing cells in the rectum, most intestinal epithelial tissues, spleen, and mesenteric and peripheral nodes. This work demonstrates that the activities of Vpx to overcome restrictions in culture in vitro are also likely to be important for establishment of infection in vivo and suggest that both the nuclear localization and DCAF1-interaction functions of Vpx are critical in vivo.


Present and Future of Surface-Enhanced Raman Scattering.
The discovery of the enhancement of Raman scattering by molecules adsorbed on nanostructured metal surfaces is a landmark in the history of spectroscopic and analytical techniques. Significant experimental and theoretical effort has been directed toward understanding the surface-enhanced Raman scattering (SERS) effect and demonstrating its potential in various types of ultrasensitive sensing applications in a wide variety of fields. In the 45 years since its discovery, SERS has blossomed into a rich area of research and technology, but additional efforts are still needed before it can be routinely used analytically and in commercial products. In this Review, prominent authors from around the world joined together to summarize the state of the art in understanding and using SERS and to predict what can be expected in the near future in terms of research, applications, and technological development. This Review is dedicated to SERS pioneer and our coauthor, the late Prof. Richard Van Duyne, whom we lost during the preparation of this article.


Closed-string tachyon condensation and the worldsheet super-higgs effect.
Alternative gauge choices for worldsheet supersymmetry can elucidate dynamical phenomena obscured in the usual superconformal gauge. In the particular example of the tachyonic E8 heterotic string, we use a judicious gauge choice to show that the process of closed-string tachyon condensation can be understood in terms of a worldsheet super-Higgs effect. The worldsheet gravitino assimilates the goldstino and becomes a dynamical propagating field. Conformal, but not superconformal, invariance is maintained throughout.


Molecular dynamics studies of irradiation effects on hydrogen isotope diffusion through nickel crystals and grain boundaries.
Experiments indicated that tritium permeation in 316 austenitic stainless steel is enhanced by a factor of ∼2-5 after irradiation as compared to the ex-reactor results. To understand this enhancement, we have performed extensive molecular dynamics simulations to study the effects of both the grain boundary structure (Σ3{111}, Σ5{100} and Σ11{311}) and the nature of point defects (vacancy, interstitial, and Frenkel pair) on hydrogen diffusivities in an exemplar fcc metal (nickel). By deriving diffusivities from mean square displacement, all possible atomic jump paths encountered during real diffusion are realistically sampled. By performing extremely long simulations, the statistical errors typically associated with this method are also significantly reduced. We found that within grains, interstitial defects increase diffusivity whereas vacancies have almost no effects. This mechanism might explain hydrogen permeation enhancements in irradiated materials with coarse grains. The largest increase in hydrogen diffusivity was found at a certain combination of grain boundary and point defect. This suggests that permeability of materials with finer grains can also be enhanced by irradiation depending on whether the grain boundary character is skewed. Our results shed new light on the enhancement of tritium permeation in 316 stainless steels during reactor operations.


Estimating energy expenditure by heart-rate monitoring without individual calibration.
Heart rate monitoring has been shown to be a valid method for measuring free-living energy expenditure at the group level, but its use in large-scale studies is limited by the need for an individual calibration of the relationship between heart rate and energy expenditure. To determine whether energy expenditure can be estimated from heart rate monitoring without individual calibration in epidemiological studies. Our previously validated heart rate monitoring method relies on measuring individual calibration parameters obtained from resting energy expenditure and the regression line between energy expenditure and heart rate during exercise. We developed prediction equations for these parameters using easily measured variables in a population-based study of 789 individuals. The predictive ability of these parameters was tested in a separate population-based sample (N = 97). Physical activity level (PAL = total energy expenditure/basal metabolic rate) using the four estimated parameters was correlated with PAL using the measured parameters (r = 0.82, P < 0.01). Comparison of measured and estimated PAL showed that 97.9% of the scores were placed in the same or adjacent quartile. A combination of simple measurements and heart rate monitoring produces estimates of energy expenditure that are highly correlated with those obtained using full individual calibration. This simplification of the heart rate monitoring method could extend its use in ranking individuals in epidemiological studies.


Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease?
To report the third case of subacute cerebellar ataxia associated with metabotropic glutamate receptor type 1 autoantibodies (mGluR1-Abs), an uncommon syndrome known to be part of the group of paraneoplastic cerebellar degeneration syndromes linked to antineuronal antibodies and previously reported in only 2 other patients with long-term remission of Hodgkin lymphoma, and to discuss the underlying immunopathogenesis. Case report. University hospital. A 50-year-old woman admitted for acute severe isolated static and kinetic cerebellar syndrome. Magnetic resonance imaging of the brain showed diffuse abnormal hyperintensity in the whole cerebellum on fluid-attenuated inversion recovery and diffusion sequences. Results of the biological workup were negative for general inflammation, vitamin deficiency, and bacterial and viral infections. Immunohistochemical analysis of the serum and cerebrospinal fluid of the patient demonstrated staining for Purkinje cell bodies and the molecular layer of the cerebellum. Finally, mGluR1-Abs were detected in serum and cerebrospinal fluid by a cell-based assay. Complete clinical examination, thoracoabdominal-pelvic computed tomography, and whole-body fludeoxyglucose F 18-positron emission tomography failed to show any underlying tumor, including Hodgkin lymphoma. The disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months. Cerebellitis associated with mGluR1-Abs should be considered in the differential diagnosis of patients with subacute cerebellar ataxia. This first case without any tumor found suggests a possible idiopathic autoimmune rather than a paraneoplastic mechanism. In consideration of this possible primitive autoimmune ataxia involving the directly pathogenic mGluR1-Abs, immunoactive therapy should be initiated as early as possible.


Prevalence and seroprevalence of Plasmodium infection in Myanmar reveals highly heterogeneous transmission and a large hidden reservoir of infection.
Malaria incidence in Myanmar has significantly reduced over recent years, however, completeness and timeliness of incidence data remain a challenge. The first ever nationwide malaria infection and seroprevalence survey was conducted in Myanmar in 2015 to better understand malaria epidemiology and highlight gaps in Annual Parasite Index (API) data. The survey was a cross-sectional two-stage stratified cluster-randomised household survey conducted from July-October 2015. Blood samples were collected from household members for ultra-sensitive PCR and serology testing for P. falciparum and P. vivax. Data was gathered on demography and a priori risk factors of participants. Data was analysed nationally and within each of four domains defined by API data. Prevalence and seroprevalence of malaria were 0.74% and 16.01% nationwide, respectively. Prevalent infection was primarily asymptomatic P. vivax, while P. falciparum was predominant in serology. There was large heterogeneity between villages and by domain. At the township level, API showed moderate correlation with P. falciparum seroprevalence. Risk factors for infection included socioeconomic status, domain, and household ownership of nets. Three K13 P. falciparum mutants were found in highly prevalent villages. There results highlight high heterogeneity of both P. falciparum and P. vivax transmission between villages, accentuated by a large hidden reservoir of asymptomatic P. vivax infection not captured by incidence data, and representing challenges for malaria elimination. Village-level surveillance and stratification to guide interventions to suit local context and targeting of transmission foci with evidence of drug resistance would aid elimination efforts.


Pregnancy in a 24 year old Nigerian woman with chronic kidney disease: challenges and outcome.
There is increasing incidence and prevalence of chronic kidney disease worldwide. The developing countries including Nigeria are facing greater challenges because of the prevailing poverty and high burden of infectious diseases. There are various prevalent co-morbid conditions that influence and are influenced by the status of the kidney function of the patient. These conditions pose some peculiar challenges and management of the challenges will determine the outcome. The aim of this report is to highlight the chalIenges of pregnancy in women with chronic kidney disease and possible outcome. We report a 24 years Nigerian woman diagnosed with chronic kidney disease who presented with 10 weeks gestation and deteriorating kidney function. Her management was associated with various challenges including non adherance to medications and not regular to follow up visits. She later developed ecclampsia and had intra uterine fetal death. She had various interventional measures including haemodialysis. She recovered kidney function appreciably but has defaulted follow up since discharge.


