Unintentional weight loss. A retrospective analysis of 154 cases.
Unintentional weight loss (UWL) was documented in 154 patients (2.8%) admitted to an internal medicine department during a two-year period. A retrospective analysis of the clinical charts showed that more than one third (36.3%) were found to have a neoplasm, involving preponderantly the gastrointestinal tract. Patients with neoplasia were older and more frequently had abnormal physical findings and significantly lower values of serum albumin as well as higher values of alkaline phosphatase than other patients. Despite extensive investigations, in 36 patients (23.3%) UWL remained unexplained even after prolonged follow-up periods. The remaining 62 patients had a variety of disorders, preponderantly gastrointestinal tract (26 patients) and psychiatric (16 patients) diseases. Endocrinologic disorders such as diabetes mellitus and hyperthyroidism were relatively uncommon (3.8%). Unintentional weight loss is a relatively common problem in clinical practice. Familiarity with the spectrum of disorders associated with UWL as well as selected clinical and laboratory values may help in the initial examination of these patients.


Is aura around citicoline fading? A systemic review.
Stroke and traumatic brain injury (TBI) are the critical public health and socioeconomic problems throughout the world. At present, citicoline is used as a coadjuvant for the management of acute ischemic stroke (AIS) and TBI in various countries. This systemic review analyzes the beneficial role of citicoline in AIS and TBI. This systemic review is based on "PubMed" and "Science Direct" search results for citicoline role in stroke and TBI. In this systemic review, we included 12 human trials. A meta-analysis was performed on the basis of neurological evaluation, functional evaluation and Glasgow outcome scale, domestic adaptation evaluation outcomes, and cognitive outcome individually. In neurological evaluation, domestic adaptation evaluation, and cognitive outcomes, there was no significant difference in both the citicoline and placebo groups (odds ratio [OR] = 1.04 [0.9-1.2, P = 0.583]; OR = 1.1 [0.94-1.27, P = 0.209]; OR = 0.953 [0.75-1.2, P = 0.691]). In evaluation of functional outcomes, there was significant difference in both groups and OR was 1.18 (1.04-1.34, P = 0.01). Functional outcomes were significantly improved by citicoline, but the positive role of this drug in neurological recovery, domestic adaptation, and cognitive outcomes is still a topic of discussion for future.


Increasing access to places for physical activity through a joint use agreement: a case study in urban Honolulu.
To increase levels of physical activity (PA), interventions that create or enhance access to places for PA are recommended. Establishing a joint use agreement is one way to increase access to existing PA and recreational facilities. The purpose of this article is to present a case study of In-Motion, a pilot joint use agreement project at one urban high school in Honolulu, Hawaii. Residents of urban Honolulu are underserved by the amount of parkland and recreational facilities available for their use. The Honolulu County Department of Parks and Recreation sought to implement a joint use agreement to use the facilities of one urban high school for a recreational program. The high school selected for the pilot project has a student population primarily from low-income and ethnic minority backgrounds. An assessment of the potential of 7 urban high schools to implement a joint use agreement was conducted to select the pilot site. In-Motion developed and implemented a joint use agreement. PA preferences of students, staff, and community members were assessed to guide recreational program offerings. Various recreational classes were offered free to the school community. Several barriers to implementing the joint use agreement and recreational program were encountered. However, participants were satisfied with the recreational classes they attended and said that the In-Motion program helped them to engage in more PA. Program awareness by high school students and staff was high. In-Motion has successfully modeled a pilot joint use agreement and provided new opportunities for PA to the high school's students, teachers, and staff, and to community residents.


Non-exponential photoluminescence decay dynamics of localized carriers in disordered InGaN/GaN quantum wells: the role of localization length.
In this article, we report a combined experimental and theoretical study on the luminescence dynamics of localized carriers in disordered InGaN/GaN quantum wells. The luminescence intensity of localized carriers is found to exhibit an unusual non-exponential decay. Adopting a new model taking the radiative recombination and phonon-assisted hopping transition between different localized states into account, which was recently developed by Rubel et al., the non-exponential decay behavior of the carriers can be quantitatively interpreted. Combining with precise structure characterization, the theoretical simulations show that the localization length of localized carriers is a key parameter governing their luminescence decay dynamics.


Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies.
The detection of antimitochondrial autoantibodies (AMAs) is critical in the diagnosis of primary biliary cirrhosis (PBC). However, conventional laboratory assays to detect AMA are dependent on the time-consuming method of immunofluorescence microscopy, a method often plagued by problems of nonspecificity. AMAs react against mitochondrial autoantigens including the E2 components of the pyruvate dehydrogenase complex (PDC-E2), the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), and the 2-oxo-glutarate dehydrogenase complex (OGDC-E2). Interestingly, the immunodominant epitopes of PDC-E2, BCOADC-E2, and OGDC-E2 are all conformational lipoate binding sites, but antibodies against them do not cross-react. Although 80% to 90% of sera from patients with PBC react to PDC-E2, approximately 10% patients with PBC react only to BCOADC-E2 and/or OGDC-E2. We have taken advantage of our epitope-mapping studies of the E2 components of PDC, BCOADC, and OGDC, and constructed a "designer" hybrid clone, designated as pML-MIT3, that coexpresses the immunodominant epitopes within the three distinct lipoyl domains. We examined a total of 321 sera, including 186 sera from patients with PBC, to test the immunoreactivity of pMIT3. Of 186 sera from patients with PBC, 152 sera (81.7%) reacted with recombinant fusion protein of PDC-E2, whereas 171 sera (91.9%) showed positive reactivities when probed by immunoblotting against the recombinant fusion protein expressed from the pML-MIT3 clone. Of 34 PBC sera that did not react with recombinant PDC-E2, 18 sera contained BCOADC-E2-specific AMA and 1 serum possessed only OGDC-E2-specific AMA. We also developed an enzyme-linked immunosorbent assay (ELISA), using affinity-purified recombinant fusion protein of pML-MIT3 clone as the antigen source, to quantify specific AMAs in patients with PBC. None of the 135 control sera from patients with primary sclerosing cholangitis (PSC), chronic autoimmune hepatitis (CAH), systemic lupus erythematosus (SLE), or healthy volunteers showed significant reactivity against pML-MIT3 recombinant fusion protein in the ELISA assay. Our results indicate that an ELISA using recombinant, cloned autoantigen of pML-MIT3 is a powerful and very specific method for the detection of AMA.


Angiogenic Factors and Cytokines in Diabetic Retinopathy.
Diabetic retinopathy (DR) is a sight-threatening complication of both type-1 and type-2 diabetes. The recent success of treatments inhibiting the function of vascular endothelial growth factor (VEGF) demonstrates that specific targeting of a growth factor responsible for vascular permeability and growth is an effective means of treating DR-associated vascular dysfunction, edema and angiogenesis. This has stimulated research of alternative therapeutic targets involved in the control of retinal vascular function. However, additional treatment options and preventative measures are still needed and these require a greater understanding of the pathological mechanisms leading to the disturbance of retinal tissue homeostasis in DR. Although severe DR can be treated as a vascular disease, abundant data suggests that inflammation is also occurring in the diabetic retina.Thus, anti-inflammatory therapies may also be useful for treatment and prevention of DR. Herein, the evidence for altered expression of angiogenic factors and cytokines in DR is reviewed and possible mechanisms by which the expression of VEGF and cytokines may be increased in the diabetic retina are examined. In addition, the potential role for microglial activation in diabetic retinal neuroinflammation is explored.


[Procalcitonin as a predictor of bacteremia in postoperative cardiosurgery patients].
To define diagnostics ability of procalcitonin (PCT) test for prediction of bacteremia of different etiology in cardio-surgical patients. 10158 pairs of blood examples from cardio-surgical patients in early postoperative period were studied from 2007 to 2012. Results of PCT test were compared with blood cultures. The data is presented as absolute values and proportions. Furthermore a mean and standard error of the mean is presented. Differences in compared groups with p < 0.05 are considered statistically significant. In average a bacteremia occurred on a 6th day of postoperative period. Frequency of the positive blood cultures was 20.7%. 972 cases of bacteremia (46.2%) was caused by Gram-positive cocci, 702 cases (33.3%) by Gram-negative bacteria and 338 (16.1%) by yeast-like fungi. Mixt-cultures were defined in 93 cases (4.4%). Monocultural bacteremia was analyzed only (n = 2012). Average level of PCT was higher (statistically significant) in cases with blood cultures than in cases without it (14.35 +/- 0.91 ng per ml vs. 7.35 +/- 0.26 ng per ml, p = 0). The highest PCT was fixed in cases of bacteremia caused by Gram-negative bacteria (26.03 +/- 2.13 ng per ml). There was no significant difference between bacteremia due to enterobacteria and non-fermenting agents (30.56 +/- 4.05 ng per ml u 22.79 +/- 0.21 ng per ml, p = 0.07). Statistically significant differences according to the average PCT were defined between bacteremia caused by Gram-negative bacteria (26.03 +/- 2.13 ng per ml), Gram-positive cocci (7.24 +/- 0.88 ng per ml, p = 0), Candida species (9.02 +/- 1.84 ng per ml, p = 0), and cases of contamination (9.92 +/- 2.79 ng per ml, p = 0). Average PCT was not significantly different in cases of bacteremia due to coagulase-negative staphylococci (5.94 +/- 0.87 ng per ml), S. aureus (4.04 +/- 0.9 ng per ml), enterococci (15.72 +/- 3.52 ng per ml), Candida species (9.02 +/- 1.84 ng per ml), in cases of contamination (9.92 +/- 2.79 ng per ml) and in cases of the negative blood cultures (7.35 +/- 0.26 ng per ml). According to ROC-analysis the optimal cut-off point for PCT as a predictor of Gram-negative bacteremia was 2.47 ng per ml, AUC 0.7 (95% DI 0.68-0.72). Index of sensitivity was 64%. PCT level in blood plasma of patients with bacteremia higher (statistically significant) than in patients with negative blood cultures. Gram-negative infection is more likely in cases when PCT higher than 2.47 ng per ml.


