Efficient screening of marine extracts for protease inhibitors by combining FRET based activity assays and surface plasmon resonance spectroscopy based binding assays.
The screening of extracts from marine organisms is a widely used strategy to discover new drug leads. A common problem in the screening process is the generation of false positive hits through unspecific effects from the complex chemical composition of the crude extracts. In this study, we explored a combination of a fluorescence resonance energy transfer (FRET) based activity assay and a surface plasmon resonance (SPR) based binding assay to avoid this problem. An aqueous extract was prepared from rest raw material of the Norwegian spring spawning herring, and further fractionated by methanol solubility and solid phase extraction. FRET based activity assays were used to determine the influence of each extract on the activity of different proteases. Several extracts showed more than 50% inhibition. The inhibition mechanisms were elucidated by SPR based competition experiments with known inhibitors. For the secreted aspartic proteases 1, 2, 3 and HIV-1 protease, the results indicated that some extracts contain inhibitors interacting specifically with the active site of the enzymes. The study shows that a combination of an activity assay and an SPR based binding assay is a powerful tool to identify potent inhibitors in marine extracts. Furthermore, the study shows that marine vertebrates offer an interesting source for new bioactive compounds, although they have rarely been explored for this purpose.


A rare variant of pilomatricoma: pseudobullous pilomatricoma.
Pilomatricoma (PM; calcifying epithelioma of Malherbe) is a benign tumor originating from the matrix of the hair follicles. Clinical types of the tumor are familial, perforating, multinodular, exophytic, anetodermic, and giant PM. The bullous type is seen only in 3 to 6% of cases. Because the bullous areas detected in PM are filled with lymphatic liquid, some authors use the term pseudobulla. This report presents a 26-year-old female patient that was diagnosed with pseudobullous PM based on clinical, radiologic, and histopathological findings, and the pathogenesis of the bullous appearance of PM is reviewed from the literature.


The general age of leadership: older-looking presidential candidates win elections during war.
As nation-state leaders age they increasingly engage in inter-state militarized disputes yet in industrialized societies a steady decrease in testosterone associated with aging is observed--which suggests a decrease in dominance behavior. The current paper points out that from modern societies to Old World monkeys increasing both in age and social status encourages dominant strategies to maintain acquired rank. Moreover, it is argued this consistency has shaped an implicit prototype causing followers to associate older age with dominance leadership. It is shown that (i) faces of older leaders are preferred during intergroup conflict and (ii) morphing U.S. Presidential candidates to appear older or younger has an overriding effect on actual election outcomes. This indicates that democratic voting can be systematically adjusted by activating innate biases. These findings appear to create a new line of research regarding the biology of leadership and contextual cues of age.


Race differences in emotional adaptation of family caregivers.
This study compares black and white caregivers of persons with Alzheimer's disease (AD) on two general measures of negative and positive emotion (depressive symptoms, positive mood) and two caregiving specific measures of negative and positive emotion (caregiver burden, caregiver satisfaction). We hypothesized that black caregivers would exhibit lower levels of negative emotion and higher levels of positive emotion over time than whites. Three hundred ninety-six caregivers were recruited from the Rush Alzheimer's Disease Center in Chicago, Illinois, as part of a longitudinal study of persons with AD. The analyses for this report are based on data from 307 caregivers who were interviewed quarterly over approximately 4 years from 1999 to 2002, an average of nine observations per person. The results showed that black caregivers reported fewer depressive symptoms over time than whites ( beta = -0.14, p < 0.01) but this finding was only for those caregivers living with the care recipient with AD. No race differences were found for measures of positive emotion. Our data add to the growing body of evidence that blacks have better emotional outcomes when exposed to the stress of providing informal care to a disabled family member.


In Vitro and In Vivo Antioxidative Activity against Radiation-Induced Damage and the Systematic Chemical Components of Different Extracts of Lagotis brevituba Maxim.
Lagotis brevituba Maxim is a perennial species distributed in the highlands of China, which has been used for more than 2000 years as a traditional Tibetan medicinal plant. However, no attention has been paid to the antioxidant activities of Lagotis brevituba Maxim in vitro or in vivo. Thus, this study aimed to evaluate the in vitro and in vivo antioxidant activity of Lagotis brevituba Maxim against radiation-induced damage as well as the systematic chemical components. To explore the relationship between the antioxidant activity and extraction solvent, Lagotis brevituba Maxim was extracted with three different solvents: methanol, water, and acetone. In antioxidant assays in vitro, the water extract had the strongest reducing power, 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity compared with the methanol and acetone extracts. However, the methanol extract was more potent in the β-carotene/linoleic acid cooxidation assay. In antioxidant assays in vivo, mice that were exposed to 6.0 Gy60Co γ-ray whole-body radiation on day 15 after administration of Lagotis brevituba Maxim decreased their level of malondialdehyde (MDA) in a dose-dependent manner compared with the control group, indicating that Lagotis brevituba Maxim had favorable antioxidant activities in vivo. In addition, a total of 44 compounds were tentatively identified by liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS/MS), including 19 flavonoids, 14 phenols, 8 phenylethanoid glycosides, 2 iridoid glycosides, and 1 carbohydrate. We obtained 25 compounds from plants in the genus Lagotis for the first time. These results suggested that Lagotis brevituba Maxim had potent antioxidant activity and could be explored as a novel natural antioxidant.