Compression Therapy to Prevent Recurrent Cellulitis of the Leg.
Chronic edema of the leg is a risk factor for cellulitis. Daily use of compression garments on the leg has been recommended to prevent the recurrence of cellulitis, but there is limited evidence from trials regarding its effectiveness. In this single-center, randomized, nonblinded trial, we assigned participants with chronic edema of the leg and recurrent cellulitis, in a 1:1 ratio, to receive leg compression therapy plus education on cellulitis prevention (compression group) or education alone (control group). Follow-up occurred every 6 months for up to 3 years or until 45 episodes of cellulitis had occurred in the trial. The primary outcome was the recurrence of cellulitis. Participants in the control group who had an episode of cellulitis crossed over to the compression group. Secondary outcomes included cellulitis-related hospital admission and quality-of-life assessments. A total of 183 patients were screened, and 84 were enrolled; 41 participants were assigned to the compression group, and 43 to the control group. At the time of a planned interim analysis, when 23 episodes of cellulitis had occurred, 6 participants (15%) in the compression group and 17 (40%) in the control group had had an episode of cellulitis (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.59; P = 0.002; relative risk [post hoc analysis], 0.37; 95% CI, 0.16 to 0.84; P = 0.02), and the trial was stopped for efficacy. A total of 3 participants (7%) in the compression group and 6 (14%) in the control group were hospitalized for cellulitis (hazard ratio, 0.38; 95% CI, 0.09 to 1.59). Most quality-of-life outcomes did not differ between the two groups. No adverse events occurred during the trial. In this small, single-center, nonblinded trial involving patients with chronic edema of the leg and cellulitis, compression therapy resulted in a lower incidence of recurrence of cellulitis than conservative treatment. (Funded by Calvary Public Hospital Bruce; Australian and New Zealand Clinical Trials Registry number, ACTRN12617000412336.).


Ischemic acute kidney injury perturbs homeostasis of serine enantiomers in the body fluid in mice: early detection of renal dysfunction using the ratio of serine enantiomers.
The imbalance of blood and urine amino acids in renal failure has been studied mostly without chiral separation. Although a few reports have shown the presence of D-serine, an enantiomer of L-serine, in the serum of patients with severe renal failure, it has remained uncertain how serine enantiomers are deranged in the development of renal failure. In the present study, we have monitored serine enantiomers using a two-dimensional HPLC system in the serum and urine of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury. In the serum, the level of D-serine gradually increased after renal IRI in parallel with that of creatinine, whereas the L-serine level decreased sharply in the early phase after IRI. The increase of D-serine was suppressed in part by genetic inactivation of a D-serine-degrading enzyme, D-amino acid oxidase (DAO), but not by disruption of its synthetic enzyme, serine racemase, in mice. Renal DAO activity was detected exclusively in proximal tubules, and IRI reduced the number of DAO-positive tubules. On the other hand, in the urine, D-serine was excreted at a rate nearly triple that of L-serine in mice with sham operations, indicating that little D-serine was reabsorbed while most L-serine was reabsorbed in physiological conditions. IRI significantly reduced the ratio of urinary D-/L-serine from 2.82 ± 0.18 to 1.10 ± 0.26 in the early phase and kept the ratio lower than 0.5 thereafter. The urinary D-/L-serine ratio can detect renal ischemia earlier than kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL) in the urine, and more sensitively than creatinine, cystatin C, or the ratio of D-/L-serine in the serum. Our findings provide a novel understanding of the imbalance of amino acids in renal failure and offer a potential new biomarker for an early detection of acute kidney injury.


From ciphers to confidentiality: secrecy, openness and priority in science.
I make three related claims. First, certain seemingly secretive behaviours displayed by scientists and inventors are expression neither of socio-professional values nor of strategies for the maximization of the economic value of their knowledge. They are, instead, protective responses to unavoidable risks inherent in the process of publication and priority claiming. Scientists and inventors fear being scooped by direct competitors, but have also worried about people who publish their claims or determine their priority: journal editors or referees who may appropriate the claims in the manuscript they review or patent clerks who may claim or leak the inventions contained in the applications that cross their desks. Second, these protective responses point to the existence of an unavoidable moment of instability in any procedure aimed at establishing priority. Making things public is an inherently risky business and it is impossible, I argue, to ensure that priority may not be lost in the very process that is supposed to establish it. Third, I offer a brief archaeology of regimes and techniques of priority registration, showing the distinctly different definitions of priority developed by each system.


Water T2 as an early, global and practical biomarker for metabolic syndrome: an observational cross-sectional study.
Metabolic syndrome (MetS) is a highly prevalent condition that identifies individuals at risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Prevention of these diseases relies on early detection and intervention in order to preserve pancreatic β-cells and arterial wall integrity. Yet, the clinical criteria for MetS are insensitive to the early-stage insulin resistance, inflammation, cholesterol and clotting factor abnormalities that characterize the progression toward type 2 diabetes and atherosclerosis. Here we report the discovery and initial characterization of an atypical new biomarker that detects these early conditions with just one measurement. Water T2, measured in a few minutes using benchtop nuclear magnetic resonance relaxometry, is exquisitely sensitive to metabolic shifts in the blood proteome. In an observational cross-sectional study of 72 non-diabetic human subjects, the association of plasma and serum water T2 values with over 130 blood biomarkers was analyzed using bivariate, multivariate and logistic regression. Plasma and serum water T2 exhibited strong bivariate correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with fasting hyperinsulinemia, dyslipidemia and subclinical inflammation. Plasma water T2 exhibited 100% sensitivity and 87% specificity for detecting early insulin resistance in normoglycemic subjects, as defined by the McAuley Index. Sixteen normoglycemic subjects with early metabolic abnormalities (22% of the study population) were identified by low water T2 values. Thirteen of the 16 did not meet the harmonized clinical criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Low water T2 values were associated with increases in the mean concentrations of 6 of the 16 most abundant acute phase proteins and lipoproteins in plasma. Water T2 detects a constellation of early abnormalities associated with metabolic syndrome, providing a global view of an individual's metabolic health. It circumvents the pitfalls associated with fasting glucose and hemoglobin A1c and the limitations of the current clinical criteria for metabolic syndrome. Water T2 shows promise as an early, global and practical screening tool for the identification of individuals at risk for diabetes and atherosclerosis.


MVP and vaults: a role in the radiation response.
Vaults are evolutionary highly conserved ribonucleoproteins particles with a hollow barrel-like structure. The main component of vaults represents the 110 kDa major vault protein (MVP), whereas two minor vaults proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (vPARP) and the 240 kDa telomerase-associated protein-1 (TEP-1). Additionally, at least one small and untranslated RNA is found as a constitutive component. MVP seems to play an important role in the development of multidrug resistance. This particle has also been implicated in the regulation of several cellular processes including transport mechanisms, signal transmission and immune responses. Vaults are considered a prognostic marker for different cancer types. The level of MVP expression predicts the clinical outcome after chemotherapy in different tumour types. Recently, new roles have been assigned to MVP and vaults including the association with the insulin-like growth factor-1, hypoxia-inducible factor-1alpha, and the two major DNA double-strand break repair machineries: non-homologous endjoining and homologous recombination. Furthermore, MVP has been proposed as a useful prognostic factor associated with radiotherapy resistance. Here, we review these novel actions of vaults and discuss a putative role of MVP and vaults in the response to radiotherapy.


