Skin color modeling using the radiative transfer equation solved by the auxiliary function method: inverse problem.
In a previous article [J. Opt. Soc. Am. A 24, 2196 (2007)] we have modeled skin color using the radiative transfer equation, solved by the auxiliary function method. Three main parameters have been determined as being predominant in the diversity of skin color: the concentrations of melanosomes and of red blood cells and the oxygen saturation of blood. From the reflectance spectrum measured on real Caucasian skin, these parameters are now evaluated by minimizing the standard deviation on the adjusted wavelength range between the experimental spectrum and simulated spectra gathered in a database.


Posttraumatic Stress Disorder after Hurricane Sandy among Persons Exposed to the 9/11 Disaster.
Traumatic exposure during a hurricane is associated with adverse mental health conditions post-event. The World Trade Center Health Registry provided a sampling pool for a rapid survey of persons directly affected by Hurricane Sandy in the New York City (NYC) metropolitan area in late October 2012. This study evaluated the relationship between Sandy experiences and Sandy-related posttraumatic stress disorder (PTSD) among individuals previously exposed to the September 11, 2001 (9/11) disaster. A total of 4,558 surveys were completed from April 10-November 7, 2013. After exclusions for missing data, the final sample included 2,214 (53.5%) respondents from FEMA-defined inundation zones and 1,923 (46.5%) from non-inundation zones. Sandy exposures included witnessing terrible events, Sandy-related injury, fearing for own life or safety of others, evacuation, living in a home that was flooded or damaged, property loss, and financial loss. Sandy-related PTSD was defined as a score of ≥44 on a Sandy-specific PTSD Checklist. PTSD prevalence was higher in the inundation zones (11.3%) and lower in the non-inundation zones (4.4%). The highest prevalence of Sandy-related PTSD was among individuals in the inundation zone who sustained an injury (31.2%), reported a history of 9/11-related PTSD (28.8%), or had low social support prior to the event (28.6%). In the inundation zones, significantly elevated adjusted odds of Sandy-related PTSD were observed among persons with a prior history of 9/11-related PTSD, low social support, and those who experienced a greater number of Sandy traumatic events. Sandy-related stress symptoms indicative of PTSD affected a significant proportion of persons who lived in flooded areas of the NYC metropolitan area. Prior 9/11-related PTSD increased the likelihood of Sandy-related PTSD, while social support was protective. Public health preparation for events similar to Sandy should incorporate outreach and linkages to care for persons with prior disaster-related trauma.


Paradox resolved: Stop signal race model with negative dependence.
The ability to inhibit our responses voluntarily is an important case of cognitive control. The stop-signal paradigm is a popular tool to study response inhibition. Participants perform a response time task (go task), and occasionally, the go stimulus is followed by a stop signal after a variable delay, indicating subjects to withhold their response (stop task). The main interest of modeling is in estimating the unobservable stop-signal processing time, that is, the covert latency of the stopping process as a characterization of the response inhibition mechanism. In the independent race model, the stop-signal task is represented as a race between stochastically independent go and stop processes. Without making any specific distributional assumptions about the processing times, the model allows estimating the mean time to cancel a response. Neurophysiological studies on countermanding saccadic eye movements, however, have shown that the neural correlates of go and stop processes consist of networks of mutually interacting gaze-shifting and gaze-holding neurons. This poses a major challenge in formulating linking propositions between the behavioral and neural findings. Here we propose a dependent race model that postulates perfect negative stochastic dependence between go and stop activations. The model is consistent with the concept of interacting processes while retaining the simplicity and elegance of the distribution-free independent race model. For mean data, the dependent model's predictions remain identical to those of the independent model. The resolution of this apparent paradox advances the understanding of mechanisms of response inhibition and paves the way for modeling more complex situations. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Chorioamnionitis and cerebral palsy: a meta-analysis.
To examine the relationships between clinical or histological chorioamnionitis and cerebral palsy using a meta-analysis approach. A systematic review of the literature appeared in PubMed between 2000 and 2009 was conducted using the search terms "cerebral palsy" and "infection," with broad-scope variations in terminology of "white matter damage," "periventricular leukomalacia," "cystic periventricular leukomalacia," "chorioamnionitis," "intrauterine infection," "intraventricular hemorrhage," "funisitis," "fetal inflammatory response," "early neonatal sepsis," "neurological impairment," "virus," "bacteria," "fungi," and "protozoa," with variations of suffixes (eg, "viral," "bacterial," "fungal," "protozoan," etc), and "urinary tract infection," "bacterial vaginosis," "bacteriuria," and "cytokines." The related key words "gestational age," "small for gestational age," "preterm," and "low birth weight" also were added to the search terms. Only studies published in English were included. Three hundred eight articles were retrieved and systematically reviewed independently by two authors. Application of four inclusion criteria led to 15 studies being considered for data abstraction. An exposure was considered relevant if it met the established criteria for clinical or histological chorioamnionitis. The outcome was a diagnosis of cerebral palsy in accordance with established criteria. The data were abstracted onto standard forms, correlated according to eight characteristics, and tabulated. Twelve of the 15 studies contained information on the association between clinical chorioamnionitis and cerebral palsy, and eight studies included information on the association between histological chorioamnionitis and cerebral palsy. The results indicated that there were significant associations between clinical chorioamnionitis or histological chorioamnionitis and cerebral palsy, for clinical chorioamnionitis (chi1=13.91; P<.001) with a pooled odds ratio of 2.42 (95% confidence interval 1.52-3.84), and for histological chorioamnionitis (chi1=6.86; P=.009) with a pooled odds ratio of 1.83 (95% confidence interval, 1.17-2.89). The data suggested increased risks of 140% and 80% for neonates exposed to clinical chorioamnionitis or histological chorioamnionitis, respectively. The significant association of clinical or histological chorioamnionitis with cerebral palsy suggested that clinical strategies to prevent or reduce chorioamnionitis would lead to a reduction in cerebral palsy. The culture techniques currently used to diagnose the presence of pathogenic microorganisms during pregnancy need to improve, both in their methodology and in the length of time they require.


Gene regulation and DNA damage in the ageing human brain.
The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.


Walking a mile in their patients' shoes: empathy and othering in medical students' education.
One of the major tasks of medical educators is to help maintain and increase trainee empathy for patients. Yet research suggests that during the course of medical training, empathy in medical students and residents decreases. Various exercises and more comprehensive paradigms have been introduced to promote empathy and other humanistic values, but with inadequate success. This paper argues that the potential for medical education to promote empathy is not easy for two reasons: a) Medical students and residents have complex and mostly unresolved emotional responses to the universal human vulnerability to illness, disability, decay, and ultimately death that they must confront in the process of rendering patient care b) Modernist assumptions about the capacity to protect, control, and restore run deep in institutional cultures of mainstream biomedicine and can create barriers to empathic relationships. In the absence of appropriate discourses about how to emotionally manage distressing aspects of the human condition, it is likely that trainees will resort to coping mechanisms that result in distance and detachment. This paper suggests the need for an epistemological paradigm that helps trainees develop a tolerance for imperfection in self and others; and acceptance of shared emotional vulnerability and suffering while simultaneously honoring the existence of difference. Reducing the sense of anxiety and threat that are now reinforced by the dominant medical discourse in the presence of illness will enable trainees to learn to emotionally contain the suffering of their patients and themselves, thus providing a psychologically sound foundation for the development of true empathy.


Pulmonary neuroepithelial bodies are polymodal airway sensors: evidence for CO2/H+ sensing.
Pulmonary neuroepithelial bodies (NEB) in mammalian lungs are thought to function as airway O2 sensors that release serotonin (5-HT) in response to hypoxia. Direct evidence that NEB cells also respond to airway hypercapnia/acidosis (CO2/H(+)) is presently lacking. We tested the effects of CO2/H(+) alone or in combination with hypoxia on 5-HT release from intact NEB cells in a neonatal hamster lung slice model. For the detection of 5-HT release we used carbon fiber amperometry. Fluorescence Ca(2+) imaging method was used to assess CO2/H(+)-evoked changes in intracellular Ca(2+). Exposure to 10 and 20% CO2 or pH 6.8-7.2 evoked significant release of 5-HT with a distinct rise in intracellular Ca(2+) in hamster NEBs. This secretory response was dependent on the voltage-gated entry of extracellular Ca(2+). Moreover, the combined effects of hypercapnia and hypoxia were additive. Critically, an inhibitor of carbonic anhydrase (CA), acetazolamide, suppressed CO2/H(+)-mediated 5-HT release. The expression of mRNAs for various CA isotypes, including CAII, was identified in NEB cells from human lung, and protein expression was confirmed by immunohistochemistry using a specific anti-CAII antibody on sections of human and hamster lung. Taken together our findings provide strong evidence for CO2/H(+) sensing by NEB cells and support their role as polymodal airway sensors with as yet to be defined functions under normal and disease conditions.


Gender and renal function influence plasma levels of copeptin in healthy individuals.
The present study sought to identify confounding factors for the interpretation of copeptin levels in healthy individuals. The natriuretic peptides are recognized as diagnostic and prognostic tools in HF (heart failure). Interpretation of BNP (brain natriuretic peptide) and NTproBNP (N-terminal pro-BNP) levels is multifaceted as their secretion is influenced by many variables. A newly identified glycopeptide called copeptin is comparable with the natriuretic peptides in the diagnosis and prognosis of HF and as a prognostic biomarker after AMI (acute myocardial infarction). Copeptin, derived from the C-terminal portion of the precursor to AVP (arginine vasopressin), is secreted stoichiometrically with vasopressin, hence it can be used as a surrogate marker of the AVP system. In the present study, 706 healthy volunteers were recruited from a local HF screening study. Participants with a history of cardiovascular disease and those with echocardiographic abnormalities were excluded from the study. Copeptin and NTproBNP levels were assayed using in-house immunoluminometric assays. Median copeptin levels were significantly higher in the male volunteers compared with the females [median (range): 4.3 (0.4-44.3) compared with 3.2 (1.0-14.8) pmol/l; P<0.001]. In males, copeptin was correlated with eGFR (estimated glomerular filtration rate; r(s)=-0.186, P<0.001). In females, the correlation of copeptin with eGFR was weak (r(s)=-0.097, P=0.095). DT (deceleration time) and left atrial size correlated with higher copeptin levels (r(s)=0.085, P=0.029 and r(s)=0.206, P<0.001 respectively). Only gender (P<0.001), eGFR (P<0.001), left atrial size (P=0.04) and DT (P=0.02) remained independently predictive of plasma copeptin. The present study suggests that gender and renal function specific partition values should be used to interpret copeptin values in future studies of this biomarker in HF or ischaemic heart disease.