Comparative studies on the usefulness of seven ecological indices for the marine coastal monitoring close to the shore on the Swedish East coast.
The simultaneous behaviour of seven ecological indices (Hurlbert's, Margalef's, Menhinick's, Shannon's, species number, Jaccard's and saprobic index) was studied based on phytoplankton data close to the shore on the East coast of Sweden during the summer 1998. The sampling stations had a similar eutrophication level and were located in bays. Standard phytoplankton databases were used in calculating the indices, which were later compared using cluster analysis. Hurlbert's, Margalef's, Menhinick's, Shannon's and species number indices, as measure of community diversity, produced similar trends which often differed from those based on Jaccard's index of similarity. However, the simultaneous use of these indices was found meaningful as a possible part of the monitoring close to the shore. The application of a saprobic index lead to erroneous conclusions in the studied case.


Workplace secondhand smoke exposure in the U.S. trucking industry.
Although the smoking rate in the United States is declining because of an increase of smoke-free laws, among blue-collar workers it remains higher than that among many other occupational groups. We evaluated the factors influencing workplace secondhand smoke (SHS) exposures in the U.S. unionized trucking industry. From 2003 through 2005, we measured workplace SHS exposure among 203 nonsmoking and 61 smoking workers in 25 trucking terminals. Workers in several job groups wore personal vapor-phase nicotine samplers on their lapels for two consecutive work shifts and completed a workplace SHS exposure questionnaire at the end of the personal sampling. Median nicotine level was 0.87 microg/m3 for nonsmokers and 5.96 microg/m3 for smokers. As expected, smokers experienced higher SHS exposure duration and intensity than did nonsmokers. For nonsmokers, multiple regression analyses indicated that self-reported exposure duration combined with intensity, lack of a smoking policy as reported by workers, having a nondriver job, and lower educational level were independently associated with elevated personal nicotine levels (model R2 = 0.52). Nondriver job and amount of active smoking were associated with elevated personal nicotine level in smokers, but self-reported exposure, lack of a smoking policy, and lower educational level were not. Despite movements toward smoke-free laws, this population of blue-collar workers was still exposed to workplace SHS as recently as 2005. The perceived (reported by the workers), rather than the official (reported by the terminal managers), smoking policy was associated with measured SHS exposure levels among the nonsmokers. Job duties and educational level might also be important predictors of workplace SHS exposure.


Abrasion Behaviour of Different Charcoal Toothpastes When Using Electric Toothbrushes.
The purpose of this in vitro study was to compare the abrasion behaviour of different charcoal toothpastes when brushing with electric toothbrushes on human enamel. A self-designed brushing machine was built using six commercially available electric toothbrushes in abrasion chambers. Each chamber was constantly supplied with a toothpaste-water mix. Pieces of human enamel, which were embedded in PMMA, were brushed for 4 h. Before and after brushing, profilometer measurements were performed in order to determine the substance loss due to brushing. The following calculated mean removal values (mean ± SD) were found: (4.6 ± 0.6) µm (Group C: Splat Blackwood), (3.2 ± 0.9) µm (Group D: Curaprox Black is White), (2.3 ± 0.7) µm (Group B: Sensodyne Pro Schmelz), (1.7 ± 0.6) µm (Group A: Water), (1.4 ± 0.6) µm (Group E: Prokudent Black Brilliant). A post hoc Tukey HSD test (p = 0.05) showed that the results for Group A/B/E, Group B/D and Group C each lie within subsets that differ statistically significantly from the other subsets. Within the limitations of this in vitro study, it can be stated that some charcoal toothpastes lead to significantly higher abrasion on human enamel, when brushing with electric brushes. As low-abrasion toothpaste is generally advisable, and some charcoal toothpastes should be viewed critically with regard to their abrasive properties.


A flexible gradient lateral flow immunochromatographic assay for qualitative, semi-quantitative, and quantitative determination of serum amyloid A.
Serum amyloid A (SAA) is an acute-phase protein produced in response to inflammatory proteins during infections, inflammation, trauma, surgery, cancer, and other conditions. Early and accurate detection of SAA is necessary for diagnosis and monitoring of disease progression. To meet this need, we developed a gradient lateral flow immunoassay test strip using Au nanoparticles as signal reporters. The test strip has three test (T1, T2, and T3) lines with progressively decreasing concentrations of SAA antibody, enabling the determination of high, medium, and low concentrations of SAA in serum. The test strip results were analyzed using three distinct readout methods, each with different sensitivity, accuracy, and precision for SAA concentration measurements. Qualitative judgment is based on the color of the T1 line. Semi-quantitative assessment of SAA concentration is determined by the number of colored T-lines. Specifically, color development in T1 line alone indicates a concentration range of 10-50 μg/mL, while T1 and T2 lines together indicate a range of 50-100 μg/mL, and development in all three lines (T1, T2, and T3) indicates a concentration of >100 μg/mL. Quantitative analysis was performed using either smartphone imaging or image scanning with ImageJ software. By using a five-parameter logistic function, we found a strong correlation (R2 = 0.998) between the ratio of signal intensities of (T1 + T2 + T3) to the control (C) line and SAA concentrations ranging from 5 to 1000 μg/mL. At lower concentrations (0-100 μg/mL), we observed a proportional relationship between the value of (T1 + T2 + T3)/C and SAA concentration. The limit of detection for SAA was 9.33 ng/mL (or 6.53 μg/mL of SAA in undiluted serum samples) for the smartphone method and 3.06 ng/mL (or 2.14 μg/mL of SAA in undiluted serum samples) for the scanner method. The gradient test strip was highly consistent with a commercially available SAA immunochromatographic test strip when tested with real human serum samples. Passing-Bablok regression indicated that results obtained using the smartphone app and scanner methods of the gradient test strip were comparable to those obtained using the commercial test strip. The gradient test strip is flexible and adaptable, providing solutions for qualitative, semi-quantitative, and quantitative SAA measurements.


Exploring the past, present, and future of the mindfulness field: A multitechnique bibliometric review.
This paper provides an overview of the mindfulness literature up until the end of 2020 by (a) uncovering its underlying intellectual structure, (b) identifying the most influential and popular themes, and (c) presenting new directions for future research on mindfulness. To this end, a systematic quantitative review based on bibliometric methods was conducted, which is perhaps less prone to researcher bias and can complement existing meta-analyses and qualitative (narrative) structured reviews as an objective approach. Three bibliometric techniques-document co-citation analysis, co-word (co-occurrence and content) analysis, and bibliographic coupling-were applied to explore the past, present, and future of mindfulness research. The co-citation analysis showed that measurement, mechanisms, mindfulness-based interventions, and examinations of the efficacy of mindfulness interventions are among the key theoretical knowledge bases from which the field of mindfulness is derived. The content analysis demonstrated the beneficial effects of mindfulness meditation for physical and mental health conditions. The bibliographic coupling revealed novel directions in cognitive behavioral therapy, emotion regulation, the application of mindfulness practice to children and adolescents, mindfulness at work, and the role of mindfulness in positive psychology. The large sample of articles that was analyzed allowed us to provide a broader and more objective overview than possible with other forms of literature reviews. The combination of the three bibliometric techniques granted deeper insights into the complex multidisciplinary field of mindfulness, along with specific suggestions for future research.


Contribution of two-pore K+ channels to cardiac ventricular action potential revealed using human iPSC-derived cardiomyocytes.
Two-pore K+ (K2p) channels have been described in modulating background conductance as leak channels in different physiological systems. In the heart, the expression of K2p channels is heterogeneous with equivocation regarding their functional role. Our objective was to determine the K2p expression profile and their physiological and pathophysiological contribution to cardiac electrophysiology. Induced pluripotent stem cells (iPSCs) generated from humans were differentiated into cardiomyocytes (iPSC-CMs). mRNA was isolated from these cells, commercial iPSC-CM (iCells), control human heart ventricular tissue (cHVT), and ischemic (iHF) and nonischemic heart failure tissues (niHF). We detected 10 K2p channels in the heart. Comparing quantitative PCR expression of K2p channels between human heart tissue and iPSC-CMs revealed K2p1.1, K2p2.1, K2p5.1, and K2p17.1 to be higher expressed in cHVT, whereas K2p3.1 and K2p13.1 were higher in iPSC-CMs. Notably, K2p17.1 was significantly lower in niHF tissues compared with cHVT. Action potential recordings in iCells after K2p small interfering RNA knockdown revealed prolongations in action potential depolarization at 90% repolarization for K2p2.1, K2p3.1, K2p6.1, and K2p17.1. Here, we report the expression level of 10 human K2p channels in iPSC-CMs and how they compared with cHVT. Importantly, our functional electrophysiological data in human iPSC-CMs revealed a prominent role in cardiac ventricular repolarization for four of these channels. Finally, we also identified K2p17.1 as significantly reduced in niHF tissues and K2p4.1 as reduced in niHF compared with iHF. Thus, we advance the notion that K2p channels are emerging as novel players in cardiac ventricular electrophysiology that could also be remodeled in cardiac pathology and therefore contribute to arrhythmias.NEW & NOTEWORTHY Two-pore K+ (K2p) channels are traditionally regarded as merely background leak channels in myriad physiological systems. Here, we describe the expression profile of K2p channels in human-induced pluripotent stem cell-derived cardiomyocytes and outline a salient role in cardiac repolarization and pathology for multiple K2p channels.


Escherichia coli bacteriuria in pregnant women in Ghana: antibiotic resistance patterns and virulence factors.
The relevance of Escherichia coli associated bacteriuria infection in pregnant women is poorly understood, despite these strains sharing a similar virulence profile with other pathogenic E. coli causing severe obstetric and neonatal infections. We characterized and determined the antimicrobial susceptibility, resistance genes and virulence profiles of 82 E. coli isolates associated with asymptomatic bacteriuria in some pregnant in Ghana from February to August 2016 using Kirby-Bauer disc diffusion and polymerase chain reaction. High levels of antimicrobial resistance were observed to ampicillin (79.3%), tetracycline (70.7%) and cotrimoxazole (59.8%), except for cefuroxime (32.9%). Resistance genes analyses revealed 58.5% were positive for BlaTEM and 7.3% for aph(3)-Ia(aphA2). Virulence factors (VFs) was more widespread in pregnant women in the 2nd and 3rd trimesters than 1st trimester. VFs relating to adhesion (papC and iha), Protectins (traT), aerobactin acquisition (iutA) and iron acquisition systems (fyuA and irp2) were more prevalent in the resistant E. coli isolates. This study provides evidence for a link in bacteriuria and transmission of extra-intestinal E. coli in pregnant women to cause multi-resistant obstetric or neonatal infections. Considering the involvement of extra-intestinal E. coli in infections, results are helpful to develop strategies to prevent maternal and/ neonatal infections.


