Two-beam-current method for e-beam writing gray-scale masks and its application to high-resolution microstructures.
A two-beam-current method is introduced for e-beam writing in the fabrication of gray-scale masks. Compared with the simpler single-current method, the two-beam-current method offers two important advantages: (a) it can achieve a much larger dynamic range for e-beam exposure; (b) the writing time for a gray-scale mask can be reduced when a large pattern is to be written. Here, the new method is first described in detail and its application to the fabrication of our new gray-scale mask is demonstrated. Then, the improved gray-scale masks were employed to fabricate large dynamic range, high-resolution micro-optical elements of less than a couple of micrometers depth, using deep ultraviolet lithography at 248 nm wavelength and an inductively coupled plasma reactive ion etching system.


Propagating waves of directionality and coordination orchestrate collective cell migration.
The ability of cells to coordinately migrate in groups is crucial to enable them to travel long distances during embryonic development, wound healing and tumorigenesis, but the fundamental mechanisms underlying intercellular coordination during collective cell migration remain elusive despite considerable research efforts. A novel analytical framework is introduced here to explicitly detect and quantify cell clusters that move coordinately in a monolayer. The analysis combines and associates vast amount of spatiotemporal data across multiple experiments into transparent quantitative measures to report the emergence of new modes of organized behavior during collective migration of tumor and epithelial cells in wound healing assays. First, we discovered the emergence of a wave of coordinated migration propagating backward from the wound front, which reflects formation of clusters of coordinately migrating cells that are generated further away from the wound edge and disintegrate close to the advancing front. This wave emerges in both normal and tumor cells, and is amplified by Met activation with hepatocyte growth factor/scatter factor. Second, Met activation was found to induce coinciding waves of cellular acceleration and stretching, which in turn trigger the emergence of a backward propagating wave of directional migration with about an hour phase lag. Assessments of the relations between the waves revealed that amplified coordinated migration is associated with the emergence of directional migration. Taken together, our data and simplified modeling-based assessments suggest that increased velocity leads to enhanced coordination: higher motility arises due to acceleration and stretching that seems to increase directionality by temporarily diminishing the velocity components orthogonal to the direction defined by the monolayer geometry. Spatial and temporal accumulation of directionality thus defines coordination. The findings offer new insight and suggest a basic cellular mechanism for long-term cell guidance and intercellular communication during collective cell migration.


Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.
Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.


Psychometric evaluation of the Brief Cancer Impact Assessment among breast cancer survivors.
The increasing number of cancer survivors brings greater attention to the biopsychosocial impact of surviving cancer. Instruments exist that measure quality of life (QOL), symptoms, and specific types of functioning after cancer; however, a reliable and valid assessment of the perceived impact of cancer (IOC) on the life plans and activities of cancer survivors has been missing. This study evaluated the psychometric properties of the 16-item Brief Cancer Impact Assessment (BCIA). Factor analysis with Promax oblique rotation established the factor structure of the BCIA in 783 ethnically diverse breast cancer survivors, >or=2 years after diagnosis. Construct validity was assessed by comparing factor-based scale means by demographic and treatment characteristics, and correlating scales with psychosocial and health-related QOL scales. Factor analysis revealed four factors measuring the IOC on caregiving and finances, exercise and diet behaviors, social and emotional functioning, and religiosity. Scale scores differed by demographic and treatment characteristics according to expectations, and the pattern of correlations with psychosocial and health-related QOL generally supported the construct validity of the scales. Including the BCIA with measures of QOL, symptoms, and functioning will allow researchers to gain a more comprehensive assessment of the biopsychosocial IOC in survivors.


Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13.
Expulsion of the gastrointestinal nematode Trichuris muris is mediated by a T helper (Th) 2 type response involving interleukin (IL)-4 and IL-13. Here we show that Th1 response-associated susceptibility involves prior activation of IL-18 and caspase-1 followed by IL-12 and interferon (IFN)-gamma in the intestine. IL-18-deficient mice are highly resistant to chronic T. muris infection and in vivo treatment of normal mice with recombinant (r)IL-18 suppresses IL-13 and IL-4 secretion but does not affect IFN-gamma. In vivo treatment of T. muris-infected IFN-gamma-deficient mice with rIL-18 demonstrated that the inhibitory effect of IL-18 on IL-13 secretion is independent of IFN-gamma. Hence, IL-18 does not function as an IFN-gamma-inducing cytokine during chronic T. muris infection but rather as a direct regulator of Th2 cytokines. These results provide the first demonstration of the critical role of IL-18 in regulating Th cell responses during gastrointestinal nematode infection.


Post-traumatic stress disorder and self-reported outcomes after traumatic brain injury in victims of assault.
Assault is the third most common cause of traumatic brain injury (TBI), after falls and road traffic collisions. TBI can lead to multiple long-term physical, cognitive and emotional sequelae, including post-traumatic stress disorder (PTSD). Intentional violence may further compound the psychological trauma of the event, in a way that conventional outcome measures, like the Glasgow Outcome Scale (GOS), fail to capture. This study aims to examine the influence of assault on self-reported outcomes, including quality of life and symptoms of PTSD. Questionnaire were completed by 256 patients attending a TBI clinic, including Quality of Life after Brain Injury (QOLIBRI) and PTSD checklist (PCL-C). Medical records provided demographics, clinical data and aetiology of injury. Subjective outcomes were compared between assault and other causes. Of 202 patients analysed, 21% sustained TBI from assault. There was no difference in severity of injuries between assault and non-assault groups. No relationship was found between self-reported outcomes and TBI severity or GOS. The assault group scored worse in all self-reported questionnaires, with statistically significant differences for measures of PTSD and post-concussion symptoms. However, using threshold scores, the prevalence of PTSD in assaulted patients was not higher than non-assault. After adjusting for age, ethnicity and the presence of extra-cranial trauma, assault did not have a significant effect on questionnaire scores. Exploratory analysis showed that assault and road traffic accidents were associated with significantly worse outcomes compared to falls. Quality of life is significantly related to functional and psychological outcomes after TBI. Assaulted patients suffer from worse self-reported outcomes than other patients, but these differences were insignificant when adjusted for demographic factors. Intentionality behind the traumatic event is likely more important than cause alone. Differences in quality of life and other self-reported outcomes are not reflected by the Glasgow Outcome Scale. This information is useful in arranging earlier and targeted review and support.


Novel agents for the management of myelodysplastic syndromes.
Therapeutic decisions in patients with myelodysplastic syndromes (MDS) are very complex. The dilemma that confronts the management of MDS is illustrated by the presence of only one agent (5-azacitidine), which has been approved by the U.S.A. Food and Drug Administration, with an indication for all subtypes of this disease and another one (lenalidomide) for the management of a specific MDS subgroup, the 5q-syndrome. Current classifications and prognostic systems do not take into account the considerable clinical heterogeneity of MDS or their diverse biology. Supportive care, low-intensity treatment, acute myeloid leukemia-type therapy, and stem cell transplantation (SCT) produce unsatisfactory results because patients continue to be exposed to the inherent complications of worsening cytopenias and leukemic transformation. Recent years have witnessed an evolution in our understanding of pathophysiology pathways in MDS. At the same time, many novel and targeted therapies are being investigated in clinical trials, offering patients the prospect of sustained benefit and changing the natural course of the disease. Hypomethylating agents, immunomodulatory drugs, and farnesyl-tranferase inhibitors have produced very promising results in terms of response and survival in MDS patients. This review summarizes all recent data on the role of novel agents and SCT in the treatment of patients with MDS in an attempt to better understand their possible therapeutic status in the management of these patients.


Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function.
Oxidative stress leads to increased risk for osteoarthritis (OA) but the precise mechanism remains unclear. We undertook this study to clarify the impact of oxidative stress on the progression of OA from the viewpoint of oxygen free radical induced genomic instability, including telomere instability and resulting replicative senescence and dysfunction in human chondrocytes. Human chondrocytes and articular cartilage explants were isolated from knee joints of patients undergoing arthroplastic knee surgery for OA. Oxidative damage and antioxidative capacity in OA cartilage were investigated in donor-matched pairs of intact and degenerated regions of tissue isolated from the same cartilage explants. The results were histologically confirmed by immunohistochemistry for nitrotyrosine, which is considered to be a maker of oxidative damage. Under treatment with reactive oxygen species (ROS; 0.1 micromol/l H2O2) or an antioxidative agent (ascorbic acid: 100.0 micromol/l), cellular replicative potential, telomere instability and production of glycosaminoglycan (GAG) were assessed in cultured chondrocytes. In tissue cultures of articular cartilage explants, the presence of oxidative damage, chondrocyte telomere length and loss of GAG to the medium were analyzed in the presence or absence of ROS or ascorbic acid. Lower antioxidative capacity and stronger staining of nitrotyrosine were observed in the degenerating regions of OA cartilages as compared with the intact regions from same explants. Immunostaining for nitrotyrosine correlated with the severity of histological changes to OA cartilage, suggesting a correlation between oxidative damage and articular cartilage degeneration. During continuous culture of chondrocytes, telomere length, replicative capacity and GAG production were decreased by treatment with ROS. In contrast, treatment with an antioxidative agent resulted in a tendency to elongate telomere length and replicative lifespan in cultured chondrocytes. In tissue cultures of cartilage explants, nitrotyrosine staining, chondrocyte telomere length and GAG remaining in the cartilage tissue were lower in ROS-treated cartilages than in control groups, whereas the antioxidative agent treated group exhibited a tendency to maintain the chondrocyte telomere length and proteoglycan remaining in the cartilage explants, suggesting that oxidative stress induces chondrocyte telomere instability and catabolic changes in cartilage matrix structure and composition. Our findings clearly show that the presence of oxidative stress induces telomere genomic instability, replicative senescence and dysfunction of chondrocytes in OA cartilage, suggesting that oxidative stress, leading to chondrocyte senescence and cartilage ageing, might be responsible for the development of OA. New efforts to prevent the development and progression of OA may include strategies and interventions aimed at reducing oxidative damage in articular cartilage.


