Nocturnal leg cramps.
Up to 60 percent of adults report that they have had nocturnal leg cramps. The recurrent, painful tightening usually occurs in the calf muscles and can cause severe insomnia. The exact mechanism is unknown, but the cramps are probably caused by muscle fatigue and nerve dysfunction rather than electrolyte or other abnormalities. Nocturnal leg cramps are associated with vascular disease, lumbar canal stenosis, cirrhosis, hemodialysis, pregnancy, and other medical conditions. Medications that are strongly associated with leg cramps include intravenous iron sucrose, conjugated estrogens, raloxifene, naproxen, and teriparatide. A history and physical examination are usually sufficient to differentiate nocturnal leg cramps from other conditions, such as restless legs syndrome, claudication, myositis, and peripheral neuropathy. Laboratory evaluation and specialized testing usually are unnecessary to confirm the diagnosis. Limited evidence supports treating nocturnal leg cramps with exercise and stretching, or with medications such as magnesium, calcium channel blockers, carisoprodol, or vitamin B(12). Quinine is no longer recommended to treat leg cramps.


Low-cost, high-resolution imaging for detecting cervical precancer in medically-underserved areas of Texas.
Cervical cancer rates in the United States have declined since the 1940's, however, cervical cancer incidence remains elevated in medically-underserved areas, especially in the Rio Grande Valley (RGV) along the Texas-Mexico border. High-resolution microendoscopy (HRME) is a low-cost, in vivo imaging technique that can identify high-grade precancerous cervical lesions (CIN2+) at the point-of-care. The goal of this study was to evaluate the performance of HRME in medically-underserved areas in Texas, comparing results to a tertiary academic medical center. HRME was evaluated in five different outpatient clinical settings, two in Houston and three in the RGV, with medical providers of varying skill and training. Colposcopy, followed by HRME imaging, was performed on eligible women. The sensitivity and specificity of traditional colposcopy and colposcopy followed by HRME to detect CIN2+ were compared and HRME image quality was evaluated. 174 women (227 cervical sites) were included in the final analysis, with 12% (11% of cervical sites) diagnosed with CIN2+ on histopathology. On a per-site basis, a colposcopic impression of low-grade precancer or greater had a sensitivity of 84% and a specificity of 45% to detect CIN2+. While there was no significant difference in sensitivity (76%, p = 0.62), the specificity when using HRME was significantly higher than that of traditional colposcopy (56%, p = 0.01). There was no significant difference in HRME image quality between clinical sites (p = 0.77) or medical providers (p = 0.33). HRME imaging increased the specificity for detecting CIN2+ when compared to traditional colposcopy. HRME image quality remained consistent across different clinical settings.


Molecular epidemiology and clinical features of rhinovirus infections among hospitalized patients in a medical center in Taiwan.
Human rhinovirus (HRV) can cause severe illnesses in hospitalized patients. However, there are no studies regarding the prevalence of HRV infection, particularly the recently identified HRV-C, in hospitalized patients reported from Taiwan. Respiratory specimens collected from 487 hospitalized patients in designated wards between 2013 and 2014 in a medical center in northern Taiwan were retrospectively detected for HRV. Positive specimens were further determined for genotyping. Medical charts of the HRV-positive patients were reviewed retrospectively. Totally, 76 patients (15.6%) were HRV positive, of which 60 were pediatric patients. HRV-A was identified in 41 (54%) patients, HRV-B in 6 patients (7.9%) and HRV-C in 29 patients (38%). A total of 47 different genotypes were identified. HRV infections were predominant during fall and winter seasons. 21.1% were affected by HRV alone and 78.9% were found to be co-infected with other microorganisms. The detection rate of HRV in children (18.6%) was significantly higher than in adults (9.6%). Compared with pediatric patients, adult patients were significantly associated with underlying disease, Pneumocystis jirovesii pneumonia co-infection, a diagnosis of pneumonia, fatal outcome, hospital acquisition of HRV, antibiotics administration and requiring intensive care, while pediatric patients were significantly associated with viral co-infection. HRV was a common cause of respiratory tract infection in Taiwan, particularly in pediatric patients. Eighty percent of HRV-infected inpatients had other microorganisms co-infection. Adult patients were more likely to be associated with a severe respiratory disease entity.


The association between regular cannabis exposure and alterations of human brain morphology: an updated review of the literature.
Cannabis is the most widely used illicit drug worldwide, though it is unclear whether its regular use is associated with persistent alterations in brain morphology. This review examines evidence from human structural neuroimaging investigations of regular cannabis users and focuses on achieving three main objectives. These include examining whether the literature to date provides evidence that alteration of brain morphology in regular cannabis users: i) is apparent, compared to non-cannabis using controls; ii) is associated with patterns of cannabis use; and with iii) measures of psychopathology and neurocognitive performance. The published findings indicate that regular cannabis use is associated with alterations in medial temporal, frontal and cerebellar brain regions. Greater brain morphological alterations were evident among samples that used at higher doses for longer periods. However, the evidence for an association between brain morphology and cannabis use parameters was mixed. Further, there is poor evidence for an association between measures of brain morphology and of psychopathology symptoms/neurocognitive performance. Overall, numerous methodological issues characterize the literature to date. These include investigation of small sample sizes, heterogeneity across studies in sample characteristics (e.g., sex, comorbidity) and in employed imaging techniques, as well as the examination of only a limited number of brain regions. These factors make it difficult to draw firm conclusions from the existing findings. Nevertheless, this review supports the notion that regular cannabis use is associated with alterations of brain morphology, and highlights the need to consider particular methodological issues when planning future cannabis research.


Late pharmacologic conditioning with volatile anesthetics after cardiac surgery.
The aim of this randomized controlled trial was to investigate whether volatile anesthetics used for postoperative sedation have any beneficial effects on myocardial injury in cardiac surgery patients after on-pump valve replacement. Anesthesia was performed with propofol. After arrival in the intensive care unit (ICU), 117 patients were randomized to be sedated for at least 4 hours with either propofol or sevoflurane. Sevoflurane was administered by using the anesthetic-conserving device. Troponin T, creatine kinase, creatine kinase from heart muscle tissue, myoglobin, and oxygenation index were determined on arrival at the ICU, 4 hours after sedation, and in the morning of the first postoperative day (POD1). Primary end points were cardiac injury markers on POD1. As secondary end points oxygenation, postoperative pulmonary complications, and ICU and hospital stay were documented. Fifty-six patients were analyzed in the propofol arm, and 46 patients in the sevoflurane arm. Treatment groups were comparable with regard to patient demographics and intraoperative characteristics. Concentration of troponin T as the most sensitive marker for myocardial injury at POD1 was significantly lower in the sevoflurane group compared with the propofol group (unadjusted difference, -0.4; 95% CI, -0.7 to -0.1; P < 0.01; adjusted difference, -0.2; 95% CI, -0.4 to -0.02; P = 0.03, respectively). The data presented in this investigation indicate that late postconditioning with the volatile anesthetic sevoflurane might mediate cardiac protection, even with a late, brief, and low-dose application. ClinicalTrials.gov: NCT00924222.


UPTAKE OF MAMMALIAN CHROMOSOMES BY MAMMALIAN CELLS.
Chromosomes isolated from mouse leukemia L1210 cells were taken up by mouse macrophages, HeLa cells, and rat embryo fibroblasts following simple exposure in vitro. The process, which resembles pinocytosis or phagocytosis, was traced by autoradiography of chromosomes prelabeled with thymidine-H(3), and by staining techniques and phase contrast microscopy. During the first six hours, the uptake of chromosomes was restricted to the cytoplasm, but there was some evidence of penetration into the nucleus after 16 and 26 hours of exposure. Treatment of rat fibroblasts with glucose and insulin markedly enhanced the uptake of chromosomes, whereas iodoacetate inhibited their penetration.


Improving newborn screening laboratory test ordering and result reporting using health information exchange.
Capture, coding and communication of newborn screening (NBS) information represent a challenge for public health laboratories, health departments, hospitals, and ambulatory care practices. An increasing number of conditions targeted for screening and the complexity of interpretation contribute to a growing need for integrated information-management strategies. This makes NBS an important test of tools and architecture for electronic health information exchange (HIE) in this convergence of individual patient care and population health activities. For this reason, the American Health Information Community undertook three tasks described in this paper. First, a newborn screening use case was established to facilitate standards harmonization for common terminology and interoperability specifications guiding HIE. Second, newborn screening coding and terminology were developed for integration into electronic HIE activities. Finally, clarification of privacy, security, and clinical laboratory regulatory requirements governing information exchange was provided, serving as a framework to establish pathways for improving screening program timeliness, effectiveness, and efficiency of quality patient care services.


New therapeutic option with N-acetylcysteine for primary sclerosing cholangitis: two case reports.
Primary sclerosing cholangitis is a progressive, cholestatic hepatic disease of unknown etiology. It is characterized by progressive inflammation, destruction, and fibrosis of the intrahepatic and extrahepatic bile ducts. Several medical therapies have been tried such as penicilamin, colchicine, methatraxate, cyclosporine, tacrolimus, and ursodeoxycholic acid. Treatment with mucolytic agents in excessively high viscosity conditions appears to have an important role. N-acetylcysteine (NAC), as a mucolytic agent, may fascilitate the drainage in partial obstructions by decreasing the mucous viscosity. We suggest that NAC and ursodeoxycholic acid have markedly positive effects on the clinical course of cholangitis and cholestasis when used together by affecting bile viscosity. Here, we present two cases treated with NAC. NAC capsul therapies at 800 mg/day were administered to two patients with primary sclerosing cholangitis. Clinical and laboratory parameters of patients saw significant improvement.