The analysis of simple and complex auditory signals in human auditory cortex: magnetoencephalographic evidence from M100 modulation.
Ecologically valid signals (e.g., vowels) have multiple components of substantially different frequencies and amplitudes that may not be equally cortically represented. In this study, we investigate a relatively simple signal at an intermediate level of complexity, two-frequency composite tones, a stimulus lying between simple sinusoids and ecologically valid signals such as speech. We aim to characterize the cortical response properties to better understand how complex signals may be represented in auditory cortex. Using magnetoencephalography, we assessed the sensitivity of the M100/N100m auditory-evoked component to manipulations of the power ratio of the individual frequency components of the two-frequency complexes. Fourteen right-handed subjects with normal hearing were scanned while passively listening to 10 complex and 12 simple signals. The complex signals were composed of one higher frequency and one lower frequency sinusoid; the lower frequency sinusoidal component was at one of the five loudness levels relative to the higher frequency one: -20, -10, 0, +10, +20 dB. The simple signals comprised all the complex signal components presented in isolation. The data replicate and extend several previous findings: (1) the systematic dependence of the M100 latency on signal intensity and (2) the dependence of the M100 latency on signal frequency, with lower frequency signals ( approximately 100 Hz) exhibiting longer latencies than higher frequency signals ( approximately 1000 Hz) even at matched loudness levels. (3) Importantly, we observe that, relative to simple signals, complex signals show increased response amplitude-as one might predict-but decreased M100 latencies. : The data suggest that by the time the M100 is generated in auditory cortex ( approximately 70 to 80 msecs after stimulus onset), integrative processing across frequency channels has taken place which is observable in the M100 modulation. In light of these data models that attribute more time and processing resources to a complex stimulus merit reevaluation, in that our data show that acoustically more complex signals are associated with robust temporal facilitation, across frequencies and signal amplitude level.


Dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features.
A 35-year-old Japanese man was admitted to the National Cancer Center, Tokyo, Japan, in December 2000, with a 2-month history of pain around the left thigh. Radiographs showed a poorly demarcated osteolytic lesion with focal mineralisation and endosteal scalloping in the left proximal femur. Biopsy showed a proliferation of highly anaplastic cells without any cartilaginous component. A wide excision of the left proximal femur with a replacement by endoprosthesis was carried out in February 2001 after treatment with methotrexate and 20 Gy radiation therapy. Pathological examination of the surgical specimen showed a focus of low-grade chondrosarcoma and the coexistence of telangiectatic osteosarcoma-like features. The patient was diagnosed with dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features. Lung metastasis appeared in July 2001 despite an adjuvant chemotherapy including methotrexate, cis-platinum and doxorubicin. The latest follow-up study in June 2004 showed multiple lung metastases. Establishing a definitive diagnosis of dedifferentiated chondrosarcoma may be difficult with limited small biopsy specimens. Dedifferentiated chondrosarcoma should be included in the differential diagnosis of osteolytic tumours with focal calcification and endosteal scalloping even if an extraosseous tumour component is not identified.


Visually Activating Pathogen Disgust: A New Instrument for Studying the Behavioral Immune System.
The emotion of disgust plays a key role in the behavioral immune system, a set of disease-avoidance processes constituting a frontline defense against pathogenic threats. In the context of growing research interest in disgust, as well as recognition of its role in several psychiatric disorders, there is need for an improved understanding of behavioral triggers of disgust and for adequate techniques to both induce disgust in experimental settings and to measure individual variability in disgust sensitivity. In this study, we sought to address these issues using a multi-stage, bottom-up approach that aimed first to determine the most widespread and effective elicitors of disgust across several cultures. Based on exploratory factor analysis of these triggers, revealing four main components of pathogen-related disgust, we then generated a novel visual stimulus set of 20 images depicting scenes of highly salient pathogen risk, along with paired control images that are visually comparable but lack the disgust trigger. We present a series of validation analyses comparing our new stimulus set (the Culpepper Disgust Image Set, C-DIS) with the most commonly used pre-existing set, a series of 7 images devised by Curtis et al. (2004). Disgust scores from participants who rated the two image sets were positively correlated, indicating cross-test concordance, but results also showed that our pathogen-salient images elicited higher levels of disgust and our control images elicited lower levels of disgust. These findings suggest that the novel image set is a useful and effective tool for use in future research, both in terms of priming disgust and for measuring individual differences in disgust sensitivity.


Investigation of Yersinia pestis Laboratory Adaptation through a Combined Genomics and Proteomics Approach.
The bacterial pathogen Yersinia pestis, the cause of plague in humans and animals, normally has a sylvatic lifestyle, cycling between fleas and mammals. In contrast, laboratory-grown Y. pestis experiences a more constant environment and conditions that it would not normally encounter. The transition from the natural environment to the laboratory results in a vastly different set of selective pressures, and represents what could be considered domestication. Understanding the kinds of adaptations Y. pestis undergoes as it becomes domesticated will contribute to understanding the basic biology of this important pathogen. In this study, we performed a parallel serial passage experiment (PSPE) to explore the mechanisms by which Y. pestis adapts to laboratory conditions, hypothesizing that cells would undergo significant changes in virulence and nutrient acquisition systems. Two wild strains were serially passaged in 12 independent populations each for ~750 generations, after which each population was analyzed using whole-genome sequencing, LC-MS/MS proteomic analysis, and GC/MS metabolomics. We observed considerable parallel evolution in the endpoint populations, detecting multiple independent mutations in ail, pepA, and zwf, suggesting that specific selective pressures are shaping evolutionary responses. Complementary LC-MS/MS proteomic data provide physiological context to the observed mutations, and reveal regulatory changes not necessarily associated with specific mutations, including changes in amino acid metabolism and cell envelope biogenesis. Proteomic data support hypotheses generated by genomic data in addition to suggesting future mechanistic studies, indicating that future whole-genome sequencing studies be designed to leverage proteomics as a critical complement.


Increased dissemination of dengue 2 virus in Aedes aegypti associated with concurrent ingestion of microfilariae of Brugia malayi.
We investigated whether concurrent ingestion of dengue 2 virus and microfilariae of Brugia malayi would increase viral infection and dissemination rates in Aedes aegypti. Infection rates were similar in mosquitoes that ingested virus alone or both virus and microfilariae concurrently. However, viral dissemination rates, as determined by recovery of dengue virus from both legs and bodies separately, were significantly greater in mosquitoes that ingested both agents concurrently than in those that ingested virus alone. This study confirms that vectorial capacity of a natural vector of an arbovirus may be enhanced by the concurrent ingestion of microfilariae.


Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study.
Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.


[Plummer-Vinson syndrome: report of a case and review of literature].
A 39-year-old woman was admitted to our hospital with an eight-month history of dyspnea on exertion, weakness and increasing fatigue. She reported repeated episodes of menometrorrhagia and underwent a myomectomy. She is not a vegetarian. Her menstrual bleeding: 3-5 days per month. Two months ago, she complained of burning sensation of the tongue upon swallowing food and noted brittle nails. She tolerated soft foods. On physical examination, she was pale; her nails were very thin, fragile and somewhat concave. Her oral examination showed angular stomatitis, depapillated tongue and glossitis. The clinical diagnosis was anemia and dysphagia. Laboratory tests were: Hb: 7.0g/dL, MCV: 57.42fL, MCH: 15.82 pg; leukocytes: 4,980; reticulocytes: 2.18%, reticulocyte index: 0.1%, serum iron: 21ug/dl, total iron binding capacity (TIBC): 286, transferrin saturation: 7% and serum ferritin: 27ng/ml. The peripheral blood smear showed anisocytosis and hypochromic microcytic cells. Thevenon test was negative. Abdominal ultrasound: uterine myoma. A barium swallow X-ray showed a 2-mm linear filling defect between the 4th and 5th cervical vertebrae in the anteroposterior and lateral view; it protruded from the anterior wall and reduced esophageal lumen by 60%. In the endoscopy, we found a fibrous web in the cricopharyngeal area. Serial dilatations were performed over a guidewire using Savary-Gilliard dilators with diameter up to 14 mm, improving dysphagia. She was treated with transfusional therapy and parenteral iron. She was discharged with ferrous sulfate and folic acid. The Plummer-Vinson syndrome, Paterson-Brown-Kelly or sideropenic dysphagia is characterized by dysphagia, irondeficiency anemia and upper esophageal web. The syndrome is described as very rare.