Impaired kidney function is associated with SYNTAX score in patients with stable coronary artery disease.
The strong relationship between severe renal dysfunction and coronary artery disease (CAD) is well-known. However, the association between kidney function with SYNTAX Score (SS) has not been investigated in patients with stable CAD with normal to mildly impaired renal function. We aimed to investigate the association between kidney function with SS. In this study, 411 stable CAD patients in whom coronary angiography (CAG) was performed were prospectively included (247 male, 164 female; mean age 58.6 ± 12.4 years). Glomerular filtration rate was estimated (eGFR) by a modification of diet in renal disease (MDRD) formula. Two different groups were determined according to median eGFR values (GFRlow group <90, and GRFhigh group ≥ 90). CAG was performed based on clinical indications. SS was determined in all patients. Patients in GFRlow group were older, and have a history of hypertension (HT) and diabetes mellitus and high body mass index. SS values of GFRlow group were higher than GFRhigh group (p<0.001 for all). Multivariate regression analysis showed that eGFR was independently associated with diabetes (ß, -0.206, p<0.001), HT (ß, -0.093, p=0.026) and SS (ß, -0.445, p<0.001). eGFR is independently associated with extent and complexity of CAD as well as diabetes and HT. Importantly, these results may explain, in part, the increase in cardiovascular risk in with slightly impaired renal function.


Impact of probiotic Saccharomyces boulardii on the gut microbiome composition in HIV-treated patients: A double-blind, randomised, placebo-controlled trial.
Dysbalance in gut microbiota has been linked to increased microbial translocation, leading to chronic inflammation in HIV-patients, even under effective HAART. Moreover, microbial translocation is associated with insufficient reconstitution of CD4+T cells, and contributes to the pathogenesis of immunologic non-response. In a double-blind, randomised, placebo-controlled trial, we recently showed that, compared to placebo, 12 weeks treatment with probiotic Saccharomyces boulardii significantly reduced plasma levels of bacterial translocation (Lipopolysaccharide-binding protein or LBP) and systemic inflammation (IL-6) in 44 HIV virologically suppressed patients, half of whom (n = 22) had immunologic non-response to antiretroviral therapy (<270 CD4+Tcells/μL despite long-term suppressed viral load). The aim of the present study was to investigate if this beneficial effect of the probiotic Saccharomyces boulardii is due to modified gut microbiome composition, with a decrease of some species associated with higher systemic levels of microbial translocation and inflammation. In this study, we used 16S rDNA gene amplification and parallel sequencing to analyze the probiotic impact on the composition of the gut microbiome (faecal samples) in these 44 patients randomized to receive oral supplementation with probiotic or placebo for 12 weeks. Compared to the placebo group, in individuals treated with probiotic we observed lower concentrations of some gut species, such as those of the Clostridiaceae family, which were correlated with systemic levels of bacterial translocation and inflammation markers. In a sub-study of these patients, we observed significantly higher parameters of microbial translocation (LBP, soluble CD14) and systemic inflammation in immunologic non-responders than in immunologic responders, which was correlated with a relative abundance of specific gut bacterial groups (Lachnospiraceae genus and Proteobacteria). Thus, in this work, we propose a new therapeutic strategy using the probiotic yeast S. boulardii to modify gut microbiome composition. Identifying pro-inflammatory species in the gut microbiome could also be a useful new marker of poor immune response and a new therapeutic target.


Detailed transcriptome atlas of the pancreatic beta cell.
Gene expression patterns provide a detailed view of cellular functions. Comparison of profiles in disease vs normal conditions provides insights into the processes underlying disease progression. However, availability and integration of public gene expression datasets remains a major challenge. The aim of the present study was to explore the transcriptome of pancreatic islets and, based on this information, to prepare a comprehensive and open access inventory of insulin-producing beta cell gene expression, the Beta Cell Gene Atlas (BCGA). We performed Massively Parallel Signature Sequencing (MPSS) analysis of human pancreatic islet samples and microarray analyses of purified rat beta cells, alpha cells and INS-1 cells, and compared the information with available array data in the literature. MPSS analysis detected around 7600 mRNA transcripts, of which around a third were of low abundance. We identified 2000 and 1400 transcripts that are enriched/depleted in beta cells compared to alpha cells and INS-1 cells, respectively. Microarray analysis identified around 200 transcription factors that are differentially expressed in either beta or alpha cells. We reanalyzed publicly available gene expression data and integrated these results with the new data from this study to build the BCGA. The BCGA contains basal (untreated conditions) gene expression level estimates in beta cells as well as in different cell types in human, rat and mouse pancreas. Hierarchical clustering of expression profile estimates classify cell types based on species while beta cells were clustered together. Our gene atlas is a valuable source for detailed information on the gene expression distribution in beta cells and pancreatic islets along with insulin producing cell lines. The BCGA tool, as well as the data and code used to generate the Atlas are available at the T1Dbase website (T1DBase.org).


Recombinant Hepatitis B Vaccine Adjuvanted With AS04 in Dialysis Patients: A Prospective Cohort Study.
Patients undergoing maintenance dialysis have an unsatisfactory response to vaccination, including to hepatitis B vaccine. A recombinant HB vaccine containing a new adjuvant system AS04 (HBV-AS04) has been recently developed; a few data exist on the immunogenicity and safety of HBV-AS04 among patients undergoing regular dialysis. All hepatitis B virus-seronegative patients with undetectable antibody against HBsAg undergoing maintenance dialysis at two units were prospectively included. Patients received four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle) at months 0,1,2, and 3. Anti-HB surface antibody concentrations were measured at intervals of 1, 2, 3, 4, and 12 months. Univariate and multivariate analyses determined which parameters predicted immunologic response to HBV-AS04 vaccine. 102 patients were enrolled and 91 completed the study. At completion of the vaccination schedule, using per-protocol analysis, 76 of 91 (84%) had antibody titers ≥10 mIU/mL with anti-HBs geometric antibody concentrations (GMCs) of 385.25 mIU/mL. The sero-protection rate at month 12 was 84% (48/57) with lower GMCs (62.74 mIU/mL, P<0.0001). Multivariate analysis revealed a detrimental role of age on the immune response to HB-AS04 vaccine (F Ratio, 4.04; P<0.04). Tolerance to HBV-AS04 was good and only minor side-effects were observed. HBV-AS04 vaccine was highly immunogenic in our cohort of patients on maintenance dialysis even if a significant number of non-responders is still present. Prospective studies with HBV-AS04 on larger study groups and with longer follow-ups are under way.


A comparison between endodontics and implantology: an 8-year retrospective study.
The aim of this study was to compare endodontic and implant treatments and to evaluate their predictability over an 8-year period on the basis of an analysis of survival data and a retrospective clinical study. A group of 40 partially edentulous patients were selected for this study. Their teeth had been endodontically treated and rehabilitated using gold alloy and ceramic restorations. In these patients, 65 osseointegrated implants were restored with single gold alloy-ceramic crowns and monitored on a yearly basis for 8 years with standardized periapical radiographs, using a polivynilsiloxane occlusal key as a positioner. A total of nine patients who did not attend the yearly follow-up were excluded from the study. The Melloning and Triplett criteria were used to evaluate the clinical results obtained in the implant sites. The clinical results of the 56 endodontically treated teeth, restored with the fixed prosthesis of 40 patients, were analyzed according to probing depth as well as an assessment of the correct apical and coronal seals. The survival rate was calculated using the Kaplan-Meier method and the statistical significance was calculated using the chi-square test. During the follow-up of the endodontically treated elements, seven failures were detected (83.34%) and the success rate of implants inserted in the same patients was equal to 80.8%, with nine implants lost in 8 years. The survival analysis of the elements treated with both therapies was not statistically significant (p = .757) and the confidence interval was between 0.2455 and 2.777. In view of the superimposable results between the two therapies, it should be noted that the endodontically treated teeth could be interested by different pathologies while the restoration of the atrophic edentulous ridge with an implant support is predictable when patients comply with correct oral hygiene and when the occlusal loads are axially distributed in implant-protected occlusion.