How is the evolution of tumour resistance at organ-scale impacted by the importance of the organ for fitness?
A strong variability in cancer incidence is observed between human organs. Recently, it has been suggested that the relative contribution of organs to organism fitness (reproduction or survival) could explain at least a part of the observed variation. The objective of this study is to investigate theoretically the main factors driving the evolution of tumour resistance mechanisms of organs when their relative contribution to organism fitness is considered. We use a population-scale model where individuals can develop a tumour in a key organ (i.e. in which even a small tumour can negatively impact organism fitness), an auxiliary organ (i.e. in which only a large tumour has a relatively significant impact) or both organs because of metastasis. Our simulations show that natural selection acts in two different ways to prevent cancer in a key and an auxiliary organs. In the key organ, the strategy mostly selected is the highest resistance and only a high cost of resistance mitigates this behavior. Inversely, we observe that a low resistance strategy can be selected in the auxiliary organ when the development of the tumour is slow and the effect of a large tumour on the mortality of the organism is relatively weak. Nevertheless, if the tumour can spread to a key organ, higher resistance strategies are selected in the auxiliary organ. Finally, our study demonstrates that the relative contribution of organs to the organism fitness and the metastatic propensity of the tumour influence the evolution of tumour resistance at organ scale and should be considered by studies aiming to explain the variability in cancer incidence at organ-scale.


Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis.
Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic neurodegeneration, mitochondrial impairment, and oxidative stress. Exposure of animals to rotenone induces a range of responses characteristic of PD, including reactive oxygen species production and dopaminergic cell death. Although l-dopa is the drug of choice for improving core symptoms of PD, it is associated with involuntary movements. The current study was directed to evaluate the neuroprotective effect of bee venom acupuncture therapy (BVA) against rotenone-induced oxidative stress, neuroinflammation, and apoptosis in PD mouse model. Forty male Swiss mice were divided into four groups: (1) received saline solution orally and served as normal control, (2) received rotenone (1.5 mg/kg, s.c. every other day for 6 doses), (3) received rotenone concomitantly with l-dopa (25 mg/kg, daily, p.o. for 6 days), and finally (4) received rotenone concomitantly with BVA (0.02 ml once every 3 days for two weeks). Rotenone-treated mice showed impairment in locomotor behavior and a significant reduction in brain dopamine, serotonin, norepinephrine, GSH levels, and paraoxonase activity, whereas a significant increase was observed in brain malondialdehyde, tumor necrosis factor-α, interleukin-β levels besides DNA damage, and over-expression of caspase-3, Bax, and Bcl-2 genes. Significant improvement of the aforementioned parameters was demonstrated after BVA compared to l-dopa therapy. In conclusion, bee venom normalized all the neuroinflammatory and apoptotic markers and restored brain neurochemistry after rotenone injury. Therefore, BVA is a promising neuroprotective therapy for PD.


Transthoracic oesophagectomy with lymphadenectomy in 100 oesophageal cancer patients: multidisciplinary approach.
OBJECTIVES Analysis of the results on the treatment of esophageal cancer by transthoracic esophagectomy by a multidisciplinary team of surgeons and oncologists. METHODS Between January 1990 and December 2009, 100 consecutive patients underwent transthoracic esophagectomy. Data were collected prospectively and clinical, pathological and histological features of the tumors were analyzed as well as the results of postoperative morbidity and mortality. RESULTS The average patient age was 55 years (range 31- 83 years). In 59 cases the tumor was located in the lower third and in 41 cases in the middle third. Forty-six patients had adenocarcinoma and 54 squamous cell carcinoma. In 54 cases radio-chemotherapy was planned preoperatively. Classifi cation according to pathological tumor stage was: stage 0 in 21 patients, stage I in 10 patients, stage IIa in 28, stage IIb in 9, stage III in 21 and stage IV in 11. The mean number of lymph nodes examined was 14 (range 0-28). Hospital mortality occurred in 4 cases and postoperative complications in 29 patients (33%). The most frequent postoperative complication was pulmonary complications in 17 cases. The average hospital stay was 15.2 days (range 10-40 days) CONCLUSIONS The results of esophageal cancer have been improved in recent years due to the formation of multidisciplinary teams in this pathology. In our study we have shown that the results obtained with the transthoracic technique for cancer of the esophagus are within the ranges reported in the literature for teams with high prevalence of the disease.


Comprehensive genome characterization of solitary fibrous tumors using high-resolution array-based comparative genomic hybridization.
Solitary fibrous tumors (SFTs) are rare spindle cell tumors with limited therapeutic options. Their molecular basis is poorly known. No consistent cytogenetic abnormality has been reported. We used high-resolution whole-genome array-based comparative genomic hybridization (Agilent 244K oligonucleotide chips) to profile 47 samples, meningeal in >75% of cases. Few copy number aberrations (CNAs) were observed. Sixty-eight percent of samples did not show any gene CNA after exclusion of probes located in regions with referenced copy number variation (CNV). Only low-level CNAs were observed. The genomic profiles were very homogeneous among samples. No molecular class was revealed by clustering of DNA copy numbers. All cases displayed a "simplex" profile. No recurrent CNA was identified. Imbalances occurring in >20%, such as the gain of 8p11.23-11.22 region, contained known CNVs. The 13q14.11-13q31.1 region (lost in 4% of cases) was the largest altered region and contained the lowest percentage of genes with referenced CNVs. A total of 425 genes without CNV showed copy number transition in at least one sample, but only but only 1 in at least 10% of samples. The genomic profiles of meningeal and extra-meningeal cases did not show any differences.


Surgical complications exert a lasting effect on disease-specific health-related quality of life for patients with colorectal cancer.
For individual patients with colorectal cancer, health-related quality of life (HRQL) after treatment is a function of several factors that include preexisting medical conditions, the disease burden, and the treatment that is rendered. The purpose of this study was to identify the factors that were associated with posttreatment HRQL. At baseline and again at 12 months after diagnosis, patients completed the colorectal cancer-specific HRQL survey: Functional Assessment of Cancer Therapy (FACT-C). Univariate and multivariate analyses were performed to test the association between patient-, tumor-, and treatment-related variables and 12-month FACT-C total scores. Seventy-one patients completed the FACT-C at diagnosis and subsequently underwent open surgical removal of their primary tumor; 63 patients completed the 12-month survey. In univariate analysis, only chronic obstructive pulmonary disease at diagnosis or the occurrences of perioperative complications were associated with a reduction in 12-month HRQL scores. Considering both the diagnosis of chronic obstructive pulmonary disease and the occurrence of perioperative complications, along with the patient's FACT-C total score at diagnosis, age, tumor location, and stage of disease in a multivariate model, only the perioperative complications (odds ratio, 10.5; 95% CI, 2.1-52) and FACT-C total score at diagnosis (odds ratio, 1.04; 95% CI, 1.005-1.07) were associated significantly with a lower than median HRQL score at 12 months. For patients who undergo treatment of colorectal cancer, HRQL at 1 year after diagnosis is still influenced significantly and negatively by the occurrence of surgical complications.


Dynamic Formation of Microvillus Inclusions During Enterocyte Differentiation in Munc18-2-Deficient Intestinal Organoids.
Microvillus inclusion disease (MVID) is a congenital intestinal malabsorption disorder caused by defective apical vesicular transport. Existing cellular models do not fully recapitulate this heterogeneous pathology. The aim of this study was to characterize 3-dimensional intestinal organoids that continuously generate polarized absorptive cells as an accessible and relevant model to investigate MVID. Intestinal organoids from Munc18-2/Stxbp2-null mice that are deficient for apical vesicular transport were subjected to enterocyte-specific differentiation protocols. Lentiviral rescue experiments were performed using human MUNC18-2 variants. Apical trafficking and microvillus formation were characterized by confocal and transmission electron microscopy. Spinning disc time-lapse microscopy was used to document the lifecycle of microvillus inclusions. Loss of Munc18-2/Stxbp2 recapitulated the pathologic features observed in patients with MUNC18-2 deficiency. The defects were fully restored by transgenic wild-type human MUNC18-2 protein, but not the patient variant (P477L). Importantly, we discovered that the MVID phenotype was correlated with the degree of enterocyte differentiation: secretory vesicles accumulated already in crypt progenitors, while differentiated enterocytes showed an apical tubulovesicular network and enlarged lysosomes. Upon prolonged enterocyte differentiation, cytoplasmic F-actin-positive foci were observed that further progressed into classic microvillus inclusions. Time-lapse microscopy showed their dynamic formation by intracellular maturation or invagination of the apical or basolateral plasma membrane. We show that prolonged enterocyte-specific differentiation is required to recapitulate the entire spectrum of MVID. Primary organoids can provide a powerful model for this heterogeneous pathology. Formation of microvillus inclusions from multiple membrane sources showed an unexpected dynamic of the enterocyte brush border.


Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.
Experiments with vesicles containing N-methyl-D-aspartate (NMDA) receptor 2B (NR2B subunit) show that they are transported along microtubules by KIF17, a neuron-specific molecular motor in neuronal dendrites. Selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of mLin-10 (Mint1/X11), which is a constituent of a large protein complex including mLin-2 (CASK), mLin-7 (MALS/Velis), and the NR2B subunit. This interaction, specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis.


Inhibition of disulfide bonding of von Willebrand protein by monensin results in small, functionally defective multimers.
The biosynthesis of von Willebrand protein by human endothelial cells was impaired by the presence of the carboxylic ionophore monensin. Several processing steps that have been localized to the Golgi apparatus were affected in a dose-dependent manner, including carbohydrate processing, dimer multimerization, and precursor cleavage. Since multimerization was more susceptible to the ionophore than was precursor cleavage, it appears that these processing steps are separate events. As expected, dimer formation, which occurs in the rough endoplasmic reticulum, was unaffected by monensin. Thus, at high concentrations of monensin, only dimer molecules were produced and secreted. The observed inhibition of multimer formation and precursor cleavage were not likely the result of incomplete carbohydrate processing, since inhibition of complex carbohydrate formation by swainsonine did not interfere with the other processing steps. Monensin also affected the capacity of endothelial cells to store von Willebrand protein, as the ratio of secreted to cell-associated protein increased dramatically in the presence of monensin, and the processed forms could not be found in the treated cells. The low molecular weight multimers produced in the presence of monensin did not incorporate in the endothelial cells' extracellular matrix nor did they bind to the matrix of human foreskin fibroblasts. In summary, the presence of monensin in human endothelial cell culture produced experimental conditions that mimic Type IIA von Willebrand disease, in that the cells synthesized and secreted only low molecular weight von Willebrand protein multimers, which were functionally defective.