Occupational exposure to wood dust and risk of lung cancer in two population-based case-control studies in Montreal, Canada.
Wood dust is one of the oldest and one of the most common occupational exposures in the world. The present analyses examine the effect of lifetime exposure to wood dust in diverse occupational settings on lung cancer risk. We conducted two population-based case-control studies in Montreal: Study I (1979-1986) included 857 cases and two sets of controls (533 population and 1349 cancer controls), and Study II (1996-2001) comprised 736 cases and 894 population controls. Detailed job histories were obtained by interview and each job was evaluated by expert chemist-hygienists to estimate the likelihood and level of exposure to many substances, one of which was wood dust. Odds ratios (ORs) were computed in relation to different indices of exposure to wood dust, adjusting for several covariates including smoking. Three datasets were analysed: Study I with population controls, Study I with cancer controls, and Study II. The most frequently exposed occupations in our study population were in construction, timber and furniture making industries. We found increased risks of lung cancer for substantial cumulative exposure to wood dust in Study I with cancer controls, (OR = 1.4: 95% confidence interval 1.0;-2.0) and in Study II (OR = 1.7: 95% confidence interval 1.1-2.7). There were no excess risks of lung cancer in any of the three datasets among workers whose cumulative exposure was not substantial. These tendencies held equally within strata of low smokers and heavy smokers. There was evidence of increased risk of lung cancer among workers with substantial cumulative exposure to wood dust.


Immunomodulatory and antioxidant effects of pomegranate peel polysaccharides on immunosuppressed mice.
This work aims to analyze the immunomodulatory effect of pomegranate peel polysaccharides (PPP) on the immunosuppressed mice induced by cyclophosphamide (CTX). All the mice were divided into 6 groups randomly and the immunoprophylaxis mice were administrated with PPP [100, 200, 400 mg/(kg·d)] by gavage for consecutive 28 days. The results showed that PPP can slow down the decline of body weight and increase the immune organ index of the immunosuppressed mice. Compared to the model mice, the enzymatic activity of LDH (lactate dehydrogenase) and ACP (acid phosphatase) of the mice spleen administrated with PPP by gavage was enhanced significantly. PPP stimulated proliferation and secretion of splenic lymphocytes and markedly increased the immunoglobulin (Ig-A, Ig-G and Ig-M) expression and the release of cytokines (TNF-α, IL-2 and INF-γ) in cyclophosphamide-induced immunosuppressed mice. Hepatic antioxidant enzymatic activities of T-AOC (total antioxidant capacity), T-SOD (total superoxide dismutase), GSH-PX (glutathione peroxidase) and CAT (catalase) were markedly increased when the mice were administrated with high dosage of PPP. So it can be concluded that PPP could be used as an efficacious adjacent immunopotentiating therapy or an alternative means in lessening chemotherapy-induced immunosuppression, and also can be utilized as immunostimulants for food and pharmaceutical industries.


Parasite Manipulation of the Invariant Chain and the Peptide Editor H2-DM Affects Major Histocompatibility Complex Class II Antigen Presentation during Toxoplasma gondii Infection.
Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, namely, the MHC-II-associated invariant chain (Ii or CD74) and the peptide editor H2-DM, in professional antigen-presenting cells (pAPCs). Genetic deletion of CD74 restored the ability of infected dendritic cells to present a parasite antigen in the context of MHC-II in vitro. CD74 mRNA and protein levels were, surprisingly, elevated in infected cells, whereas MHC-II and H2-DM expression was inhibited. CD74 accumulated mainly in the endoplasmic reticulum (ER), and this phenotype required live parasites, but not active replication. Finally, we compared the impacts of genetic deletion of CD74 and H2-DM genes on parasite dissemination toward lymphoid organs in mice, as well as activation of CD4(+) T cells and interferon gamma (IFN-γ) levels during acute infection. Cyst burdens and survival during the chronic phase of infection were also evaluated in wild-type and knockout mice. These results highlight the fact that the infection is influenced by multiple levels of parasite manipulation of the MHC-II antigen presentation pathway.


Microhabitat Conditions in Wyoming's Sage-Grouse Core Areas: Effects on Nest Site Selection and Success.
The purpose of our study was to identify microhabitat characteristics of greater sage-grouse (Centrocercus urophasianus) nest site selection and survival to determine the quality of sage-grouse habitat in 5 regions of central and southwest Wyoming associated with Wyoming's Core Area Policy. Wyoming's Core Area Policy was enacted in 2008 to reduce human disturbance near the greatest densities of sage-grouse. Our analyses aimed to assess sage-grouse nest selection and success at multiple micro-spatial scales. We obtained microhabitat data from 928 sage-grouse nest locations and 819 random microhabitat locations from 2008-2014. Nest success was estimated from 924 nests with survival data. Sage-grouse selected nests with greater sagebrush cover and height, visual obstruction, and number of small gaps between shrubs (gap size ≥0.5 m and <1.0 m), while selecting for less bare ground and rock. With the exception of more small gaps between shrubs, we did not find any differences in availability of these microhabitat characteristics between locations within and outside of Core Areas. In addition, we found little supporting evidence that sage-grouse were selecting different nest sites in Core Areas relative to areas outside of Core. The Kaplan-Meier nest success estimate for a 27-day incubation period was 42.0% (95% CI: 38.4-45.9%). Risk of nest failure was negatively associated with greater rock and more medium-sized gaps between shrubs (gap size ≥2.0 m and <3.0 m). Within our study areas, Wyoming's Core Areas did not have differing microhabitat quality compared to outside of Core Areas. The close proximity of our locations within and outside of Core Areas likely explained our lack of finding differences in microhabitat quality among locations within these landscapes. However, the Core Area Policy is most likely to conserve high quality habitat at larger spatial scales, which over decades may have cascading effects on microhabitat quality available between areas within and outside of Core Areas.


Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.


Clinicopathological Features and Predictive Factors for Colorectal Cancer Outcome in the Kingdom of Saudi Arabia.
Colorectal cancer (CRC) is the most frequent cancer and a leading cause of cancer death in the Kingdom of Saudi Arabia (KSA). To date, no nationwide screening programs have been adopted. This prospective, longitudinal study investigated factors influencing the outcome of CRC in Saudi patients. Patients completed a CRC awareness questionnaire. Colonoscopy, CT/MRI, histopathology of tumor biopsies, and KRAS and BRAF testing were performed. Patients were treated according to their stage. All patients were followed until the end of the study and 3- and 5-year survival was assessed. Sixty percent of study patients with sporadic CRC presented with significantly advanced disease (stages III and IV) with or without metastases at entry. Patients showed low levels of awareness of the risk factors and signs of CRC. Patients presented at a median age of 50 years. Family history of CRC and ulcerative colitis were positive in 11 and 6% of patients, respectively. Stage III/IV tumors with distant metastases at enrollment, right-sided tumors, mucinous tumors, lymphovascular invasion, and KRAS (51%) or BRAF (28%) mutations predicted poor prognosis and survival. CRC in KSA is usually diagnosed at advanced stages with metastases and KRAS/BRAF, and is associated with poor prognosis and short survival. Nationwide awareness campaigns and screening programs for CRC are critical for prevention, early detection and adequate management of CRC.