Interval brain imaging for adults with cerebral glioma.
Clinical practice guidelines suggest that magnetic resonance imaging (MRI) of the brain should be performed at certain time points or intervals distant from diagnosis (interval or surveillance imaging) of cerebral glioma, to monitor or follow up the disease; it is not known, however, whether these imaging strategies lead to better outcomes among patients than triggered imaging in response to new or worsening symptoms. To determine the effect of different imaging strategies (in particular, pre-specified interval or surveillance imaging, and symptomatic or triggered imaging) on health and economic outcomes for adults with glioma (grades 2 to 4) in the brain. The Cochrane Gynaecological, Neuro-oncology and Orphan Cancers (CGNOC) Group Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase up to 18 June 2019 and the NHS Economic Evaluation Database (EED) up to December 2014 (database closure). We included randomised controlled trials, non-randomised controlled trials, and controlled before-after studies with concurrent comparison groups comparing the effect of different imaging strategies on survival and other health outcomes in adults with cerebral glioma; and full economic evaluations (cost-effectiveness analyses, cost-utility analyses and cost-benefit analyses) conducted alongside any study design, and any model-based economic evaluations on pre- and post-treatment imaging in adults with cerebral glioma. We used standard Cochrane review methodology with two authors independently performing study selection and data collection, and resolving disagreements through discussion. We assessed the certainty of the evidence using the GRADE approach. We included one retrospective, single-institution study that compared post-operative imaging within 48 hours (early post-operative imaging) with no early post-operative imaging among 125 people who had surgery for glioblastoma (GBM: World Health Organization (WHO) grade 4 glioma). Most patients in the study underwent maximal surgical resection followed by combined radiotherapy and temozolomide treatment. Although patient characteristics in the study arms were comparable, the study was at high risk of bias overall. Evidence from this study suggested little or no difference between early and no early post-operative imaging with respect to overall survival (deaths) at one year after diagnosis of GBM (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.61 to 1.21; 48% vs 55% died, respectively; very low certainty evidence) and little or no difference in overall survival (deaths) at two years after diagnosis of GBM (RR 1.06, 95% CI 0.91 to 1.25; 86% vs 81% died, respectively; very low certainty evidence). No other review outcomes were reported. We found no evidence on the effectiveness of other imaging schedules. In addition, we identified no relevant economic evaluations assessing the efficiency of the different imaging strategies. The effect of different imaging strategies on survival and other health outcomes remains largely unknown. Existing imaging schedules in glioma seem to be pragmatic rather than evidence-based. The limited evidence suggesting that early post-operative brain imaging among GBM patients who will receive combined chemoradiation treatment may make little or no difference to survival needs to be further researched, particularly as early post-operative imaging also serves as a quality control measure that may lead to early re-operation if residual tumour is identified. Mathematical modelling of a large glioma patient database could help to distinguish the optimal timing of surveillance imaging for different types of glioma, with stratification of patients facilitated by assessment of individual tumour growth rates, molecular biomarkers and other prognostic factors. In addition, paediatric glioma study designs could be used to inform future research of imaging strategies among adults with glioma.


Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response.
Interleukin (IL)-17F is a recently described human cytokine belonging to the IL-17 gene family, but its in vivo function remains to be determined. To this end, a full-length mouse IL-17F cDNA sequence with a 483-bp coding region sequence was first identified. Pulmonary gene transfer of an IL-17F expression construct (pcDNAmIL-17F) in mice was used to investigate its regulatory role. The results showed first that a significant increase in the number of neutrophils was seen in the bronchoalveolar lavage fluids of IL-17F-transduced mice, concomitant with increased expression of genes encoding C-X-C chemokines and inflammatory cytokines when compared with mock and phosphate-buffered saline control animals. Mucosal transfer of the IL-17F gene in ovalbumin (OVA)-sensitized mice before antigen (Ag) challenge enhanced the levels of Ag-induced pulmonary neutrophilia, but not eosinophilia, goblet cell hyperplasia, and mucin gene expression. However, no significant change in the levels of Th2 cytokine expression was noted. A significant enhancement of ventilatory timing in response to inhaled methacholine was also seen in IL-17F-transduced, Ag-sensitized mice, whereas a small but significant increase was found in IL-17F-transduced, naive mice. These results suggest a role for IL-17F in the induction of neutrophilia in the lungs and in the exacerbation of Ag-induced pulmonary inflammation.


LONG-TERM FOLLOW-UP OF PATIENTS WITH RETINITIS PIGMENTOSA TYPE 12 CAUSED BY CRB1 MUTATIONS: A Severe Phenotype With Considerable Interindividual Variability.
To examine the long-term clinical course and variability in a large pedigree segregating CRB1 type autosomal recessive retinitis pigmentosa. An observational case study of 30 patients with CRB1 type autosomal recessive retinitis pigmentosa, homozygous for the CRB1 c.3122T > C; p.(Met1041Thr) mutation from a Dutch genetically isolated population in which the CRB1 gene was originally identified. The authors evaluated medical records, analyzed a questionnaire, and performed a comprehensive ophthalmic examination, including optical coherence tomography. Mean follow-up was 19 years (range 0-45 years, SD 15 years). With aging, patients showed progressive visual decline, deterioration of visual fields, increasing narrowing of the anterior chamber, increased prevalence of cataract, and an increase in the amount of intraretinal pigmentations. Fifty percent of patients had a visual acuity of ≤0.3 at Age 18 and of ≤0.1 at Age 35. Electroretinogram responses were severely reduced or absent already at a young age and optical coherence tomography showed increased retinal thickness with often cystoid maculopathy at young age, and thinning of the retina and disorientation of the photoreceptor layer in the late stages. The clinical course showed considerable interindividual variability, but intraindividual similarity between both eyes was the rule. The wide and variable clinical spectrum in patients with the same CRB1 mutation supports the hypothesis that the CRB1 type autosomal recessive retinitis pigmentosa-phenotype is modulated by other factors. The clinical variability will make it harder to evaluate the effect of (upcoming) therapies for retinitis pigmentosa, although because of the intraindividual similarity between both eyes, the contralateral eye can be used as an excellent internal control.


Red Blood Cell Distribution Width and Pediatric Community-Acquired Pneumonia Disease Severity.
No standardized risk assessment tool exists for community-acquired pneumonia (CAP) in children. This study aims to investigate the association between red blood cell distribution width (RDW) and pediatric CAP. Data prospectively collected by the Etiology of Pneumonia in the Community study (2010-2012) was used. Study population was pediatric patients admitted to tertiary care hospitals in Nashville and Memphis, Tennessee with clinically and radiographically confirmed CAP. The earliest measured RDW value on admission was used, in quintiles and also as a continuous variable. Outcomes analyzed were: severe CAP (requiring ICU, mechanical ventilation, vasopressor support, or death) or moderate CAP (hospital admission only). Analysis used multivariable logistic regression and restricted cubic splines modeling. In 1459 eligible children, the median age was 29 months (interquartile range: 12-73), median RDW was 13.3% (interquartile range: 12.5-14.3), and 289 patients (19.8%) developed severe disease. In comparison with the lowest RDW quintile (Q1), the adjusted odds ratio (95% CI) for severe CAP in subsequent quintiles were, Q2: 1.20 (0.72-1.99); Q3: 1.28 (0.76-2.14); Q4: 1.69 (1.01-2.82); Q5: 1.25 (0.73-2.13). Consistently, RDW restricted cubic splines demonstrated an independent, nonlinear, positive association with CAP severity (P = .027), with rapid increases in the risk of severe CAP with RDW values up to 15%. Higher presenting RDW was associated with an increased risk of severe CAP in hospitalized children. Widely available and inexpensive, RDW can serve as an objective data point to help with clinical assessments.


Human language reveals a universal positivity bias.
Using human evaluation of 100,000 words spread across 24 corpora in 10 languages diverse in origin and culture, we present evidence of a deep imprint of human sociality in language, observing that (i) the words of natural human language possess a universal positivity bias, (ii) the estimated emotional content of words is consistent between languages under translation, and (iii) this positivity bias is strongly independent of frequency of word use. Alongside these general regularities, we describe interlanguage variations in the emotional spectrum of languages that allow us to rank corpora. We also show how our word evaluations can be used to construct physical-like instruments for both real-time and offline measurement of the emotional content of large-scale texts.


Optical design at kodak.
The persons and the methods they employed for designing Kodak camera lenses are recalled, from the earliest, almost symmetrical four-element air spaced lenses, designed by hand, through the large lenses made for aerial cameras during World War II and the introduction of rare-earth glasses and then plastics, to very high resolution modern lenses for microfilm cameras and high quality zoom lenses for Super-8-mm motion picture equipment, designed almost completely automatically by electronic computers. The most modern and powerful methods of evaluating optical-image quality, including the role of the humaneye, and the use of those methods for lens design and system and production engineering are described.


Prescription extraction using CRFs and word embeddings.
In medical practices, doctors detail patients' care plan via discharge summaries written in the form of unstructured free texts, which among the others contain medication names and prescription information. Extracting prescriptions from discharge summaries is challenging due to the way these documents are written. Handwritten rules and medical gazetteers have proven to be useful for this purpose but come with limitations on performance, scalability, and generalizability. We instead present a machine learning approach to extract and organize medication names and prescription information into individual entries. Our approach utilizes word embeddings and tackles the task in two extraction steps, both of which are treated as sequence labeling problems. When evaluated on the 2009 i2b2 Challenge official benchmark set, the proposed approach achieves a horizontal phrase-level F1-measure of 0.864, which to the best of our knowledge represents an improvement over the current state-of-the-art.


Quality of life in dementia: more than just cognition. An analysis of associations with quality of life in dementia.
To explore the extent to which commonly used measures of specific outcomes in dementia are an appropriate proxy for quality of life in dementia. This was a cross sectional study set in communities in London and Nottingham, comprising 101 people with dementia and their 99 main family caregivers. The main outcome measures were health related quality of life in dementia (measured by the DEMQOL-Proxy), cognition (Mini Mental State Examination), functional impairment (Barthel Index), behavioural and psychological symptoms in dementia (Neuropsychiatric Inventory; NPI), and carer mental health (General Health Questionnaire). On univariate analysis, decreased quality of life was statistically significantly correlated with higher levels of behavioural and psychological disturbance (NPI total score and its agitation, depression, anxiety, disinhibition, and irritability subscales); younger age of the person with dementia; and poorer mental health of the carer. Quality of life was not statistically significantly associated with cognition or carer age. In a multivariate model, psychological and behavioural disturbance and patient age remained statistically significantly associated with quality of life. Carer mental health was no longer statistically significantly associated, and cognition and functional limitation remained statistically insignificant. These data suggest that quality of life in dementia is complex, and that simple proxy substitutions of discrete measures such as cognition or function are likely to miss important factors.