[Ethical dilemmas of nurses concerning informational privacy of persons with HIV/AIDS. An exploratory study of the kinds of dilemmas, emotional experiences and coping strategies].
This paper reports on the results of a study conducted in 1994. The aim of the study was to gain insight into nurses' perceptions of ethical dilemmas concerning informational privacy of patients with hiv/aids. The chosen research method was descriptive, from a qualitative research perspective (Grounded Theory). The purposive sample consisted of seven nurses working in a university hospital. Data were collected by means of in-depth interviews and the critical incidents method. The description of the dilemmas led to a central theme: the nurses' choice whether or not to give information revealing the diagnosis seropositivity or aids to patient's relatives or partner. The core categories were derived from analysis of the descriptions given by the nurses. They are split up into experiences of the nurses and the way nurses cope with these dilemmas. Recommendations are given for promotion of expertise and education.


Chikungunya virus dissemination from the midgut of Aedes aegypti is associated with temporal basal lamina degradation during bloodmeal digestion.
In the mosquito, the midgut epithelium is the initial tissue to become infected with an arthropod-borne virus (arbovirus) that has been acquired from a vertebrate host along with a viremic bloodmeal. Following its replication in midgut epithelial cells, the virus needs to exit the midgut and infect secondary tissues including the salivary glands before it can be transmitted to another vertebrate host. The viral exit mechanism from the midgut, the midgut escape barrier (MEB), is poorly understood although it is an important determinant of mosquito vector competence for arboviruses. Using chikungunya virus (CHIKV) as a model in Aedes aegypti, we demonstrate that the basal lamina (BL) of the extracellular matrix (ECM) surrounding the midgut constitutes a potential barrier for the virus. The BL, predominantly consisting of collagen IV and laminin, becomes permissive during bloodmeal digestion in the midgut lumen. Bloodmeal digestion, BL permissiveness, and CHIKV dissemination are coincident with increased collagenase activity, diminished collagen IV abundance, and BL shredding in the midgut between 24-32 h post-bloodmeal. This indicates that there may be a window-of-opportunity during which the MEB in Ae. aegypti becomes permissive for CHIKV. Matrix metalloproteinases (MMPs) are the principal extracellular endopeptidases responsible for the degradation/remodeling of the ECM including the BL. We focused on Ae. aegypti (Ae)MMP1, which is expressed in midgut epithelial cells, is inducible upon bloodfeeding, and shows collagenase (gelatinase) activity. However, attempts to inhibit AeMMP activity in general or specifically that of AeMMP1 did not seem to affect its function nor produce an altered midgut escape phenotype. As an alternative, we silenced and overexpressed the Ae. aegypti tissue inhibitor of metalloproteinases (AeTIMP) in the mosquito midgut. AeTIMP was highly upregulated in the midgut during bloodmeal digestion and was able to inhibit MMP activity in vitro. Bloodmeal-inducible, midgut-specific overexpression of AeTIMP or its expression via a recombinant CHIKV significantly increased midgut dissemination rates of the virus. Possibly, AeTIMP overexpression affected BL degradation and/or restoration thereby increasing the midgut dissemination efficiency of the virus.


Accuracy of diagnostic tests for respiratory syncytial virus infection within a paediatric hospital population in Kilifi County, Kenya.
Background: Respiratory syncytial virus (RSV)-induced lower respiratory tract disease is a prominent cause of hospitalisation among children aged <5 years in developing countries. Accurate and rapid diagnostic tests are central to informing effective patient management and surveillance efforts geared towards quantifying RSV disease burden. This study sought to estimate the sensitivity (Se), specificity (Sp) (along with the associated factors) and predictive values of a direct immunofluorescence test (IFAT), and two real-time reverse transcription polymerase chain reaction (rRT-PCR) assays for RSV infection within a paediatric hospital population: a multiplex rRT-PCR (MPX) and Fast-Track Diagnostics ® (FTD) Respiratory Pathogens 33 (Resp-33) rRT-PCR. Methods: The study enlisted 1458 paediatrics aged ≤59 months admitted with acute respiratory illness at the Kilifi County Hospital between August 2011 and December 2013. A Bayesian latent class modelling framework was employed to infer the tests' estimates based on the patients' diagnostic data from the three tests. Results: The tests posted statistically similar Se estimates: IFAT (93.7%, [90.7; 95.0]), FTD (97.8%, [94.6; 99.4]) and MPX (97.5%, [94.2; 99.3]). As for Sp, FTD registered a lower estimate (97.4%, [96.2; 98.2]) than MPX (99.7%, [99.0; 100.0]) but similar to IFAT (99.0%, [98.2; 99.6]). The negative and positive predictive values were strong (>91%) and closely mimicked the pattern given by the Se and Sp values respectively. None of the examined covariates (age, sex and pneumonia status) significantly influenced the accuracy of the tests. Conclusions: The evaluation found little to choose between the three diagnostic tests. Nonetheless, with its relative affordability, the conventional IFAT continues to hold promise for use in patient care and surveillance activities for RSV infection within settings where children are hospitalised with severe acute respiratory illness.


Factors associated with breast cancer prevention communication between mothers and daughters.
Mother-daughter communication may be a potential pathway between family history and cancer prevention behavior. We examined the degree to which mothers reported providing advice on breast cancer prevention to their daughters, the content of such advice, and correlates of providing such advice. Data were collected via a mailed questionnaire to 1773 women from 355 families in the Minnesota Breast Cancer Family Study. Women were asked whether or not they had provided advice to their daughters on what they should do to prevent breast cancer. An additional open-ended question asked them to describe the types of advice they had provided. Nine hundred seventy-six (55%) of the women reported providing breast cancer prevention advice to their daughters. The most frequent types of advice were to have a mammogram (51%), perform breast self-examination (BSE) (39%), have a clinical breast examination (CBE) (30%), and maintain a healthy lifestyle (21%). From multivariate logistic regression, older age (p < 0.001), having a personal history of breast cancer (p < 0.001), higher degree of breast cancer worry/concern (p < 0.001), engaging in a higher number of health-promoting behaviors (p < 0.001), and ever performing a BSE (p = 0.04) were factors independently associated with the provision of advice. Analyses accounting for sample nonindependence did not change our results. Breast cancer prevention behaviors were associated with providing advice. By better understanding the pathways through which breast cancer family history is associated with screening mammography and other prevention behaviors, researchers can develop more effective, tailored prevention interventions at the family level.


Dietary interventions for obesity: clinical and mechanistic findings.
Dietary modification is central to obesity treatment. Weight loss diets are available that include various permutations of energy restriction, macronutrients, foods, and dietary intake patterns. Caloric restriction is the common pathway for weight reduction, but different diets may induce weight loss by varied additional mechanisms, including by facilitating dietary adherence. This narrative Review of meta-analyses and select clinical trials found that lower-calorie diets, compared with higher-calorie regimens, reliably induced larger short-term (<6 months) weight losses, with deterioration of this benefit over the long term (>12 months). Few significant long-term differences in weight loss were observed for diets of varying macronutrient composition, although some regimens were found to have short-term advantages (e.g., low carbohydrate versus low fat). Progress in improving dietary adherence, which is critical to both short- and long-term weight loss, could result from greater efforts to identify behavioral and metabolic phenotypes among dieters.


"Finding a safe space": A qualitative study of what makes help helpful for adolescents bereaved by suicide.
Experiencing a death by suicide is a devastating event in the lives of adolescents; however, little is known about what makes help helpful according to their experiences. Thematic analysis of individual and group interview data (N = 18) yielded four themes: feeling connected with, and understood by a helper, having a sense of control over, and access to the help as needed. Findings indicate that help should be based on supportive and educational approaches with respect to the adolescents' agency and the family context. Help must be accessible on a long-term basis while catering for flexible usage.


Linked color imaging versus white light imaging colonoscopy for colorectal adenoma detection: A randomized controlled trial.
The adenoma detection rate is an important indicator of colonoscopy quality and colorectal cancer incidence. We compared the adenoma detection rates between white light imaging (WLI) and linked color imaging (LCI) colonoscopy. Patients undergoing colonoscopy for positive fecal immunochemical tests, follow-up of colon polyps, and abdominal symptoms at three institutions were randomly assigned to the LCI or WLI groups. Mean adenoma number per patient (including based on endoscopists' experience), adenoma detection rate, cecal intubation time, withdrawal time, mean adenoma number per location, and adenoma size were compared. The LCI and WLI groups comprised 494 and 501 patients, respectively. No significant differences in the cecal intubation rate (LCI vs WLI: 99.5% vs 99.4%), cecal intubation time, and withdrawal time were noted between groups. The mean adenoma number per patient was significantly higher in the LCI group than in the WLI group (1.07 vs 0.88, P = 0.04), particularly in the descending [0.12 (58/494) vs 0.07 (35/501), P = 0.01] and sigmoid colon [0.41 (201/494) vs 0.30 (149/501), P ≤ 0.001]. However, the adenoma detection rate was 47.1% in the LCI group and 46.9% in the WLI group, with no significant difference (P = 0.93). The total number of sessile-type adenomas was significantly higher in the LCI group than in the WLI group (346/494 vs 278/501, P = 0.04). As for polyp size, small polyps (≤ 5 mm) were detected at a significantly higher rate in the LCI group (271/494 vs 336/501, P = 0.04). Linked color imaging is significantly superior to WLI in terms of mean adenoma number per patient.