Revalidation of the Perceptions of Conscience Questionnaire (PCQ) and the Stress of Conscience Questionnaire (SCQ).
The Perceptions of Conscience Questionnaire (PCQ) and the Stress of Conscience Questionnaire (SCQ) have previously been developed and validated within the 'Stress of Conscience Study'. The aim was to revalidate these two questionnaires, including two additional, theoretically and empirically significant items, on a sample of healthcare personnel working in direct contact with patients. The sample consisted of 503 healthcare personnel. To test variation and distribution among the answers, descriptive statistics, item analysis and principal component analysis (PCA) were used to examine the underlying factor structure of the questionnaires. Support for adding the new item to the PCQ was found. No support was found for adding the new item to the SCQ. Both questionnaires can be regarded as valid for Swedish settings but can be improved by rephrasing some of the PCQ items and by adding items about private life to the SCQ.


In Vitro Systems for Toxicity Evaluation of Microbial Volatile Organic Compounds on Humans: Current Status and Trends.
Microbial volatile organic compounds (mVOC) are metabolic products and by-products of bacteria and fungi. They play an important role in the biosphere: They are responsible for inter- and intra-species communication and can positively or negatively affect growth in plants. But they can also cause discomfort and disease symptoms in humans. Although a link between mVOCs and respiratory health symptoms in humans has been demonstrated by numerous studies, standardized test systems for evaluating the toxicity of mVOCs are currently not available. Also, mVOCs are not considered systematically at regulatory level. We therefore performed a literature survey of existing in vitro exposure systems and lung models in order to summarize the state-of-the-art and discuss their suitability for understanding the potential toxic effects of mVOCs on human health. We present a review of submerged cultivation, air-liquid-interface (ALI), spheroids and organoids as well as multi-organ approaches and compare their advantages and disadvantages. Furthermore, we discuss the limitations of mVOC fingerprinting. However, given the most recent developments in the field, we expect that there will soon be adequate models of the human respiratory tract and its response to mVOCs.


Recommendations for diagnosing STIC: a systematic review and meta-analysis.
Our understanding of the oncogenesis of high-grade serous cancer of the ovary and its precursor lesions, such as serous tubal intraepithelial carcinoma (STIC), has significantly increased over the last decades. Adequate and reproducible diagnosis of these precursor lesions is important. Diagnosing STIC can have prognostic consequences and is an absolute requirement for safely offering alternative risk reducing strategies, such as risk reducing salpingectomy with delayed oophorectomy. However, diagnosing STIC is a challenging task, possessing only moderate reproducibility. In this review and meta-analysis, we look at how pathologists come to a diagnosis of STIC. We performed a literature search identifying 39 studies on risk reducing salpingo-oophorectomy in women with a known BRCA1/2 PV, collectively reporting on 6833 patients. We found a pooled estimated proportion of STIC of 2.8% (95% CI, 2.0-3.7). We focused on reported grossing protocols, morphological criteria, level of pathologist training, and the use of immunohistochemistry. The most commonly mentioned morphological characteristics of STIC are (1) loss of cell polarity, (2) nuclear pleomorphism, (3) high nuclear to cytoplasmic ratio, (4) mitotic activity, (5) pseudostratification, and (6) prominent nucleoli. The difference in reported incidence of STIC between studies who totally embedded all specimens and those who did not was 3.2% (95% CI, 2.3-4.2) versus 1.7% (95% CI, 0.0-6.2) (p 0.24). We provide an overview of diagnostic features and present a framework for arriving at an adequate diagnosis, consisting of the use of the SEE-FIM grossing protocol, evaluation by a subspecialized gynecopathologist, rational use of immunohistochemical staining, and obtaining a second opinion from a colleague.