Regional variation in spending and survival for older adults with advanced cancer.
Medicare spending varies substantially across the United States. We evaluated the association between mean regional spending and survival in advanced cancer. We identified 116 523 subjects with advanced cancer from 2002 to 2007, using Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. Subjects were aged 65 years and older with non-small cell lung, colon, breast, prostate, or pancreas cancer. Of these subjects, 61 083 had incident advanced-stage cancer (incident cohort) and 98 935 had death from cancer (decedent cohort); 37% of subjects were included in both cohorts. Subjects were linked to one of 80 hospital referral regions within SEER areas. We estimated mean regional spending in both cohorts. We assessed the primary outcome, survival, in the incident cohort; the exposure measure was the quintile of regional spending in the decedent cohort. Survival in quintiles 2 through 5 was compared with that in quintile 1 (lowest spending quintile) using Cox regression models. From quintile 1 to 5, mean regional spending increased by 32% and 41% in the incident and decedent cohorts (incident cohort: $28 854 to $37 971; decedent cohort: $27 446 to $38 630). The association between spending and survival varied by cancer site and quintile; hazard ratios ranged from 0.92 (95% confidence interval [CI] = 0.82 to 1.04, pancreas cancer quintile 5) to 1.24 (95% CI = 1.11 to 1.39, breast cancer quintile 3). In most cases, differences in survival between quintile 1 and quintiles 2 through 5 were not statistically significant. There is substantial regional variation in Medicare spending for advanced cancer, yet no consistent association between mean regional spending and survival.


Persisting disparities between sexes in outcomes of ruptured abdominal aortic aneurysm hospitalizations.
We sought to describe and analyze discrepancies between sexes in the outcomes of patients hospitalized for ruptured abdominal aortic aneurysms (rAAA) by conducting a retrospective analysis of the Nationwide Inpatient Sample. The review included all adult patients (≥18 years old) hospitalized with a primary diagnosis of rAAA between January 2002 and December 2014. In-hospital mortality differences between females and males were analyzed overall and separately among those receiving endovascular AAA repair (EVAR) or open AAA repair (OAR). In-hospital mortality for females declined from 61.0% in 2002 to 49.0% in 2014 (P for trend <0.001), while mortality for males declined from 48.6% in 2002 to 32.2% in 2014 (P for trend <0.001). Among those receiving EVAR, females were significantly more likely to die in the hospital than males (adjusted odds ratio [OR], 1.44; 95% CI, 1.12-1.84). In addition, the odds of mortality among those receiving OAR were higher for females than males (adjusted OR, 1.14; 95% CI: 1.00-1.31). These data provide evidence that despite overall decreasing trends in mortality for both sexes, females remain at higher risk of death compared with males regardless of surgical repair procedure.


Adrenergic mechanisms in human hypertension and in spontaneously hypertensive rats.
1. The role of adrenergic neuronal mechanisms in the development of early hypertension in man and the spontaneously hypertensive rat has been explored. 2. In both, a hyperkinetic circulatory state is associated with reduced parasympathetic and increased adrenergic cardiac influences. 3. Spontaneously hypertensive and normotensive control rats were treated with propranolol from conception until 12 weeks. Although heart rate and output remained reduced, there was no difference in growth or elaboration of pressure with respect to their untreated controls. 4. After another series of spontaneously hypertensive and control rats received cardiac autonomic blockade (atropine and timolol), they sequentially received alpha-adrenergic blockade (phenoxybenzamine), ganglionic blockade (trimethaphan) and smooth-muscle vasodilatation (hydralazine). These studies revealed only a small pressure differential between the two groups before hydralazine and still less thereafter; unlike the control rats, pressure in spontaneously hypertensive rats fell markedly after ganglionic blockade as a result of reduced output, indicating greater adrenergic control mediated through venoconstriction. 5. These findings indicate: increased cardiovascular adrenergic control in young spontaneously hypertensive rats, the hyperkinetic circulation merely reflecting one aspect of increased total cardiovascular input. Structural alterations seem to participate minimally. 6. These experimental observations closely, resemble findings in early hypertensive man, and it is suggested that altered total cardiovascular adrenergic input is responsible for the elaboration, development, and maintenance of essential hypertension in man.


The rise of cholesterol testing: how much is unnecessary.
Laboratory testing has increased dramatically over recent decades, which is a consequence particularly of repeat testing or monitoring, as either a response to treatment or follow-up. To assess rates of measurement of lipid levels (total cholesterol, high-density lipoprotein, triglyceride) for diagnosis and monitoring over the last 20 years. Audit of electronic database. A single region in the UK (Oxfordshire). Specimens from individual patients were matched over time. All tests that were the third or more in a 3-year period were considered to be for monitoring, while the first and second were considered to be for diagnosis. As recent evidence-based recommendations suggest that frequent monitoring of cholesterol may reflect measurement error rather than true changes, between one and three tests in each 3-year period were considered to be 'necessary'. Over the 20 years from 1987 there has been a more than 15-fold rise in the overall number of lipid tests requested. After a small decline in the early 1990s, testing rose steadily after publication of several large statin trials, particularly tests requested in primary rather than secondary care. Repeat testing (likely to be for monitoring) rose from 24% of tests (1993-1995) to 61% (2005-2007), with between 42% and 79% of tests in 2005-2007 possibly being unnecessary. Mean cholesterol values declined over time from 1996 onwards. In the last decade, the number of cholesterol tests performed in Oxfordshire has risen dramatically. Much of this appears to be for monitoring purposes rather than case finding or risk assessment. The majority of cholesterol tests requested may be unnecessary.


Integration and application of a home treatment program: a study of parents and occupational therapists.
The purpose of this article is to describe parental adherence to home treatment programs. A qualitative exploratory study with six parents and eight occupational therapists who used the brushing and compression technique (Wilbarger Protocol) was conducted. Participants were interviewed one or two times, exploring their experiences in adhering to the protocol. Data analysis focused on facilitators and hindrances to parental adherence and on occupational therapists' strategies used to encourage it. Parents identified their children's responses to brushing, its perceived efficacy, and interaction of the protocol with family daily schedules, as factors influencing their adherence. Occupational therapists identified only family daily schedules as influencing parental adherence. The findings are discussed in the context of the ecocultural theory of family accommodations.


Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT2A agonist and NMDA antagonist model of psychosis.
Attentional deficits are common symptoms in schizophrenia. Recent evidence suggests that schizophrenic patients show abnormalities in spatial orienting of attention, particularly a deficit of inhibition of return (IOR). IOR is mostly thought to reflect an automatic, inhibitory mechanism protecting the organism from redirecting attention to previously scanned, insignificant locations. Pharmacologic challenges with hallucinogens have been used as models for psychosis. The aim of this study was to investigate the neural correlates underlying orienting of attention in the human N-methyl-D-aspartic acid antagonist and 5-HT2A agonist models of psychosis. Fourteen healthy volunteers participated in a randomized, double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. We administered a covert orienting of attention task with nonpredictive peripheral cues, and we scanned the subjects on two separate days at least 14 days apart with a placebo and a verum condition on each day. DMT, but not S-ketamine, slowed down reaction times significantly. IOR was blunted after DMT, but not after S-ketamine. Relative to placebo, S-ketamine increased activation in the IOR condition in the right superior frontal gyrus, left superior temporal gyrus, and right midfrontal frontal gyrus. The discrepancy between the behavioral and functional imaging outcome indicates that pharmacological fMRI might be a sensitive tool to detect drug-modulated blood oxygenation level-dependent signal changes in the absence of behavioral abnormalities. Our findings might help to further clarify the contradictory findings of IOR in schizophrenic patients and might, thus, shed more light on possible differential pathomechanisms of schizophrenic symptoms.


A versatile toolbox for multiplexed protein micropatterning by laser lithography.
Photocleavable oligohistidine peptides (POHP) allow in situ spatial organization of multiple His-tagged proteins onto surfaces functionalized with tris(nitrilotriacetic acid) (tris-NTA). Here, a second generation of POHPs is presented with improved photoresponse and site-specific covalent coupling is introduced for generating stable protein assemblies. POHPs with different numbers of histidine residues and a photocleavable linker based on the 4,5-dimethoxy-o-nitrophenyl ethyl chromophore are prepared. These peptides show better photosensitivity than the previously used o-nitrophenyl ethyl derivative. Efficient and stable caging of tris-NTA-functionalized surfaces by POHPs comprising 12 histidine residues is demonstrated by multiparameter solid-phase detection techniques. Laser lithographic uncaging by photofragmentation of the POHPs is possible with substantially reduced photodamage as compared to previous approaches. Thus, in situ micropatterning of His-tagged proteins under physiological conditions is demonstrated for the first time. In combination with a short peptide tag for a site-specific enzymatic coupling reaction, covalent immobilization of multiple proteins into target micropatterns is possible under physiological conditions.