Development and maintenance of a community-based hepatitis C registry.
To develop a model for community-population- or health system-based registries of all patients with diagnosed hepatitis C, to facilitate clinical care and epidemiologic studies. Geographically defined, population-based cohort study. Registry subjects were identified using January 1, 1990, to December 31, 1999, data from the Rochester Epidemiology Project (REP), which lists all diagnoses for Olmsted County residents recorded by clinicians during visits to Olmsted County medical providers. We supplemented diagnostic data with information from laboratory databases that record all hepatitis C testing in Olmsted County. All diagnoses based on the REP and laboratory databases were confirmed by medical record review. Proposed data elements to be included in a hepatitis C registry were identified and defined, and data collection methodology was tested. A total of 355 subjects (62% male) were identified in the total community population of 130,000. Both the diagnostic summary database (n = 309, 87%) and the laboratory database (n = 46, 133%) were important in the identification of subjects for the registry. Nine additional subjects with diagnostic or laboratory evidence of hepatitis C refused the legislatively mandated (Minnesota statute) medical records research authorization and could not be included in the registry. Most desired data elements were available in the medical records. Both medical visit diagnostic summaries (administrative or billing data) and laboratory databases are required to identify subjects with physician-based diagnoses of hepatitis C. Few patients refused the authorization required for inclusion in a research registry.


Distribution of Alexandrium fundyense (Dinophyceae) cysts in Greenland and Iceland, with an emphasis on viability and growth in the Arctic.
The bloom-forming dinoflagellate Alexandrium fundyense has been extensively studied due its toxin-producing capabilities and consequent impacts to human health and economies. This study investigated the prevalence of resting cysts of A. fundyense in western Greenland and Iceland to assess the historical presence and magnitude of bloom populations in the region, and to characterize environmental conditions during summer, when bloom development may occur. Analysis of sediments collected from these locations showed that Alexandrium cysts were present at low to moderate densities in most areas surveyed, with highest densities observed in western Iceland. Additionally, laboratory experiments were conducted on clonal cultures established from isolated cysts or vegetative cells from Greenland, Iceland, and the Chukchi Sea (near Alaska) to examine the effects of photoperiod interval and irradiance levels on growth. Growth rates in response to the experimental treatments varied among isolates, but were generally highest under conditions that included both the shortest photoperiod interval (16h:8h light:dark) and higher irradiance levels (~146-366 μmol photons m-2 s-1), followed by growth under an extended photoperiod interval and low irradiance level (~37 μmol photons m-2 s-1). Based on field and laboratory data, we hypothesize that blooms in Greenland are primarily derived from advected Alexandrium populations, as low bottom temperatures and limited light availability would likely preclude in situ bloom development. In contrast, the bays and fjords in Iceland may provide more favorable habitat for germling cell survival and growth, and therefore may support indigenous, self-seeding blooms.


Improving heterologous production of phenylpropanoids in Saccharomyces cerevisiae by tackling an unwanted side reaction of Tsc13, an endogenous double-bond reductase.
Phenylpropanoids, such as flavonoids and stilbenoids, are of great commercial interest, and their production in Saccharomyces cerevisiae is a very promising strategy. However, to achieve commercially viable production, each step of the process must be optimised. We looked at carbon loss, known to occur in the heterologous flavonoid pathway in yeast, and identified an endogenous enzyme, the enoyl reductase Tsc13, which turned out to be responsible for the accumulation of phloretic acid via reduction of p-coumaroyl-CoA. Tsc13 is an essential enzyme involved in fatty acid synthesis and cannot be deleted. Hence, two approaches were adopted in an attempt to reduce the side activity without disrupting the natural function: site saturation mutagenesis identified a number of amino acid changes which slightly increased flavonoid production but without reducing the formation of the side product. Conversely, the complementation of TSC13 by a plant gene homologue essentially eliminated the unwanted side reaction, while retaining the productivity of phenylpropanoids in a simulated fed batch fermentation.


Quantitative Doppler for Estimation of Paravalvular Leakage after Transcatheter Aortic Valve Implantation.
The echocardiographic grading of paravalvular aortic leakage (PVL) after transcatheter aortic valve implantation (TAVI) severity is challenging. The study aim was to assess the value of quantitative Doppler echocardiography to monitor PVL severity. A total of 100 subjects was enrolled in the study, including 65 consecutive patients who had undergone TAVI with a CoreValve prosthesis and without valvular aortic regurgitation, and 35 normal controls. The PVL volume was calculated using the quantitative Doppler method as the difference of left and right ventricular stroke volume (SV). PVL severity was assessed both visually and quantitatively as the circumferential extent on a short-axis view (SAX). The inter-observer variabilities for SVs in TAVI patients were disappointing: 14 ± 11% for the left ventricular SV and 18 ± 14% for right ventricular SV. The correlation (r2) between the averaged regurgitant PVL volume and circumferential SAX extent of PVL was 0.02 (p = NS). The relationship between PVL volumes and categories, defined quantitatively by the circumferential SAX extent of PVL and qualitatively by visual assessment of severity of PVL were poor. The results improved when only patients with optimal quality images were included but were still statistically non-significant. The relationship between calculated PVL volume in TAVI patients and other estimates of PVL severity was poor, most likely due to intrinsic errors made in the quantitative Doppler method. Therefore, one should be prudent to include the quantitative Doppler method in TAVI patients in clinical trials and clinical decision-making, in particular in patients with reduced image quality.


The accuracy of a near-infrared spectroscopy cerebral oximetry device and its potential value for estimating jugular venous oxygen saturation.
An intriguing potential clinical use of cerebral oximeter measurements (SctO2) is the ability to noninvasively estimate jugular bulb venous oxygen saturation (SjvO2). Our purpose in this study was to determine the accuracy of the FORE-SIGHT(®) (CAS Medical Systems, Branford, CT), which is calibrated to a weighted average of 70% (SjvO2) and 30% arterial saturation, for Food and Drug Administration pre-market approval 510(k) certification by adapting an industry standard protocol, ISO 9919:2005 (www.ISO.org) (used for pulse oximeters), and to evaluate the use of SctO2 and SpO2 measurements to noninvasively estimate jugular venous oxygen saturation (SnvO2). Paired blood gas samples from the radial artery and the jugular venous bulb were collected from 20 healthy volunteers undergoing progressive oxygen desaturation from 100% to 70%. The blood sample pairs were analyzed via co-oximetry and used to calculate the approximate mixed vascular cerebral blood oxygen saturation, or reference SctO2 values (refSctO2), during increasing hypoxia. These reference values were compared to bilateral FORE-SIGHT SctO2 values recorded simultaneously with the blood gas draws to determine its accuracy. Bilateral SctO2 and SpO2 measurements were then used to calculate SnvO2 values which were compared to SjvO2. Two hundred forty-six arterial and 253 venous samples from 18 subjects were used in the analysis. The ipsilateral FORE-SIGHT SctO2 values showed a tolerance interval (TI) of [-10.72 to 10.90] and Lin concordance correlation coefficient (CCC) with standard error (SE) of 0.83 ± 0.073 with the refSctO2 values calculated using arterial and venous blood gases. The ipsilateral data had a CCC of 0.81 + 0.059 with TI of [-9.22 to 9.40] with overall bias of 0.09%, and amplitude of the root mean square of error after it was corrected with random effects analysis was 2.92%. The bias and variability values between the ipsilateral and the contralateral FORE-SIGHT SctO2 measurements varied from person to person. The SnvO2 calculated from the ipsilateral SctO2 and SpO2 data showed a CCC ± SE of 0.79 ± 0.088, TI = [-14.93 to 15.33], slope of 0.98, y-intercept of 1.14% with SjvO2 values with a bias of 0.20% and an Arms of 4.08%. The SnvO2 values calculated independently from contralateral forehead FORE-SIGHT SctO2 values were not as correlated with the SjvO2 values (contralateral side CCC + SE = 0.72 ± 0.118, TI = [-14.86 to 15.20], slope of 0.66, and y-intercept of 20.36%). The FORE-SIGHT cerebral oximeter was able to estimate oxygen saturation within the tissues of the frontal lobe under conditions of normocapnia and varying degrees of hypoxia (with 95% confidence interval of [-5.60 to 5.78] with ipsilateral blood sample data). These findings from healthy volunteers also suggest that the use of the calculated SnvO2 derived from SctO2 and SpO2 values may be a reasonable noninvasive method of estimating SjvO2 and therefore global cerebral oxygen consumption in the clinical setting. Further laboratory and clinical research is required to define the clinical utility of near-infrared spectroscopy determination of SctO2 and SnvO2 in the operating room setting.


The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection.
Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood. We have previously shown that the Arg (also known as Abl2) non-receptor tyrosine kinase facilitates L. amazonensis amastigote uptake by macrophages. Using small-molecule inhibitors and primary macrophages lacking specific Src family kinases, we now demonstrate that the Hck, Fgr and Lyn kinases are also necessary for amastigote uptake by macrophages. Src-mediated Arg activation is required for efficient uptake. Interestingly, the dual Arg and Src kinase inhibitor bosutinib, which is approved to treat cancer, not only decreases amastigote uptake, but also significantly reduces disease severity and parasite burden in Leishmania-infected mice. Our results suggest that leishmaniasis could potentially be treated with host-cell-active agents such as kinase inhibitors.