Societal Preferences for EQ-5D Health States from a Brazilian Population Survey.
To elicit preference weights for a subset of EuroQol five-dimensional (EQ-5D) questionnaire health states from a representative sample for the state of Minas Gerais, Brazil, using a time trade-off (TTO) method and to analyze these data so as to estimate social preference weights for the complete set of 243 states. Data came from a valuation study with 3362 literate individuals aged between 18 and 64 years living in urban areas. The present study was based on quota sampling by age and sex. Face-to-face interviews were conducted in participants' own homes. A total of 99 EQ-5D questionnaire health states were selected, presorted into 26 blocks of six unique health states. Each participant valued one block together with the full health, worst health, and dead states. Each health state was evaluated by more than 100 individuals. TTO data were modeled at both individual and aggregate levels by using ordinary least squares and random effects methods. Values estimated by different models yielded very similar results with satisfactory goodness-of-fit statistics: the mean absolute error was around 0.03 and fewer than 25% of the states had a mean absolute error greater than 0.05. Dummies coefficients for each level within the EQ-5D questionnaire dimensions of health displayed an internally consistent ordering, with the mobility dimension demonstrating the largest value decrement. The values of mean observed transformed TTO values range from 0.869 to-0.235. The study demonstrates the feasibility of conducting face-to-face interviews using TTO in a Brazilian population setting. The estimated values for EQ-5D questionnaire health states based on this Minas Gerais survey represent an important first step in establishing national Brazilian social preference weights for the EQ-5D questionnaire.


Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells.
The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for the treatment of cancer. In this study, we show that proteasome inhibitor MG-132 suppressed gastric cancer cell proliferation and induced macroautophagy. The induction of macroautophagy was evidenced by the formation of LC3(+) autophagosomes and the accumulation of acidic vesicular organelles and autolysosomes and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Abolition of macroautophagy by knockdown of Class III phosphatidylinositol-3 kinase Vps34 or ATG5/7 sensitized gastric cancer cells to the antiproliferative effect of MG-132 by promoting G(2)/M cell cycle arrest. In addition, MG-132 increased ERK phosphorylation whose inhibition by MEK inhibitor significantly enhanced the antiproliferative effect of proteasome inhibition. To conclude, this study demonstrates that macroautophagy and ERK phosphorylation serve as protective mechanisms to counteract the antiproliferative effect of proteasome inhibition. This discovery may have implications for the application of proteasome-directed therapy for the treatment of cancer.


beta-Endorphin and adrenocorticotropin are selected concomitantly by the pituitary gland.
The opiate-like peptide beta-endorphin and adrenocorticotropin are concomitantly secreted in increased amounts by the adenohypophysis in response to acute stress or long-term adrenalectomy as well as in vitro in response to purified corticotropin releasing factor and other secretagogues. Conversely, administration of the synthetic glucocorticoid dexamethasone inhibits the secretion of both adrenocorticotropin and beta-endorphin. Thus, both hormones possess common and identical regulatory mechanisms and there may be a functional role for circulating beta-endorphin.


Gender Differences in the Relationship Between Financial Stress and Metabolic Abnormalities.
Financial stress is associated with higher prevalence of metabolic abnormalities and cardiovascular disease, but the extent to which this association differs by type of metabolic abnormalities or gender is unclear. The study aims were (a) to examine the association between financial stress and the prevalence of common metabolic abnormalities and (b) to test the association for gender differences. A cross-sectional secondary analysis was conducted using data from the Retirement and Sleep Trajectories study, an ancillary study of the Wisconsin Sleep Cohort study. Composite indicator structural equation alpha modeling with a stacking approach was applied in the data analysis. After controlling for covariates, financial stress was positively associated with the prevalence of abdominal obesity, metabolic syndrome, and dyslipidemia, with significant gender differences. Among men, financial stress was positively associated with the prevalence of hypertriglyceridemia. Among women, financial stress was positively associated with the prevalence of prediabetes, abdominal obesity, metabolic syndrome, and dyslipidemia. Men living with financial stress are more likely to have hypertriglyceridemia, a specific metabolic abnormality and risk factor for acute cardiovascular events. However, financial stress in women is associated with a broader array of metabolic abnormalities (e.g., dyslipidemia, prediabetes, abdominal obesity, metabolic syndrome), highlighting a potential risk of multiple chronic conditions later in life.