Enhanced apoptotic activity of a structurally optimized form of galectin-1.
Galectin-1 is a homodimeric protein with potent anti-inflammatory properties due to its ability to induce apoptosis in thymocytes and T cells. The galectin-1 subunits are not covalently linked but the monomers are in a dynamic equilibrium with the dimeric form. Since the affinity of the monomers for each other is rather low (in the range of 10(-5)M), the in vivo efficacy of galectin-1 is limited because the equilibrium is shifted towards the inactive monomeric form at lower concentrations. In order to overcome this problem, we designed a covalently linked form of the dimer based on the galectin-1 crystal structure. Here we show that this irreversibly dimeric form of galectin-1 is a potent inducer of apoptosis in murine thymocytes as well as murine mature T cells at concentrations 10-fold lower than wild-type galectin-1. This structurally optimized form of galectin-1 may therefore be a potentially powerful tool to treat chronic inflammatory diseases.


NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.


Imagery of local defects in multilayer components by short coherence length interferometry.
We propose to image local defects inside multidielectric optical components by using a special configuration Linnik interference microscope, along with a CCD camera and a dedicated detection, to extract the amplitude scattered by the defects in the interference image. The use of a short coherence length source allows one to obtain interference only from a thin slice (~1microm) within the observed object. The object is tilted to permit the use of a dark-field configuration to enhance the defect contrast. We describe the experimental setup and the detection scheme. Images that exhibit local point defects on the interfaces of various multilayer optical components (laser mirrors) are presented.


Influence of glucose concentration on light scattering in tissue-simulating phantoms.
The presence of glucose dissolved in an aqueous solution increases the refractive index of the solution and therefore has an influence on the scattering properties of any particles suspended within it. We present experimental data on the effect of glucose concentration on the scattering coefficient of a suspension of spherical polystyrene particles. The experimental results are in good agreement with Mie theory. The effect of glucose on light transport in highly scattering, tissue-simulating phantoms is demonstrated both experimentally and theoretically by application of diffusion theory. The possible application of this effect for noninvasive glucose monitoring of diabetic patients is discussed.


The response of human bone marrow to chronic cigarette smoking.
Chronic cigarette smoking in humans causes leukocytosis. Animal studies show that chronic smoking shortens the transit time of polymorphonuclear leukocytes (PMNLs) through the bone marrow. The present study examines the response of human bone marrow to chronic cigarette smoking. Three characteristics of peripheral blood PMNLs that indicate active bone marrow release (band cell counts, surface L-selectin expression and myeloperoxidase (MPO) content), were measured in 38 healthy chronic smokers (23+/-5 pack-yrs) and 15 age- and sex-matched nonsmoking controls. The total white cell (6.8+/-0.3x10(9) versus 5.3+/-0.2x10(9) cells x L(-1), p<0.0001) and PMNL (4.2+/-0.18x10(9) versus 3.2+/-0.1x10(9) cells x L(-1), p<0.003) counts were higher in smokers as were the percentage (4.8+/-0.6 versus 1.1+/-0.2, p<0.0001) and total number (0.21+/-0.04x10(9) versus 0.03+/-0.001x10(9) cells x L(-1), p<0.01) of band cells. Flow cytometry showed that the mean fluorescence intensity (MFI) of L-selectin (3.2+/-0.2 versus 2.6+/-0.1, p<0.05) on PMNLs was higher in smokers. There was no difference in the baseline or N-formyl-methionyl-leucyl-phenylalanine-stimulated expression of CD63 or CD18/CD11b (surface markers of PMNL activation) between smokers and controls. The MPO content of PMNLs was higher in smokers (3.4+/-0.3 versus 1.7+/-0.2 MFI, p<0.05). Smokers with a low (<75% of the predicted value) diffusing capacity of the lung for carbon monoxide had higher PMNL MPO levels than smokers with a diffusing capacity of >75% pred (p<0.05). In conclusion, chronic smoking causes phenotypic changes in circulating polymorphonuclear leukocytes that are characteristic of chronic stimulation of the bone marrow and it is speculated that the increased number of immature polymorphonuclear leukocytes contributes to the chronic lung inflammation associated with cigarette smoking.


Evidence based acupuncture practice recommendations for peripheral facial paralysis.
The objective is to analyze the treatment used in relatively high quality randomized controlled trials to identify any similarities of therapeutic approaches and subsequently present recommendations for a standard acupuncture procedure for the treatment of peripheral facial paralysis (PFP). We searched Chinese and English language literatures through MEDLINE (January 1966 to October 2007), EMbase (January 1980 to October 2007), Chinese Biomedical Database (January 1978 to October 2007) and China National Knowledge Infrastructure (January 1979 to October 2007) for randomized controlled trials. With independent assessment by 2 observers, 33 of 386 originally identified articles were finally included. The extracted information from these articles was focused on the selection of meridians and acupoints, types of stimulation and duration of treatment. On the whole, when treating PFP, the best acupoints options are Dicang (ST4), Xiaguan (ST7), Jiache (ST6), Chengjiang (CV24), Yingxiang (LI20), Quanliao (SI18), Yifeng (TE17), Yangbai (GB14), Sibai (ST2), Fengchi (GB20), Shuigou (GV26), Yuyao (EX-HN4) and Hegu (LI4). Manual stimulation or electro-acupuncture combined with moxibustion is recommended. Moreover, the suggested duration of acupuncture treatment refers to once a day, 10 times for each course, 2 to 5 days as courses interval, and 20 to 40 treatments in total.


The Zn(II)2Cys6-Type Transcription Factor ADA-6 Regulates Conidiation, Sexual Development, and Oxidative Stress Response in Neurospora crassa.
Conidiation and sexual development are critical for reproduction, dispersal and better-adapted survival in many filamentous fungi. The Neurospora crassa gene ada-6 encodes a Zn(II)2Cys6-type transcription factor, whose deletion resulted in reduced conidial production and female sterility. In this study, we confirmed the positive contribution of ada-6 to conidiation and sexual development by detailed phenotypic characterization of its deletion mutant and the complemented mutant. To understand the regulatory mechanisms of ADA-6 in conidiation and sexual development, transcriptomic profiles generated by RNA-seq from the Δada-6 mutant and wild type during conidiation and sexual development were compared. During conidial development, differential expressed genes (DEGs) between the Δada-6 mutant and wild type are mainly involved in oxidation-reduction process and single-organism metabolic process. Several conidiation related genes are positively regulated by ADA-6, including genes that positively regulate conidiation (fluffy and acon-3), and genes preferentially expressed during conidial development (eas, con-6, con-8, con-10, con-13, pcp-1, and NCU9357), as the expression of these genes were lower in the Δada-6 mutant compared to wild type during conidial development. Phenotypic observation of deletion mutants for other genes with unknown function down-regulated by ada-6 deletion revealed that deletion mutants for four genes (NCU00929, NCU05260, NCU00116, and NCU04813) produced less conidia than wild type. Deletion of ada-6 resulted in female sterility, which might be due to that ADA-6 affects oxidation-reduction process and transmembrane transport process, and positively regulates the transcription of pre-2, poi-2, and NCU05832, three key genes participating in sexual development. In both conidiation and the sexual development process, ADA-6 regulates the transcription of cat-3 and other genes participating in reactive oxygen species production according to RNA-seq data, indicating a role of ADA-6 in oxidative stress response. This was further confirmed by the results that deletion of ada-6 led to hypersensitivity to oxidants H2O2 and menadione. Together, these results proved that ADA-6, as a global regulator, plays a crucial role in conidiation, sexual development, and oxidative stress response of N. crassa.


Financial Burden Borne by Laparoscopic Living Kidney Donors.
Living kidney donors have donation-related out-of-pocket costs (direct costs) and/or ongoing daily expenses while losing income (indirect costs). Yet there is little information about how much of a subjective burden these constitute for the donors. From December 2003 through December 2014, we surveyed donors 6 months postdonation to determine their financial burden related to donation (on a scale of 1 to 10) and what resources were used to cover expenses. Of 1136 surveyed, 796 (70%) responded. Among respondents, mean age at donation was 43.6 ± 10.6 years, 64% were women, 96% were white, and 53% were related by blood to their recipient. Overall, 26% scored their financial burden as 5 or higher; 8% scored it as 8 or higher. Increased expenses were associated with a higher reported burden; however, significant burden was reported by some with no out-of-pocket expenses (presumably due to lost wages and continuing expenses). The burden was scored as 5 or higher by 27% of those employed outside the home (n = 660), 15% homemakers, 13% retirees, 40% students; 28% unemployed; and 26% whose occupation was unknown. Over half (51%) of those receiving a local or (means-tested) national grant still reported moderate to severe burden. Besides grants, donors used a variety of sources to help offset expenses: dipped into savings, borrowed from friends or family, took out a loan, and/or had a fundraiser. Those with the highest burden reported using the most additional sources. Donors should not have to incur costs or a financial burden to donate; the transplant community should strive to make donation financially neutral.


New perspectives of the cardiac cellular landscape: mapping cellular mediators of cardiac fibrosis using single-cell transcriptomics.
Single-cell transcriptomics enables inference of context-dependent phenotypes of individual cells and determination of cellular diversity of complex tissues. Cardiac fibrosis is a leading factor in the development of heart failure and a major cause of morbidity and mortality worldwide with no effective treatment. Single-cell RNA-sequencing (scRNA-seq) offers a promising new platform to identify new cellular and molecular protagonists that may drive cardiac fibrosis and development of heart failure. This review will summarize the application scRNA-seq for understanding cardiac fibrosis and development of heart failure. We will also discuss some key considerations in interpreting scRNA-seq data and some of its limitations.