Effects of ouabain and vagal stimulation on sinus nodal function in conscious dogs.
We studied the effects of intravenous ouabain administration (15 micrograms/kg) and vagal stimulation on instrumented conscious dogs. In these dogs, a special electrode was implanted on the epicardial surface over the sinus node and plaque electrodes were placed on the superior vena cava and left atrial appendage. Unipolar sinus electrograms were recorded through the terminals of the sinus electrode paired with the superior vena caval electrode. An electrode also was implanted around the desheathed cervical vagosympathetic trunk, and a coiled polyethylene tube with side holes was implanted cranial to it. Ouabain administration resulted in: (1) an increase in the sinus cycle lengths and sinoatrial intervals and increase in beat-to-beat variation of the sinus cycles and sinoatrial intervals, and (2) periods of sinus pacemaker shift, sinus arrest and sinoatrial block that occurred spontaneously or after atrial overdrive stimulation delivered through the electrode on the left atrial appendage. These effects of ouabain were abolished by intravenous administration of atropine (2 mg). Prior to vagal stimulation, intravenous propranolol (0.5 mg/kg) was administered to block sympathetic responses and 0.75% bupivacaine was injected through the polyethylene tube to block afferent transmission. Vagal stimulation in conscious dogs resulted in two types of responses: (1) slowing of sinus pacemaker rate accompanied by a decrease in diastolic slope and followed by sinus pacemaker shifts, and (2) gradual prolongation of the sinoatrial intervals followed by failure of sinoatrial conduction. An intravenous bolus of acetylcholine (0.1 mg) resulted in a response of type 2 in dogs in which vagal stimulation produced a response of type 1. The marked similarity between the effects of ouabain and vagal stimulation on sinus function and the abolition of the effects of ouabain by atropine suggest that the ouabain effects are vagally mediated.


Facilitated transport and diffusion take distinct spatial routes through the nuclear pore complex.
Transport across the nuclear envelope is regulated by nuclear pore complexes (NPCs). Much is understood about the factors that shuttle and control the movement of cargos through the NPC, but less has been resolved about the translocation process itself. Various models predict how cargos move through the channel; however, direct observation of the process is missing. Therefore, we have developed methods to accurately determine cargo positions within the NPC. Cargos were instantly trapped in transit by high-pressure freezing, optimally preserved by low-temperature fixation and then localized by immunoelectron microscopy. A statistical modelling approach was used to identify cargo distribution. We found import cargos localized surprisingly close to the edge of the channel, whereas mRNA export factors were at the very centre of the NPC. On the other hand, diffusion of GFP was randomly distributed. Thus, we suggest that spatially distinguished pathways exist within the NPC. Deletion of specific FG domains of particular NPC proteins resulted in collapse of the peripheral localization and transport defects specific to a certain karyopherin pathway. This further confirms that constraints on the route of travel are biochemical rather than structural and that the peripheral route of travel is essential for facilitated import.


Rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles.
An unusual rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles is described. These studies show that (Z)-vinylcarbenoids have a greater tendency than (E)-vinylcarbenoids to react at the vinylogous position of the carbenoid rather than at the carbenoid center.


Non-steroidal anti-inflammatory drugs and risk of heart failure exacerbation: A systematic review and meta-analysis.
The association between exacerbation of heart failure (HF) and use of non-steroidal anti-inflammatory drugs (NSAIDs) has long been recognized but the data on this adverse effect are limited. To further characterize this possible association, we conducted a systematic review and meta-analysis of observation studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of exacerbation of HF in patients with pre-existing HF who took NSAIDs versus non-users. Pooled risk ratios (RR) and 95% confidence intervals for conventional NSAIDs, celecoxib and rofecoxib were calculated using random-effect, generic inverse variance method. Six studies were identified and included in our data analysis. Use of conventional NSAIDs was associated with a significantly higher risk of development of exacerbation of HF with the pooled RR of 1.39 (95% CI 1.20-1.62). Elevated risk was also observed among celecoxib and rofecoxib users (RR 1.34, 95% CI 0.98-1.85 and RR 2.04, 95% CI 1.68-2.48). The pooled RR of rofecoxib was significantly higher than conventional NSAIDs (p=0.02). Use of NSAIDs is associated with an increased risk of HF exacerbation among patients with pre-existing HF. The excess risk was approximately 40% for conventional NSAIDs and celecoxib. The highest risk was observed among rofecoxib users.


14-Year Survey in a Swedish County Reveals a Pronounced Increase in Bloodstream Infections (BSI). Comorbidity - An Independent Risk Factor for Both BSI and Mortality.
we assessed the incidence, risk factors and outcome of BSI over a 14-year period (2000-2013) in a Swedish county. retrospective cohort study on culture confirmed BSI among patients in the county of Östergötland, Sweden, with approximately 440,000 inhabitants. A BSI was defined as either community-onset BSI (CO-BSI) or hospital-acquired BSI (HA-BSI). of a total of 11,480 BSIs, 67% were CO-BSI and 33% HA-BSI. The incidence of BSI increased by 64% from 945 to 1,546 per 100,000 hospital admissions per year during the study period. The most prominent increase, 83% was observed within the CO-BSI cohort whilst HA-BSI increased by 32%. Prescriptions of antibiotics in outpatient care decreased with 24% from 422 to 322 prescriptions dispensed/1,000 inhabitants/year, whereas antibiotics prescribed in hospital increased by 67% (from 424 to 709 DDD per 1,000 days of care). The overall 30-day mortality for HA-BSIs was 17.2%, compared to 10.6% for CO-BSIs, with an average yearly increase per 100,000 hospital admissions of 2 and 5% respectively. The proportion of patients with one or more comorbidities, increased from 20.8 to 55.3%. In multivariate analyses, risk factors for mortality within 30 days were: HA-BSI (2.22); two or more comorbidities (1.89); single comorbidity (1.56); CO-BSI (1.21); male (1.05); and high age (1.04). this survey revealed an alarming increase in the incidence of BSI over the 14-year study period. Interventions to decrease BSI in general should be considered together with robust antibiotic stewardship programmes to avoid both over- and underuse of antibiotics.


Automated Digital Image Analysis (TrichoScan®) for Human Hair Growth Analysis: Ease versus Errors.
TrichoScan(®) is considered to be time-saving, easy to perform and consistent for quantifying hair loss/growth. Conflicting results of our study lead us to closely observe the image analysis, and certain repeated errors in the detection of hair were highlighted. To assess the utility of TrichoScan in quantification of diffuse hair loss in males with androgenetic alopecia (AGA) and females with diffuse telogen hair loss, with regard to total hair density (THD), telogen and vellus hair percentages. TrichoScan procedure was performed on 77 cases and 20 controls. In the cases, THD decreased with increasing severity of alopecia. Surprisingly, more than 85% of the healthy volunteers had an unexplained abnormal telogen hair percentage of more than 20. Also, the telogen hair percentages were not significantly different between cases and controls. Also, 65% of the patients with advanced thinning of hair did not have the expected elevation of vellus hair percentages on TrichoScan evaluation. Multiple errors were highlighted in hair detection by the software. Errors were noted at the exit points of follicular ostia, at places where hair strand thickness was not uniform throughout its length, where there was crossing, overlapping of the neighboring strands, and when more than one hair emerged from a single ostium. TrichoScan is promoted as a validated and precise tool for measurement of hair growth parameters. Under certain conditions, it may seem suitable for clinical trials evaluating treatment response. We provide evidence that this is an overstatement. This study concludes that TrichoScan-analyzed anagen/telogen hair detection is not optimal; moreover, there is overestimation of THD and the vellus hair percentage does not correlate with clinical severity of alopecia. The current form of TrichoScan, though easy to use, is error-prone and awaits refinement.


Evaluation of virus reduction efficiency in wastewater treatment unit processes as a credit value in the multiple-barrier system for wastewater reclamation and reuse.
The virus reduction efficiency of each unit process is commonly determined based on the ratio of virus concentration in influent to that in effluent of a unit, but the virus concentration in wastewater has often fallen below the analytical quantification limit, which does not allow us to calculate the concentration ratio at each sampling event. In this study, left-censored datasets of norovirus (genogroup I and II), and adenovirus were used to calculate the virus reduction efficiency in unit processes of secondary biological treatment and chlorine disinfection. Virus concentration in influent, effluent from the secondary treatment, and chlorine-disinfected effluent of four municipal wastewater treatment plants were analyzed by a quantitative polymerase chain reaction (PCR) approach, and the probabilistic distributions of log reduction (LR) were estimated by a Bayesian estimation algorithm. The mean values of LR in the secondary treatment units ranged from 0.9 and 2.2, whereas those in the free chlorine disinfection units were from -0.1 and 0.5. The LR value in the secondary treatment was virus type and unit process dependent, which raised the importance for accumulating the data of virus LR values applicable to the multiple-barrier system, which is a global concept of microbial risk management in wastewater reclamation and reuse.


Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.
Many epigenetically inactivated genes involved in ovarian cancer (OC) development and progression remain to be identified. In this study we undertook an integrated approach that consisted of identification of genome-wide expression patterns of primary OC samples and normal ovarian surface epithelium along with a pharmacologic unmasking strategy using 3 OC and 3 immortalized normal ovarian epithelial cell lines. Our filtering scheme identified 43 OC specific methylated genes and among the 5 top candidates (GULP1, CLIP4, BAMBI, NT5E, TGFβ2), we performed extended studies of GULP1. In a training set, we identified GULP1 methylation in 21/61 (34%) of cases with 100% specificity. In an independent cohort, the observed methylation was 40% (146/365) in OC, 12.5% (2/16) in borderline tumors, 11% (2/18) in cystadenoma and 0% (0/13) in normal ovarian epithelium samples. GULP1 methylation was associated with clinicopathological parameters such as stage III/IV (p = 0.001), poorly differentiated grade (p = 0.033), residual disease (p < 0.0003), worse overall (p = 0.02) and disease specific survival (p = 0.01). Depletion of GULP1 in OC cells led to increased pro-survival signaling, inducing survival and colony formation, whereas reconstitution of GULP1 negated these effects, suggesting that GULP1 is required for maintaining cellular growth control.