Pediatric endocrinology.
Endocrine and metabolic disorders affecting puppies and kittens from birth until 6 months of age may manifest as clinical problems related to growth or to water metabolism (polydipsia and polyuria). Most commonly,endocrine and metabolic disorders affect growth of the animal,and puppies are often presented to the veterinarian for assessment of delayed or aberrant growth. Other endocrine disorders of small animals,such as juvenile-onset diabetes insipidus or diabetes mellitus, affect water metabolism, resulting in excessive thirst and urination and resultant difficulty in house-breaking.


Flow cytometric enumeration of CD34+ hematopoietic stem and progenitor cells in leukapheresis product and bone marrow for clinical transplantation: a comparison of three methods.
Flow cytometric enumeration of CD34+ hematopoietic stem and progenitor cells (HSCs) is widely used for evaluation of graft adequacy of peripheral blood and bone marrow stem cell grafts. In the present study, we review and compare the major counting techniques of stem and progenitor cells. The methods are: the Milan/Mullhouse protocol, two-platform ISHAGE (International Society of Hematotherapy and Graft Engineering) and single-platform ISHAGE analysis system. According to the Milan/Mulhouse protocol, HSCs are identified by CD34 antibody staining and easy gating strategy. The ISHAGE guidelines for detection of CD34+ cells are based on a four-parameter flow cytometry method (CD34PE/CD45PerCP staining, side and forward angle light scatter) thus employing multiparameter gating strategy. With two-platform ISHAGE protocol, an absolute CD34+ count is generated by incorporating the leukocyte count from an automated hematology analyser. The single-platform ISHAGE method to determine the absolute CD34+ count directly from a flow cytometer includes the use of Trucount tubes (Becton Dickinson) with a known number of fluorescent beads. CD34+ cells were quantified in mobilized peripheral blood, collected by leukapheresis, and bone marrow from 42 samples from patients with hematological malignancies. The differences against the means display low disagreement between the Milan/Mulhouse and ISHAGE protocols, with discrepancies of up to 2.5% (two-platform ISHAGE)--2.6% (single-platform ISHAGE) in enumeration of CD34+ cells in leukapheresis product and 4.8% (two-platform ISHAGE)--4.9% (single-platform ISHAGE) in bone marrow. Our results show high correlation among all three methods. Since the three protocols are compatible, choosing the most convenient in terms of costs, simplicity and compliance with clinical results appears to be a logical consequence.


Operative management of patients with non-spinal metastatic bone disease. Does it actually improve quality of life?
To determine the survival rate and functional outcome of skeletal stabilisation in patients with metastatic bone disease. The retrospective study was conducted at Aga Khan University Hospital, Karachi, and comprised data of patients with non-spinal metastatic bone disease managed surgically from January 2002 to December 2010. All patients had been managed by experienced orthopaedic, oncology and multidisciplinary teams. Patients managed by non-oncologic orthopaedic surgeons were excluded. The prognostic influence of clinical, pathological and treatment variables on Musculoskeletal Tumour Society score, range of motion, local complications and death rate were measured. SPSS 19 was used for statistical analysis. Of the 49 patients whose records were included in the study, 21(42.9%) males and 28(57.1%) females with an overall median age of 59 years. Most common primary tumour site was breast in 15(3.8%) followed by lungs in 11(22.4%), Open reduction and internal fixation was the mpst commonly used procedure in 18(36.7%) patients. Mean duration of follow-up was 30.20±29.2 SD months (range: 10-48 months). The median patient survival was 23 months. 23% patients have superficial surgical site infection. Mean Musculoskeletal Tumour Society score was 23.73±14.3 SD. The results confirm the principle that surgery for metastatic disease is done primarily to improve quality of life and ambulation status, and to alleviate pain.


The effect of Gilbert's syndrome on the dispersions of QT interval and P-wave: an observational study.
Gilbert's syndrome (GS) decreases the incidence of atherosclerotic heart disease. The aim of the study was to evaluate whether the arrhythmia risk markers such as P-wave dispersion (Pd), QT dispersion (QTd) are reduced in patients with GS compared with healthy subjects. Sixty-one patients diagnosed with GS (31 females, 30 males) who had applied to the internal medicine outpatient clinic in the hospital were included in this cross-sectional, observational study. A control group of 61 healthy persons (31 females, 30 males), who were non-smokers and drinkers, were included. Both groups were between 16-45 years old. Results of anthropometric measurements, laboratory assays and electrocardiographic findings were recorded for each participant. Independent sample t-test and nested ANOVA were used for data analysis. In the GS group were Pd value 36±16.7 msec, QTd 48.7±10.7 msec and heart rate (HR) 74±8 beat/min. In the control group were Pd 51±28 msec, QTd 53±12 msec and HR 78±10 beat/min. The Pd of patients group (p<0.001), QTd (p=0.038) and HR (p=0.021) were significantly lower than the control group. According to our study's results, in these patients, increased bilirubin levels are associated with decrease in HR, Pd and QTd, which consequently might decrease the incidence of cardiac arrhythmias and coronary artery disease. Further studies are needed to clarify the protective role of bilirubin in risk of arrhythmias in this category of patients.


BigWig and BigBed: enabling browsing of large distributed datasets.
BigWig and BigBed files are compressed binary indexed files containing data at several resolutions that allow the high-performance display of next-generation sequencing experiment results in the UCSC Genome Browser. The visualization is implemented using a multi-layered software approach that takes advantage of specific capabilities of web-based protocols and Linux and UNIX operating systems files, R trees and various indexing and compression tricks. As a result, only the data needed to support the current browser view is transmitted rather than the entire file, enabling fast remote access to large distributed data sets. Binaries for the BigWig and BigBed creation and parsing utilities may be downloaded at http://hgdownload.cse.ucsc.edu/admin/exe/linux.x86_64/. Source code for the creation and visualization software is freely available for non-commercial use at http://hgdownload.cse.ucsc.edu/admin/jksrc.zip, implemented in C and supported on Linux. The UCSC Genome Browser is available at http://genome.ucsc.edu.


Overexpression of the endothelial protein C receptor is detrimental during pneumonia-derived gram-negative sepsis (Melioidosis).
The endothelial protein C receptor (EPCR) enhances anticoagulation by accelerating activation of protein C to activated protein C (APC) and mediates anti-inflammatory effects by facilitating APC-mediated signaling via protease activated receptor-1. We studied the role of EPCR in the host response during pneumonia-derived sepsis instigated by Burkholderia (B.) pseudomallei, the causative agent of melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia. Soluble EPCR was measured in plasma of patients with septic culture-proven melioidosis and healthy controls. Experimental melioidosis was induced by intranasal inoculation of B. pseudomallei in wild-type (WT) mice and mice with either EPCR-overexpression (Tie2-EPCR) or EPCR-deficiency (EPCR(-/-)). Mice were sacrificed after 24, 48 or 72 hours. Organs and plasma were harvested to measure colony forming units, cellular influxes, cytokine levels and coagulation parameters. Plasma EPCR-levels were higher in melioidosis patients than in healthy controls and associated with an increased mortality. Tie2-EPCR mice demonstrated enhanced bacterial growth and dissemination to distant organs during experimental melioidosis, accompanied by increased lung damage, neutrophil influx and cytokine production, and attenuated coagulation activation. EPCR(-/-) mice had an unremarkable response to B. pseudomallei infection as compared to WT mice, except for a difference in coagulation activation in plasma. Increased EPCR-levels correlate with accelerated mortality in patients with melioidosis. In mice, transgenic overexpression of EPCR aggravates outcome during Gram-negative pneumonia-derived sepsis caused by B. pseudomallei, while endogenous EPCR does not impact on the host response. These results add to a better understanding of the regulation of coagulation during severe (pneumo)sepsis.


Survival of batch numbers within dental implants following incineration as an aid to identification.
Dental implants have become a popular choice of treatment in replacing individual lost teeth or entire dentitions. The physical properties of high corrosion resistance, high structural strength and high melting point, suggest the retention of intact implants following most physical assaults. As the implants are machine made, they lack the individualisation required for their use as identifiers of the deceased, however the Straumann™ Company (Waldenburg, Switzerland) has recently released information that within the chamber of their implants they have laser etched batch numbers. The number of implants with the same batch number varies from 24 to 2400. The purpose of this study was to ascertain if the batch number was still identifiable following intense heat exposure in a furnace. A Straumann™ Standard Plus 3.3 x 8 mm implant, with no healing cap nor abutment attached was incinerated to 1125 degrees Celsius. Another Straumann™ Standard Plus 3.3 x 8 mm implant was also incinerated in the same way as the first implant but with an abutment attached. The results indicated that the first implant had totally oxidised within the internal chamber whilst the second implant following the removal of the abutment revealed an intact identifiable batch number. If the companies constructing implants were to place individual serial numbers rather than batch numbers on these implants then the potential exists for a new approach to be established for the identification of the deceased.