Retention patterns of asbestos fibres in lung tissue among asbestos cement workers.
Retention patterns in lung tissue (determined by transmission electron microscopy and energy dispersive spectrometry) of chrysotile, tremolite, and crocidolite fibres were analysed in 69 dead asbestos cement workers and 96 referents. There was an accumulation of tremolite with time of employment. Among workers who died within three years of the end of exposure, the 13 with high tremolite concentrations had a significantly longer duration of exposure than seven in a low to intermediate category (medians 32 v 20 years; p = 0.018, one sided). Crocidolite showed similar patterns of accumulation. In workers who died more than three years after the end of exposure, there were no correlations between concentrations of amphibole fibres and time between the end of exposure and death. Chrysotile concentrations among workers who died shortly after the end of exposure were higher than among the referents (median difference in concentrations 13 million fibres (f)/g dry weight; p = 0.033, one sided). No quantitative differences in exposure (duration or intensity) could be shown between workers with high and low to intermediate concentrations. Interestingly, all seven workers who had had a high intensity at the end of exposure (> 2.5 f/ml), had low to intermediate chrysotile concentrations at death, whereas those with low exposure were evenly distributed (31 subjects in both concentration categories); hence, there was a dependence between last intensity of exposure and chrysotile concentration (p = 0.014). Among 14 workers with a high average intensity of exposure, both those (n = 5) with high tissue concentrations of chrysotile and those (n = 10) with high tissue concentrations of tremolite fibres had more pronounced fibrosis than those with low to intermediate concentrations (median fibrosis grades for chrysotile: 2 v 1, p = 0.021; for tremolite: 2 v 0.5, p = 0.012). Additionally, workers who died shortly after the end of exposure with high concentrations of chrysotile and crocidolite had smoked more than those with low intermediate concentrations (medians for chrysotile 35 v 15 pack-years, p = 0.030; for crocidolite 37 v 15 pack-years, p = 0.012). The present data indicate that chrysotile has a relatively rapid turnover in human lungs, whereas the amphiboles, tremolite and crocidolite, have a slower turnover. Further, chrysotile retention may be dependent on dose rate. Chrysotile and crocidolite deposition and retention may be increased by tobacco smoking; chrysotile and tremolite by fibrosis.


Mobile phone radiation does not induce pro-apoptosis effects in human spermatozoa.
Abstract Recent reports suggest that mobile phone radiation may diminish male fertility. However, the effects of this radiation on human spermatozoa are largely unknown. The present study examined effects of the radiation on induction of apoptosis-related properties in human spermatozoa. Ejaculated, density-purified, highly motile human spermatozoa were exposed to mobile phone radiation at specific absorption rates (SARs) of 2.0 and 5.7 W/kg. At various times after exposure, flow cytometry was used to examine caspase 3 activity, externalization of phosphatidylserine (PS), induction of DNA strand breaks, and generation of reactive oxygen species. Mobile phone radiation had no statistically significant effect on any of the parameters studied. This suggests that the impairment of fertility reported in some studies was not caused by the induction of apoptosis in spermatozoa.


Cricothyroid approximation for voice and swallowing rehabilitation of high vagal paralysis secondary to skull base neoplasms.
This study documents the speech and swallowing outcomes of isolated ipsilateral cricothyroid approximation (aka tensioning thyroplasty; Type IV thyroplasty) for the treatment of high vagal paralysis (combined superior laryngeal nerve and recurrent laryngeal nerve paralysis). This is a pilot study of five cases with high vagal paralysis consequent to skull base neoplasms. Unilateral cricothyroid tensioning sutures were used. In all cases, vocal fold tensioning and vertical realignment of lax vocal folds were achieved. A partial, but acceptable medialization of vocal cord position was achieved. In all cases, aspiration was minimized and normal swallow function was restored by 6 weeks. The voice outcome was excellent in four cases and acceptable in one. Cricothyroid approximation restores vocal fold tension; in addition, it restores vertical vocal fold position and partially restores horizontal vocal fold position. Good voice and swallowing outcomes have been achieved. The procedure is quick, safe, and convenient when combined with a skull-base excision procedure. Further evaluation is merited.


Molecular dipole moment learning via rotationally equivariant derivative kernels in molecular-orbital-based machine learning.
This study extends the accurate and transferable molecular-orbital-based machine learning (MOB-ML) approach to modeling the contribution of electron correlation to dipole moments at the cost of Hartree-Fock computations. A MOB pairwise decomposition of the correlation part of the dipole moment is applied, and these pair dipole moments could be further regressed as a universal function of MOs. The dipole MOB features consist of the energy MOB features and their responses to electric fields. An interpretable and rotationally equivariant derivative kernel for Gaussian process regression (GPR) is introduced to learn the dipole moment more efficiently. The proposed problem setup, feature design, and ML algorithm are shown to provide highly accurate models for both dipole moments and energies on water and 14 small molecules. To demonstrate the ability of MOB-ML to function as generalized density-matrix functionals for molecular dipole moments and energies of organic molecules, we further apply the proposed MOB-ML approach to train and test the molecules from the QM9 dataset. The application of local scalable GPR with Gaussian mixture model unsupervised clustering GPR scales up MOB-ML to a large-data regime while retaining the prediction accuracy. In addition, compared with the literature results, MOB-ML provides the best test mean absolute errors of 4.21 mD and 0.045 kcal/mol for dipole moment and energy models, respectively, when training on 110 000 QM9 molecules. The excellent transferability of the resulting QM9 models is also illustrated by the accurate predictions for four different series of peptides.


Network dynamics and cell physiology.
Complex assemblies of interacting proteins carry out most of the interesting jobs in a cell, such as metabolism, DNA synthesis, movement and information processing. These physiological properties play out as a subtle molecular dance, choreographed by underlying regulatory networks. To understand this dance, a new breed of theoretical molecular biologists reproduces these networks in computers and in the mathematical language of dynamical systems.


Collaborative research networks in health: a pragmatic scoping study for the development of an imaging network.
Collaborative research networks are often touted as a solution for enhancing the translation of knowledge, but questions remain about how to evaluate their impact on health service delivery. This pragmatic scoping study explored the enabling factors for developing and supporting a collaborative imaging network in a metropolitan university in Australia. An advisory group was established to provide governance and to identify key informants and participants. Focus group discussions (n = 2) and semi-structured interviews (n = 22) were facilitated with representatives from a broad range of disciplines. In addition, a survey, a review of relevant websites (n = 15) and a broad review of the literature were undertaken to elicit information on collaborative research networks and perceived needs and factors that would support their involvement in a multi-disciplinary collaborative research network. Findings were de-identified and broad themes were identified. Participants identified human factors as having priority for developing and sustaining a collaborative research network. In particular, leadership, a shared vision and a communication plan that includes social media were identified as crucial for sustaining an imaging network in health research. It is important to develop metrics that map relationships between network members and the role that communication tools can contribute to this process. This study confirms that human factors remain significant across a range of collaborative endeavours. The use of focus group discussions, interviews, and literature and website reviews means we can now strongly recommend the primacy of human factors. More work is needed to identify how the network operates and what specific indicators or metrics help build the capacity of clinicians and scientists to participate in translational research.


Systemic delay propagation in the US airport network.
Technologically driven transport systems are characterized by a networked structure connecting operation centers and by a dynamics ruled by pre-established schedules. Schedules impose serious constraints on the timing of the operations, condition the allocation of resources and define a baseline to assess system performance. Here we study the performance of an air transportation system in terms of delays. Technical, operational or meteorological issues affecting some flights give rise to primary delays. When operations continue, such delays can propagate, magnify and eventually involve a significant part of the network. We define metrics able to quantify the level of network congestion and introduce a model that reproduces the delay propagation patterns observed in the U.S. performance data. Our results indicate that there is a non-negligible risk of systemic instability even under normal operating conditions. We also identify passenger and crew connectivity as the most relevant internal factor contributing to delay spreading.


Influence of deoxyribonucleic acid damage on fertilization and pregnancy.
To investigate sperm DNA damage in relation to fertilization and pregnancy. Prospective study. The Institute of Reproductive Medicine, Giessen, Germany. Semen collected from 249 patients attending the IVF program. The percentage of terminal deoxynucleotidyl transferase-mediated dUDP nick-end labeling- (TUNEL-), Fas-, and annexin-V-positive sperm and the proportion of green-fluorescing sperm in the acridine orange stain was determined and correlated with sperm concentration, motility, fertilization, and pregnancy. Significant correlations with the concentration of motile sperm were only found for the acridine orange stain (before and after sperm separation) and for the TUNEL assay (after sperm separation). Moreover, patients whose sperm had a high percentage of DNA fragmentations showed significantly lower pregnancy rates (TUNEL assay: 19.05% vs. 34.65%; acridine orange stain: 24.58% vs. 37.93%). The apoptosis parameters (annexin V binding and Fas expression) showed no statistically significant differences. Our data clearly demonstrate that DNA fragmentation, as determined by the TUNEL assay, is predictive for pregnancy in IVF. This implies that spermatozoa with DNA fragmentation can still fertilize an oocyte but that when paternal genes are "switched on," further embryonic development stops, resulting in failed pregnancy. It seems that, at least in the patients we analyzed, apoptosis in the sperm does not play a role for fertilization. This would imply that DNA fragmentation in human spermatozoa is caused by external factors, such as reactive oxygen species, rather than by apoptosis.


Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy.
Auditory neuropathy is a particular type of hearing impairment in which neural transmission of the auditory signal is impaired, while cochlear outer hair cells remain functional. Here we report on DFNB59, a newly identified gene on chromosome 2q31.1-q31.3 mutated in four families segregating autosomal recessive auditory neuropathy. DFNB59 encodes pejvakin, a 352-residue protein. Pejvakin is a paralog of DFNA5, a protein of unknown function also involved in deafness. By immunohistofluorescence, pejvakin is detected in the cell bodies of neurons of the afferent auditory pathway. Furthermore, Dfnb59 knock-in mice, homozygous for the R183W variant identified in one DFNB59 family, show abnormal auditory brainstem responses indicative of neuronal dysfunction along the auditory pathway. Unlike previously described sensorineural deafness genes, all of which underlie cochlear cell pathologies, DFNB59 is the first human gene implicated in nonsyndromic deafness due to a neuronal defect.


Driving forces for adsorption of amphiphilic peptides to the air-water interface.
We have studied the partitioning of amphiphilic peptides at the air-water interface. The free energy of adsorption from bulk to interface was calculated by determining the potential of mean force via atomistic molecular dynamics simulations. To this end a method is introduced to restrain or constrain the center of mass of a group of molecules in a periodic system. The model amphiphilic peptides are composed of alternating valine and asparagine residues. The decomposition of the free energy difference between the bulk and interface is studied for different peptide block lengths. Our analysis revealed that for short amphiphilic peptides the surface driving force dominantly stems from the dehydration of hydrophobic side chains. The only opposing force is associated with the loss of orientational freedom of the peptide at the interface. For the peptides studied, the free energy difference scales linearly with the size of the molecule, since the peptides mainly adopt extended conformations both in bulk and at the interface. The free energy difference depends strongly on the water model, which can be rationalized through the hydration thermodynamics of hydrophobic solutes. Finally, we measured the reduction of the surface tension associated with complete coverage of the interface with peptides.


Psychotropic effects of antimicrobials and immune modulation by psychotropics: implications for neuroimmune disorders.
Antimicrobial compounds and psychotropic medications often share overlapping mechanisms of actions and pharmacological effects. The immune system appears to be an important site of interaction as several antimicrobials display neurological and, at times, direct psychotropic effects, while psychotropics have shown significant immunomodulatory properties. The isoniazid class of antibiotics for example has been shown to possess monoamine oxidase activity, while selective serotonin reuptake inhibitors have shown significant effects on leukocyte populations. As the importance of the immune system's role in CNS homeostasis and disease continues to move to the forefront of neuropsychiatric research, these shared pharmacological effects may provide an important insight, elucidating the complexities in neuroimmune pathophysiology and guiding the development of potential treatments.


Prevalences of endoscopic and histological findings in subjects with and without dyspepsia.
To examine the association between dyspeptic symptoms and endoscopic and histological diagnoses. Cross sectional study of people with dyspepsia and controls matched for age and sex identified by questionnaire survey of all inhabitants aged 20 to 69. Endoscopy and histological examination was performed with the examiner blind to whether or not the patient had dyspepsia. Population based survey in Sørreisa, Norway. All people with dyspepsia and age and sex matched people without dyspepsia were offered endoscopy. A total of 309 people with dyspepsia and 310 without dyspepsia underwent endoscopy, giving 273 matched pairs. Prevalences of endoscopic and histological diagnoses made according to internationally accepted standards. In all, 1802 of 2027 (88.9%) people returned the questionnaire. Of the 163 subjects who refused endoscopy, 114 were controls. Of five endoscopic and four histological diagnoses only peptic ulcer disease, endoscopic duodenitis, and active chronic gastritis were diagnosed significantly more often in people with dyspepsia. In all, 30% to 50% of the diagnoses of mucosal inflammation and peptic ulcer disease were made among subjects without dyspepsia, and only 10% of both those with and those without dyspepsia had normal endoscopic findings. The diagnostic findings, with possible exceptions of peptic ulcer disease and endoscopic duodenitis, showed no association of clinical value with dyspeptic symptoms. The small number of "normal" endoscopic findings in both those with and those without dyspepsia challenge well accepted endoscopic and histological diagnostic criteria with relation to the upper gastrointestinal tract.


Effects of pneumoperitoneum induced at various pressures on cardiorespiratory function and working space during laparoscopy in cats.
To evaluate the effect of pneumoperitoneum on cardiorespiratory variables and working space during experimental induction of 3 intra-abdominal pressures (IAPs) in cats. 6 healthy young adult neutered male domestic shorthair cats. All cats were anesthetized through use of a standardized protocol. A catheter was placed in the right femoral artery for blood pressure and blood gas monitoring. A thermodilution catheter was placed in the right jugular vein via fluoroscopic guidance. Cardiopulmonary variables were measured before (baseline) and 2 and 30 minutes after initiation of pneumoperitoneum at IAPs of 4, 8, and 15 mm Hg; these were created through the use of a mechanical insufflator. At each IAP, abdominal dimensions (height, width, and circumference) were measured at a standardized location. At 4 mm Hg and 8 mm Hg IAP, no clinically important changes were identified in cardiorespiratory values. Heart rate, cardiac index, and stroke volume index remained unchanged throughout the study at all IAPs. Mean arterial blood pressure began to increase at 8 mm Hg and was significantly higher, compared with baseline, at both time points at 15 mm Hg. At 15 mm Hg, Paco2 was significantly higher and cats were more acidotic than at baseline. Working space was subjectively greater at 8 mm Hg than at 4 mm Hg IAP; however, at 15 mm Hg, no clinically important enlargement of the working space was identified, compared with at 8 mm Hg. Values of cardiopulmonary variables were largely unchanged by induction of pneumoperitoneum in healthy cats up to an IAP of 8 mm Hg, and no clinically important increases in working space were evident at an IAP of 15 versus 8 mm Hg. These findings provide little justification for use of IAPs > 8 mm Hg in healthy cats undergoing laparoscopic procedures; however, whether the situation is similar in diseased or elderly cats remains to be determined.


Protocol for the Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography (P-DROWS-E) study: a prospective observational study of delirium in elderly cardiac surgical patients.
Delirium is a potentially preventable disorder characterised by acute disturbances in attention and cognition with fluctuating severity. Postoperative delirium is associated with prolonged intensive care unit and hospital stay, cognitive decline and mortality. The development of biomarkers for tracking delirium could potentially aid in the early detection, mitigation and assessment of response to interventions. Because sleep disruption has been posited as a contributor to the development of this syndrome, expression of abnormal electroencephalography (EEG) patterns during sleep and wakefulness may be informative. Here we hypothesise that abnormal EEG patterns of sleep and wakefulness may serve as predictive and diagnostic markers for postoperative delirium. Such abnormal EEG patterns would mechanistically link disrupted thalamocortical connectivity to this important clinical syndrome. P-DROWS-E (Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography) is a 220-patient prospective observational study. Patient eligibility criteria include those who are English-speaking, age 60 years or older and undergoing elective cardiac surgery requiring cardiopulmonary bypass. EEG acquisition will occur 1-2 nights preoperatively, intraoperatively, and up to 7 days postoperatively. Concurrent with EEG recordings, two times per day postoperative Confusion Assessment Method (CAM) evaluations will quantify the presence and severity of delirium. EEG slow wave activity, sleep spindle density and peak frequency of the posterior dominant rhythm will be quantified. Linear mixed-effects models will be used to evaluate the relationships between delirium severity/duration and EEG measures as a function of time. P-DROWS-E is approved by the ethics board at Washington University in St. Louis. Recruitment began in October 2018. Dissemination plans include presentations at scientific conferences, scientific publications and mass media. NCT03291626.


Advances in asthma and COPD treatment: combination therapy with inhaled corticosteroids and long-acting beta 2-agonists.
Asthma treatment guidelines advocate the use of long-acting beta2-agonists (LABA) in addition to inhaled corticosteroids (ICS) in patients whose asthma is uncontrolled by ICS alone, thereby addressing two processes fundamental to asthma: bronchoconstriction and inflammation. Superior control--including a reduction in severe exacerbations--of asthma and COPD by ICS/LABA combination therapy has been demonstrated. Results from clinical studies suggest additive and potentially synergistic effects when the two agents are used in combination. No new safety-related issues have been identified with ICS/LABA compared with the monocomponents. The exact mechanisms for the enhanced efficacy of ICS/LABA combinations are under investigation but likely include drug interactions at the receptor level and interwoven signalling pathways, which may result in improved function of 2- adrenoceptors and steroid receptors. Data from preclinical studies provide evidence of additive, compensatory, complementary and synergistic effects of ICS and LABA in the control of inflammation and airway and lung remodelling. These effects may contribute to the improved efficacy seen when treating asthma and COPD with ICS/LABA combinations in clinical studies. Two ICS/LABA combination products are available: budesonide/formoterol (Symbicort) and salmeterol/fluticasone propionate (SeretideTM). An ICS/LABA combination in a single inhaler represent safe, effective and convenient treatment options for the management of patients with asthma and COPD. Clinical results also suggest that adjustable dosing with budesonide/formoterol provides better asthma control than fixed dosing. Further elucidation of the underlying mechanisms responsible for this superior disease control is needed.


[Eating disorders (I)--medical and psychiatric aspects].
Adolescent, predominantly female patients suffering from eating disorders usually reveal characteristic personality traits which should be taken into account during the treatment of such cases. Some patients deny their illness, others again feel ashamed of it. At any rate, we ought to respect the patients' integrity and their sense of self-worth. Such disorders tend to result from the stress of being unable to cope with the multiple demands made by the biological and social changes of the patients' development into full maturity. Additional predisposing factors should be noted. Eating disorders are often accompanied by specific psychic and somatic symptoms in terms of comorbidity. These symptoms have to be anamnestically accounted for since they may later result in oral symptoms. A considerable number of these patients suffering from eating disorders either do not completely recover or else tend to relapse.