Hematopoietic neoplasia in C57BL/6 mice exposed to split-dose ionizing radiation and circularly polarized 60 Hz magnetic fields.
This study assessed the effect of chronic exposure to a 60 Hz circularly polarized magnetic field on the occurrence of ionizing radiation-induced lymphoma and other hematopoietic neoplasia in mice. Female C57BL/6 mice received lifetime exposure to either a magnetic field flux density of 1.42 mT for 18 h/day, or an ambient magnetic field of 0.13 microT. Beginning on the first day of magnetic field exposure, 1710 mice were treated with one of three levels of split-dose Cobalt-60 gamma-radiation (cumulative 3.0, 4.0 or 5.1 Gy). The remaining 570 mice received sham irradiation treatment. Sections from 10 lymphoid tissues were evaluated histopathologically for hematopoietic neoplasia. The primary statistical analysis used the Poly3 method to compare lymphoma incidences in magnetic field (MF)-exposed and control mice. Secondary analyses used the Cox proportional hazards model to analyze incidence rates for mortality and development of specific types of neoplasia. The mortality incidence rate was increased by ionizing radiation treatment, and all neoplasms were observed sooner in irradiated mice. However, the lifetime incidence of hematopoietic neoplasia was similar in all experimental groups, including those that were not exposed to ionizing radiation. Chronic exposure to MFs did not affect the mortality incidence rates and did not change the relative incidences of hematopoietic neoplasia in mice that received the same ionizing radiation treatment, with the exception of a marginally significant reduced relative risk of 0.97 (P = 0.05) for lymphoblastic lymphoma in mice exposed to a magnetic field and treated with 5.1 Gy. Lymphomas and histiocytic sarcomas were first observed approximately 50 days sooner in mice that were exposed to magnetic fields but not ionizing radiation, although this comparison was not statistically significant and the incidence of hematopoietic neoplasia in these mice was not different from that of mice in the 0 T/0 Gy group.


Testing the effect of specific socioeconomic factors on the ischemic mortality rate. The case of Greece.
In this paper we present a model to evaluate the effect of certain majors socioeconomic factors (such as alcohol and fat consumption, cigarettes smoking, unemployment rate as a proxy for uncertainty which results frustration, number of passenger cars as a proxy for physical exercise and per capita GDP as a proxy for nutrition quality), to the ischemic mortality rate. Since the existing research works on this field, suffer from the proper model testing, we analytically present all the tests necessary to justify the reliability of the result obtained. For this purpose, after specifying and estimating the model, we applied the specification error test, the linearity, multicollinearity and heteroscedasticity tests, the autocorrelation and stability tests and the ARCH effect test. Finally, we present the aggregate effect of the above socioeconomic factors. In brief, we found that an increase of cigarettes smoked, of fat and alcohol consumption and the number of passenger cars will result to a relevant increase regarding mortality. The latter one is also affected by the changes in unemployment rate. On the other hand, an increase of personal disposable income may negatively affect mortality, by almost the same portion.


Global systems biology and personalized healthcare solutions.
Most drugs don't work optimally in most patients. The same drug can exert a significant overall therapeutic benefit in some patients while post a pronounced overall toxicity risk in others with the same disease. Pharmacogenomics has progressively received attention in the drug development process. But genetics is not the only factor that contributes to the differences that individual patients respond to drugs. Enter global systems biology.


Prostate-specific antigen screening trials and prostate cancer deaths: the androgen deprivation connection.
Major clinical trials using prostate-specific antigen (PSA) as the screening test to detect localized early-stage prostate cancer and to attempt to change its natural history with early intervention have yielded conflicting interpretations. The US Prostate, Lung, Colorectal, and Ovarian (US PLCO) cancer screening trial concluded that PSA-based screening conferred no meaningful survival benefit, whereas the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the GOTEBORG clinical trial (GOTEBORG) trials claimed statistically significant life-saving benefits. These divergent outcomes have not provided physicians with clarity on the best evidence-based treatment. To determine the extent to which these divergent outcomes are clinically meaningful, we evaluated these data and those of a long-term prospective cohort study in the context of the clinically documented harms of androgen deprivation therapy (ADT). We noted the unheralded fact that in both European trials far more patients received hormonal treatment in the control than the prostatectomy arm, whereas hormonal therapy in the US trial was balanced between arms. We examined this imbalance in ADT treatment and prostate cancer-related deaths in the contexts of contamination, stage migration, and attribution of cause of death, all of which impinge on data interpretation. The ERSPC and GOTEBORG data are compatible with the hypothesis that ADT treatment contributes differentially to an increase in prostate cancer deaths in control patients. If so, the claim of a reduction in prostate cancer deaths in the screened cohort requires reappraisal. The conventional interpretation that PSA screening and radical treatment intervention are the major contributors to the results of these two studies needs more rigorous scientific scrutiny, as does the role of ADT treatment of nonmetastatic disease.


Generative embedding for model-based classification of fMRI data.
Decoding models, such as those underlying multivariate classification algorithms, have been increasingly used to infer cognitive or clinical brain states from measures of brain activity obtained by functional magnetic resonance imaging (fMRI). The practicality of current classifiers, however, is restricted by two major challenges. First, due to the high data dimensionality and low sample size, algorithms struggle to separate informative from uninformative features, resulting in poor generalization performance. Second, popular discriminative methods such as support vector machines (SVMs) rarely afford mechanistic interpretability. In this paper, we address these issues by proposing a novel generative-embedding approach that incorporates neurobiologically interpretable generative models into discriminative classifiers. Our approach extends previous work on trial-by-trial classification for electrophysiological recordings to subject-by-subject classification for fMRI and offers two key advantages over conventional methods: it may provide more accurate predictions by exploiting discriminative information encoded in 'hidden' physiological quantities such as synaptic connection strengths; and it affords mechanistic interpretability of clinical classifications. Here, we introduce generative embedding for fMRI using a combination of dynamic causal models (DCMs) and SVMs. We propose a general procedure of DCM-based generative embedding for subject-wise classification, provide a concrete implementation, and suggest good-practice guidelines for unbiased application of generative embedding in the context of fMRI. We illustrate the utility of our approach by a clinical example in which we classify moderately aphasic patients and healthy controls using a DCM of thalamo-temporal regions during speech processing. Generative embedding achieves a near-perfect balanced classification accuracy of 98% and significantly outperforms conventional activation-based and correlation-based methods. This example demonstrates how disease states can be detected with very high accuracy and, at the same time, be interpreted mechanistically in terms of abnormalities in connectivity. We envisage that future applications of generative embedding may provide crucial advances in dissecting spectrum disorders into physiologically more well-defined subgroups.


A Randomized Controlled Trial of Enhanced Recovery After Surgery Versus Standard of Care Recovery for Emergency Cesarean Deliveries at Mbarara Hospital, Uganda.
Enhanced recovery after surgery (ERAS) expedites return to patient baseline and functional status by reducing surgical trauma, stress, and organ dysfunction. Despite the potential benefits of enhanced recovery protocols, limited research has been done in low-resource settings, where 95% of cesarean deliveries are emergent and could possibly benefit from the application of ERAS protocols. In a prospective, randomized, single-blind, controlled trial, mothers delivering by emergency cesarean delivery were randomly assigned to either an ERAS or a standard of care (SOC) recovery arm. Patients in the ERAS arm were treated with a modified ERAS protocol that included modified counseling and education, prophylactic antibiotics, antiemetics, normothermia, restrictive fluid administration, and multimodal analgesia. They also received early initiation of mobilization, feeding, and urethral catheter removal. The primary end point was length of hospital stay. The secondary end points were complications and readmission rates. Mean length of stay in the intervention and control arms were compared using t tests. Statistical analyses were performed using STATA version 13 (College Station, TX). A total of 160 patients were enrolled in the study, with 80 randomized to each arm. There was a statistically significant shorter length of stay for the ERAS arm compared to SOC, with a difference of -18.5 hours (P < .001, 95% confidence interval [CI], -23.67, -13.34). The incidence of complications of severe pain and headache was lower in the ERAS arm compared to SOC (P = .001 for both complications). However, pruritus was more common in the ERAS arm compared to SOC (P = .023). Use of an ERAS protocol for women undergoing emergency cesarean delivery in a low-income setting is feasible and reduces length of hospital stay without generally increasing the complication rate.


Chronic rhinosinusitis confers an increased risk of acute myocardial infarction.
The link between chronic inflammatory disease and cardiovascular disease (CVD) is recognized. Chronic rhinosinusitis (CRS) is one of the most common chronic inflammatory diseases. However, whether CRS increases the risk for CVD is still unknown. This epidemiology study investigated the risk for acute myocardial infarction (AMI) in patients with CRS using a large-scale population-based cohort study. Data on all study cohorts were retrieved from the Longitudinal Health Insurance Database in Taiwan. In total, data on 7975 CRS subjects from 2001 to 2003 were extracted for the study cohort. We selected 39,875 comparison subjects whose demographic variables matched those of the study cohort. We individually tracked each subject for a 6-year period (from 2001 to 2009) to identify which subjects subsequently received a diagnosis of AMI. A stratified Cox proportional hazards regression was used to compare the 6-year risk of a subsequent AMI after a diagnosis of CRS. Among the 47,850 sampled subjects, the incidence rate of AMI during the 6-year follow-up period was 5.66/1000 person-years; rates were 8.49 and 5.09/1000 person-years for the study and comparison cohort, respectively. The hazard ratio (HR) for AMI during the 6-year follow-up period for subjects with CRS was 1.70 (95% confidence interval [CI], 1.52~1.91). In addition, after adjusting for cardiovascular risk factors, the HR of AMI for subjects with CRS was 1.48 (95% CI, 1.32~1.67) compared with subjects without CRS. Patients with CRS were at higher risk for AMI occurrence in the 6-year follow-up.