Reduced infectivity of waterborne viable but nonculturable Helicobacter pylori strain SS1 in mice.
Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of viable but nonculturable (VBNC) H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne VBNCH. pylori could cause gastric infection. We performed five mouse experiments to assess the infectivity of VBNCH. pylori in various exposure scenarios. VBNC viability was examined using Live/Dead staining and Biolog phenotype metabolism arrays. High doses of VBNCH. pylori in water were chosen to test the "worst-case" scenario for different periods of time. One experiment also investigated the infectious capabilities of VBNC SS1 using gavage. Further, immunocompromised mice were exposed to examine infectivity among potentially vulnerable groups. After exposure, mice were euthanized and their stomachs were examined for H. pylori infection using culture and PCR methodology. VBNC cells were membrane intact and retained metabolic activity. Mice exposed to VBNCH. pylori via drinking water and gavage were not infected, despite the various exposure scenarios (immunocompromised, high doses) that might have permitted infection with VBNCH. pylori. The positive controls exposed to viable, culturable H. pylori did become infected. While other studies that have used viable, culturable SS1 via gavage or drinking water exposures to successfully infect mice, in our study, waterborne VBNC SS1 failed to colonize mice under all test conditions. Future studies could examine different H. pylori strains in similar exposure scenarios to compare the relative infectivity of the VBNC vs the viable, culturable state, which would help inform future risk assessments of H. pylori in water.


Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules.
Protein-protein interactions (PPIs) are involved in many of life's essential biological functions yet are also an underlying cause of several human diseases, including amyloidosis. The modulation of PPIs presents opportunities to gain mechanistic insights into amyloid assembly, particularly through the use of methods which can trap specific intermediates for detailed study. Such information can also provide a starting point for drug discovery. Here, we demonstrate that covalently tethered small molecule fragments can be used to stabilize specific oligomers during amyloid fibril formation, facilitating the structural characterization of these assembly intermediates. We exemplify the power of covalent tethering using the naturally occurring truncated variant (ΔN6) of the human protein β2-microglobulin (β2m), which assembles into amyloid fibrils associated with dialysis-related amyloidosis. Using this approach, we have trapped tetramers formed by ΔN6 under conditions which would normally lead to fibril formation and found that the degree of tetramer stabilization depends on the site of the covalent tether and the nature of the protein-fragment interaction. The covalent protein-ligand linkage enabled structural characterization of these trapped, off-pathway oligomers using X-ray crystallography and NMR, providing insight into why tetramer stabilization inhibits amyloid assembly. Our findings highlight the power of "post-translational chemical modification" as a tool to study biological molecular mechanisms.


Self-directed rehabilitation training intensity thresholds for efficient recovery of skilled forelimb function in rats with cervical spinal cord injury.
Task specific rehabilitation training is commonly used to treat motor dysfunction after neurological injures such as spinal cord injury (SCI), yet the use of task specific training in preclinical animal studies of SCI is not common. This is due in part to the difficulty in training animals to perform specific motor tasks, but also due to the lack of knowledge about optimal rehabilitation training parameters to maximize recovery. The single pellet reaching, grasping and retrieval (SPRGR) task (a.k.a. single pellet reaching task or Whishaw task) is a skilled forelimb motor task used to provide rehabilitation training and test motor recovery in rodents with cervical SCI. However, the relationships between the amount, duration, intensity, and timing of training remain poorly understood. In this study, using automated robots that allow rats with cervical SCI ad libitum access to self-directed SPRGR rehabilitation training, we show clear relationships between the total amount of rehabilitation training, the intensity of training (i.e., number of attempts/h), and performance in the task. Specifically, we found that rats naturally segregate into High and Low performance groups based on training strategy and performance in the task. Analysis of the different training strategies showed that more training (i.e., increased number of attempts in the SPRGR task throughout rehabilitation training) at higher intensities (i.e., number of attempts per hour) increased performance in the task, and that improved performance in the SPRGR task was linked to differences in corticospinal tract axon collateral densities in the injured spinal cords. Importantly, however, our data also indicate that rehabilitation training becomes progressively less efficient (i.e., less recovery for each attempt) as both the amount and intensity of rehabilitation training increases. Finally, we found that Low performing animals could increase their training intensity and transition to High performing animals in chronic SCI. These results highlight the rehabilitation training strategies that are most effective to regain skilled forelimb motor function after SCI, which will facilitate pre-clinical rehabilitation studies using animal models and could be beneficial in the development of more efficient clinical rehabilitation training strategies.


[Case report revisited: review of the 6 cases].
Out of the cases we experienced in our 11-year service in sanatorium, 6 cases were selected to review the medical care and social environment that each patient was involved. Two cases were the residents in a sanatorium and 4 cases were in the community, including 2 cases having foreign nationality. The review of these cases drew the following conclusions. 1. We must be aware of our responsibility for early diagnosis and treatment of leprosy to prevent tragic disability. 2. The fixed duration of MDT/MB may not be enough for LL cases having high bacterial load before treatment. Enough duration of chemotherapy and follow-up is desired to prevent avoidable disability. 3. Basically, the treatment of leprosy should be carried on in outpatient clinic. The duration of hospitalization, if necessary, should be shortest to enhance patient's motive for treatment. 4. Intermittent administration of RFP must be done under direct observation. 5. For foreign patients not accustomed to the life in Japan or elderly patient living by oneself, various supports from community are greatly helpful to achieve the long course of leprosy treatment. Through these supports, we can expect community enlightening that may promote rehabilitation of the people once suffered from leprosy.


Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD.
Extracellular matrix (ECM) remodeling of the lung tissue releases protein fragments into the blood, where they may be detected as serologic surrogate markers of disease activity in COPD. Our goal was to assess the association of ECM turnover with severity and outcome of COPD. In a prospective, observational, multicenter study including 506 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grades II to IV), serum samples were analyzed at stable state, exacerbation, and 4 weeks after exacerbation. The analysis comprised a panel of five novel neoepitopes, including fragments of collagen type III (C3M) and collagen type VI (C6M), pro-forms of collagen type III (Pro-C3) and type VI (Pro-C6), and neutrophil elastase-generated fragments of elastin (EL-NE) according to enzyme-linked immunosorbent assay. These neoepitopes were also measured at stable state in a derivation cohort that included 100 patients with COPD. Serum levels of C3M, C6M, Pro-C3, Pro-C6, and EL-NE were associated with lung function. Patients with the lowest levels of Pro-C3 and Pro-C6 had more severe airflow limitation, hyperinflation, air trapping, and emphysema. C3M and C6M were associated with dyspnea. All ECM biomarkers, except Pro-C6, were increased at exacerbation compared with stable state but, except EL-NE, did not differ between stable state and exacerbation follow-up in the crude and adjusted analyses. In Cox regression adjusted analyses, Pro-C3 was associated with a shorter time to exacerbation (hazard ratio, 0.72; CI, 0.59-0.89; P = .002) and Pro-C6 with survival (hazard ratio, 2.09; CI, 1.18-3.71; P = .011). Serum biomarkers of ECM turnover were significantly associated with disease severity and clinically relevant outcomes in patients with COPD. No.: ISRCTN99586989; URL: www.controlled-trials.com.


Human germinal center transcriptional programs are de-synchronized in B cell lymphoma.
Most adult B cell lymphomas originate from germinal center (GC) B cells, but it is unclear to what extent B cells in overt lymphoma retain the functional dynamics of GC B cells or are blocked at a particular stage of the GC reaction. Here we used integrative single-cell analysis of phenotype, gene expression and variable-region sequence of the immunoglobulin heavy-chain locus to track the characteristic human GC B cell program in follicular lymphoma B cells. By modeling the cyclic continuum of GC B cell transitional states, we identified characteristic patterns of synchronously expressed gene clusters. GC-specific gene-expression synchrony was lost in single lymphoma B cells. However, distinct follicular lymphoma-specific cell states co-existed within single patient biopsies. Our data show that lymphoma B cells are not blocked in a GC B cell state but might adopt new dynamic modes of functional diversity, which opens the possibility of novel definitions of lymphoma identity.


F-actin stabilization increases tension cost during contraction of permeabilized airway smooth muscle in dogs.
1. Dynamic actin reorganization involving actin polymerization and depolymerization may play an important functional role in smooth muscle. 2. This study tested the hypothesis that F-actin stabilization by phalloidin increases tension cost (i.e. ATP hydrolysis rate per unit of isometric force) during Ca2+-induced activation of Triton X-100-permeabilized canine tracheal smooth muscle. 3. Adenosine 5'-triphosphate (ATP) hydrolysis rate was quantified using an enzyme-coupled NADH fluorometric technique, regulatory myosin light chain (rMLC) phosphorylation was measured by Western blot analysis, and maximum unloaded shortening velocity (Vmax) was estimated by interpolation of the force-velocity relationship to zero load during isotonic loading. 4. Maximal activation with 10 microM free Ca2+ induced sustained increases in isometric force, stiffness, and rMLC phosphorylation. However, the increase in ATP hydrolysis rate initially reached peak values, but then declined to steady-state levels above that of the unstimulated muscle. Thus, tension cost decreased throughout steady-state isometric force. 5. Following incubation of permeabilized strips with 50 microM phalloidin for 1 h, the increases in isometric force and stiffness were not sustained despite a sustained increase in rMLC phosphorylation. Also, after an initial decline, tension cost increased throughout activation. Phalloidin had no effect on Vmax during steady-state isometric force or on rMLC phosphorylation. 6. These findings suggest that dynamic reorganization of actin is necessary for optimal energy utilization during contraction of permeabilized airway smooth muscle.


Rituximab and tocilizumab for the treatment of rheumatoid arthritis.
The aim of this study was to evaluate the efficacy and safety of rituximab and tocilizumab compared with adalimumab, etanercept, and infliximab, in patients with rheumatoid arthritis not responding to first-line treatment, and to compare the efficacy and safety of rituximab versus tocilizumab in patients not responding to anti-tumor necrosis factor α (anti-TNF) therapy. A literature search of randomized controlled trials, controlled clinical trials, and systematic reviews was performed to evaluate efficacy and safety of rituximab and tocilizumab. Twenty-four RCTs were included in this systematic review with 6,357 participants; 3,450 treated with biological DMARD and 2,907 with standard care. In patients not responding to first-line treatment, rituximab shows lower response rate in at least 50 percent improvement in the American College of Rheumatology criteria (ACR50) and ACR70 compared with etanercept, at 6 months of follow-up. Tocilizumab shows higher ACR70 response rate compared with infliximab, at the same follow-up time. Other results showed no significant differences. Indirect comparisons between rituximab and tocilizumab in patients not responding for at least one anti-TNF, shows higher ACR20 response rate for tocilizumab at 6 months of follow-up. Regarding safety, adalimumab and etanercept were associated with significant fewer withdrawals due to adverse events compared with infliximab. Considering efficacy, safety, and the availability of 3 anti-TNFs in the National Medicines Formulary (adalimumab, etanercept, and infliximab), it seems appropriate to remove infliximab from the coverage, and introduce tocilizumab for patients not responding for at least one anti-TNF.