No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma.
Previous epidemiologic studies that have examined the relationship between renal cell carcinoma (RCC) risk and intakes of plant foods and antioxidant nutrients have yielded inconsistent results. We therefore examined the associations between intakes of fruit, vegetables, carotenoids, flavonoids, vitamin E and vitamin C and RCC risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. At baseline, 27,062 male Finnish smokers aged 50-69 years completed a 276-item dietary questionnaire that included questions on frequency of consumption and portion size. During up to 19 years of follow-up, 255 men developed RCC. Cox proportional hazards models were utilized to estimate relative risks (RR) and 95% confidence intervals (CI). Despite a large range in intake, no association was observed between fruit, vegetables or antioxidant nutrients and RCC risk. For example, multivariate RRs and 95% CIs for the highest versus the lowest quartile of intake were 0.79 (0.55-1.14), 1.23 (0.85-1.79), 1.09 (0.74-1.60), 0.83 (0.57-1.21), 1.09 (0.73-1.64) and 0.99 (0.67-1.46) for fruit, vegetables, total carotenoids, total flavonoids, total vitamin E and vitamin C, respectively (all p values for trend > 0.05). Our results indicate that diet may not play a large role in the etiology of RCC in male smokers, although further examination of these associations in nonsmokers, women and diverse racial populations is warranted.


alpha thalassemia in black populations.
The different alpha thalassemia genotypes in American and Jamaican black populations have been defined by hematologic and globin-chain synthesis studies, alpha/beta globin messenger RNA ratios and restriction endonuclease mapping of DNA. The results indicate that the common form of alpha thalassemia in these populations is the deletion type of alpha-thalassemia 2 (- alpha/alpha alpha). The homozygous state (- alpha/alpha- alpha) is expressed at birth by the presence of more than 2--3% hemoglobin Bart's; in adult life it has the same phenotype as the heterozygous state for the deletion form of alpha-thalassemia 1 (--/alpha alpha). The heterozygous state is not always associated with detectable amounts of hemoglobin Bart's at birth or with recognizable hematologic changes in adults.


New developments in the treatment of obsessive-compulsive disorder.
The treatment of obsessive-compulsive disorder (OCD) has changed dramatically in the last 10 years. Currently, the serotonin reuptake inhibitors (SRIs) and the serotonin selective reuptake inhibitors (SSRIs) are considered the "first choice" agents for pharmacologic treatment of OCD, although few head-to-head comparisons exist between any two specific agents. Strategies for nonresponders and partial responders to the SRI/SSRIs are reviewed. The only agents that have shown significant improvement as augmenting agents to an SRI/SSRI in systematic trials have been clonazepam and haloperidol. Predictors of response to pharmacotherapy have been limited, but several reports have found that an early age at onset of OCD has been associated with a poorer response to medications. Long-term maintenance medication may be necessary for some, although behavioral therapy may improve the need for extended pharmacotherapy. Cognitive behavioral therapy, specifically exposure with response prevention, still remains an effective and important component of treatment for many. One of the newest developments is the identification of a pediatric subtype of OCD characterized by prepubertal acute onset after group A beta-hemolytic streptococcal pharyngitis. Investigation trials with these children include immunomodulatory therapies and penicillin treatment and prophylaxis. If a unique subgroup of children with OCD can be identified, then novel treatments may prove effective and have a role in long-term prophylaxis.


Specific reading disability (dyslexia): what have we learned in the past four decades?
We summarize some of the most important findings from research evaluating the hypothesized causes of specific reading disability ('dyslexia') over the past four decades. After outlining components of reading ability, we discuss manifest causes of reading difficulties, in terms of deficiencies in component reading skills that might lead to such difficulties. The evidence suggests that inadequate facility in word identification due, in most cases, to more basic deficits in alphabetic coding is the basic cause of difficulties in learning to read. We next discuss hypothesized deficiencies in reading-related cognitive abilities as underlying causes of deficiencies in component reading skills. The evidence in these areas suggests that, in most cases, phonological skills deficiencies associated with phonological coding deficits are the probable causes of the disorder rather than visual, semantic, or syntactic deficits, although reading difficulties in some children may be associated with general language deficits. Hypothesized deficits in general learning abilities (e.g., attention, association learning, cross-modal transfer etc.) and low-level sensory deficits have weak validity as causal factors in specific reading disability. These inferences are, by and large, supported by research evaluating the biological foundations of dyslexia. Finally, evidence is presented in support of the idea that many poor readers are impaired because of inadequate instruction or other experiential factors. This does not mean that biological factors are not relevant, because the brain and environment interact to produce the neural networks that support reading acquisition. We conclude with a discussion of the clinical implications of the research findings, focusing on the need for enhanced instruction.


Valve replacement with a stentless bioprosthesis: versatility of the porcine aortic root.
Stentless valves convey important hemodynamic benefits but are used selectively depending on aortic root structure. The Freestyle valve (Medtronic, Inc, Minneapolis, Minn) is a versatile device that can be implanted by different methods depending on operating conditions. We aimed to demonstrate that a stentless valve could be used in every patient without increased risk of morbidity or mortality. We documented the effects of this valve on clinical outcome and left ventricular mechanics. The Freestyle valve was implanted by the modified subcoronary method into 200 consecutive unselected patients who received a tissue valve in the aortic position and by root replacement in 2. Forty-three percent were older than 75 years. Forty percent underwent coronary bypass. Detailed clinical and echocardiographic follow-up (Food and Drug Administration protocol) was used out to 3 years. Mean ischemic time was 43+/-6 minutes for isolated aortic valve replacement and 63+/-14 minutes with concomitant procedures. Thirty-day mortality was 6%, none of the deaths being valve related. Hemodynamic function improved progressively with falling valve gradients and increased effective orifice areas. Left ventricular mass fell within normal limits over 2 years, but at 3 years there was a non-valve-related upswing. No instances of valve thrombosis, hemolysis, or paravalvular leak were noted. Less than 5% had mild to moderate aortic regurgitation. The Freestyle valve can be used in virtually every patient with aortic valve disease and provides superlative hemodynamic outcome. Hospital mortality and morbidity are similar to those reported for stented valves in an elderly population.


Accelerated healing of complex open pilonidal wounds using MatriStem extracellular matrix xenograft: nine cases.
Complex open pilonidal wounds represent a challenging wound healing problem. Nine cases of complex open pilonidal wounds are described. Each of them was treated at the time of primary wide excision with placement of xenograft extracellular matrix material derived from urinary bladder (MatriStem, ACell Corporation). The patients left the xenograft material and dressings intact and returned to our clinic at weekly intervals for inspection of the wounds. All of the cases of complex open pilonidal wounds healed without infection and without requiring re-operation. The average time to healing in this series was 7 weeks. Treatment of complex open pilonidal wounds with MatriStem extracellular matrix derived from urinary bladder in this fashion results in favorable wound healing of complex open pilonidal wounds.