Towards a Maturity Model for Clinical Decision Support Operations.
Clinical decision support (CDS) systems delivered through the electronic health record are an important element of quality and safety initiatives within a health care system. However, managing a large CDS knowledge base can be an overwhelming task for informatics teams. Additionally, it can be difficult for these informatics teams to communicate their goals with external operational stakeholders and define concrete steps for improvement. We aimed to develop a maturity model that describes a roadmap toward organizational functions and processes that help health care systems use CDS more effectively to drive better outcomes. We developed a maturity model for CDS operations through discussions with health care leaders at 80 organizations, iterative model development by four clinical informaticists, and subsequent review with 19 health care organizations. We ceased iterations when feedback from three organizations did not result in any changes to the model. The proposed CDS maturity model includes three main "pillars": "Content Creation," "Analytics and Reporting," and "Governance and Management." Each pillar contains five levels-advancing along each pillar provides CDS teams a deeper understanding of the processes CDS systems are intended to improve. A "roof" represents the CDS functions that become attainable after advancing along each of the pillars. Organizations are not required to advance in order and can develop in one pillar separately from another. However, we hypothesize that optimal deployment of preceding levels and advancing in tandem along the pillars increase the value of organizational investment in higher levels of CDS maturity. In addition to describing the maturity model and its development, we also provide three case studies of health care organizations using the model for self-assessment and determine next steps in CDS development.


Hemoglobinuria detection in 195 urology patients.
There is a definite need for the development of a specific and sensitive diagnostic test for the detection of hematuria in patients with bladder and kidney cancer. It is well established that hemoglobin in the urine may be indicative of bladder and/or kidney cancer as well as other types of lesions of the urinary tract. We have developed a specific and sensitive immunological assay for the detection of human hemoglobin in urine. This test has several important advantages over the currently used chemical tests. A mouse monoclonal antibody specific for human hemoglobin was produced and used in the development of a double-antibody biotinylated enzyme-linked immunosorbent assay (ELISA) that specifically detected hemoglobin in the urine of 195 urology patients. The results from this assay were compared with data from an evaluation of the same specimen using a polyclonal antibody biotinylated ELISA (PE) as well as a dipstick test in a blind screening study. The monoclonal antibody biotinylated ELISA (ME) possessed a much higher level of sensitivity and specificity over the dipstick test. In addition, we determined that monoclonal as well as polyclonal antibody can detect not only normal hemoglobin but also abnormal hemoglobins in urine. Of the total 195 urology patients in all diagnostic categories, the ME test was positive for detection of hemoglobin in 28 more patients (35% more) than were detected by the dipstick test. Importantly, four of these 28 patients detected by the ME but undetected by the dipstick were patients with bladder or kidney cancer.(ABSTRACT TRUNCATED AT 250 WORDS)


Replication and expression of Xenopus laevis globin genes injected into fertilized Xenopus eggs.
Cloned Xenopus adult alpha 1- and beta 1-globin genes were injected into fertilized Xenopus eggs, and the eggs were allowed to develop into swimming tadpoles. The injected DNA replicated during early Xenopus development but did not become methylated de novo. When DNA was modified with Hpa II methylase before injection, methylation was maintained during replication. Although the Xenopus adult globin genes are not normally expressed until metamorphosis, both the unmethylated and in vitro methylated adult alpha- and beta-globin genes were transcribed at low levels, but from the correct promoters, during early development.


Molecules mimicking Smad1 interacting with Hox stimulate bone formation.
Bone morphogenetic proteins (BMPs) induce osteoblast differentiation and bone formation. Smads, a group of functionally and structurally related intracellular effectors, mediate signaling initiated by BMPs and regulate cell definite commitment. Previously, we showed that Smad1 activates osteopontin and osteoprotegerin gene expression by dislodging Hoxc-8 from its DNA binding sites. A domain of Smad1, termed Smad1C, was characterized as interacting with Hoxc-8 and then crippling its DNA-binding ability. Ectopic expression of Smad1C is able to bypass BMP signaling in the induction of osteoblast differentiation and bone formation in vitro. To test the function of Smad1C on osteogenesis in vivo, we generated transgenic mice in which Smad1C expression was induced with doxycycline and localized in bone by using a tetracycline-inducible expression system (Tet-on) modified with a bone-specific gene promoter, type I collagen alpha1. The mice expressing Smad1C showed increased skeletal bone mineral density compared with their littermates. Bone histomorphometric analysis of mouse tibiae showed that Smad1C significantly increases trabecular bone area and length of trabecular surface covered with osteoid and up-regulates bone marker gene (OPN, Cbfa1, Col I alpha1, BSP, ALP) expression in vivo. Moreover, stromal cells isolated from mice expressing Smad1C displayed a higher potential for differentiating into osteoblasts than the other mice. These results indicate that Smad1C mimics BMPs in the induction of osteogenesis in vivo. Most important, using a high throughput screening assay based on mimicking Smad1C's displacement of Hoxc-8 binding to DNA, we identified chemical entities that exhibit bone anabolic activity in cell and bone organ cultures, suggesting the possibility that the compounds may be used as bone anabolic agents to treat bone pathologies.


Periostin Promotes Cell Proliferation and Macrophage Polarization to Drive Repair after AKI.
The matricellular protein periostin has been associated with CKD progression in animal models and human biopsy specimens. Periostin functions by interacting with extracellular matrix components to drive collagen fibrillogenesis and remodeling or by signaling through cell-surface integrin receptors to promote cell adhesion, migration, and proliferation. However, its role in AKI is unknown. We used mice with conditional tubule-specific overexpression of periostin or knockout mice lacking periostin expression in the renal ischemia-reperfusion injury model, and primary cultures of isolated tubular cells in a hypoxia-reoxygenation model. Tubular epithelial cells showed strong production of periostin during the repair phase of ischemia reperfusion. Periostin overexpression protected mice from renal injury compared with controls, whereas knockout mice showed increased tubular injury and deteriorated renal function. Periostin interacted with its receptor, integrin-β1, to inhibit tubular cell cycle arrest and apoptosis in in vivo and in vitro models. After ischemia-reperfusion injury, periostin-overexpressing mice exhibited diminished expression of proinflammatory molecules and had more F4/80+ macrophages compared with knockout mice. Macrophages from periostin-overexpressing mice showed increased proliferation and expression of proregenerative factors after ischemia-reperfusion injury, whereas knockout mice exhibited the opposite. Coculturing a macrophage cell line with hypoxia-treated primary tubules overexpressing periostin, or treating such macrophages with recombinant periostin, directly induced macrophage proliferation and expression of proregenerative molecules. In contrast to the detrimental role of periostin in CKD, we discovered a protective role of periostin in AKI. Our findings suggest periostin may be a novel and important mediator of mechanisms controlling renal repair after AKI.


Bifurcation geometry and the presence of cerebral artery aneurysms.
The angles of arterial bifurcations are governed by principles of work minimization (optimality principle). This determines the relationship between the angle of a bifurcation and the radii of the vessels. Nevertheless, the model is predicated on an absence of significant communication between these branches. The circle of Willis changes this relationship because the vessels proximal to the ring of vessels have additional factors that determine work minimization compared with more distal branches. This must have an impact on understanding of the relationship between shear stress and aneurysm formation. The authors hypothesized that normal bifurcations of cerebral arteries beyond the circle of Willis would follow optimality principles of minimum work and that the presence of aneurysms would be associated with deviations from optimum bifurcation geometry. Nevertheless, the vessels participating in (or immediately proximal to) the circle of Willis may not follow the geometric model as it is generally applied and this must also be investigated. One hundred seven bifurcations of the middle cerebral artery (MCA), distal internal carotid artery (ICA), and basilar artery (BA) were studied in 55 patients. The authors analyzed three-dimensional reconstructions of digital subtraction angiography images with respect to vessel radii and bifurcation angles. The junction exponent (that is, a calculated measure of the division of flow at the bifurcation) and the difference between the predicted optimal and observed branch angles were used as measures of deviation from the geometry thought best to minimize work. The mean junction exponent for MCA bifurcations was 2.9 +/- 1.2 (mean +/- standard deviation [SD]), which is close to the theoretical optimum of 3, but it was significantly smaller (p < 0.001; 1.7 +/- 0.8, mean +/- SD) for distal ICA bifurcations. In a multilevel multivariate logistic regression analysis, only the observed branch angles were significant independent predictors for the presence of an aneurysm. The odds ratio (OR) (95% confidence interval) for the presence of an aneurysm was 3.46 (1.02-11.74) between the lowest and highest tertile of the observed angle between the parent vessel and the largest branch. The corresponding OR for the smallest branch was 48.06 (9.7-238.2). The bifurcation beyond the circle of Willis (that is, the MCA) closely approximated optimality principles, whereas the bifurcations within the circle of Willis (that is, the distal ICA and BA) did not. This indicates that the confluence of hemodynamic forces plays an important role in the distribution of work at bifurcations within the circle of Willis. In addition, the observed branch angles were predictors for the presence of aneurysms.


Anomalous transient behavior from an inhomogeneous initial optical vortex density.
Inhomogeneous optical vortex densities can be produced in stochastic optical fields by a combination of coherent and incoherent superposition of speckle fields. During subsequent propagation, the inhomogeneity in the vortex density decays away. However, the decay curves contain oscillatory features that are counterintuitive: for a short while, the inhomogeneity actually increases. We provide numerical simulations and analytic calculations to study the appearance of the anomalous features in the decay curves.