Dynamical modeling of viral spread in spatially distributed populations: stochastic origins of oscillations and density dependence.
In order to understand the spatio-temporal structure of epidemics beyond that permitted with classical SIR (susceptible-infective-recovered)-type models, a new mathematical model for the spread of a viral disease in a population of spatially distributed hosts is described. The positions of the hosts are randomly generated in a rectangular habitat. Encounters between any pair of individuals are according to a Poisson process with a mean rate that declines exponentially as the distance between them increases. The contact rate allows the mean rates to be set at a certain number of encounters per day on average. The relevant state variables for each individual at any time are given by the solution of a pair of coupled differential equations for the viral load and the quantity of general immune system effectors which reduce the viral load. The parameters describing within-host viral-immune system dynamics are generated randomly to reflect variability across a population. Transmission is assumed to depend on the viral loads in donors and occurs with a probability ptrans. The initial conditions are such that one randomly chosen individual carries a randomly chosen amount of the virus, whereas the rest of the population is uninfected. Simulations reveal local or whole-population responses. Whole-population disease spread may be in the form of isolated or multiple occurrences, the latter often being approximately periodic. The mechanisms of this oscillatory behaviour are analyzed in terms of several parameters and the distribution of critical points in the host dynamical systems. Increased contact rate, increased probability of transmission and decreased threshold for viral transmission, decreased immune strength and increased viral growth rate all increase the probability of multiple outbreaks and the distribution of the critical points also plays a role.


Lupus nephritis: current issues.
Despite the development of new modalities, cyclophosphamide (CYC) remains the preferred initial treatment for severe proliferative lupus nephritis. Controversies continue about the best route, dosage, and duration of CYC treatment. For recalcitrant disease, new immunosuppressive and immunomodulating agents, immunoablative high dose CYC, nucleoside analogues, apheresis, and the biological response modifiers can be considered.


Repression of the Glucocorticoid Receptor Aggravates Acute Ischemic Brain Injuries in Adult Mice.
Strokes are one of the leading causes of mortality and chronic morbidity in the world, yet with only limited successful interventions available at present. Our previous studies revealed the potential role of the glucocorticoid receptor (GR) in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). In the present study, we investigate the effect of GR knockdown on acute ischemic brain injuries in a model of focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) in adult male CD1 mice. GR siRNAs and the negative control were administered via intracerebroventricular (i.c.v.) injection 48 h prior to MCAO. The cerebral infarction volume and neurobehavioral deficits were determined 48 h after MCAO. RT-qPCR was employed to assess the inflammation-related gene expression profiles in the brain before and after MCAO. Western Blotting was used to evaluate the expression levels of GR, the mineralocorticoid receptor (MR) and the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling. The siRNAs treatment decreased GR, but not MR, protein expression, and significantly enhanced expression levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in the brain. Of interest, GR knockdown suppressed BDNF/TrkB signaling in adult mice brains. Importantly, GR siRNA pretreatment significantly increased the infarction size and exacerbated the neurobehavioral deficits induced by MCAO in comparison to the control group. Thus, the present study demonstrates the important role of GR in the regulation of the inflammatory responses and neurotrophic BDNF/TrkB signaling pathway in acute ischemic brain injuries in adult mice, revealing a new insight into the pathogenesis and therapeutic potential in acute ischemic strokes.


Boolean models of genomic regulatory networks: reduction mappings, inference, and external control.
Computational modeling of genomic regulation has become an important focus of systems biology and genomic signal processing for the past several years. It holds the promise to uncover both the structure and dynamical properties of the complex gene, protein or metabolic networks responsible for the cell functioning in various contexts and regimes. This, in turn, will lead to the development of optimal intervention strategies for prevention and control of disease. At the same time, constructing such computational models faces several challenges. High complexity is one of the major impediments for the practical applications of the models. Thus, reducing the size/complexity of a model becomes a critical issue in problems such as model selection, construction of tractable subnetwork models, and control of its dynamical behavior. We focus on the reduction problem in the context of two specific models of genomic regulation: Boolean networks with perturbation (BN(P)) and probabilistic Boolean networks (PBN). We also compare and draw a parallel between the reduction problem and two other important problems of computational modeling of genomic networks: the problem of network inference and the problem of designing external control policies for intervention/altering the dynamics of the model.


Hyperacute therapies for childhood stroke: a case report and review of the literature.
Objective. The optimal management of pediatric patients with arterial ischemic stroke (AIS) is not known. Despite this, goal-oriented, time-sensitive therapies geared to rapid reestablishment of arterial blood flow are occasionally applied with beneficial effects. The inconsistent approach to AIS is in part due to a lack of knowledge and preparedness. Methods. Case report of a 12-year-old male with right middle cerebral artery (MCA) occlusion resulting in dense left hemiplegia and mutism and review of the literature. Intervention(s). Mechanical thrombectomy, intra-arterial administration of rt-PA, vasodilators, and platelet inhibitors, and systemic anticoagulation and subsequent critical care support. Results. Restoration of right MCA blood flow and complete resolution of neurologic deficits. Conclusion. We report the gratifying outcome of treatment of a case of AIS in a pediatric patient treated with hyperacute therapies geared to arterial recanalization and subsequent neurologic critical care and review the pertinent literature. Guidelines for the emergency room management of pediatric AIS from prospective, randomized trials are needed.


Discitis due to Clostridium perfringens.
Diagnosis of the infectious process of the intervertebral disc is often delayed due to the lack of specifity of the clinical picture. This delay in diagnosis and consequently in treatment can lead to severe neurologic sequela. In these cases, punction biopsy of the intervertebral disc is of special value. The authors found no mention in the literature concerning Chlostridium perfringens discitis verified by aspiration and fluid culture extracted by intervertebral disc puncture.


The socioeconomic gradient of alcohol use: an analysis of nationally representative survey data from 55 low-income and middle-income countries.
Alcohol is a leading risk factor for over 200 conditions and an important contributor to socioeconomic health inequalities. However, little is known about the associations between individuals' socioeconomic circumstances and alcohol consumption, especially heavy episodic drinking (HED; ≥5 drinks on one occasion) in low-income or middle-income countries. We investigated the association between individual and household level socioeconomic status, and alcohol drinking habits in these settings. In this pooled analysis of individual-level data, we used available nationally representative surveys-mainly WHO Stepwise Approach to Surveillance surveys-conducted in 55 low-income and middle-income countries between 2005 and 2017 reporting on alcohol use. Surveys from participants aged 15 years or older were included. Logistic regression models controlling for age, country, and survey year stratified by sex and country income groups were used to investigate associations between two indicators of socioeconomic status (individual educational attainment and household wealth) and alcohol use (current drinking and HED amongst current drinkers). Surveys from 336 287 participants were included in the analysis. Among males, the highest prevalence of both current drinking and HED was found in lower-middle-income countries (L-MICs; current drinking 49·9% [95% CI 48·7-51·2] and HED 63·3% [61·0-65·7]). Among females, the prevalence of current drinking was highest in upper-middle-income countries (U-MIC; 29·5% [26·1-33·2]), and the prevalence of HED was highest in low-income countries (LICs; 36·8% [33·6-40·2]). Clear gradients in the prevalence of current drinking were observed across all country income groups, with a higher prevalence among participants with high socioeconomic status. However, in U-MICs, current drinkers with low socioeconomic status were more likely to engage in HED than participants with high socioeconomic status; the opposite was observed in LICs, and no association between socioeconomic status and HED was found in L-MICs. The findings call for urgent alcohol control policies and interventions in LICs and L-MICs to reduce harmful HED. Moreover, alcohol control policies need to be targeted at socially disadvantaged groups in U-MICs. Deutsche Forschungsgemeinschaft and the National Center for Advancing Translational Sciences of the US National Institutes of Health.


Colonic injury following percutaneous endoscopic-guided gastrostomy insertion.
Percutaneous endoscopic gastrostomy (PEG) is a common practice usually offered to patients who are unable to tolerate or swallow oral feed and require long-term nutrition. We present a case of early pneumoperitoneum after a PEG placement due to colonic perforation. The patient was severely malnourished and had a medical history of brain injury, cerebrovascular accident cerebrovascular accident (CVA) and bilateral below knee amputations from a bomb blast 13 years ago. The PEG tube was placed under sedation. On the first postoperative day, the patient had a subtle pneumoperitoneum that was considered secondary to the procedure. On the third postoperative day, the patient became tachycardiac with abdominal distension. A CT scan showed the PEG tube traversing through the transverse colon. The patient underwent a laparotomy and repair of colonic injury and made an uneventful recovery.


Loading Pistacia atlantica essential oil in solid lipid nanoparticles and its effect on apoptosis of breast cancer cell line MDA-MB-231.
Pistacia atlantica has an anti-cancer effect due to its essential oil which is the major constituent of P. atlantica. Unfortunately, this essential oil evaporates easily and makes it less effective. The current research, therefore, aimed to improve the anti-cancer effect of P. atlantica essential oil (PAEO) in solid lipid nanoparticles (SLN). The chemical components of PAEO were assessed by gas chromatography. PAEO-SLNs were prepared by the probe-ultrasonication method, and their particle size, polydispersity index and zeta potential were determined. Encapsulation Efficiency (EE%) and Loading Capacity (LC%) of formulations was also calculated. Transmission electron microscopy was employed to determine the morphology of optimal formulation (PAEO-SLN4). Furthermore, the anticancer effects of PAEO-SLN4 against MDA-MB-231 cells were evaluated by cellular assays. The results showed that the type of surfactant and loading of the essential oil had a significant effect on size distribution, zeta potential and the polydispersity index. The encapsulation efficiency (EE%) and loading capacity for PAEO-SLN4 were 97.3% and 9.6%, respectively. The cellular assay demonstrates that PAEO-SLN4 could lead MDA-MB-231 cells to apoptosis. The findings also revealed that PAEO-SLN4 can stimulate apoptosis in MDA-MB-231 cells more than the placebo and free PAEO thereby indicating PAEO-SLN4 to be beneficial in breast cancer treatment.