[Airway autonomic nervous system dysfunction and asthma].
Airways are richly innervated by 4 nervous systems, namely adrenergic, cholinergic, inhibitory nonadrenergic noncholinergic (i-NANC), and excitatory NANC (e-NANC) nervous systems. Dysfunction or hyperfunction of these systems may be involved in the inflammation or airway hyperresponsiveness observed in asthmatic patients. The cholinergic nervous system is the predominant neural bronchoconstrictor pathway in humans. Airway inflammation shows exaggerated acetylcholine release from cholinergic nerves via dysfunction of the autoreceptor, muscarinic M2, which is possibly caused by major basic protein or IgE. Vasoactive intestinal peptide (VIP) and nitric oxide (NO) released from i-NANC nerves act as an airway smooth muscle dilator. The effects of VIP and NO are diminished after allergic reaction by inflammatory cell-mediated tryptase and reactive oxygen species. Thus, in asthmatic airways, the inflammatory change-mediated neural imbalance may result in airway hyperresponsiveness. Tachykinins derived from e-NANC nerves have a variety of actions including airway smooth muscle contraction, mucus secretion, vascular leakage, and neutrophil attachment, and may be involved in the pathogenesis of asthma. Since tachykinin receptor antagonists are effective for bradykinin- and exercise-induced bronchoconstriction in asthmatic patients, these drugs may be useful for asthma therapy.


Experimental evidence for reduced mortality of Agaricia lamarcki on a mesophotic reef.
Mesophotic Coral Ecosystems (MCEs) may act as a refuge for impacted shallow reefs as some of the stressors affecting tropical reefs attenuate with depth. A less impacted population at depth could provide recruits to recolonise shallow reefs. Recently, disturbance has been reported on several mesophotic reefs including storm damage, biological invasions, and coral bleaching; calling into question the extent of deep reef refuges. We report on a reciprocal transplant experiment between shallow and mesophotic reefs in the Caribbean, which occurred during a period of coral bleaching. 102 fragments of Agaricia lamarcki were collected down a continuous depth gradient at two sites to a maximum depth of 60m. Fragments were transplanted to either a shallow or mesophotic station at a third site, with controls. This allowed the disaggregation of the effect of the disturbance experienced during the observation period, and any potential acclimation resulting from the historical location of a fragment. Mortality and bleaching were quantitatively assessed. We found the relocation depth of a coral fragment had the strongest effect on both survival and the degree of bleaching recorded. The site a fragment was collected from, and the original collection depth, failed to explain mortality or bleaching with statistical significance. This experiment provides support for the assumption that mesophotic corals may be protected in comparison to shallow reefs, in spite of the potential effects of differing susceptibilities to stress.


Choosing Wisely: Law's Contribution as a Cause of and a Cure for Unwise Health Care Choices.
The provision of unnecessary health care is a serious problem in Australia and involves two key legal issues. First, doctors' fear of litigation drives defensive practices - ordering tests and procedures, making referrals, and prescribing drugs to reduce perceived legal risks, rather than to advance patient care. Second, suboptimal communication and decision-making processes undermine a patient's right to make informed health care choices. This article critically analyses these problems and proposes solutions. An extensive body of medico-legal literature is synthesised to highlight the gaps between legal requirements and what happens in practice. Negligence case law is discussed to clarify legal principles and shows that courts discourage defensive practice. Finally, the article presents practical strategies to enhance communication and shared decisionmaking in the clinical encounter.


Anion-exchange chromatography mass spectrometry provides extensive coverage of primary metabolic pathways revealing altered metabolism in IDH1 mutant cells.
Altered central carbon metabolism is a hallmark of many diseases including diabetes, obesity, heart disease and cancer. Identifying metabolic changes will open opportunities for better understanding aetiological processes and identifying new diagnostic, prognostic, and therapeutic targets. Comprehensive and robust analysis of primary metabolic pathways in cells, tissues and bio-fluids, remains technically challenging. We report on the development and validation of a highly reproducible and robust untargeted method using anion-exchange tandem mass spectrometry (IC-MS) that enables analysis of 431 metabolites, providing detailed coverage of central carbon metabolism. We apply the method in an untargeted, discovery-driven workflow to investigate the metabolic effects of isocitrate dehydrogenase 1 (IDH1) mutations in glioblastoma cells. IC-MS provides comprehensive coverage of central metabolic pathways revealing significant elevation of 2-hydroxyglutarate and depletion of 2-oxoglutarate. Further analysis of the data reveals depletion in additional metabolites including previously unrecognised changes in lysine and tryptophan metabolism.


High-resolution MS, MS/MS, and UV database of fungal secondary metabolites as a dereplication protocol for bioactive natural products.
A major problem in the discovery of new biologically active compounds from natural products is the reisolation of known compounds. Such reisolations waste time and resources, distracting chemists from more promising leads. To address this problem, dereplication strategies are needed that enable crude extracts to be screened for the presence of known compounds before isolation efforts are initiated. In a project to identify anticancer drug leads from filamentous fungi, a significant dereplication challenge arises, as the taxonomy of the source materials is rarely known, and, thus, the literature cannot be probed to identify likely known compounds. An ultraperformance liquid chromatography-photodiode array-high-resolution tandem mass spectrometric (UPLC-PDA-HRMS-MS/MS) method was developed for dereplication of fungal secondary metabolites in crude culture extracts. A database was constructed by recording HRMS and MS/MS spectra of fungal metabolites, utilizing both positive- and negative-ionization modes. Additional details, such as UV-absorption maxima and retention times, were also recorded. Small-scale cultures that showed cytotoxic activities were dereplicated before engaging in the scale-up or purification processes. Using these methods, approximately 50% of the cytotoxic extracts could be eliminated from further study after the confident identification of known compounds. The specific attributes of this dereplication methodology include a focus on bioactive secondary metabolites from fungi, the use of a 10 min chromatographic method, and the inclusion of both HRMS and MS/MS data.


A model of the innate immune response to SARS-CoV-2 in the alveolar epithelium.
We present a differential equation model of the innate immune response to SARS-CoV-2 within the alveolar epithelium. Critical determinants of the viral dynamics and host response, including type I and type II alveolar epithelial cells, interferons, chemokines, toxins and innate immune cells, are included. We estimate model parameters, compute the within-host basic reproductive number, and study the impacts of therapies, prophylactics, and host/pathogen variability on the course of the infection. Model simulations indicate that the innate immune response suppresses the infection and enables the alveolar epithelium to partially recover. While very robust antiviral therapy controls the infection and enables the epithelium to heal, moderate therapy is of limited benefit. Meanwhile interferon therapy is predicted to reduce viral load but exacerbate tissue damage. The deleterious effects of interferon therapy are especially apparent late in the infection. Individual variation in ACE2 expression, epithelial cell interferon production, and SARS-CoV-2 spike protein binding affinity are predicted to significantly impact prognosis.


An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs.
In order to investigate the evolution of binding efficiency in successful drug discovery programs, a data set of 60 lead/drug pairs with known binding affinities has been compiled and analyzed. Low-end thresholds for the binding efficiencies of viable leads and drugs have been derived. On average, the drugs in the set are significantly larger and more potent but have similar lipophilicity relative to their originating leads, suggesting that the ability to maintain low levels of lipophilicity while increasing molecular weight is one of the keys to a successful drug discovery program. A number of examples demonstrate that large increases in binding efficiency from leads to more elaborate drugs sharing the same scaffold can be achieved. The importance of dissecting a lead structure to identify the most efficient fragments and the option of sacrificing binding efficiency to optimize other properties are discussed, and relevant examples are highlighted.


Nurses' knowledge and attitudes towards cancer-related fatigue.
Fatigue is the most common symptom associated with cancer and cancer treatment and is now widely recognized as a significant problem for patients with cancer (Ream & Richardson 1999). Although the profile of cancer-related fatigue has grown over the past few years within the specialty of oncology, not all patients with cancer receive care from cancer specialists. As a result of restructuring of cancer services, the majority of patients within the UK receive their cancer treatment outwith a cancer centre and are supported by District General Hospitals and community-based services. Consequently, it is appropriate to evaluate nurses' fatigue knowledge and attitudes across a range of clinical settings caring for patients with cancer. Nurses were recruited from community, general medical, general surgical and oncology clinical settings (n=470). A postal questionnaire to evaluate fatigue knowledge and attitudes was administered. A response rate of 43% was achieved. Data were analysed descriptively. Underestimation of fatigue incidence (by 28% of respondents), poor knowledge and practice regarding fatigue assessment and management, and poor fatigue communication practices were common throughout all clinical areas. However, nurses from all settings consistently demonstrated a good understanding of the impact of fatigue on patients with cancer and an appreciation of the importance of the role of the nurse in fatigue management. While oncology nurses demonstrated the greatest fatigue knowledge, these were not significantly better than the other specialties. A significant proportion of nurses caring for patients with cancer are unaware of fatigue's incidence, assessment and management. As cancer incidence rates are set to rise and the spectrum of clinical settings in which patients receive their care is increasing, it is imperative that this common and debilitating symptom receives appropriate recognition from health-care professionals. A number of strategies to enhance knowledge and information dissemination should be initiated to ensure that patient outcomes in relation to cancer-related fatigue are improved.


Symptoms and symptom distress in localized prostate cancer.
For over a decade, symptom distress has been a key concept in several studies of cancer. However, the definition of symptom distress is still unclear, and there are few measures targeting symptom distress, in general, and specific cancers, in particular. Prostate cancer is the sixth most common cancer worldwide and the second leading cause of death in American men. Many men with clinically localized prostate cancer may experience unique and multidimensional symptoms that occur from diagnosis through treatment, and thereafter. These symptoms associated with the disease and its treatments are in the form of physical and psychological sequelae such as urinary and bowel problems and sexual dysfunction. The purposes of this article are to (1) systematically review literature on symptoms and symptom distress in localized prostate cancer and (2) synthesize evidence of symptom distress applications and measurement in this group. A comprehensive, systematic review was conducted to identify original, data-based studies of symptoms and symptom distress in localized prostate cancer. Clarification of symptom distress and more comprehensive information about symptoms and symptom distress will provide nurses with a better foundation for developing self-management interventions aimed at ameliorating symptom distress and, ultimately, enhancing the quality of life of patients with localized prostate cancer.