Molecular mechanisms of anesthesia.
Anesthesia was a blessing to humankind. It is a miracle that simple molecules such as chloroform (CHCl3), diethyl ether (CH3.CH2.O.CH2.CH3), or nitrous oxide (N2O) induce a state of unconsciousness where patients can tolerate surgery. The diversity of the structures of these molecules indicates that there are no common receptors. The action of anesthetics is nonspecific and physical. After the demonstration by Meyer and Overton that anesthetic potencies correlate to their solubility into olive oil, the nonspecific lipid theories monopolized anesthesia theories for almost a century. The dominance of lipid theories invited repulsions against the nonspecificity idea. Protein theories that stress receptor bindings became the top mode. Nevertheless, the wide varieties of anesthetic molecules and the wide varieties of responding systems are difficult to reconcile with the specific interaction concept. This article discusses the recent progress and controversies on the molecular mechanisms of anesthesia. Anesthetics are unique drugs in pharmacology. They affect all macromolecules. The only comparable drugs are disinfectants. Both are nonspecific drugs. We use alcohols and phenols to wipe off the injection sites. We do not use penicillin or any other antibiotics for this purpose, because they are specific binders. Interestingly, these two nonspecific drugs opened the window for the modern medicine.


Strengthening systems for integrated early childhood development services: a cross-national analysis of governance.
While there has been substantial growth in early childhood development (ECD) services in low- and middle-income countries (LMICs), there is considerable inequity in their distribution and quality. Evidence-based governance strategies are necessary, but currently they are insufficient for widespread, quality implementation. In particular, there is a limited understanding of the use of systems approaches for the analysis of ECD services as they go to scale. The aim of this paper is to present findings from four countries, using a cross-national case study approach to explore governance mechanisms required to strengthen national systems of ECD services. While different sets of governance strategies and challenges were identified in each country, overarching themes also emerged with implications for systems strengthening. Study results focus on local, mid-level and central governance, with recommendations for effective coordination and the integration of ECD services in LMICs.


Artichoke leaf extract reduces symptoms of irritable bowel syndrome and improves quality of life in otherwise healthy volunteers suffering from concomitant dyspepsia: a subset analysis.
Does artichoke leaf extract (ALE) ameliorate symptoms of Irritable bowel syndrome (IBS) in otherwise healthy volunteers suffering concomitant dyspepsia? A subset analysis of a previous dose-ranging, open, postal study, in adults suffering dyspepsia. Two hundred and eight (208) adults were identified post hoc as suffering with IBS. IBS incidence, self-reported usual bowel pattern, and the Nepean Dyspepsia Index (NDI) were compared before and after a 2-month intervention period. There was a significant fall in IBS incidence of 26.4% (p < 0.001) after treatment. A significant shift in self-reported usual bowel pattern away from "alternating constipation/diarrhea" toward "normal" (p < 0.001) was observed. NDI total symptom score significantly decreased by 41% (p < 0.001) after treatment. Similarly, there was a significant 20% improvement in the NDI total quality-of-life (QOL) score in the subset after treatment. This report supports previous findings that ALE ameliorates symptoms of IBS, plus improves health-related QOL.


Infantile meningitis in England and Wales: a two year study.
A two year prospective study identified 1922 cases of meningitis in children under 1 year of age. A further 201 cases were identified from other sources. The annual incidence of meningitis during the first year of life was 1.6/1000; during the first 28 days of life it was 0.32/1000, and among postneonatal infants it was 1.22/1000. The male:female ratio was 1.4:1. The overall case fatality rate was 19.8% for neonates and 5.4% for postneonatal infants. Two thirds of deaths identified in the study, 50% of all deaths, were not attributed to meningitis by the Office of Population Censuses and Surveys. Group B beta haemolytic streptococci (28%), Escherichia coli (18%), and Listeria monocytogenes (5%) were most frequently isolated from neonates and Neisseria meningitidis (31%), Haemophilus influenzae (30%), and Streptococcus pneumoniae (10%) from postneonatal infants. At 2-6 months of age N meningitidis meningitis was most common, and at 7-12 months H influenzae predominated. Meningitis caused by group B beta haemolytic streptococci occurred up to 6 months of age and had a consistent mortality of 25%. Neonatal meningitis due to Gram negative enteric rods had a mortality of 32%. Low birth weight was a significant predisposing factor for both neonates and postneonatal infants. In both groups mortality was significantly higher among children admitted in coma. There was no seasonal variation in incidence in either group. Neonates were treated with either group. Neonates were treated with either chloramphenicol (50%) or gentamicin (48%) usually in combination with a penicillin; 40% received a third generation cephalosporin. Of the 1472 postneonatal infants treated 84% received chloramphenicol with a penicillin and 10% received a third generation cephalosporin. Relapse occurred in 49 patients and three died. Eighteen babies coned as a result of raised intracranial pressure, including four neonates, and four died. Mortality among the 133 (7%) children who received steroids was significantly higher than in the rest of the study group.


Prevention of influenza by targeting host receptors using engineered proteins.
There is a need for new approaches for the control of influenza given the burden caused by annual seasonal outbreaks, the emergence of viruses with pandemic potential, and the development of resistance to current antiviral drugs. We show that multivalent biologics, engineered using carbohydrate-binding modules specific for sialic acid, mask the cell-surface receptor recognized by the influenza virus and protect mice from a lethal challenge with 2009 pandemic H1N1 influenza virus. The most promising biologic protects mice when given as a single 1-μg intranasal dose 7 d in advance of viral challenge. There also is sufficient virus replication to establish an immune response, potentially protecting the animal from future exposure to the virus. Furthermore, the biologics appear to stimulate inflammatory mediators, and this stimulation may contribute to their protective ability. Our results suggest that this host-targeted approach could provide a front-line prophylactic that has the potential to protect against any current and future influenza virus and possibly against other respiratory pathogens that use sialic acid as a receptor.


Anatomical and functional alterations in semantic dementia: a voxel-based MRI and PET study.
Rare studies have used magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to assess atrophy, and only two positron emission tomography (PET) studies used SPM to examine functional changes in semantic dementia (SD). Our aim was to highlight both morphological and functional abnormalities in a same group of 10 SD patients, in the entire brain, using a "state of the art" methodology (optimized VBM procedure, PET data corrected for partial volume effects and voxel-based analyses). We also used an extensive neuropsychological battery. We showed that main alterations concerned the left temporal lobe, in accordance with the striking impairment of semantic memory in SD patients, as well as the hippocampal region, which may partly explain their moderate episodic memory deficits. Hypometabolism was more extensive than grey matter loss in both temporal lobes, and specifically concerned the orbitofrontal areas, consistent with the moderate impairment of executive functions and behavioural changes. While PET is more sensitive than MRI, there is striking concordance between morphological and functional abnormalities, which contrasts with the discordance observed in Alzheimer's disease and might be a typical feature of SD.


Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study.
Sleep-wake disturbances (SWD) are common after traumatic brain injury (TBI). In acute TBI, we recently found decreased CSF levels of hypocretin-1, a wake-promoting neurotransmitter. In the present study, we aimed to delineate the frequency and clinical characteristics of post-traumatic SWD, to assess CSF hypocretin-1 levels 6 months after TBI, and to identify risk factors for posttraumatic SWD. A total of 96 consecutive patients were enrolled within the first 4 days after TBI. Six months later, out of 76 TBI patients, who did not die and who did not move to foreign countries, we included 65 patients (86%, 53 males, mean age 39 years) in our study. Patients were examined using interviews, questionnaires, clinical examinations, computed tomography of the brain, laboratory tests (including CSF hypocretin-1 levels, and HLA typing), conventional polysomnography, maintenance of wakefulness and multiple sleep latency tests (MSLT) and actigraphy. Potential causes of post-traumatic SWD were assessed according to international criteria. New-onset sleep-wake disturbances following TBI were found in 47 patients (72%): subjective excessive daytime sleepiness (EDS; defined by the Epworth Sleepiness Scale > or = 10) was found in 18 (28%), objective EDS (as defined by mean sleep latency < 5 min on MSLT) in 16 (25%), fatigue (daytime tiredness without signs of subjective or objective EDS) in 11 (17%), post-traumatic hypersomnia 'sensu strictu' (increased sleep need of > or = 2 h per 24 h compared to pre-TBI) in 14 (22%) patients and insomnia in 3 patients (5%). In 28 patients (43% of the study population), we could not identify a specific cause of the post-traumatic SWD other than TBI. Low CSF hypocretin-1 levels were found in 4 of 21 patients 6 months after TBI, as compared to 25 of 27 patients in the first days after TBI. Hypocretin levels 6 months after TBI were significantly lower in patients with post-traumatic EDS. There were no associations between post-traumatic SWD and severity or localization of TBI, general clinical outcome, gender, pathological neurological findings and HLA typing. However, post-traumatic SWD correlated with impaired quality of life. These results suggest that sleep-wake disturbances, particularly EDS, fatigue and hypersomnia are common after TBI, and significantly impair quality of life. In almost one out of two patients, post-traumatic SWD appear to be directly related to the TBI. An involvement of the hypocretin system in the pathophysiology of post-traumatic SWD appears possible. Other risk factors predisposing towards the development of post-traumatic SWD were not identified.