Slow EEG amplitude oscillations during NREM sleep and reading disabilities in children with dyslexia.
To analyze non-rapid eye movement (NREM) sleep microstructure of children with dyslexia, by means of cyclic alternating pattern (CAP) analysis and to correlate CAP parameters with neuropsychological measures. Cross-sectional study using polysomnographic recordings and neuropsychological assessments. Sleep laboratory in academic center. Sixteen subjects with developmental dyslexia (mean age 10.8 years) and 11 normally reading children (mean age 10.1 years) underwent overnight polysomnographic recording. N/A. Sleep architecture parameters only showed some statistically significant differences: number of sleep stage shifts per hour of sleep, percentage of N3, and number of R periods were significantly lower in dyslexic children versus controls. CAP analysis revealed a higher total CAP rate and A1 index in stage N3. A2% and A2 index in stage N2 and N3 were lower in dyslexic children while no differences were found for A3 CAP subtypes. The correlation analysis between CAP parameters and cognitive-behavioral measures showed a significant positive correlation between A1 index in N3 with Verbal IQ, full-scale IQ, and Memory and Learning Transfer reading test; while CAP rate in N3 was positively correlated with verbal IQ. To overcome reading difficulties, dyslexic subjects overactivate thalamocortical and hippocampal circuitry to transfer information between cortical posterior and anterior areas. The overactivation of the ancillary frontal areas could account for the CAP rate modifications and mainly for the increase of CAP rate and of A1 index in N3 that seem to be correlated with IQ and reading abilities.


Understanding the functional neuroanatomy of acquired prosopagnosia.
One of the most remarkable disorders following brain damage is prosopagnosia, the inability to recognize faces. While a number of cases of prosopagnosia have been described at the behavioral level, the functional neuroanatomy of this face recognition impairment, and thus the brain regions critically involved in normal face recognition, has never been specified in great detail. Here, we used anatomical and functional magnetic resonance imaging (fMRI) to present the detailed functional neuroanatomy of a single case of acquired prosopagnosia (PS; Rossion, B., Caldara, R., Seghier, M., Schuller, A.-M., Lazeyras, F., Mayer, E., 2003a. A network of occipito-temporal face-sensitive areas besides the right middle fusiform gyrus is necessary for normal face processing. Brain 126, 2381-95; Rossion, B., Joyce, C.A., Cottrell, G.W., Tarr, M.J., 2003b. Early lateralization and orientation tuning for face, word, and object processing in the visual cortex. Neuroimage 20, 1609-24) with normal object recognition. First, we clarify the exact anatomical location and extent of PS' lesions in relation to (a) retinotopic cortex, (b) face-preferring regions, and (c) other classical visual regions. PS' main lesion - most likely causing her prosopagnosia - is localized in the posterior part of the right ventral occipitotemporal cortex. This lesion causes a left superior paracentral scotoma, as frequently observed in cases of prosopagnosia. While the borders of the early visual areas in the left hemisphere could be delineated well, the extensive posterior right-sided lesion hampered a full specification of the cortical representation of the left visual field. Using multiple scanning runs, face-preferring activation was detected within the right middle fusiform gyrus (MFG) in the so-called 'fusiform face area' ('FFA'), but also in the left inferior occipital gyrus (left 'OFA'), and in the right posterior superior temporal sulcus (STS). The dorsal part of the lateral occipital complex (LOC) and the human middle temporal cortex (hMT+/V5) were localized bilaterally. The color-preferring region V4/V8 was localized only in the left hemisphere. In the right hemisphere, the posterior lesion spared the ventral part of LOC, a region that may be critical for the preserved object recognition abilities of the patient, and the restriction of her deficit to the category of faces. The presumptive functions of both structurally damaged and preserved regions are discussed and new hypotheses regarding the impaired and preserved abilities of the patient during face and non-face object processing are derived. Fine-grained neurofunctional analyses of brain-damaged single cases with isolated recognition deficits may considerably improve our knowledge of the brain regions critically involved in specific visual functions, such as face recognition.


The pattern of visual deficits in amblyopia.
Amblyopia is usually defined as a deficit in optotype (Snellen) acuity with no detectable organic cause. We asked whether this visual abnormality is completely characterized by the deficit in optotype acuity, or whether it has distinct forms that are determined by the conditions associated with the acuity loss, such as strabismus or anisometropia. To decide this issue, we measured optotype acuity, Vernier acuity, grating acuity, contrast sensitivity, and binocular function in 427 adults with amblyopia or with risk factors for amblyopia and in a comparison group of 68 normal observers. Optotype acuity accounts for much of the variance in Vernier and grating acuity, and somewhat less of the variance in contrast sensitivity. Nevertheless, there are differences in the patterns of visual loss among the clinically defined categories, particularly between strabismic and anisometropic categories. We used factor analysis to create a succinct representation of our measurement space. This analysis revealed two main dimensions of variation in the visual performance of our abnormal sample, one related to the visual acuity measures (optotype, Vernier, and grating acuity) and the other related to the contrast sensitivity measures (Pelli-Robson and edge contrast sensitivity). Representing our data in this space reveals distinctive distributions of visual loss for different patient categories, and suggests that two consequences of the associated conditions--reduced resolution and loss of binocularity--determine the pattern of visual deficit. Non-binocular observers with mild-to-moderate acuity deficits have, on average, better monocular contrast sensitivity than do binocular observers with the same acuity loss. Despite their superior contrast sensitivity, non-binocular observers typically have poorer optotype acuity and Vernier acuity, at a given level of grating acuity, than those with residual binocular function.


[The serum levels of glycosaminoglycans and hydroxyproline in relation to the age, gender, and blood group of apparently healthy individuals].
The paper gives the results of a study of the levels of glycosaminoglycans (GAG) and hydroxyproline (HOP) in 87 apparently healthy individuals of both sexes, aged 19 to 60 years. There is a decrease in the levels of GAG, total HOP, and peptide-bound HOP with advanced age. These indices are higher in subjects less than 45 years old than in those over the age. The found age differences are comparable with higher serum hyaluronidase and collagenolytic activities in subjects younger than 45 years than in those over the age 45 years. Collagen metabolism occurs more intensively in young subjects (under 45 years of age) than in old ones (over 45). There are also gender-related differences: the men had higher levels of GAG and peptide-bound HOP and serum hyaluronidase activity than the women, which suggests that the metabolic rates of collagen and proteoglycans are higher. This difference is complimented by the qualitative characteristics of the process: there is a preponderance of the synthesis of collagen over its degradation with the accelerated degradation of proteoglycans in the young men. In Rh-positive subjects, the content of GAG was 22-fold higher than that in Rh-negative ones.


Calorie restriction-mediated replicative lifespan extension in yeast is non-cell autonomous.
In laboratory yeast strains with Sir2 and Fob1 function, wild-type NAD+ salvage is required for calorie restriction (CR) to extend replicative lifespan. CR does not significantly alter steady state levels of intracellular NAD+ metabolites. However, levels of Sir2 and Pnc1, two enzymes that sequentially convert NAD+ to nicotinic acid (NA), are up-regulated during CR. To test whether factors such as NA might be exported by glucose-restricted mother cells to survive later generations, we developed a replicative longevity paradigm in which mother cells are moved after 15 generations on defined media. The experiment reveals that CR mother cells lose the longevity benefit of CR when evacuated from their local environment to fresh CR media. Addition of NA or nicotinamide riboside (NR) allows a moved mother to maintain replicative longevity despite the move. Moreover, conditioned medium from CR-treated cells transmits the longevity benefit of CR to moved mother cells. Evidence suggests the existence of a longevity factor that is dialyzable but is neither NA nor NR, and indicates that Sir2 is not required for the longevity factor to be produced or to act. Data indicate that the benefit of glucose-restriction is transmitted from cell to cell in budding yeast, suggesting that glucose restriction may benefit neighboring cells and not only an individual cell.


Overuse of colonoscopy for colorectal cancer screening and surveillance.
Ongoing efforts to increase colorectal cancer (CRC) screening rates have raised concerns that these exams may be overused, thereby subjecting patients to unnecessary risks and wasting healthcare resources. Our aim was to measure overuse of screening and surveillance colonoscopies among average-risk adults, and to identify correlates of overuse. Our approach was a retrospective cohort study using electronic health record data for patients 50-65 years old with no personal history of CRC or colorectal adenomas with an incident CRC screening colonoscopy from 2001 to 2010 within a multispecialty physician group practice. We measured time to next screening or surveillance colonoscopy and predictors of overuse (exam performed more than one year earlier than guideline recommended intervals) of colonoscopies. We identified 1,429 adults who had an incident colonoscopy between 2001 and 2010, and they underwent an additional 871 screening or surveillance colonoscopies during a median follow-up of 6 years. Most follow-up screening colonoscopies (88%) and many surveillance colonoscopies (49%) repeated during the study represented overuse. Time to next colonoscopy after incident screening varied by exam findings (no polyp: median 6.9 years, interquartile range [IQR]: 5.1-10.0; hyperplastic polyp: 5.7 years, IQR: 4.9-9.7; low-risk adenoma: 5.1 years, IQR: 3.3-6.3; high-risk adenoma: 2.9 years, IQR: 2.0-3.4, p < 0.001). In logistic regression models of colonoscopy overuse, an endoscopist recommendation for early follow-up was strongly associated with overuse of screening colonoscopy (OR 6.27, 95% CI: 3.15-12.50) and surveillance colonoscopy (OR 13.47, 95% CI 6.61-27.46). In a multilevel logistic regression model, variation in the overuse of screening colonoscopy was significantly associated with the endoscopist performing the previous exam. Overuse of screening and surveillance exams are common and should be monitored by healthcare systems. Variations in endoscopist recommendations represent targets for interventions to reduce overuse.