Lizard tricks: overcoming conflicting requirements of speed versus climbing ability by altering biomechanics of the lizard stride.
Adaptations promoting greater performance in one habitat are thought to reduce performance in others. However, there are many examples of animals in which, despite habitat differences, such predicted differences in performance do not occur. One such example is the relationship between locomotory performance to habitat for varanid lizards. To explain the lack of difference in locomotor performance we examined detailed observations of the kinematics of each lizard's stride. Differences in kinematics were greatest between climbing and non-climbing species. For terrestrial lizards, the kinematics indicated that increased femur adduction, femur rotation and ankle angle all contributed positively to changes in stride length, but they were constrained for climbing species, probably because of biomechanical restrictions on the centre of mass height (to increase stability on vertical surfaces). Despite climbing species having restricted stride length, no differences have been previously reported in sprint speed between climbing and non-climbing varanids. This is best explained by climbing varanids using an alternative speed modulation strategy of varying stride frequency to avoid the potential trade-off of speed versus stability on vertical surfaces. Thus, by measuring the relevant biomechanics for lizard strides, we have shown how kinematic differences among species can mask performance differences typically associated with habitat variation.


Malaysian cockle (Anadara granosa) allergy: Identification of IgE-binding proteins and effects of different cooking methods.
The purpose of this study was to evaluate the effect of different cooking methods on the allergenicity of cockle and to identify proteins most frequently bound by IgE antibodies using a proteomics approach. Raw, boiled, fried and roasted extracts of the cockle were prepared. The protein profiles of the extracts were obtained by separation using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and 2-dimensional gel electrophoresis (2-DE). IgE-immunoblotting was then performed with the use of individual sera from patients with cockle allergy and the major IgE-binding proteins were analyzed by mass-spectrometry. SDS-PAGE of raw extract showed 13 protein bands. Smaller numbers of protein bands were detected in the boiled, fried and roasted extracts. The 2-DE gel profile of the raw extract further separated the protein bands to ~50 protein spots with molecular masses between 13 to 180 kDa and isoelectric point (pI) values ranging from 3 to 10. Immunoblotting of raw extract exhibited 11 IgE-binding proteins with two proteins of 36 and 40 kDa as the major IgE-binding proteins, while the boiled extract revealed 3 IgE-binding proteins. Fried and roasted extracts only showed a single IgE-binding protein at 36 kDa. 2-DE immunoblotting of raw extract demonstrated 5 to 20 IgE reactive spots. Mass spectrometry analysis led to identification of 2 important allergens, tropomyosin (36 kDa) and arginine kinase (40 kDa). Heated extracts showed a reduction in the number of IgE-reactive bands compared with raw extract, which suggest that thermal treatment can be used as a tool in attempting to reduce cockle allergenicity. The degree of allergenicity of cockle was demonstrated in the order raw > boiled > fried ≈ roasted. Two important allergens reacting with more than 50% of patients' sera identified using mass spectrometric approaches were tropomyosin and arginine kinase. Thus, allergens found in this study would help in component based diagnosis, management of cockle allergic patients and to the standardisation of allergenic test products as tools in molecular allergology.


FASpecT/CT, A New SPECT/CT Acquisition With Higher Sensitivity and Efficiency in Radioiodine Thyroid Cancer Imaging.
This article demonstrates the use of a new SPECT/CT acquisition protocol in patients with differentiated thyroid cancer (DTC). SPECT/CT scans (FASpecT/CT) with fewer angle acquisitions were retrospectively reviewed in 30 DTC patients treated with radioiodine at University Hospital, San Antonio, Tex, from July 2017 to March 2019. This FASpecT/CT of 12 versus 60 to 64 sampled views for convention SPECT was made possible by iterative reconstruction. The FASpecT/CT protocol was judged to increase lesion detection in patients with low count rates. Furthermore, in patients with higher count rates, this technique reduced the acquisition time. FASpecT/CT patient images are shown as case examples in 4 of the 30 patients reviewed. This FASpecT/CT acquisition in radioiodine-treated DTC offers the potential of higher sensitivity for metastatic lymph node detection in low count rates and a significant decrease in imaging time in high count rates. These advantages make SPECT/CT imaging more acceptable for patients who have difficulty with longer imaging times, to include the pediatric population.


Beating-heart mitral valve surgery: preliminary model and methodology.
It is our hypothesis that image-guided mitral valve repair can be performed on the beating heart without cardiopulmonary bypass. As a first phase, we tested the feasibility of suturing the anterior and posterior mitral valve leaflets under image guidance. In a water bath model, imaging approaches and suturing techniques were developed. Then, in 6 pigs, the left atrium was cannulated with a custom-made 15-mm valved port through a left thoracotomy. Atrial pressure was elevated by shunting of arterial blood to minimize air induction. A multiplane transesophageal echocardiographic probe was evaluated in the intraesophageal and epicardial positions. With a commercial endoscopic suturing device, sutures were placed through the anterior and posterior mitral leaflets under echocardiographic guidance. The animals were killed, and suture accuracy was evaluated by measuring the distance from the intended target areas on the anterior and posterior mitral leaflets. Air induction was monitored by echocardiography and graded as minimal to severe. There were no cases of hemodynamic instability or significant arrhythmia. The most effective imaging plane was a short-axis view that used the transesophageal echocardiographic probe epicardially at the heart base. Air induction was minimal in 2 animals, mild in 3, and moderate in 1. Sutures were successfully placed 9 of 12 times (mean error 0.8 +/- 0.5 cm). With these methods, off-pump, image-guided suturing of the beating-heart mitral valve was possible. This model may be a useful starting point for developing off-pump mitral valve repair procedures.


Tumor Hypervascularity and hand-foot-skin reaction predict better outcomes in combination treatment of TACE and Sorafenib for intermediate hepatocellular carcinoma.
To validate the robust predictive values of tumor vascularity and hand-foot-skin reaction (HFSR) in combination treatment of transarterial chemoembolization (TACE) and sorafenib for patients with intermediate hepatocellular carcinoma (HCC), and then select the potential candidates who would survive best from such treatment. A total of 132 treatment-naive patients with intermediate HCC undergoing combination therapy of TACE and sorafenib were recruited between January 2010 and December 2014. The tumor vascularity was defined according to digital subtraction angiography (DSA) and HFSR was assessed by the national cancer institute common terminology criteria for adverse events (NCI-CTCAE). The Mann-Whitney U test was used to assess the correlation between vascularity and radiologic response; time to radiologic progression (TTP) and overall survival (OS) were evaluated using Kaplan-Meier techniques and compared by log-rank test; factors associated with them were evaluated using multivariate Cox regression analysis. During a median follow up of 17.3 months, it was revealed that hypervascularity and development of ≥2 grade of HFSR within 60 days after sorafenib initiation were favorable predictors for TTP (HR 0.378, p < 0.001; HR 0.627, p = 0.018) and OS (HR 0.499, p = 0.002; HR 0.555, p = 0.004). The median TTP and OS for patients with both were 12.2 and 29.1 months, which were better than patients with either of them (6.0 months, HR 1.74, p = 0.012; 16.5 months, HR 1.73, p = 0.021), as well as those with neither (2.9 months, HR 3.74, p < 0.001; 11.9 months, HR 3.17, p < 0.001). Tumor hypervascularity and development of ≥2 grade of HFSR within 60 days were favorable predictive factors for the combination treatment of TACE and sorafenib, with both of which the patients survived longest and might be the potential candidates.


Characterization of the Aspergillus parasiticus niaD and niiA gene cluster.
The nitrate reductase gene (niaD) and nitrite reductase gene (niiA) of Aspergillus parasiticus are clustered and are divergently transcribed from a 1.6-kb intergenic region (niaD-niiA). The deduced aminoacid sequence of the A. parasiticus nitrate reductase demonstrated a high degree of homology to those of other Aspergillus species, as well as to Leptosphaeria maculans, Fusarium oxysporum, Gibberella fujikuroi and Neurospora crassa, particularly in the cofactor-binding domains for molybdenum, heme and FAD. A portion of the deduced nitrite reductase sequence was homologous to those of A. nidulans and N. crassa. The nucleotide sequences in niaD-niiA of A. parasiticus and of A. oryzae were 95% identical, indicating that these two species are closely related. Several GATA motifs, the recognition sites for the N. crassa positive-acting global regulatory protein NIT2 in nitrogen metabolism, were found in A. parasiticus niaD-niiA. Two copies of the palindrome TCCGCGGA and other partial palindromic sequences similar to the target sites for the pathway specific regulatory proteins, N. crassa NIT4 and A. nidulans NirA, in nitrate assimilation, were also identified. A recombinant protein containing the A. nidulans AreA (the NIT2 equivalent) zinc finger and an adjacent basic region was able to bind to segments of niaD-niiA encompassing the GATA motifs. These results suggest that the catalytic and regulatory mechanisms of nitrate assimilation are well conserved in Aspergillus.


The impact of selected methodological factors on data collection outcomes in observational studies of device-measured physical behaviour in adults: A systematic review.
Accelerometer measures of physical behaviours (physical activity, sedentary behaviour and sleep) in observational studies offer detailed insight into associations with health and disease. Maximising recruitment and accelerometer wear, and minimising data loss remain key challenges. How varying methods used to collect accelerometer data influence data collection outcomes is poorly understood. We examined the influence of accelerometer placement and other methodological factors on participant recruitment, adherence and data loss in observational studies of adult physical behaviours. The review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). Observational studies of adults including accelerometer measurement of physical behaviours were identified using database (MEDLINE (Ovid), Embase, PsychINFO, Health Management Information Consortium, Web of Science, SPORTDiscus and Cumulative Index to Nursing & Allied Health Literature) and supplementary searches to May 2022. Information regarding study design, accelerometer data collection methods and outcomes were extracted for each accelerometer measurement (study wave). Random effects meta-analyses and narrative syntheses were used to examine associations of methodological factors with participant recruitment, adherence and data loss. 123 accelerometer data collection waves were identified from 95 studies (92.5% from high-income countries). In-person distribution of accelerometers was associated with a greater proportion of invited participants consenting to wear an accelerometer (+ 30% [95% CI 18%, 42%] compared to postal distribution), and adhering to minimum wear criteria (+ 15% [4%, 25%]). The proportion of participants meeting minimum wear criteria was higher when accelerometers were worn at the wrist (+ 14% [ 5%, 23%]) compared to waist. Daily wear-time tended to be higher in studies using wrist-worn accelerometers compared to other wear locations. Reporting of information regarding data collection was inconsistent. Methodological decisions including accelerometer wear-location and method of distribution may influence important data collection outcomes including recruitment and accelerometer wear-time. Consistent and comprehensive reporting of accelerometer data collection methods and outcomes is needed to support development of future studies and international consortia. Review supported by the British Heart Foundation (SP/F/20/150002) and registered (Prospero CRD42020213465).