Comparative evaluation of apically extruded debris with V-Taper, ProTaper Next, and the Self-adjusting File systems.
Complete cleaning of the root canal is the goal for ensuring success in endodontics. Removal of debris plays an important role in achieving this goal. In spite of advancements in instrument design, apical extrusion of debris remains a source of inflammation in the periradicular region. To comparatively evaluate the amount of apically extruded debris with V-Taper, ProTaper Next, and the self-adjusting File (SAF) system. Sixty-four extracted human mandibular teeth with straight root canals were taken. Access openings were done and working length determined. The samples were randomly divided into three groups: Group I - V-Taper files (n = 20), Group II - ProTaper Next (n = 20), Group III - SAF (n = 20). Biomechanical preparation was completed and the debris collected in vials to be quantitatively determined. The data obtained was statistically analyzed using ANOVA and post hoc Tukey's test. All the specimens showed apical debris extrusion. SAF showed significantly less debris extrusion compared to V-Taper and ProTaper Next (P < 0.001). Among Groups I and II, ProTaper Next showed lesser debris extrusion as compared to V-Taper, but it was not significant (P = 0.124). The SAF showed least amount of apical debris extrusion when compared to newer rotary endodontic instruments. This indicates that the incidence of inter-treatment flare-ups due to debris extrusion would be less with the SAF.


Performance of five different assays for the quantification of viral load in persons infected with various subtypes of HIV-1. Swiss HIV Cohort Study.
Five methods for the assessment of plasma viral load (VL) were evaluated in 103 seropositive patients infected with various subtypes of HIV-1. The methods included three RNA-based assays (Amplicor Monitor 1.5, Quantiplex version 2.0, NucliSens), one ultrasensitive reverse transcriptase (PERT) assay and one "boosted" p24 antigen (Ag) enzyme immunoassay (EIA). Subtyping was based on sequencing in env. The sensitivities were, in decreasing order, Amplicor > PERT > p24 Ag > NucliSens > Quantiplex. The low sensitivity of NucliSens was related to the missing of several non-B (A, E, F, G) or recombinant strains, whereas that of Quantiplex did not depend on subtype. In the 1 group O sample and 4 group M samples, only PERT assay or p24Ag EIA produced a positive result. In the quantitative range, correlation was best between Amplicor and Quantiplex (r = 0.8848), fair between Amplicor and NucliSens (r = 0.7064) or PERT assay (r = 0.7266), lowest between Amplicor and p24Ag EIA (r = 0.3989). Amplicor underestimated VL in 1 subtype E sample. Thus, Amplicor performed best in terms of sensitivity (compared with all other assays) and accuracy (compared with NucliSens, PERT assay, and p24Ag) for non-B subtypes in group M samples. PERT assay appears useful for VL assessment in infections by group O or other highly divergent viruses.


Cancer in Adolescents and Young Adults: A Narrative Review of the Current Status and a View of the Future.
Although cancer remains the most common cause of disease-related death in adolescents and young adults (AYAs) in high-income countries, their overall survival rates continue to increase and now exceed 80% at 5 years in several high-income countries. This has been accomplished through progressive improvements in active treatment and supportive care, although accrual rates to therapeutic clinical trials remain disappointing. Recognition of the unique distribution of diseases in the AYA population with cancer and further understanding of the distinctive biology of cancers in AYAs will lead to continuing gains in clinical outcomes. Many of the challenges faced by AYAs with a diagnosis of malignant disease are shared by others with chronic medical conditions and even their healthy peers, such as a sense of invulnerability that may contribute to delays in diagnosis. A particular need for psychological support has been identified for AYAs with cancer, even after active therapy has been completed and especially in the context of palliative care. Notable needs also include fertility preservation and navigation through the multiple transitions in the cancer journey. Additionally, there is a "cost of cure." This is not only in the form of short-term, treatment-related morbidity and mortality but also in the burden of "late effects," including second cancers, that compromise quality of life and limit life expectancy. Establishing clinical programs devoted to AYAs with cancer, with complementary educational initiatives, will strengthen the advances made. It is anticipated that clinical trial accrual will increase substantially, providing further gains in survival. Likewise, addressing the challenges of survivorship, including secondary prevention of long-term morbidity and mortality, will lead to additional improvements in clinical outcomes. Transferring this knowledge to the care of an estimated 1 million incident cases of cancer in AYAs worldwide, most of whom do not live in high-income countries, remains a considerable challenge.


Expanding the mutational spectrum of the ABCB4 gene in inherited adult cholestatic liver disorders with four novel pathogenic variants.
Low phospholipid-associated cholelithiasis and intrahepatic cholestasis of pregnancy are two MDR3-related inherited liver disorders caused by biallelic or monoallelic ABCB4 loss-of-function variants. Low phospholipid-associated cholelithiasis is clinically characterized by the early onset of symptomatic cholelithiasis in young adults while intrahepatic cholestasis of pregnancy is a distinct clinical entity associated with adverse fetal outcomes. Of note, patients carrying ABCB4 sequence variations commonly exhibit phenotypic expression over a wide continuum due to environmental and hormonal contributing factors and genetic modifiers. Patients with an early diagnosis of MDR3-related diseases could benefit from ursodeoxycholic acid treatment in order to prevent acute and chronic complications as well as adverse pregnancy outcomes. We herein report five patients with an overlapping phenotype from low phospholipid-associated cholelithiasis to intrahepatic cholestasis of pregnancy, harboring five ABCB4 missense variants, four of which were novel. Our study highlights the phenotypic and genetic heterogeneity of inherited cholestatic liver diseases and also expands the mutation spectrum of ABCB4 sequence variations in adult cholestatic liver diseases.


A rigorous unidirectional method for designing finite aperture diffractive optical elements.
We have developed a rigorous unidirectional method for designing finite-aperture diffractive optical elements (DOE's) that employs a micro-genetic algorithm (microGA) for global optimization in conjunction with a 2-D Finite-Difference Time-Domain (FDTD) method for rigorous electromagnetic computation. The theory and implementation of this microGA-FDTD design method for normally incident TE illumination are briefly discussed. Design examples are presented, including a micro-lens, a 1-to-2 beam-fanner and a 1-to-3 beam-fanner.