Blepharophimosis syndrome with absent tear production.
The purpose of this report was to present a case of congenital alacrima in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). A 9-month-old boy presented with characteristic clinical findings of BPES confirmed by genetic testing. On further history taking and evaluation, the patient was noted to have no tear production, despite clinically present palpebral lobes of the lacrimal glands. BPES is an autosomal dominant condition characterized by narrowed horizontal palpebral fissures, severe bilateral symmetric ptosis, epicanthus inversus, and telecanthus. To the authors' knowledge, this represents the second reported case of congenital alacrima in this syndrome. The first case described in the literature was in a 9-month-old girl who had congenital absence of the lacrimal glands. BPES may present with alacrima requiring vigilant lifelong lubrication and careful consideration in decisions for eyelid surgery including ptosis repair.


Effect of a Concise Educational Program on COVID-19 Vaccination Attitudes.
Background: Vaccination has been recognized as a vital step for containing the COVID-19 outbreak. To ensure the success of immunization efforts as a public health containment measure, a high level of public vaccination compliance is essential. Targeted educational programs can be utilized to improve attitudes toward vaccination and improve the public's uptake of protective measures. Methods: In this cross-sectional study, we aimed to evaluate the impact of a concise educational program on perceived knowledge regarding the COVID-19 vaccine, vaccine importance and trust, protection and fear from COVID-19, trust in authorities, as well as individual resilience. Results: The study evaluated 503 participants that completed the questionnaire before and after viewing a concise video tutorial on vaccination. Following the educational program, scores of five variables increased significantly compared to their pre-viewing level: knowledge, personal resilience, trust in authorities, vaccine importance, as well as perceived protection. Those that were vaccinated and/or intend to be vaccinated (N = 394) report higher levels of knowledge, trust in authorities, vaccine importance, vaccine trust, and fear of being infected as compared to those that are unwilling to get vaccinated. Positive significant correlations were found between resilience and trust in authorities (r = 0.169, p < 0.001), vaccine importance (r = 0.098, p = 0.028), and feeling protected (r = 0.310, p < 0.001). Trust in authorities was positively correlated with vaccine importance (r = 0.589, p < 0.001) and vaccine trust (r = 0.177, p < 0.001). Vaccine importance was positively correlated with vaccine trust (r = 0.149, p = 0.001), but not correlated with knowledge score. Conclusion: The findings of the study demonstrate the benefits of educational programs on improving attitudes toward vaccination acceptability. Incorporation of such concise educational programs by authorities may improve uptake of COVID-19 vaccination and help overcome public vaccine hesitancy. We recommend that such a concise and easily implementable educational program be incorporated as a response component to the current and future outbreaks.


Helium structures around SF5+ and SF6+: novel intermolecular potential and mass spectrometry experiments.
Helium clusters around the recently experimentally observed sulphur hexafluoride SF6+ and sulphur pentafluoride SF5+ ions are investigated using a combined experimental and theoretical effort. Mass spectrometry ion yields are obtained and the energetics and structure of the corresponding HeN-SF6+ and HeN-SF5+ clusters are analyzed using path integral molecular dynamics calculations as a function of N, the number of He atoms, employing a new intermolecular potential describing the interaction between the dopant and the surrounding helium. The new force field is optimized on benchmark potential energy ab initio calculations and represented by improved Lennard-Jonnes analytical expressions. This procedure improves the previous potentials employed in similar simulations for neutral SF6 attached to helium nanodroplets. The theoretical analysis explains the characteristic features observed in the experimental ion yields which suggest the existence of stable configurations at specific sizes.


Contribution of CD1d-unrestricted hepatic DX5+ NKT cells to liver injury in Plasmodium berghei-parasitized erythrocyte-injected mice.
Inoculation with erythrocytes infected with Plasmodium berghei, a protozoan causing mouse lethal malaria, induces liver injury in mice, although the parasite cannot invade host hepatocytes at this infectious stage. As previously reported, hepatic infiltrates participate in this liver injury by exerting their perforin-dependent killing action. Here, we have investigated the cellular mechanisms underlying P. berghei-induced incidental liver injury. Hepatic lymphocytes from P. berghei-infected mice killed normal hepatocytes, but not ConA-induced lymphoblasts. Furthermore, the hepatic lymphocytes from infected C57BL/6 mice displayed cytotoxicity against hepatocytes from C57BL/6 and BALB/c mice, indicating MHC-unrestricted hepatocytotoxicity by these hepatic lymphocytes. NK cells were not involved in this hepatocytotoxicity. However, DX5+ cells sorted from the liver of infected CD1d-deficient mice killed normal hepatocytes, indicating that CD1d-independent DX5+ T cells are the effector cells. The hepatocytotoxicity of these hepatic DX5+ T cells did not require TCR engagement. These findings indicate that hepatic CD1d-independent DX5+ T cells play a critical role in P. berghei-induced liver injury. Our studies may have general implications for tissue injuries that are caused by 'bystander killing' or other poorly defined cell-mediated killing mechanisms.


Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell-Mediated Antitumor Immunity.
Stressful conditions in the harsh tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. However, autophagy also causes post-translational modification of proteins that are recognized by the immune system. In particular, modified self-antigens can trigger CD4(+) T-cell responses that might be exploited to boost antitumor immune defenses. In this study, we investigated the ability of CD4 cells to target tumor-specific self-antigens modified by citrullination, which converts arginine residues in proteins to citrulline. Focusing on the intermediate filament protein vimentin, which is frequently citrullinated in cells during epithelial-to-mesenchymal transition of metastasizing epithelial tumors, we generated citrullinated vimentin peptides for immunization experiments in mice. Immunization with these peptides induced IFNγ- and granzyme B-secreting CD4 T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. This antitumor response was dependent on CD4 cells and not CD8(+) T cells. These results show how CD4 cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides may offer especially attractive vaccine targets for cancer therapy.


A randomized control trial of bupivacaine and fentanyl versus fentanyl-only for epidural analgesia during the second stage of labor.
The purpose of this prospective, double-blinded, parallel-arm, randomized trial was to examine the effects of epidural bupivacaine on the length of the second stage of labor in nulliparous women. The authors assessed length of second-stage labor, degree of motor blockade, mode of delivery, and visual analog scores in 310 nulliparous women with labor epidurals randomized to receive either: (1) 0.125% bupivacaine and fentanyl 2 μg/ml or (2) fentanyl 10 μg/ml alone via epidural using double blinding. The median duration of the second stage was 75 min (41, 128) in the bupivacaine/fentanyl group versus 73 min (42, 120) in the fentanyl-only group (P = 0.17) with a median difference of 6.0 (95% CI, -6.0 to 18.0). Furthermore, there was no difference in degree of motor blockade, incidence of operative delivery, visual analog scores, or neonatal outcomes between the two groups. No adverse events were reported. Use of epidural bupivacaine/fentanyl or a fentanyl-only infusion during the second stage of labor did not affect the duration of the second stage of labor, degree of motor blockade, mode of delivery, pain relief, and maternal or neonatal outcomes. However, in the fentanyl-only infusion group, there was a fivefold increase in opioid exposure to the fetus with unknown effects on neurobehavior, an outcome not assessed beyond the immediate postnatal period in this study.


Commensal bacteria, redox stress, and colorectal cancer: mechanisms and models.
The potential role for commensal bacteria in colorectal carcinogenesis is explored in this review. Most colorectal cancers (CRCs) occur sporadically and arise from the gradual accumulation of mutations in genes regulating cell growth and DNA repair. Genetic mutations followed by clonal selection result in the transformation of normal cells into malignant derivatives. Numerous toxicological effects of colonic bacteria have been reported. However, those recognized as damaging epithelial cell DNA are most easily reconciled with the currently understood genetic basis for sporadic CRC. Thus, we focus on mechanisms by which particular commensal bacteria may convert dietary procarcinogens into DNA damaging agents (e.g., ethanol and heterocyclic amines) or directly generate carcinogens (e.g., fecapentaenes). Although these and other metabolic activities have yet to be linked directly to sporadic CRC, several lines of investigation are reviewed to highlight difficulties and progress in the area. Particular focus is given to commensal bacteria that alter the epithelial redox environment, such as production of oxygen radicals by Enterococcus faecalis or production of hydrogen sulfide by sulfate-reducing bacteria (SRB). Super-oxide-producing E. faecalis has conclusively been shown to cause colonic epithelial cell DNA damage. Though SRB-derived hydrogen sulfide (H(2)S) has not been reported thus far to induce DNA damage or function as a carcinogen, recent data demonstrate that this reductant activates molecular pathways implicated in CRC. These observations combined with evidence that SRB carriage may be genetically encoded evoke a working model that incorporates multifactorial gene-environment interactions that appear to underlie the development of sporadic CRC.


In Vitro Mineralization of Collagen.
Collagen mineralization is a biological process in many skeletal elements in the animal kingdom. Examples of these collagen-based skeletons are the siliceous spicules of glass sponges or the intrafibrillar hydroxyapatite platelets in vertebrates. The mineralization of collagen in vitro has gained interest for two reasons: understanding the processes behind bone formation and the synthesis of scaffolds for tissue engineering. In this paper, the efforts toward collagen mineralization in vitro are reviewed. First, general introduction toward collagen type I, the main component of the extracellular matrix in animals, is provided, followed by a brief overview of collagenous skeletons. Then, the in vitro mineralization of collagen is critically reviewed. Due to their biological abundance, hydroxyapatite and silica are the focus of this review. To a much lesser extent, also some efforts with other minerals are outlined. Combining all minerals and the suggested mechanisms for each mineral, a general mechanism for the intrafibrillar mineralization of collagen is proposed. This review concludes with an outlook for further improvement of collagen-based tissue engineering scaffolds.


Surgical outcomes in gastroenterological surgery in Japan: Report of the National Clinical Database 2011-2018.
The National Clinical Database (NCD) of Japan grew rapidly, harvesting over 11 million cases of data between 2011 and 2018 from more than 5000 facilities. This is the Report of the NCD based upon gastrointestinal surgery information in 4 420 175 cases from 2011 to 2018. More than 70% of all gastrointestinal surgeries were performed at certified institutions, and the percentage of surgeries performed at certified institutions was particularly high for the esophagus (93.8% in 2018), liver (89.4%), pancreas (91.3%), and spleen (86.9%). Also, more than 70% of the surgeries were performed with the participation of the board-certified surgeon. As the patients have been getting older, the morbidities have been increasing. However, the mortalities have been kept at a low level. The rates of endoscopic surgery have been increasing year by year, especially high in low anterior resection (67.0%) and esophagectomy (61.0%). Nationwide, this database is surely expecting to ensure the quality of board certification system and surgical outcomes in gastroenterological surgery.