Cisplatin exposure impairs ionocytes and hair cells in the skin of zebrafish embryos.
This study aimed to assess the sublethal effects of a platinum-based compound, cisplatin, using a zebrafish model. Zebrafish embryos were incubated in different concentrations of cisplatin at 0-96 h post-fertilization. Using a non-invasive, scanning ion-selective electrode technique (SIET), we measured the functions of hair cells (Ca2+ influx) and ionocytes ([H+] gradients). The survival rate, hatching rate, phenotype, body length, whole-body ion (Na+, Cl-, and Ca2+) and Pt contents were also determined. The effects of cisplatin on zebrafish embryos were demonstrated as first impairing hair cell function (at 1 μM of cisplatin), the hair cell number, and body ion content of Cl- (at 10 μM of cisplatin), then decreasing ionocyte acid secretion and overall body ion contents of Na+ and Ca2+ (at 50 μM of cisplatin). The body length and ionocyte density decreased at 100 μM of cisplatin, and survival decreased at 500 μM of cisplatin. As the cisplatin concentration increased, the accumulation of Pt in fish embryos also increased. These results revealed that hair cells are significantly more susceptible to cisplatin toxicity than ionocytes. By determining the lowest observed effective concentration of cisplatin that caused in vivo functional alterations of zebrafish hair cells and skin ionocytes, this model demonstrated 500-fold greater sensitivity than by detecting changes in survival, for early assessment of the effects of platinum-based chemotherapeutic drugs on fish.


[Severe respiratory disease in an intensive care unit during influenza A(H1N1) 2009 pandemia].
We describe characteristics of patients admitted to our intensive care unit with severe acute respiratory illness and influenza-like syndrome during the first months of the pandemic influenza A(H1N1) 2009 in Argentina. We analyzed clinical data, severity scores, laboratory tests, microbiological and radiological findings at admission, clinical outcomes and in-hospital mortality. H1N1 was confirmed by RT-PCR. Data from positive and negative PCR patients were compared. We admitted 31 adult patients between June and July 2009; median age: 54 years (IQR 33-66). A 54% (17) had positive PCR; 16 patients presented underlying medical conditions. Bilateral interstitial opacities were observed in chest radiography in 20 cases; 5 had unilateral lobar consolidation. Bacterial co-infection (isolation or IgM antibodies for bacterial infections) was found in 21 patients. Mechanical ventilation was required in 23 patients and 18 developed ARDS. Lymphopenia and increased creatine kinase levels were frequently observed (83% and 65% among PCR+ and PCR- respectively). Six patients died (19%); they were all over 75 years old, had cancer or immune-suppression. Early antiviral treatment (≤ 48 hours from symptoms onset) was associated with less frequency of mechanical ventilation (54% vs. 89%, p: 0.043). There were no differences in analyzed variables when comparing H1N1 positive and H1N1 negative patients; which suggests this approach as a most correct in future epidemic outbreaks. H1N1 infection was associated with severe respiratory illness and ARDS. Fatal outcome was observed in very old patients, or in those with major co-morbidities.


AVIATOR: An open international registry to evaluate medical and surgical outcomes of aortic valve insufficiency and ascending aorta aneurysm.
Current national registries are lacking detailed pathology-driven analysis and long-term patients outcomes. The Heart Valve Society (HVS) aortic valve (AV) repair research network started the Aortic Valve Insufficiency and ascending aorta Aneurysm InternATiOnal Registry (AVIATOR) to evaluate long-term patient outcomes of AV repair and replacement. The purpose of the current report is to describe the AVIATOR initiative and report in a descriptive manner the patients included. The AV repair research network includes surgeons, cardiologists, and scientists and established an online database compliant with the guidelines for reporting valve-related events. Prospective inclusion started from January 2013. Adult patients (18 years or older) who were operated on between 1995 and 2017 with complete procedural specification of the type of repair/replacement were selected for descriptive analysis. Currently 58 centers from 17 countries include 4896 patients with 89% AV repair (n = 4379) versus 11% AV replacement (n = 517). AV repair was either isolated (28%), or associated with tubular/partial root replacement (22%) or valve-sparing root replacement (49%) with an in-hospital mortality of 0.5%, 1.7%, and 1.2%, respectively. AV replacement was either isolated (24%), associated with tubular/partial root replacement (17%) or root replacement (59%) with an in-hospital mortality of 1%, 2.6%, and 2.0%, respectively. The multicenter surgical AVIATOR registry, by applying uniform definitions, should provide a solid evidence base to evaluate the place of repair versus replacement on the basis of long-term patient outcomes. Obtaining data completeness and adequate representation of all surgery types remain challenging. Toward the near future AVIATOR-medical will start to study natural history, as will AVIATOR-kids, with a focus on pediatric disease.


Specific inhibition of beta-tryptase expression in a human mast cell line by granulocyte-macrophage colony-stimulating factor produced by airways structural cells.
The growth and differentiation of mast cells are regulated by cytokines produced in tissue microenvironments. We previously reported that mast cells isolated from the epithelial compartment of nasal polyp tissue contain significantly less tryptase when compared with mast cells isolated from the stroma of the same tissue. In an attempt to explore this finding, we analyzed the ability of supernatants obtained from cultured nasal polyp epithelial cells (NP-EpCM) or nasal polyp fibroblasts (NP-FbCM) to regulate the tryptase content of the immature human mast cell line HMC-1. HMC-1 cells were cultured for 7 days in Iscove's modified Dulbecco's medium (IMDM) with 30% of either NP-FbCM or NP-EpCM or 20% MoCM (supernatant of a leukemic T cell line). As assessed by radioimmunoassay and test for enzymatic activity, all three conditioned media were shown to significantly decrease tryptase protein expression in HMC-1, when compared with cultures performed with IMDM alone (NP-EpCM P < 0.001; NP-FbCM P < 0.04; MoCM P < 0.004). In addition, Northern blot analysis demonstrated lower tryptase mRNA levels upon exposure to all three conditioned media tested, suggesting that tryptase downregulation occurs at the transcriptional level. In further studies we found that preincubation of MoCM with anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) completely blocked the observed downregulation of tryptase expression mediated by this conditioned medium. The findings suggest that GM-CSF has a suppressive effect on expression of protease in mast cells, and may thus play a modulatory role in determining the extent of tissue inflammation in allergic airways disease.


Effect of long-term exposure to fluoride in drinking water on risks of bone fractures.
Findings on the risk of bone fractures associated with long-term fluoride exposure from drinking water have been contradictory. The purpose of this study was to determine the prevalence of bone fracture, including hip fracture, in six Chinese populations with water fluoride concentrations ranging from 0.25 to 7.97 parts per million (ppm). A total of 8266 male and female subjects > or =50 years of age were enrolled. Parameters evaluated included fluoride exposure, prevalence of bone fractures, demographics, medical history, physical activity, cigarette smoking, and alcohol consumption. The results confirmed that drinking water was the only major source of fluoride exposure in the study populations. A U-shaped pattern was detected for the relationship between the prevalence of bone fracture and water fluoride level. The prevalence of overall bone fracture was lowest in the population of 1.00-1.06 ppm fluoride in drinking water, which was significantly lower (p < 0.05) than that of the groups exposed to water fluoride levels > or =4.32 and < or =0.34 ppm. The prevalence of hip fractures was highest in the group with the highest water fluoride (4.32-7.97 ppm). The value is significantly higher than the population with 1.00-1.06 ppm water fluoride, which had the lowest prevalence rate. It is concluded that long-term fluoride exposure from drinking water containing > or =4.32 ppm increases the risk of overall fractures as well as hip fractures. Water fluoride levels at 1.00-1.06 ppm decrease the risk of overall fractures relative to negligible fluoride in water; however, there does not appear to be similar protective benefits for the risk of hip fractures.


Vitisin A, a Resveratrol Tetramer, Improves Scopolamine-Induced Impaired Learning and Memory Functions in Amnesiac ICR Mice.
Resveratrol has been reported to exhibit neuroprotective activities in vitro and in vivo. However, little is known about resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B with the same molecular mass in the improvement of degenerative disorders. In this study, two 95% ethanol extracts (95EE) from stem parts of Vitis thunbergii Sieb. & Zucc. (VT-95EE) and from the root (R) parts of Vitis thunbergii var. taiwaniana (VTT-R-95EE) showed comparable acetylcholinesterase (AChE) inhibitory activities. It was found that VT-95EE and VTT-R-95EE showed different distribution patterns of identified resveratrol and resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B based on the analyses of HPLC chromatographic profiles. The hopeaphenol, vitisin A, and vitisin B, showed AChE and monoamine oxidase-B inhibitions in a dose-dependent manner, among which vitisin B and vitisin A exhibited much better activities than those of resveratrol, and had neuroprotective activities against methylglyoxal-induced SH-SY5Y cell deaths. The scopolamine-induced amnesiac ICR mice treated with VT-95EE and its ethyl acetate-partitioned fraction (VT-95EE-EA) at doses of 200 and 400 mg/kg, or vitisin A at a dose of 40 mg/kg, but not vitisin B (40 mg/kg), were shown significantly to improve the impaired learning behaviors by passive avoidance tests compared to those in the control without drug treatments (p < 0.05). Compared to mice in the control group, the brain extracts in the vitisin A-treated mice or donepezil-treated mice showed significant reductions in AChE activities and malondialdehyde levels (p < 0.05), and elevated the reduced protein expressions of brain-derived neurotrophic factor (BDNF) and BDNF receptor, tropomyosin receptor kinase B (TrkB). These results revealed that vitisin A was the active constituent in the VT-95EE and VTT-95EE, and the VT medicinal plant and that the endemic variety of VTT has potential in developing functional foods for an unmet medical need for neurodegenerative disorders.


Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice.
Serine protease inhibitor Kazal type 1 (SPINK1), which is structurally similar to epidermal growth factor, is thought to inhibit trypsin activity and to prevent pancreatitis. Point mutations in the SPINK1 gene seem to predispose humans to pancreatitis; however, the clinical significance of SPINK1 mutations remains controversial. This study aimed to elucidate the role of SPINK1. We generated Spink3-deficient (Spink3(-/-)) mice by gene targeting in mouse embryonic stem cells. Embryonic and neonatal pancreases were analyzed morphologically and molecularly. Specific probes were used to show the typical autophagy that occurs during acinar cell death. In Spink3(-/-) mice, the pancreas developed normally up to 15.5 days after coitus. However, autophagic degeneration of acinar cells, but not ductal or islet cells, started from day 16.5 after coitus. Rapid onset of cell death occurred in the pancreas and duodenum within a few days after birth and resulted in death by 14.5 days after birth. There was limited inflammatory cell infiltration and no sign of apoptosis. At 7.5 days after birth, residual ductlike cells in the tubular complexes strongly expressed pancreatic duodenal homeodomain-containing protein 1, a marker of pancreatic stem cells, without any sign of acinar cell regeneration. The progressive disappearance of acinar cells in Spink3(-/-) mice was due to autophagic cell death and impaired regeneration. Thus, Spink3 has essential roles in the maintenance of integrity and regeneration of acinar cells.


Women's perspectives on maternity services in Sweden: processes, problems, and solutions.
Most measures of health care quality focus on medical outcomes rather than patients' assessments of quality. Drawing on data from a national survey of Swedish women, this study describes women's opinions about what is important to them during pregnancy and birth. This qualitative study is based on responses of 827 pregnant women to an open question completed in the second trimester. In total, 2061 separate statements were analyzed. Using content analysis, these statements were clustered into 4 themes: desirable characteristics of midwife, prenatal care during pregnancy, care during labor and birth, and care after birth. Within those themes, 13 categories were found. Findings suggest areas for improvement in maternity services including: the timing and length of prenatal visits, making parent education classes available to all women, prelabor visits to the maternity ward, continuous information about the progress of labor, flexibility in time of discharge, and postpartum support for families. Women also stated that characteristics of the midwife, such as being supportive, friendly, attentive, respectful, and nonjudgemental, were important. A patient-centered and individualized approach, with women and their partners as the subjects rather than the objects of care, would increase satisfaction and the overall quality of maternity services in Sweden.


Racial-ethnic disparities in management and outcomes among children with type 1 diabetes.
Previous research has documented racial/ethnic disparities in diabetes treatments and outcomes. It remains controversial whether these disparities result from differences in socioeconomic status (SES) or other factors. We examined racial/ethnic disparities in therapeutic modalities and diabetes outcomes among the large number of pediatric participants in the T1D Exchange Clinic Registry. The cohort included 10 704 participants aged <18 years with type 1 diabetes for ≥1 year (48% female; mean age: 11.9 ± 3.6 years; diabetes duration: 5.2 ± 3.5 years). Diabetes management and clinical outcomes were compared among 8841 non-Hispanic white (white) (83%), 697 non-Hispanic black (black) (7%), and 1166 Hispanic (11%) participants. The population included 214 high-income black and Hispanic families. Insulin pump use was higher in white participants than in black or Hispanic participants (61% vs 26% and 39%, respectively) after adjusting for gender, age, diabetes duration, and SES (P < .001). Mean hemoglobin A1c was higher (adjusted P < .001) in black participants than in white or Hispanic participants (9.6%, 8.4%, and 8.7%). More black participants experienced diabetic ketoacidosis and severe hypoglycemic events in the previous year than white or Hispanic participants (both, P < .001). There were no significant differences in hemoglobin A1c, diabetic ketoacidosis, or severe hypoglycemia between white and Hispanic participants after adjustment for SES. Even after SES adjustment, marked disparities in insulin treatment method and treatment outcomes existed between black versus Hispanic and white children within this large pediatric cohort. Barriers to insulin pump use and optimal glycemic control beyond SES should be explored in all ethnic groups.


General anesthesia in infants: neurobiological and neuropsychological concerns.
General anesthetics are crucial drugs for surgical interventions, which are indicated to induce analgesia, diminish pain, and reduce anxiety in order to facilitate invasive procedures. In pediatric patients, benefits of general anesthetics also include abolishment of motility. Besides their probed benefits on surgery, the recent warning of the Food and Drug Administration (FDA) on the use of general anesthetics in children yielded a controversy on their potential neurotoxic effects. In this review, the main facts of the cerebral development are studied, and the available evidence concerning the use of general anesthesia on the neuropsychological development of children is analyzed. Most of the studies found were uncontrolled retrospective cohorts for which conclusions are difficult to obtain. However, a few group of controlled studies, including the Mayo Anesthesia Safety in Kids study (MASK), have partially supported the FDA warning. Cumulated evidence appears to support the safety use of general anesthetics, but no conclusive data supporting that it may induce massive effects on the cognitive development of exposed children has been reported. Important evidence suggests that specific cognitive functions may result altered under long-term expositions. Such data must be considered for those involved in anesthetic procedures.


Mechanism of primer-template-dependent conversion of dNTP leads to dNMP by T5 DNA polymerase.
T5 DNA polymerase catalyzes both 5' leads to 3' polymerization and 3' leads to 5' hydrolysis in a processive fashion. This knowledge has been utilized to obtain evidence indicating that the enzyme has a single primer-template binding site which can function as either polymerase or exonuclease, perhaps with the cooperation of additional or different side groups. Template-dependent conversion of dNTP leads to dNMP was observed with an excess of either primer-template or enzyme. With primer-template excess, practically all the enzymes were functional as polymerase; with enzyme excess, all primer-templates were extended during the first cycle of catalysis. These observations suggest that turnover takes place at the points of chain growth. Evidence is also provided which demonstrates that the enzyme is capable of switching its direction of catalysis from 3' leads to 5' to 5' leads to 3' without leaving the primer-template. A clear correspondence between the relative amount of hydrolysis of a terminally labeled residue on the primer and the relative amount of turnover suggests that (a) the probability of hydrolysis of a given type of residue in contact with the "active site" is constant, and (b) during each turnover episode enzyme usually takes only one step in the 3' leads to 5' direction. A simple probabilistic model of turnover is discussed.


White-tailed eagle (Haliaeetus albicilla) feathers from Norway are suitable for monitoring of legacy, but not emerging contaminants.
While feathers have been successfully validated for monitoring of internal concentrations of heavy metals and legacy persistent organic pollutants (POPs), less is known about their suitability for monitoring of emerging contaminants (ECs). Our study presents a broad investigation of both legacy POPs and ECs in non-destructive matrices from a bird of prey. Plasma and feathers were sampled in 2015 and 2016 from 70 whitetailed eagle (Haliaeetus albicilla) nestlings from two archipelagos in Norway. Preen oil was also sampled in 2016. Samples were analysed for POPs (polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and organochlorinated pesticides (OCPs)) and ECs (per- and polyfluoroalkyl substances (PFASs), dechlorane plus (DPs), phosphate and novel brominated flame retardants (PFRs and NBFRs)). A total of nine PCBs, three OCPs, one PBDE and one PFAS were detected in over 50% of the plasma and feather samples within each sampling year and location. Significant and positive correlations were found between plasma, feathers and preen oil concentrations of legacy POPs and confirm the findings of previous research on the usefulness of these matrices for non-destructive monitoring. In contrast, the suitability of feathers for ECs seems to be limited. Detection frequencies (DF) of PFASs were higher in plasma (mean DF: 78%) than in feathers (mean DF: 38%). Only perfluoroundecanoic acid could be quantified in over 50% of both plasma and feather samples, yet their correlation was poor and not significant. The detection frequencies of PFRs, NBFRs and DPs were very low in plasma (mean DF: 1-13%), compared to feathers (mean DF: 10-57%). This may suggest external atmospheric deposition, rapid internal biotransformation or excretion of these compounds. Accordingly, we suggest prioritising plasma for PFASs analyses, while the sources of PFRs, NBFRs and DPs in feathers and plasma need further investigation.


Association between complement factor H gene polymorphisms and neovascular age-related macular degeneration in Koreans.
This study was undertaken to investigate the association between the complement factor H (CFH) gene and exudative age-related macular degeneration (AMD) in Korean patients. Genomic DNA was isolated from the peripheral leukocytes of patients with exudative AMD (n = 114) and control subjects (n = 187). The sole criterion for exudative AMD was the presence of choroidal neovascularization. Four single-nucleotide polymorphisms (SNPs: -275C>T, I62V, Y402H, and IVS15) located in promoter, exon 2, exon 9, and intron 15 of the CFH gene were genotyped by PCR-based direct sequencing. The frequency of the C allele of Y402H (AMD, 10.5%; control, 6.5%) was found to be lower in Koreans than in Caucasians. In the present study, the difference between the frequencies of Y402H in cases and control subjects did not reach statistical significance (P = 0.071). However, the frequencies of the major alleles of three SNPs (-275C>T, I62V, and IVS15) were significantly different in patients and control subjects, and these SNPs were found to be separately associated with an elevated risk of exudative AMD. Seven haplotypes were identified in Koreans. Haplotype analysis showed that two haplotypes (TGTG, CGTG) conferred significantly higher risks of exudative AMD (P = 0.013, 0.035), and one haplotype (CATA) was significantly protective (P < 0.001). In Korean subjects, CFH polymorphism appears to be a considerable hereditary contributor to exudative AMD. Y402H polymorphism which has been suggested to be a major risk factor of AMD in Caucasians was found to be only marginally associated with exudative AMD with low frequency, whereas three adjacent SNPs in the CFH gene were significantly associated with AMD in Koreans.


Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells.
Wolfram Syndrome is an autosomal recessive degenerative disorder of the neuroendocrine system. Diabetes mellitus is its lead symptom. Patients show mutations in the wolframin (WFS1) gene coding for a hydrophobic transmembrane protein of 890 amino acids. This protein was preliminarily localised in the endoplasmatic reticulum (ER) in cells of mice and rats. Mice lacking the WFS1 gene display degeneration of pancreatic beta-cells following induction of ER stress. We here used antibodies against substructures of the wolframin protein in order to analyse its expression and localisation. Expression was detected in both pancreatic beta-cells and the limbic system of mice. Using the rat insulinoma cell line RIN 5AH and fractionated mouse brain tissue, we confirmed wolframin localisation to the endoplasmic reticulum. Expression profiling on patient's primary fibroblasts revealed down-regulation of the diabetes associated plasma membrane glycoprotein (PC-1) gene, and up-regulation of fibulin-3, a gene connected to senescence. However, cell proliferation was indistinguishable from non-mutated cells. In contrast to data obtained on murine pancreatic islets, we found no increased apoptosis following induction of ER stress but rather by staurosporine treatment in the absence of WFS1 function. This indicates a new role of WFS1 deficiency in programmed cell death.


Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis.
Acute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes. We searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation. Thirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) -1.34, 95% CI -2.97 to 0.29, I2=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD -3.22, 95% CI -5.49 to -0.96, I2=89%, very low certainty). Our findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF. CRD42018095408.


Measuring patient satisfaction with exercise therapy for knee osteoarthritis: evaluating the utility of the physiotherapy outpatient survey.
To assess patient satisfaction with exercise for knee osteoarthritis (OA). A convenience sample of 27 patients recruited to a randomized controlled trial (RCT) comparing open kinetic chain and closed kinetic chain exercises for knee OA were reassessed at nine months post-randomization. Clinical outcomes included self-report and physical performance measures of function and pain severity. Patients also completed the Physiotherapy Outpatient Survey (POPS), which is a multi-dimensional measure of patient satisfaction with physiotherapy. There was no significant difference in satisfaction between the two intervention groups. Overall mean satisfaction for the entire cohort was 4.07 of a maximum score of 5 (standard deviation (SD) = 0.52). Lower levels of satisfaction with outcome (mean = 3.56, SD = 0.8) were reported compared with other domains of expectations, communication, organization and the therapist (mean = 3.79-4.49; SDs = 0.42-0.92). Both intervention groups improved from baseline on clinical outcomes of pain, self-report function and walking distance, with no significant differences between the two groups. High levels of satisfaction were reported in this subsample of knee OA patients participating in an RCT evaluating the effects of different exercise approaches for knee OA. Satisfaction varied depending on the satisfaction domain, with lower satisfaction with outcome compared with other aspects of care. The POPS questionnaire can be used to measure the multi-dimensional aspects of satisfaction with physiotherapy.


Dissecting a wildlife disease hotspot: the impact of multiple host species, environmental transmission and seasonality in migration, breeding and mortality.
Avian influenza viruses (AIVs) have been implicated in all human influenza pandemics in recent history. Despite this, surprisingly little is known about the mechanisms underlying the maintenance and spread of these viruses in their natural bird reservoirs. Surveillance has identified an AIV 'hotspot' in shorebirds at Delaware Bay, in which prevalence is estimated to exceed other monitored sites by an order of magnitude. To better understand the factors that create an AIV hotspot, we developed and parametrized a mechanistic transmission model to study the simultaneous epizootiological impacts of multi-species transmission, seasonal breeding, host migration and mixed transmission routes. We scrutinized our model to examine the potential for an AIV hotspot to serve as a 'gateway' for the spread of novel viruses into North America. Our findings identify the conditions under which a novel influenza virus, if introduced into the system, could successfully invade and proliferate.


Mesoporous α-Fe2O3 thin films synthesized via the sol-gel process for light-driven water oxidation.
This work reports a facile and cost-effective method for synthesizing photoactive α-Fe(2)O(3) films as well as their performances when used as photoanodes for water oxidation. Transparent α-Fe(2)O(3) mesoporous films were fabricated by template-directed sol-gel chemistry coupled with the dip-coating approach, followed by annealing at various temperatures from 350 °C to 750 °C in air. α-Fe(2)O(3) films were characterized by X-ray diffraction, XPS, FE-SEM and electrochemical measurements. The photoelectrochemical performance of α-Fe(2)O(3) photoanodes was characterized and optimized through the deposition of Co-based co-catalysts via different methods (impregnation, electro-deposition and photo-electro-deposition). Interestingly, the resulting hematite films heat-treated at relatively low temperature (500 °C), and therefore devoid of any extrinsic dopant, achieve light-driven water oxidation under near-to-neutral (pH = 8) aqueous conditions after decoration with a Co catalyst. The onset potential is 0.75 V vs. the reversible hydrogen electrode (RHE), thus corresponding to 450 mV light-induced underpotential, although modest photocurrent density values (40 μA cm(-2)) are obtained below 1.23 V vs. RHE. These new materials with a very large interfacial area in contact with the electrolyte and allowing for a high loading of water oxidation catalysts open new avenues for the optimization of photo-electrochemical water splitting.


The dynamical lorentz shift in an extended optically dense superradiant amplifier.
We compute the spectral distributions of the transmitted and reflected signals from an extended optically dense superradiant amplifier. We show that, if the amplifier length is in the neighborhood of an integer multiple of the resonance transition half-wavelength, the frequency shift in the spectral distributions of the transmitted and reflected signals are modified by the Dynamical Lorentz Shift. The broken spatial inversion symmetry, manifested through an asymmetrical distribution of the population difference with respect to a spatial inversion around the midpoint of the sample, is shown to be at the origin of this spectral asymmetry in these so-called asymmetrical transition domains.


Tea consumption and risk of stroke: a dose-response meta-analysis of prospective studies.
To determine the association between tea consumption and the risk of stroke. We searched the PubMed database from January 1966 to March 2012 and reviewed reference lists of retrieved articles to identify relevant studies. Studies were included if they reported relative risks (RRs) and corresponding 95% confidence intervals (CIs) of stroke with respect to three or more categories of tea consumption. A random-effects model was used to combine the study-specific risk estimates. Fourteen studies, consisting of 513,804 participants with a median follow-up of 11.5 years, were included in this meta-analysis. We observed a modest but statistically significant inverse association between tea consumption and risk of stroke. An increase of three cups/d in tea consumption was associated with a 13% decreased risk of stroke (RR 0.87; 95% CI, 0.81-0.94). The decreased risk of stroke with tea consumption was consistent among most subgroups. Based on the three studies that provided results for stroke subtypes, tea consumption was also inversely associated with the risk of ischemic stroke (RR 0.76; 95% CI, 0.69-0.84), but not cerebral hemorrhage (RR 0.96; 95% CI, 0.82-1.11) or subarachnoid hemorrhage (RR 0.81; 95% CI, 0.57-1.16). Tea consumption is associated with a decreased risk of stroke, particularly ischemic stroke. More well-designed, rigorously conducted studies are needed in order to make confident conclusions about the association between tea consumption and stroke subtypes.


Predictors of perceived breast cancer risk and the relation between perceived risk and breast cancer screening: a meta-analytic review.
Perceived risk is a principal variable in theoretical models that attempt to predict the adoption of health-protective behaviors. This meta-analysis synthesizes findings from 42 studies, identified in PubMed and PsycInfo from 1985 onward. Studies examined demographic and psychological variables as predictors of perceived breast cancer risk and the relationship between perceived risk and breast cancer screening. Statistical relationships, weighted for sample size, were transformed to effect sizes and 95% CIs. Women do not have accurate perceptions of their breast cancer risk (N = 5561, g = 1.10). Overall, they have an optimistic bias about their personal risk (g = 0.99). However, having a positive family history (N = 70660, g = 0.88), recruitment site, and measurement error confounded these results. Perceived risk is weakly influenced by age (N = 38000, g = 0.13) and education (N = 1979, g = 0.16), and is moderately affected by race/culture (N = 2192, g = 0.38) and worry (N = 6090, g = 0.49). There is an association between perceived risk and mammography screening (N = 52766, g = 0.19). It is not clear whether perceived risk influences adherence to breast self-examination. Women who perceived a higher breast cancer risk were more likely to pursue genetic testing or undergo prophylactic mastectomy. Perceived breast cancer risk depends on psychological and cognitive variables and influences adherence to mammography screening guidelines.


Surgery for obesity: panacea or Pandora's box?
Given the increasing prevalence of obesity, healthcare providers should be cognizant of various non-operative (diet, exercise, behavior therapy, and medications) and operative obesity treatments. This review critically evaluates these treatments, especially bariatric surgeries. Medline analyses using a combination of the following terms: obesity, bariatric surgery, and outcomes were performed with particular emphasis on prospective studies and randomized trials. Non-operative treatments result in modest sustained weight loss (5-8%) at one year. Surgery is recommended for those with BMI >40 or >35 with comorbidities. Laparoscopic adjustable gastric banding, a restrictive procedure, causes 35-54% excess weight loss (EWL) at 1 year. Malabsorptive procedures (biliopancreatic diversions with and without duodenal switch) induce 72-77% EWL but are only performed at few centers. Roux-en-Y gastric bypass, acting through a combination of restriction and malabsorption, results in 69% EWL at 1 year and 49% at 14 years. Each procedure is associated with unique anatomic and nutritional complications. Overall, operative treatment improves comorbidities and may improve all-cause mortality. Surgery is an effective long-term treatment for selected obese patients who have failed other treatments. Further research is needed on prospective comparisons of procedures, evaluation of long-term outcomes, especially between centers and increasingly unrealistic patient expectations.