Overtraining Syndrome (OTS) and Relative Energy Deficiency in Sport (RED-S): Shared Pathways, Symptoms and Complexities.
The symptom similarities between training-overload (with or without an Overtraining Syndrome (OTS) diagnosis) and Relative Energy Deficiency in Sport (RED-S) are significant, with both initiating from a hypothalamic-pituitary origin, that can be influenced by low carbohydrate (CHO) and energy availability (EA). In this narrative review we wish to showcase that many of the negative outcomes of training-overload (with, or without an OTS diagnosis) may be primarily due to misdiagnosed under-fueling, or RED-S, via low EA and/or low CHO availability. Accordingly, we undertook an analysis of training-overload/OTS type studies that have also collected and analyzed for energy intake (EI), CHO, exercise energy expenditure (EEE) and/or EA. Eighteen of the 21 studies (86%) that met our criteria showed indications of an EA decrease or difference between two cohorts within a given study (n = 14 studies) or CHO availability decrease (n = 4 studies) during the training-overload/OTS period, resulting in both training-overload/OTS and RED-S symptom outcomes compared to control conditions. Furthermore, we demonstrate significantly similar symptom overlaps across much of the OTS (n = 57 studies) and RED-S/Female Athlete Triad (n = 88 studies) literature. It is important to note that the prevention of under-recovery is multi-factorial, but many aspects are based around EA and CHO availability. Herein we have demonstrated that OTS and RED-S have many shared pathways, symptoms, and diagnostic complexities. Substantial attention is required to increase the knowledge and awareness of RED-S, and to enhance the diagnostic accuracy of both OTS and RED-S, to allow clinicians to more accurately exclude LEA/RED-S from OTS diagnoses.


Evaluation of bifurcation stenting techniques at Catharina Hospital, Eindhoven in 2013.
Percutaneous coronary intervention (PCI) of bifurcation lesions can be performed using various techniques. The aim of this study was to analyse the outcome of various techniques of bifurcation stenting in all patients undergoing bifurcation stenting at one large intervention centre in 2013, taking into account that more complex lesions might more often warrant a two-stent technique. This retrospective study included 260 consecutive patients who underwent non-primary PCI of a bifurcation lesion at the Catharina Hospital, Eindhoven, in 2013. Patients were classified into two groups: one-stent technique (provisional stenting), and two-stent techniques (culotte, crush and T‑stenting). The primary endpoint was the rate of restenosis at 1 year. The secondary endpoints were procedural complications (side branch occlusion, periprocedural infarction, and death) and major adverse cardiac events (MACE) at 1 year. Periprocedural complications occurred in 15 patients (5.8 %) with no difference between the groups (p = 0.27). After 1 year, restenosis occurred in 3.2 % of the patients in the one-stent technique group and 7.3 % in the two-stent technique group (p = 0.20). MACE at 1 year did not differ between the groups at 11.9 % and 12.2 % respectively (p = 1.00). This study shows that there is no significant difference between restenosis rate, or any other outcome parameter, with the different techniques of bifurcation stenting. Since provisional stenting is the simplest, most straightforward and cheapest approach, if technically feasible this technique has our preference as the initial approach, and an upgrade can be considered if the result is insufficient.


Correlation of severity of chronic obstructive pulmonary disease with serum vitamin-D level.
The global scenario of illness is shifting from infectious diseases to non-communicable diseases, with chronic conditions such as heart diseases, stroke and Chronic Obstructive Pulmonary Disease (COPD) now being chief causes of death globally and more than 90% of deaths due to COPD occur in low and midline income countries.[1] Low serum vitamin D level is associated with various lung diseases and decreased lung function.[2]. This study was designed to study the serum vitamin D level and its correlation with severity of COPD as assessed by spirometry, COPD assessment test (CAT) and exercise capacity and BMI of COPD patients. Observational cross sectional study conducted on patients of COPD attending the outpatient department. One hundred sixty consecutive patients of COPD attending the outpatient Department were included in the study. Pack years, CAT score, 6 minute walk distance, post bronchodilator spirometry values and BMI was recorded along with complete history and physical examination. Data analysis was done using IBM SPSS 23 software. Descriptive statistics, Independent sample t test, ANOVA and Pearson correlation were applied. A significant positive correlation was found between FeV1% of predicted and serum Vitamin D level(r = 0.291; P < 0.001). A negative correlation was found between serum Vitamin D level and severity of COPD as assessed by CAT score (r = -0.355; P < 0.001). Also, a significant positive correlation was found between vitamin D levels and exercise capacity as assessed by 6 minute walk test (6MsWT) (r = 0.648; P < 0.001). COPD patients with more severe disease tend to have lower serum Vitamin D levels. As it is an immunomodulator affecting various inflammatory pathways, it is imperative that we give due consideration to Vitamin D levels in managing patients of COPD.


A More Detailed Understanding Of Factors Associated With Hospital Profitability.
To identify the characteristics of the most profitable US hospitals, we examined the profitability of acute care hospitals in fiscal year 2013, measured as net income from patient care services per adjusted discharge. Based on Medicare Cost Reports and Final Rule Data, the median hospital lost $82 for each such discharge. Forty-five percent of hospitals were profitable, with 2.5 percent earning more than $2,475 per adjusted discharge. The ten most profitable hospitals, seven of which were nonprofit, each earned more than $163 million in total profits from patient care services. Hospitals with for-profit status, higher markups, system affiliation, or regional power, as well as those located in states with price regulation, tended to be more profitable than other hospitals. Hospitals that treated a higher proportion of Medicare patients, had higher expenditures per adjusted discharge, were located in counties with a high proportion of uninsured patients, or were located in states with a dominant insurer or greater health maintenance organization (HMO) penetration had lower profitability than hospitals that did not have these characteristics. These findings can inform policy reforms, while providing a baseline against which to measure the impact of any subsequent reforms.


Quantum dot-polymer conjugates for stable luminescent displays.
The broad absorption of light in the UV-Vis-NIR region and the size-based tunable photoluminescence color of semiconductor quantum dots make these tiny crystals one of the most attractive antennae in solar cells and phosphors in electrooptical devices. One of the primary requirements for such real-world applications of quantum dots is their stable and uniform distribution in optically transparent matrices. In this work, we prepare transparent thin films of polymer-quantum dot conjugates, where CdSe/ZnS quantum dots are uniformly distributed at high densities in a chitosan-polystyrene copolymer (CS-g-PS) matrix. Here, quantum dots in an aqueous solution are conjugated to the copolymer by a phase transfer reaction. With the stable conjugation of quantum dots to the copolymer, we prevent undesired phase separation between the two and aggregation of quantum dots. Furthermore, the conjugate allows us to prepare transparent thin films in which quantum dots are uniformly distributed at high densities. The CS-g-PS copolymer helps us in not only preserving the photoluminescence properties of quantum dots in the film but also rendering excellent photostability to quantum dots at the ensemble and single particle levels, making the conjugate a promising material for photoluminescence-based devices.


Anti-type II collagen ELISA. Increased disease specificity following removal of anionic contaminants from salt-fractionated type II collagen.
The purification of type II collagen, for the detection of anti-type II collagen antibodies by ELISA procedures, involves removal of proteoglycans by guanidine-HCl, followed by pepsin solubilisation and salt fractionation. However, type II collagen purified in this way may contain contaminants, despite the apparent purity on SDS-polyacrylamide gels. In this paper we demonstrate how additional purification by DEAE chromatography reduces the degree of background binding in the type II collagen ELISA, leading to an increase in disease specificity. The contaminants included proteoglycan and bound serum IgG from both rheumatoid arthritis (RA) patients and healthy controls in ELISA. Furthermore, positive correlations were observed in the sera (n = 24) between degree of reactivity to the contaminants and to (1) purified proteoglycan (r = 0.50, P = 0.01) and (2) pepsin (r = 0.65, P = 0.001). Thus, inadequate purification of type II collagen produces false positive reactions in the collagen ELISA and gives rise to a high background. A lack of specificity has been frequently associated with this assay.