Effects of dietary stachyose levels on caecal skatole concentration, hepatic cytochrome P450 mRNA expressions and enzymatic activities in broilers.
Effects of dietary supplemental stachyose on caecal skatole concentration, hepatic cytochrome P450 (CYP450, CYP) mRNA expressions and enzymatic activities in broilers were evaluated. Arbor Acre commercial mixed male and female chicks were assigned randomly into six treatments. The positive control (PC) diet was based on maize-soyabean meal, and the negative control (NC) diet was based on maize-non-soyabean meal. The NC diet was then supplemented with 4, 5, 6 and 7 g/kg stachyose to create experimental diets, named S-4, S-5, S-6 and S-7, respectively. Each diet was fed to six replicates of ten birds from days 1 to 49. On day 49, the caecal skatole concentrations in the PC, S-4, S-5, S-6 and S-7 groups were lower than those in the NC group by 42·28, 23·68, 46·09, 15·31 and 45·14 % (P < 0·01), respectively. The lowest pH value was observed in the S-5 group (P < 0·05). The stachyose-fed groups of broilers had higher caecal acetate and propionate levels compared with control groups, and propionate levels in the S-6 and S-7 groups were higher than those in the S-4 and S-5 groups (P < 0·001). The highest CYP3A4 expression was found in the S-7 group (P < 0·05), but this was not different from PC, S-4, S-5 and S-6 treatments. There was no significant difference in CYP450 (1A2, 2D6 and 3A4) enzymatic activities among the groups (P > 0·05). In conclusion, caecal skatole levels can be influenced by dietary stachyose levels, and 5 g/kg of stachyose in the diet was suggested.


Preoperative fasting induces protection against renal ischemia/reperfusion injury by a corticosterone-independent mechanism.
Three days of fasting protects mice against lethal renal ischemia-reperfusion (I/R) injury. We hypothesize that the protection imposed by fasting is mediated by increased levels of corticosterone, induced by the stress of food deprivation. C57Bl/6 mice were fasted for 3 days after which serum corticosterone levels were determined. Mice underwent a bilateral adrenalectomy (ADX). Ten days later, they were either fasted or given a corticosterone receptor antagonist while fasting. Bilateral renal I/R injury was induced by clamping the artery and vein of the left and right kidney simultaneously for 37 min. Survival and kidney function were determined. Fasting significantly increased corticosterone levels. Only 8% of the ADX mice which were fasted prior to I/R injury survived, whereas all sham-ADX operated mice survived I/R injury after fasting. After ADX and fasting, 70% of the mice subjected to sham I/R succumbed to the surgical procedure. After fasting with concomitant blockade of the glucocorticoid receptor all animals survived renal I/R. Three days of fasting protects against I/R injury and increases serum corticosterone levels. ADX renders mice incapable of withstanding subsequent abdominal surgery. Glucocorticoid receptor blockade does not interfere with the protective effects of fasting. Thus, the protection against renal I/R injury induced by preoperative fasting is mediated by corticosterone-independent mechanisms.


Development of a Real-Time Thermoplastic Mask Compression Force Monitoring System Using Capacitive Force Sensor.
Purpose: Thermoplastic masks keep patients in an appropriate position to ensure accurate radiation delivery. For a thermoplastic mask to maintain clinical efficacy, the mask should wrap the patient's surface properly and provide uniform pressure to all areas. However, to our best knowledge, no explicit method for achieving such a goal currently exists. Therefore, in this study, we intended to develop a real-time thermoplastic mask compression force (TMCF) monitoring system to measure compression force quantitatively. A prototype system was fabricated, and the feasibility of the proposed method was evaluated. Methods: The real-time TMCF monitoring system basically consists of four force sensor units, a microcontroller board (Arduino Bluno Mega 2560), a control PC, and an in-house software program. To evaluate the reproducibility of the TMCF monitoring system, both a reproducibility test using a micrometer and a setup reproducibility test using a head phantom were performed. Additionally, the reproducibility tests of mask setup and motion detection tests were carried out with a cohort of six volunteers. Results: The system provided stable pressure readings in all 10 trials during the sensor unit reproducibility test. The largest standard deviation (SD) among trials was about 36 gf/cm2 (∼2.4% of the full-scale range). For five repeated mask setups on the phantom, the compression force variation of the mask was less than 39 gf/cm2 (2.6% of the full-scale range). We were successful in making masks together with the monitoring system connected and demonstrated feasible utilization of the system. Compression force variations were observed among the volunteers and according to the location of the sensor (among forehead, both cheekbones, and chin). The TMCF monitoring system provided the information in real time on whether the mask was properly pressing the human subject as an immobilization tool. Conclusion: With the developed system, it is possible to monitor the effectiveness of the mask in real time by continuously measuring the compression force between the mask and patient during the treatment. The graphical user interface (GUI) of the monitoring system developed provides a warning signal when the compression force of the mask is insufficient. Although the number of volunteers participated in the study was small, the obtained preliminary results suggest that the system could ostensibly improve the setup accuracy of a thermoplastic mask.