Metabolic energy cost of workers in agriculture, construction, manufacturing, tourism, and transportation industries.
The assessment of energy cost (EC) at the workplace remains a key topic in occupational health due to the ever-increasing prevalence of work-related issues. This review provides a detailed list of EC estimations in jobs/tasks included in tourism, agriculture, construction, manufacturing, and transportation industries. A total of 61 studies evaluated the EC of 1,667 workers while performing a large number of tasks related to each of the aforementioned five industries. Agriculture includes the most energy-demanding jobs (males: 6.0 ± 2.5 kcal/min; females: 2.9 ± 1.0 kcal/min). Jobs in the construction industry were the 2nd most demanding (males: 4.9 ± 1.6 kcal/min; no data for females). The industry with the 3rd highest EC estimate was manufacturing (males: 3.8 ± 1.1 kcal/min; females: 3.0 ± 1.3 kcal/min). Transportation presented relatively moderate EC estimates (males: 3.1 ± 1.0 kcal/min; no data for females). Tourism jobs demonstrated the lowest EC values (2.5 ± 0.9 kcal/min for males and females). It is hoped that this information will aid the development of future instruments and guidelines aiming to protect workers' health, safety, and productivity. Future research should provide updated EC estimates within a wide spectrum of occupational settings taking into account the sex, age, and physiological characteristics of the workers as well as the individual characteristics of each workplace.


CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia.
Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor. A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry-based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning. Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR, 2.0) in a Cox model adjusted for clinical and biologic prognosticators. Hierarchic trees including all patients or restricted to those with early-stage disease or those age ≤ 65 years always selected CD49d as the most important flow cytometry-based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patient subsets with poorer outcome independent of CD38 and ZAP-70. In this analysis of approximately 3,000 patients, CD49d emerged as the strongest flow cytometry-based predictor of OS and TFS in CLL.


The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 A resolution.
The fungal pathogen Pneumocystis carinii causes a pneumonia which is an opportunistic infection of AIDS patients. Current therapy includes the dihydrofolate reductase (DHFR) inhibitor trimethoprim which is selective but only a relatively weak inhibitor of the enzyme for P. carinii. Determination of the three-dimensional structure of the enzyme should form the basis for design of more potent and selective therapeutic agents for treatment of the disease. The structure of P. carinii DHFR in complex with reduced nicotinamide adenine dinucleotide phosphate and trimethoprim has accordingly been solved by X-ray crystallography. The structure of the ternary complex has been refined at 1.86 A resolution (R = 0.181). A similar ternary complex with piritrexim (which is a tighter binding, but less selective inhibitor) has also been solved, as has the binary complex holoenzyme, both at 2.5 A resolution. These structures show how two drugs interact with a fungal DHFR. A comparison of the three-dimensional structure of this relatively large DHFR with bacterial or mammalian enzyme-inhibitor complexes determined previously highlights some additional secondary structure elements in this particular enzyme species. These comparisons provide further insight into the principles governing DHFR-inhibitor interaction, in which the volume of the active site appears to determine the strength of inhibitor binding.


Prevalence of refractive errors in Colombia: MIOPUR study.
To determine the prevalence of refractive errors in Colombia and its relations with demographic and socioeconomic variables. A cross-sectional study performed in 10 Colombian administrative districts (MIOPUR study), including children and adolescents from 8 to 17 years old and adults from 35 to 55 years old. 3608 individuals (100% of whom agreed to participate) were included. Prevalence estimates of refractive errors were: hyperopia 32.3% (95% CI 30.7 to 33.8), myopia 12.9% (95% CI 11.8 to 14.0), mixed astigmatism 2.8% (95% CI 2.2 to 3.3) and anisometropia 1.9% (95% CI 1.4 to 2.3). Prevalence of myopia in 15-year-old adolescents was 14.7%. In children and adolescents, the hyperopia prevalence decreased while myopia prevalence increased with age. In the adults group, the tendency was the contrary. Myopia prevalence reached 15.7% in urban and 9.2% in rural areas, and for hyperopia, the rates were 29.4% in urban and 36.1% in rural areas. In the multivariate analysis, living in an urban area significantly increased the risk of having myopia (OR: 1.45 (1.12 to 1.89); p<0.01). There were significant regional differences among diverse zones of the country. Prevalence estimates of myopia and hyperopia in Colombia were found to be at an intermediate point compared with global data. In adults, myopia frequency was lower than in European and Asian studies. The prevalence of myopia increased during childhood and adolescence and was higher in middle-aged adults (35-39 years) than in older adults. On the other hand, hyperopia rates increased with age, findings that suggest a cohort effect. In the multivariate analysis, residence in urban areas and living in a medium-high socioeconomic status were linked to myopia.


[Skin lesions and their distribution in the cat: lessons to be drawn].
The specialty of dermatology has the invaluable advantage to provide direct visual access to the organ of interest, which therefore is characterised by a complex and complete semiology. This allows the clinician to efficiently limit the differential diagnosis. However, whereas in most species the focus lies in the assessment of the primary lesion resulting directly from the underlying pathologic process, in cats the assessment of the lesions' localisation and distribution is more important. The goal of this article is to illustrate the importance of considering the lesions' distribution and resulting reactive pattern at least as much as the nature of the lesion itself.


Fibrocartilage tissue engineering: the role of the stress environment on cell morphology and matrix expression.
Although much is known about the effects of uniaxial mechanical loading on fibrocartilage development, the stress fields to which fibrocartilaginous regions are subjected to during development are mutiaxial. That fibrocartilage develops at tendon-to-bone attachments and in compressive regions of tendons is well established. However, the three-dimensional (3D) nature of the stresses needed for the development of fibrocartilage is not known. Here, we developed and applied an in vitro system to determine whether fibrocartilage can develop under a state of periodic hydrostatic tension in which only a single principal component of stress is compressive. This question is vital to efforts to mechanically guide morphogenesis and matrix expression in engineered tissue replacements. Mesenchymal stromal cells in a 3D culture were exposed to compressive and tensile stresses as a result of an external tensile hydrostatic stress field. The stress field was characterized through mechanical modeling. Tensile cyclic stresses promoted spindle-shaped cells, upregulation of scleraxis and type one collagen, and cell alignment with the direction of tension. Cells experiencing a single compressive stress component exhibited rounded cell morphology and random cell orientation. No difference in mRNA expression of the genes Sox9 and aggrecan was observed when comparing tensile and compressive regions unless the medium was supplemented with the chondrogenic factor transforming growth factor beta3. In that case, Sox9 was upregulated under static loading conditions and aggrecan was upregulated under cyclic loading conditions. In conclusion, the fibrous component of fibrocartilage could be generated using only mechanical cues, but generation of the cartilaginous component of fibrocartilage required biologic factors in addition to mechanical cues. These studies support the hypothesis that the 3D stress environment influences cell activity and gene expression in fibrocartilage development.


Migration of Parabens, Bisphenols, Benzophenone-Type UV Filters, Triclosan, and Triclocarban from Teethers and Its Implications for Infant Exposure.
Parabens (p-hydroxybenzoic acid esters), bisphenols, benzophenone-type UV filters, triclosan, and triclocarban are used in a variety of consumer products, including baby teethers. Nevertheless, the exposure of infants to these chemicals through the use of teethers is still unknown. In this study, 59 teethers, encompassing three types, namely solid plastic, gel-filled, and water-filled (most labeled "bisphenol A-free"), were collected from the U.S. market and analyzed for 26 potential endocrine-disrupting chemicals (EDCs) from intact surfaces through migration/leaching tests performed with Milli-Q water and methanol. The total amount of the sum of six parent parabens (Σ6 Parabens) leached from teethers ranged from 2.0 to 1990 ng, whereas that of their four transformation products (Σ4 Parabens) ranged from 0.47 to 839 ng. The total amount of the sum of nine bisphenols (Σ9 bisphenols) and 5 benzophenones (Σ5 benzophenones) leached from teethers ranged from 1.93 to 213 ng and 0.59 to 297 ng, respectively. Triclosan and triclocarban were found in the extracts of teethers at approximately 10-fold less amounts than were bisphenols and benzophenones. Based on the amount leached into Milli-Q water, daily intake of these chemicals was estimated from the use of teethers by infants at 12 months of age. This is the first study to document the occurrence and migration of a wide range EDCs from intact surfaces of baby teethers.


Uptake of Al3+ into the N-lobe of human serum transferrin.
We have studied the binding of Al3+ to human serum apotransferrin (80 kDa) and recombinant N-lobe human apotransferrin (40 kDa) in 0.1 M-sodium bicarbonate solution at a pH meter reading in 2H2O (pH*) of 8.8 using 1H n.m.r. spectroscopy. The results show that for the intact protein, preferential binding of Al3+ to the N-lobe occurs. Molecular modelling combined with an analysis of ring-current-induced shifts suggest that n.m.r. spectroscopy can be used to probe hinge bending processes which accompany metal uptake in solution.


Triple-negative breast cancers: Are they always different from nontriple-negative breast cancers? An experience from a tertiary center in India.
Triple-negative breast cancers (TNBCs) are known for early age at presentation, large tumor sizes, and overall poor prognosis. However, Indian studies are scarce with limited follow-up data. Hence, the present study is aimed at characterizing nonmetastatic TNBC patients in our population and comparing their outcome with non-TNBC subset. This is a retrospective observational study of nonmetastatic breast cancer patients accrued over 14 years. The demographic, clinical, and pathological profiles of TNBCs and their patterns of recurrences and survivals were compared to that of non-TNBC. Overall and disease-free survival (DFSs) were calculated from the time of initiation of therapy to the occurrence of event, i.e., death or recurrence. TNBC constituted 21.8% of all patients. Patients with triple-negative subtype were significantly younger and more likely to be premenopausal. Higher proportion of TNBC presented in locally advanced stage and had a higher proportion of node-positive patients compared to their non-TNBC counterparts. Although taxane-based neoadjuvant therapy was associated with significantly higher pathological complete responses, recurrences occurred earlier in TNBC. Even though inferior overall and DFSs were encountered in TNBC, statistical significance could not be derived. TNBCs are a subset of tumors with a poorly understood tumor biology and behavior. Despite being labeled as having an aggressive tumor biology and behavior, not many differences are seen in their clinical outcomes when they present as locally advanced cases.