Electrochemical and surface plasmon insulin assays on clinical samples.
Diabetes is a complex immune disorder that requires extensive medical care beyond glycemic control. Recently, the prevalence of diabetes, particularly type 1 diabetes (T1D), has significantly increased from 5% to 10%, and this has affected the health-associated complication incidences in children and adults. The 2012 statistics by the American Diabetes Association reported that 29.1 million Americans (9.3% of the population) had diabetes, and 86 million Americans (age ≥20 years, an increase from 79 million in 2010) had prediabetes. Personalized glucometers allow diabetes management by easy monitoring of the high millimolar blood glucose levels. In contrast, non-glucose diabetes biomarkers, which have gained considerable attention for early prediction and provide insights about diabetes metabolic pathways, are difficult to measure because of their ultra-low levels in blood. Similarly, insulin pumps, sensors, and insulin monitoring systems are of considerable biomedical significance due to their ever-increasing need for managing diabetic, prediabetic, and pancreatic disorders. Our laboratory focuses on developing electrochemical immunosensors and surface plasmon microarrays for minimally invasive insulin measurements in clinical sample matrices. By utilizing antibodies or aptamers as the insulin-selective biorecognition elements in combination with nanomaterials, we demonstrated a series of selective and clinically sensitive electrochemical and surface plasmon immunoassays. This review provides an overview of different electrochemical and surface plasmon immunoassays for insulin. Considering the paramount importance of diabetes diagnosis, treatment, and management and insulin pumps and monitoring devices with focus on both T1D (insulin-deficient condition) and type 2 diabetes (insulin-resistant condition), this review on insulin bioassays is timely and significant.


Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges.
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by a multi-systemic vascular dysplasia and hemorrhage. The precise factors leading to these vascular malformations are not yet understood and robust animal models of HHT are essential to gain a detailed understanding of the molecular and cellular events that lead to clinical symptoms, as well as to test new therapeutic modalities. Most cases of HHT are caused by mutations in either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). Both genes are associated with TGFβ/BMP signaling, and loss of function mutations in the co-receptor ENG are causal in HHT1, while HHT2 is associated with mutations in the signaling receptor ACVRL1. Significant advances in mouse genetics have provided powerful ways to study the function of Eng and Acvrl1 in vivo, and to generate mouse models of HHT disease. Mice that are null for either Acvrl1 or Eng genes show embryonic lethality due to major defects in angiogenesis and heart development. However mice that are heterozygous for mutations in either of these genes develop to adulthood with no effect on survival. Although these heterozygous mice exhibit selected vascular phenotypes relevant to the clinical pathology of HHT, the phenotypes are variable and generally quite mild. An alternative approach using conditional knockout mice allows us to study the effects of specific inactivation of either Eng or Acvrl1 at different times in development and in different cell types. These conditional knockout mice provide robust and reproducible models of arteriovenous malformations, and they are currently being used to unravel the causal factors in HHT pathologies. In this review, we will summarize the strengths and limitations of current mouse models of HHT, discuss how knowledge obtained from these studies has already informed clinical care and explore the potential of these models for developing improved treatments for HHT patients in the future.


Modulation of excitatory synaptic transmission by glycine and zinc in cultures of mouse hippocampal neurons.
The monosynaptic EPSP between cultured hippocampal neurons is mediated by activation of 2 classes of excitatory amino acid receptors. Kainate or quisqualate receptors generate a fast conventional EPSP, while NMDA receptors mediate a slow, voltage-sensitive EPSP. Recently, 2 substances have been shown to modulate the activity of the NMDA receptor-channel complex: glycine increases the probability of channel opening, while zinc acts as a noncompetitive antagonist. Since these substances are present in the CNS and thus may function as neuromodulators, we have examined their role in excitatory synaptic transmission in hippocampal cultures using the whole-cell-patch-recording technique. The slow, NMDA-receptor-mediated EPSP was strikingly dependent on the presence of a conditioning substance that gradually accumulated in the extracellular fluid during a 30 min incubation in physiological saline. Washout of the conditioned medium eliminated the slow EPSP, and perfusion with physiological saline containing 1 microM glycine restored the slow EPSP to control levels. Furthermore, conditioned medium collected from astroglial-only cultures also potentiated the response to NMDA. Zinc (20-50 microM) overcame the potentiation of the response by glycine and resulted in a reversible block of the slow EPSP, providing the first evidence for a direct action of zinc on excitatory synaptic transmission. Our results show that the expression of the slow EPSP may be subject to regulation by several endogenous substances: positive modulation by glycine (or a glycine-like substance), which can be released from astroglial cells, and negative modulation by physiological levels of zinc.(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacological studies on the mode of action of flavoxate.
Previous studies on the mode of action of flavoxate have shown that the drug exerts a selective and direct muscle relaxant activity. In order to study the mode of action of flavoxate, the following activities were investigated: calcium blocking, inhibition of cyclic AMP phosphodiesterase (PDE), local anaesthetic activity, the effects on the synthesis and release of prostaglandins. In the K+-depolarized guinea-pig taenia coli, contracted by CaCl2, flavoxate and papaverine showed a moderate calcium antagonistic activity. Anticholinergic drugs, such as atropine and emepronium, did not exert a similar action. The antispasmodic activity of a drug can be correlated with inhibition of cyclic AMP phosphodiesterase, and since papaverine is a potent PDE inhibitor, we tested flavoxate for this activity. Flavoxate exerted a PDE inhibitory activity about three and five times greater than that of aminophylline in tissues homogenates of guinea-pig ureter and urinary bladder, respectively. It also showed the same local anaesthetic activity of lidocaine. Finally, the synthesis and release of prostaglandins by urinary bladder muscle in vitro have been investigated before and after treatment with flavoxate. Myolytic activity of papaverine and flavoxate do not involve inhibition of prostaglandins synthesis in rat urinary bladder in vitro. Therefore, the mode of action of flavoxate can be related to a superimposition of myotropic, calcium antagonistic and local anaesthetic activity.


Endovascular Management for Symptomatic Chronic Mesenteric Ischemia: A Single-Center Experience.
Chronic mesenteric ischemia (CMI) is an uncommon condition encountered by clinicians. Presentation may vary from asymptomatic to classical intestinal ischemia, although a clear pathophysiology has yet to be elucidated. Here, we have presented our institution's experience in the management of symptomatic CMI. From February 2007 to February 2016, a retrospective study was performed of all consecutive patients with symptomatic CMI managed by endovascular treatment (ET). We reviewed these patients' demographics, comorbidities, clinical presentations, and treatment modalities. Perioperative and midterm outcomes included technical success, clinical symptom relief, complications, symptomatic recurrence, mortality, restenosis, and reintervention. Thirty-five mesenteric arteries (74.3% stenotic/25.7% occluded) identified in 32 patients (12 females, 20 males) were treated with endovascular procedures. There were no 30-day deaths; the perioperative complication rate was 12.5%. Overall, the median postprocedural time to symptom relief was 7.6 days (range: 1-30 days). Twenty-two (68.8%) had complete remission of symptom, whereas 7 (21.9%) had partial improvement in symptom after ET. After a mean follow-up of 35.4 (25.9) months, 5 (15.6%) patients developed recurrent symptoms, with 4 requiring reinterventions. The primary patency was 93.7%, 82.6%, and 73.1% at 12, 24, and 36 months, respectively, and the freedom from symptomatic recurrence was 90.6%, 84.0%, 84.0%, and 84.0% at 6, 12, 24, and 36 months, respectively. Endovascular treatment for patients with CMI had a high technical success rate and satisfactory clinical outcomes. Symptomatic recurrence was not frequent but found mainly within 12 months following the initial procedure.


Evaluation of different fast melting disintegrants by means of a central composite design.
Fast-disintegration technologies have encountered increased interest from industries in the past decades. In order to orientate the formulators to the choice of the best disintegrating agent, the most common disintegrants were selected and their ability to quickly disintegrate direct compressed tablets was evaluated. For this study, a central composite design was used. The main factors included were the concentration of disintegrant (X1) and the compression force (X2). These factors were studied for tablets containing either Zeparox or Pearlitol 200 as soluble diluents and six different disintegrants: L-HPC LH11 and LH31, Lycatab PGS, Vivasol, Kollidon CL, and Explotab. Their micromeritics properties were previously determined. The response variables were disintegration time (Y1), tensile strength (Y2), and porosity (Y3). Whatever the diluent, the longest disintegration time is obtained with Vivasol as the disintegrant, while Kollidon CL leads to the shortest disintegration times. Exception for Lycatab PGS and L-HPC LH11, formulations with Pearlitol 200 disintegrate faster. Almost the same results are obtained with porosity: no relevant effect of disintegrant concentration is observed, since porosity is mainly correlated to the compression force. In particular, highest values are obtained with Zeparox as the diluent when compared to Pearlitol 200 and, as the type of disintegrant is concerned, no difference is observed. Tensile strength models have been all statistically validated and are all highly dependent on the compression force. Lycatab PGS concentration does not affect disintegration time, mainly increased by the increase of compression pressure. When Pearlitol 200 is used with Vivasol, disintegration time is more influenced by the disintegrant concentration than by the compression pressure, an increase in concentration leading to a significant and relevant increase of the disintegration time. With Zeparox, the interaction between the two controlled variables is more complex: there is no effect of compression force on the disintegration time for a small amount of disintegrant, but a significant increase for higher concentrations. With Kollidon CL, the main factor influencing the disintegration time is the compression force, rather than the disintegrant concentration. Increasing both the compression force and the disintegrant concentration leads to an increase of the disintegration time. For lower Kollidon CL percentages, the compression pressure increases dramatically the tablet disintegration. With the Explotab, whatever the increase of compression force, the disintegrant concentration leads to an increase of the disintegration time. According to Student's t-test, only the compression force significantly and strongly influences the disintegration time when Pearlitol 200 is used. A slight interaction and some trends nevertheless appear: above 150 MPa, increasing the disintegrant concentration leads to a shortened disintegration time, below this limit the opposite effect is observed.