Induced nitric oxide synthesis in the gut of Manduca sexta protects against oral infection by the bacterial pathogen Photorhabdus luminescens.
Injecting the insect pathogenic bacterium Photorhabdus luminescens into the blood system of the model lepidopteran insect Manduca sexta induces nitric oxide synthase (NOS) expression in the fat body and blood cells (haemocytes), whereas following oral ingestion of bacteria NOS expression is limited to the gut. We used RNA interference to knock-down expression of NOS throughout the insect. Preventing NOS induction in this way adversely affected the survival of orally infected insects and caused a significant increase in the number of bacteria crossing into the haemolymph. By contrast, knock-down of NOS had no effect on the mortality rate of insects infected with P. luminescens by injection. Pharmacological inhibition of NOS decreased both nitric oxide (NO) levels in the gut wall and survival of orally infected insects, whereas elevation of gut wall NO using an NO donor increased survival of NOS silenced caterpillars. Together, our results imply that induced synthesis of NO is important in mediating insect immune defence against the pathogen by inhibiting transfer of bacteria across the gut wall.


Diagnosis of lung adenocarcinoma in situ and minimally invasive adenocarcinoma from intraoperative frozen sections: an analysis of 136 cases.
To determine the diagnostic accuracy and contraindications for intraoperative diagnosis of lung adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) from frozen sections. A retrospective analysis of data from 136 patients pathologically diagnosed with early-stage (T1N0M0) AIS or MIA from paraffin-embedded sections. The rate of concordance between the diagnoses from intraoperative frozen sections and paraffin-embedded sections was determined, and the interpretive features that contributed to errors and deferrals in frozen-section diagnoses were identified. Of the 136 patients, diagnoses from frozen sections and paraffin-embedded sections were concordant in 86 (63.24%) cases intraoperatively diagnosed with AIS or MIA, and 44 (32.35%) cases were intraoperatively diagnosed with adenocarcinoma as the range of infiltration could not be determined from the frozen sections. From the remaining six (4.41%) cases, the frozen section and paraffin-embedded section diagnoses were discordant. The reasons for frozen section errors and deferrals included larger tumour volume, tumour located close to the visceral pleura, interstitial inflammation or fibrosis, absence of prominent atypia and differential morphology in the deeper levels of the paraffin block. Diagnosis of AIS and MIA from intraoperative frozen sections is feasible. We provide several modifications that may improve the diagnostic accuracy of intraoperative frozen sections for early-stage lung adenocarcinoma.


Creating spaces in intensive care for safe communication: a video-reflexive ethnographic study.
The built environment in acute care settings is a new focus in patient safety research, with few studies focusing primarily on the design of ward environments and the location and choice of material objects such as light fittings and hand-washing basins. We report on an interventionist video-reflexive ethnographic (VRE) study that explored how clinicians used the built environment to achieve safe communication in an intensive care unit (ICU) in a metropolitan Sydney hospital. We conducted 40 semistructured interviews, 5 weeks of observation and four reflexive focus groups with a total of 87 participants (including medical, nursing, allied health and clerical staff). We found that the accessibility of staff and patients in the open spaces of the ICU was both a safety feature and a safety risk, enabling safe communication flow, but also allowing potentially unsafe interruptions. Staff managed interruptions while allowing for a safe degree of accessibility by creating temporary protected spaces, using physical markers such as curtains, tape and signs as well as behavioural cues, movement and the development of policies restricting activities at certain areas. Furthermore, clinicians were able to use the VRE method to gain insight into their own practices and problems, and to develop meaningful solutions for other problematic spaces. ICU staff enable safe communication in their wards by creating temporary spaces that are both 'connected' and 'protected'. The flexibility of these 'soft' strategies is especially well suited to the fast-paced clinical context of intensive care.


Role of Rho-kinase in reexpansion pulmonary edema in rabbits.
Reexpansion of a collapsed lung increases the microvascular permeability and causes reexpansion pulmonary edema. Neutrophils and their products have been implicated in the development of this phenomenon. The small GTP-binding proteins Rho and its target Rho-kinase (ROCK) regulate endothelial permeability, although their roles in reexpansion pulmonary edema remain unclear. We studied the contribution of ROCK to pulmonary endothelial and epithelial permeability in a rabbit model of this disorder. Endothelial and epithelial permeability was assessed by measuring the tissue-to-plasma (T/P) and bronchoalveolar lavage (BAL) fluid-to-plasma (B/P) ratios with (125)I-labeled albumin. After intratracheal instillation of (125)I-albumin, epithelial permeability was also assessed from the plasma leak (PL) index, the ratio of (125)I-albumin in plasma/total amount of instilled (125)I-albumin. T/P, B/P, and PL index were significantly increased in the reexpanded lung. These increases were attenuated by pretreatment with Y-27632, a specific ROCK inhibitor. However, neutrophil influx, neutrophil elastase activity, and malondialdehyde concentrations in BAL fluid collected from the reexpanded lung were not changed by Y-27632. In endothelial monolayers, Y-27632 significantly attenuated the H(2)O(2)-induced increase in permeability and mitigated the morphological changes in the actin microfilament cytoskeleton of endothelial cells. These in vivo and in vitro observations suggest that the Rho/ROCK pathway contributes to the increase in alveolar barrier permeability associated with reexpansion pulmonary edema.


Iron absorption in non-transfused iron loading anaemias: prediction of risk for iron loading, and response to iron chelation treatment, in beta thalassaemia intermedia and congenital sideroblastic anaemias.
A variable rate of iron loading, reaching toxic levels in some patients, was seen in a series of non-transfused patients with beta thalassaemia intermedia or sideroblastic anaemia. The degree of anaemia was a poor guide to the risk of iron overload. However the extent of erythroid hyperplasia, judged by ferrokinetic studies or more simply by bone marrow aspiration, was useful in predicting both the rate of iron loading and the need for iron chelation therapy.


Sulfonamide allergy and cross-reactivity.
Concerns about cross-allergenicity between sulfonamide antibiotics and nonantibiotic sulfonamide-containing drugs continue to complicate pharmacotherapy. Several elegant investigations have demonstrated unequivocal lack of interaction between the sulfonamide group and either cellular or humoral immunity. The immunologic determinant of type I immunologic responses to sulfonamide antibiotics is the N1 heterocyclic ring, and nonantibiotic sulfonamides lack this structural feature. Many non-type I hypersensitivity responses to sulfonamide antibiotics are attributable to reactive metabolites that cause either direct cytotoxicity or humoral or cellular responses. Metabolite formation is stereospecific to the N4 amino nitrogen of the sulfonamide antibiotics, a structure not found on any nonantibiotic sulfonamide drugs. Cellular immune responses to sulfonamide antibiotics are responsible for many non-immunoglobulin E-mediated dermatologic reactions; however, the stereospecificity of T-cell response renders cross-reactivity between sulfonamide antibiotics and nonantibiotics highly unlikely. Apparent cross-reactivity responses to sulfonamide-containing drugs likely represent multiple concurrent, rather than linked, drug hypersensitivities.


Exposure to neighborhood green space and mental health: evidence from the survey of the health of Wisconsin.
Green space is now widely viewed as a health-promoting characteristic of residential environments, and has been linked to mental health benefits such as recovery from mental fatigue and reduced stress, particularly through experimental work in environmental psychology. Few population level studies have examined the relationships between green space and mental health. Further, few studies have considered the role of green space in non-urban settings. This study contributes a population-level perspective from the United States to examine the relationship between environmental green space and mental health outcomes in a study area that includes a spectrum of urban to rural environments. Multivariate survey regression analyses examine the association between green space and mental health using the unique, population-based Survey of the Health of Wisconsin database. Analyses were adjusted for length of residence in the neighborhood to reduce the impact of neighborhood selection bias. Higher levels of neighborhood green space were associated with significantly lower levels of symptomology for depression, anxiety and stress, after controlling for a wide range of confounding factors. Results suggest that "greening" could be a potential population mental health improvement strategy in the United States.


Development and validation of a predictive model of drug-resistant genetic generalized epilepsy.
To develop and validate a clinical prediction model for antiepileptic drug (AED)-resistant genetic generalized epilepsy (GGE). We performed a case-control study of patients with and without drug-resistant GGE, nested within ongoing longitudinal observational studies of AED response at 2 tertiary epilepsy centers. Using a validation dataset, we tested the predictive performance of 3 candidate models, developed from a training dataset. We then tested the candidate models' predictive ability on an external testing dataset. Of 5,189 patients in the ongoing longitudinal study, 121 met criteria for AED-resistant GGE and 468 met criteria for AED-responsive GGE. There were 66 patients with GGE in the external dataset, of whom 17 were cases. Catamenial epilepsy, history of a psychiatric condition, and seizure types were strongly related with drug-resistant GGE case status. Compared to women without catamenial epilepsy, women with catamenial epilepsy had about a fourfold increased risk for AED resistance. The calibration of 3 models, assessing the agreement between observed outcomes and predictions, was adequate. Discriminative ability, as measured with area under the receiver operating characteristic curve (AUC), ranged from 0.58 to 0.65. Catamenial epilepsy, history of a psychiatric condition, and the seizure type combination of generalized tonic clonic, myoclonic, and absence seizures are negative prognostic factors of drug-resistant GGE. The AUC of 0.6 is not consistent with truly effective separation of the groups, suggesting other unmeasured variables may need to be considered in future studies to improve predictability.


Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates.
Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.