Trypanosoma brucei aquaglyceroporin 2 is a high-affinity transporter for pentamidine and melaminophenyl arsenic drugs and the main genetic determinant of resistance to these drugs.
Trypanosoma brucei drug transporters include the TbAT1/P2 aminopurine transporter and the high-affinity pentamidine transporter (HAPT1), but the genetic identity of HAPT1 is unknown. We recently reported that loss of T. brucei aquaglyceroporin 2 (TbAQP2) caused melarsoprol/pentamidine cross-resistance (MPXR) in these parasites and the current study aims to delineate the mechanism by which this occurs. The TbAQP2 loci of isogenic pairs of drug-susceptible and MPXR strains of T. brucei subspecies were sequenced. Drug susceptibility profiles of trypanosome strains were correlated with expression of mutated TbAQP2 alleles. Pentamidine transport was studied in T. brucei subspecies expressing TbAQP2 variants. All MPXR strains examined contained TbAQP2 deletions or rearrangements, regardless of whether the strains were originally adapted in vitro or in vivo to arsenicals or to pentamidine. The MPXR strains and AQP2 knockout strains had lost HAPT1 activity. Reintroduction of TbAQP2 in MPXR trypanosomes restored susceptibility to the drugs and reinstated HAPT1 activity, but did not change the activity of TbAT1/P2. Expression of TbAQP2 sensitized Leishmania mexicana promastigotes 40-fold to pentamidine and >1000-fold to melaminophenyl arsenicals and induced a high-affinity pentamidine transport activity indistinguishable from HAPT1 by Km and inhibitor profile. Grafting the TbAQP2 selectivity filter amino acid residues onto a chimeric allele of AQP2 and AQP3 partly restored susceptibility to pentamidine and an arsenical. TbAQP2 mediates high-affinity uptake of pentamidine and melaminophenyl arsenicals in trypanosomes and TbAQP2 encodes the previously reported HAPT1 activity. This finding establishes TbAQP2 as an important drug transporter.


NSAIDs and incident Alzheimer's disease. The Rotterdam Study.
Recent studies suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk for Alzheimer's disease (AD). We investigated the relation of NSAID use over a 10-year period and the risk for incident AD using a nested case-control design in the population-based Rotterdam Study. The study was performed in 306 subjects; 74 Alzheimer patients diagnosed according to NINCDS-ADRDRA criteria and 232 age and sex-matched controls. NSAID use was abstracted from general practitioners' medical records and expressed as cumulative prescription days. The relative risk for AD associated with long-term use (> or = 2 months) was 0.95 (95% CI: 0.46-1.99) as compared to nonusers, after controlling for possible confounders. In a separate examination, subjects who had more than 6 months of prescription days had a reduced relative risk for AD (RR = 0.74 (95% CI: 0.20-2.72). In an age-stratified analysis the effect in long-term users was evident in those aged 85 and under; 0.53 (95% CI: 0.15-1.77). All risk estimates were lower when the last 2 years of exposure were excluded from the analyses. Our point estimates in subjects younger than 85 years and in subjects using NSAIDs for 6 months or more are consistent with the hypothesis that long-term use of NSAIDs reduces the risk for AD. However, overall there was no association between NSAID use and the risk for incident AD.


Antibody-guided alpha radiation effectively damages fungal biofilms.
The use of indwelling medical devices--pacemakers, prosthetic joints, catheters--is rapidly growing and is often complicated by infections with biofilm-forming microbes that are resistant to antimicrobial agents and host defense mechanisms. We investigated for the first time the use of microbe-specific monoclonal antibodies (MAbs) as delivery vehicles for targeting biofilms with cytocidal radiation. MAb 18B7 (immunoglobulin G1 [IgG1]), which binds to capsular polysaccharides of the human pathogenic fungus Cryptococcus neoformans, penetrated cryptococcal biofilms, as shown by confocal microscopy. When the alpha radiation-emitter 213-Bismuth ((213)Bi) was attached to MAb 18B7 and the radiolabeled MAb was added to C. neoformans biofilms, there was a 50% reduction in biofilm metabolic activity. In contrast, when the IgM MAb 13F1 labeled with (213)Bi was used there was no penetration of the fungal biofilm and no damage. Unlabeled 18B7, (213)Bi-labeled nonspecific MAbs, and gamma and beta types of radiation did not have an effect on biofilms. The lack of efficacy of gamma and beta radiation probably reflects the radioprotective properties of polysaccharide biofilm matrix. Our results indicate that C. neoformans biofilms are susceptible to treatment with antibody-targeted alpha radiation, suggesting a novel option for the prevention or treatment of microbial biofilms on indwelling medical devices.


Carbamazepine-induced hyponatremia in patients with mental retardation.
Carbamazepine-induced hyponatremia has been reported in 21.7% of 61 patients with mental retardation who received the medication for a variety of reasons. We studied 40 patients with mental retardation receiving carbamazepine to determine the prevalence of hyponatremia. Overall, hyponatremia was found in only 5.0% of these patients. Correlations with sodium level and carbamazepine dose, serum drug level, and concomitant neuroleptic and anticonvulsant polytherapy were also examined. Treatment with carbamazepine resulted in a statistically, but not clinically, significant decrease in serum sodium levels in patients receiving anticonvulsant polytherapy. Decreases in serum sodium were not related to carbamazepine dose or blood levels. Only one patient with underlying schizophrenia and psychogenic polydipsia demonstrated clinically significant hyponatremia during carbamazepine therapy.


Rapid auditory processing and phonological ability in normal readers and readers with dyslexia.
According to a prominent theory, the phonological difficulties in dyslexia are caused by an underlying general impairment in the ability to process sequences of rapidly presented, brief sounds. Two studies examined this theory by exploring the relationships between rapid auditory processing and phonological processing in a sample of 82 normally reading children (Study 1) and by comparing 17 children with dyslexia to chronological-age and reading-age control participants on these tasks (Study 2). In the normal readers, moderate correlations were found between the measure of rapid auditory processing (Auditory Repetition Task, or ART) and phonological ability. On the ART, the dyslexia group performed at a level similar to that of the reading-age control group but obtained scores that were significantly below those of the chronological-age control group. This difference was due to a subgroup of 4 children in the dyslexia group who had particular difficulty with the ART. The phonological skills of these individuals were not worse than those of the children in the dyslexia group who were unimpaired on the ART. The discussion argues that there is no evidence that phonoogical difficulties are secondary to impairments of rapid auditory processing, as measured by the ART, and highlights the need to examine the strategic and cognitive demands involved in tasks of rapid auditory processing.


Social motivation and conflict resolution tactics as potential building blocks of sociality in cichlid fishes.
Even closely related and ecologically similar cichlid species of Lake Tanganyika exhibit an impressive diversity of social systems, and therefore these fishes offer an excellent opportunity to examine the evolution of social behaviour. Sophisticated social relationships are thought to have evolved via a building block design where more fundamental social behaviours and cognitive processes have been combined, incrementally modified, and elaborated over time. Here, we studied two of these putative social building blocks in two closely related species of cichlids: Neolamprologus pulcher, a group-living species, and Telmatochromis temporalis, a non-grouping species. Otherwise well matched in ecology, this pair of species provide an excellent comparison point to understand how behavioural processes may have been modified in relation to the evolution of sociality. Using social assays in both the laboratory and in the field, we explored each species' motivation to interact with conspecifics, and each species' conflict resolution tactics. We found that individuals of the group living species, N. pulcher, displayed higher social motivation and were more likely to produce submission displays than were individuals of the non-grouping species, T. temporalis. We argue that the motivation to interact with conspecifics is a necessary prerequisite for the emergence of group living, and that the use of submission reduces the costs of conflict and facilitates the maintenance of close social proximity. These results suggest that social motivation and conflict resolution tactics are associated with social complexity, and that these behavioural traits may be functionally significant in the evolution and maintenance of sociality.


Sitosterolaemia and xanthomatosis in a child.
A 4-year-old boy presented with multiple tuberous xanthomata and a fasting plasma sterol concentration of 18.3 mmol/L, consisting primarily of cholesterol. Two months after changing from an unrestricted diet to a cholesterol-lowering diet, the plasma sterol concentration decreased to 4 mmol/L. Fasting plasma cholesterol levels for his father and mother were 7.3 mmol/L and 6.0 mmol/L, respectively. The degree and rapidity of the child's response to dietary control, together with the fasting cholesterol results of both parents suggested a diagnosis of sitosterolaemia. Gas chromatography and mass spectrometry of the patient's plasma sterol levels showed that the percentage of beta-sitosterol was raised at 12.76%, as was campesterol (6.26%), and stigmasterol (0.71%), confirming the diagnosis of sitosterolaemia. The addition of cholestyramine 4 g/day to a low sterol diet maintained the plasma sterol concentration at 4 to 5 mmol/L, and gradual regression of the xanthoma was observed. These findings indicate that a diagnosis of sitosterolaemia, a treatable cause of premature atherosclerosis, should be considered in children with severe hypercholesterolaemia whose plasma cholesterol level is highly responsive to dietary manipulation.


Functional recovery is considered the most important target: a survey of dedicated professionals.
The aim of this study was to survey the relative importance of postoperative recovery targets and perioperative care items, as perceived by a large group of international dedicated professionals. A questionnaire with eight postoperative recovery targets and 13 perioperative care items was mailed to participants of the first international Enhanced Recovery After Surgery (ERAS) congress and to authors of papers with a clear relevance to ERAS in abdominal surgery. The responders were divided into categories according to profession and region. The recovery targets 'To be completely free of nausea', 'To be independently mobile' and 'To be able to eat and drink as soon as possible' received the highest score irrespective of the responder's profession or region of origin. Equally, the care items 'Optimizing fluid balance', 'Preoperative counselling' and 'Promoting early and scheduled mobilisation' received the highest score across all groups. Functional recovery, as in tolerance of food without nausea and regained mobility, was considered the most important target of recovery. There was a consistent uniformity in the way international dedicated professionals scored the relative importance of recovery targets and care items. The relative rating of the perioperative care items was not dependent on the strength of evidence supporting the items.


Looking at non-communicable diseases in Uganda through a local lens: an analysis using locally derived data.
The demographic and nutritional transitions taking place in Uganda, just as in other low- and middle-income countries (LMIC), are leading to accelerating growth of chronic, non-communicable diseases (NCDs). Though still sparse, locally derived data on NCDs in Uganda has increased greatly over the past five years and will soon be bolstered by the first nationally representative data set on NCDs. Using these available local data, we describe the landscape of the globally recognized major NCDs- cardiovascular disease, diabetes, cancer, and chronic respiratory disease- and closely examine what is known about other locally important chronic conditions. For example, mental health disorders, spawned by an extended civil war, and highly prevalent NCD risk factors such as excessive alcohol intake and road traffic accidents, warrant special attention in Uganda. Additionally, we explore public sector capacity to tackle NCDs, including Ministry of Health NCD financing and health facility and healthcare worker preparedness. Finally, we describe a number of promising initiatives that are addressing the Ugandan NCD epidemic. These include multi-sector partnerships focused on capacity building and health systems strengthening; a model civil society collaboration leading a regional coalition; and a novel alliance of parliamentarians lobbying for NCD policy. Lessons learned from the ongoing Ugandan experience will inform other LMIC, especially in sub-Saharan Africa, as they restructure their health systems to address the growing NCD epidemic.


Mapping existing hip and knee replacement registries in Europe.
The general shortage of evidence regarding benefits and harms of medical devices has been highlighted following the serious safety concerns with metal-on-metal hip replacements and silicone breast implants and was again pointed out in a recent survey of European Health Technology Assessment institutions. In this context the new European medical device regulation will enforce post-marketing surveillance of existing and new implants. The usefulness of registry data as a source of information for medical device real-world clinical performance and safety has been demonstrated. However, these data might be under-used by researchers and policy makers. One reason for this is the insufficient awareness of their existence. The aim of this review is to provide information to relevant stakeholders on the extent and breadth of the data currently collected in European joint replacement registries. We identified 24 registries, most of them of national coverage. Total numbers of primary total hip and knee replacements included were over 3.1 and 2.5 million records, respectively. The current focus of these registries is on whole-lifespan implant surveillance via revision rate monitoring, quality assessment of surgical and perioperative care, and hospital performance assessment. More recently, national and international comparison and benchmarking have increasingly become part of their endeavors.


The association between ownership of common household devices and obesity and diabetes in high, middle and low income countries.
Household devices (e.g., television, car, computer) are common in high income countries, and their use has been linked to obesity and type 2 diabetes mellitus. We hypothesized that device ownership is associated with obesity and diabetes and that these effects are explained through reduced physical activity, increased sitting time and increased energy intake. We performed a cross-sectional analysis using data from the Prospective Urban Rural Epidemiology study involving 153,996 adults from high, upper-middle, lower-middle and low income countries. We used multilevel regression models to account for clustering at the community and country levels. Ownership of a household device increased from low to high income countries (4% to 83% for all 3 devices) and was associated with decreased physical activity and increased sitting, dietary energy intake, body mass index and waist circumference. There was an increased odds of obesity and diabetes with the ownership of any 1 household device compared to no device ownership (obesity: odds ratio [OR] 1.43, 95% confidence interval [CI] 1.32-1.55; diabetes: OR 1.38, 95% CI 1.28-1.50). Ownership of a second device increased the odds further but ownership of a third device did not. Subsequent adjustment for lifestyle factors modestly attenuated these associations. Of the 3 devices, ownership of a television had the strongest association with obesity (OR 1.39, 95% CI 1.29-1.49) and diabetes (OR 1.33, 95% CI 1.23-1.44). When stratified by country income level, the odds of obesity and diabetes when owning all 3 devices was greatest in low income countries (obesity: OR 3.15, 95% CI 2.33-4.25; diabetes: OR 1.97, 95% CI 1.53-2.53) and decreased through country income levels such that we did not detect an association in high income countries. The ownership of household devices increased the likelihood of obesity and diabetes, and this was mediated in part by effects on physical activity, sitting time and dietary energy intake. With increasing ownership of household devices in developing countries, societal interventions are needed to mitigate their effects on poor health.


KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases.
The cyclin-dependent kinases are key cell cycle regulators whose activation is required for passage from one cell cycle phase to the next. In mammalian cells, CDK2 has been implicated in control of the G1 and S phases. We have used a two-hybrid protein interaction screen to identify cDNAs encoding proteins that can interact with CDK2. Among those identified was a protein (KAP), which contained the HCXX-XXGR motif characteristic of protein tyrosine phosphatases. KAP showed phosphatase activity toward substrates containing either phosphotyrosine or phosphoserine residues. Since KAP is not significantly similar to known phosphatases beyond the catalytic core motif, it represents an additional class of dual specificity phosphatase. KAP interacted with cdc2 and CDK2 in yeast. In mammalian cells, KAP also associated with cdc2 and CDK2 but showed a preference for cdc2. The ability of KAP to bind multiple cyclin-dependent kinases suggests that it may play a role in cell cycle regulation.


Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis.
Atopic dermatitis (AD) is a common chronic illness of childhood. To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD. A prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation. Self-reported outcome of whether a child's skin had no symptoms of AD and required no medications for 6 months at 6-month intervals. We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86). The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.


Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants.
Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumors with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia.


Enhanced dimension-specific visual working memory in grapheme-color synesthesia.
There is emerging evidence that the encoding of visual information and the maintenance of this information in a temporarily accessible state in working memory rely on the same neural mechanisms. A consequence of this overlap is that atypical forms of perception should influence working memory. We examined this by investigating whether having grapheme-color synesthesia, a condition characterized by the involuntary experience of color photisms when reading or representing graphemes, would confer benefits on working memory. Two competing hypotheses propose that superior memory in synesthesia results from information being coded in two information channels (dual-coding) or from superior dimension-specific visual processing (enhanced processing). We discriminated between these hypotheses in three n-back experiments in which controls and synesthetes viewed inducer and non-inducer graphemes and maintained color or grapheme information in working memory. Synesthetes displayed superior color working memory than controls for both grapheme types, whereas the two groups did not differ in grapheme working memory. Further analyses excluded the possibilities of enhanced working memory among synesthetes being due to greater color discrimination, stimulus color familiarity, or bidirectionality. These results reveal enhanced dimension-specific visual working memory in this population and supply further evidence for a close relationship between sensory processing and the maintenance of sensory information in working memory.


Randomised controlled trial of anti-smoking advice: final (20 year) results.
The aim was to measure experimentally the effects in middle aged men of stopping smoking. The study was a randomised controlled trial. The subjects were 1445 male smokers, initially aged 40-59 years, who were selected from the Whitehall study survey of 16,016 civil servants on the basis of a high risk of cardiorespiratory disease. During the next 20 years there were 620 deaths (231 from coronary heart disease), 96 cases of lung cancer, and 159 other cancers. Comparing the intervention with the normal care group, total mortality was 7% lower, fatal coronary heart disease was 13% lower, and lung cancer (deaths+registrations) was 11% lower. An excess rate for other cancers, reported previously, did not persist into the second decade of the trial. The results are consistent with observational studies, implying that smoking cessation by middle aged men substantially improves their changes of avoiding lung cancer or a fatal heart attack. Our estimate from the trial is that out of every 100 men who stopped smoking, between six and 10 were in consequence alive 20 years later.


N-terminal β-strand underpins biochemical specialization of an ATG8 isoform.
Autophagy-related protein 8 (ATG8) is a highly conserved ubiquitin-like protein that modulates autophagy pathways by binding autophagic membranes and a number of proteins, including cargo receptors and core autophagy components. Throughout plant evolution, ATG8 has expanded from a single protein in algae to multiple isoforms in higher plants. However, the degree to which ATG8 isoforms have functionally specialized to bind distinct proteins remains unclear. Here, we describe a comprehensive protein-protein interaction resource, obtained using in planta immunoprecipitation (IP) followed by mass spectrometry (MS), to define the potato ATG8 interactome. We discovered that ATG8 isoforms bind distinct sets of plant proteins with varying degrees of overlap. This prompted us to define the biochemical basis of ATG8 specialization by comparing two potato ATG8 isoforms using both in vivo protein interaction assays and in vitro quantitative binding affinity analyses. These experiments revealed that the N-terminal β-strand-and, in particular, a single amino acid polymorphism-underpins binding specificity to the substrate PexRD54 by shaping the hydrophobic pocket that accommodates this protein's ATG8-interacting motif (AIM). Additional proteomics experiments indicated that the N-terminal β-strand shapes the broader ATG8 interactor profiles, defining interaction specificity with about 80 plant proteins. Our findings are consistent with the view that ATG8 isoforms comprise a layer of specificity in the regulation of selective autophagy pathways in plants.


Phase behavior and morphology of multicomponent liquid mixtures.
Multicomponent systems are ubiquitous in nature and industry. While the physics of few-component liquid mixtures (i.e., binary and ternary ones) is well-understood and routinely taught in undergraduate courses, the thermodynamic and kinetic properties of N-component mixtures with N > 3 have remained relatively unexplored. An example of such a mixture is provided by the intracellular fluid, in which protein-rich droplets phase separate into distinct membraneless organelles. In this work, we investigate equilibrium phase behavior and morphology of N-component liquid mixtures within the Flory-Huggins theory of regular solutions. In order to determine the number of coexisting phases and their compositions, we developed a new algorithm for constructing complete phase diagrams, based on numerical convexification of the discretized free energy landscape. Together with a Cahn-Hilliard approach for kinetics, we employ this method to study mixtures with N = 4 and 5 components. We report on both the coarsening behavior of such systems, as well as the resulting morphologies in three spatial dimensions. We discuss how the number of coexisting phases and their compositions can be extracted with Principal Component Analysis (PCA) and K-means clustering algorithms. Finally, we discuss how one can reverse engineer the interaction parameters and volume fractions of components in order to achieve a range of desired packing structures, such as nested "Russian dolls" and encapsulated Janus droplets.