Carvedilol: just another Beta-blocker or a powerful cardioprotector?
Beta-blockers have been used to treat ischemic heart disease, due to negative chronotropic and inotropic properties, thus inducing a decrease in myocardial consumption of oxygen and nutrients, allowing a better balance between nutritional needs and the supply provided by the coronary blood flow. Recent developments in cell biology allowed us to understand that not all beta-blockers are equal, as their intracellular mechanisms of action can be very different. This paper will focus on carvedilol, a non-selective beta-blocker with alfa-blocker properties, currently used to treat hypertension, heart failure and coronary artery disease. Effects of carvedilol on cardiac mitochondria, their relation to its antioxidant properties, and how these can improve cardiomyocyte resistance to aggression and cardiac function will be discussed. We will begin by depicting the effect of carvedilol on mitochondrial parameters, namely oxidative phosphorylation, calcium homeostasis and energy production. Then we will focus on the mitochondrial permeability transition (MPT) and how the antioxidant properties of carvedilol can be used to minimize oxidative stress, a powerful inducer of MPT. Carvedilol will also be highlighted as an enzyme modulator, focusing on its importance to prevent doxorubicin (DOX) cardiotoxicity. The mitochondrial-related mechanism of cardioprotection involving carvedilol will also be addressed, as we will discuss some clinical pieces of evidence showing the importance of mechanisms previously depicted. In conclusion, based upon its molecular mechanisms of action, carvedilol seems to be a unique beta-blocker. These unique characteristics can help us understand the positive impact of carvedilol on the prognosis of patients with heart disease.


The aminopeptidase activity in the human T-cell lymphoma line (Jurkat) is not at the cell surface and is not aminopeptidase N (CD-13).
Although lymphocytes are CD-13-negative and therefore should not express the ectoenzyme aminopeptidase N (AP-N), there have been a number of reports suggesting the presence of a cell-surface aminopeptidase with many similarities to AP-N. We have determined aminopeptidase activity with 4-methyl-7-coumarylamide (NMec) derivatives of alanine, leucine, lysine and arginine in Jurkat cells (a human T-cell lymphoma line) and in HL60 cells (a CD-13-positive myeloid leukaemia line) and compared the activities with those of purified pig AP-N and human renal microvillar membranes. Jurkat cell aminopeptidase activity doubled on disrupting the cells and the sensitivity to amastatin increased. When the cells were fractionated only 4% of the activity was recovered in the membrane fraction, compared with 87% recovery for alkaline phosphatase. The profile of activities for intact Jurkat cells was Leu > Ala > Lys > Arg, changing in the cytosolic fraction to Lys > or = Arg > Leu = Ala; the profiles for intact HL60 cells and AP-N were identical, namely Ala > Leu > Arg > Lys. The Km values for the hydrolysis of Ala-NMec and Leu-NMec by Jurkat cells were 65 microM and 11 microM, in each case some 6-fold lower than those for AP-N. The pH-activity curves for the hydrolysis of Ala-NMec by Jurkat cells and human renal microvillar membranes were displaced by almost 1 pH unit and the activity was not sensitive to the anionic composition of the buffers. However, a 3-fold activation of the cytosolic activity by 0.1 M NaCl was observed with Arg-NMec as substrate. With Ala-NMec as substrate, the sensitivity of the aminopeptidase activity to inhibitors increased markedly after disrupting the cells, but still differed from that observed with purified pig AP-N; the concentrations giving 50% inhibition were as follows (values for AP-N in parentheses): amastatin. 28 nM (150 nM); bestatin, 12 microM (43 microM), probestin, 100 nM (< 10 nM), puromycin, 30 microM (> 1 mM). Anion exchange chromatography on Mono Q revealed two activities: that of peak I preferentially hydrolysed Arg-NMec, was activated by NaCl and was insensitive to amastatin; while that of peak II was strongly inhibited by amastatin and had a broad specificity.(ABSTRACT TRUNCATED AT 400 WORDS)


Indolethylamine-N-methyltransferase Polymorphisms: Genetic and Biochemical Approaches for Study of Endogenous N,N,-dimethyltryptamine.
N,N-dimethyltryptamine (DMT) is a powerful serotonergic psychedelic whose exogenous administration elicits striking psychedelic effects in humans. Studies have identified DMT and analogous compounds (e.g., 5-hydroxy-DMT, 5-methoxy-DMT) alongside of an enzyme capable of synthesizing DMT endogenously from tryptamine, indolethylamine-N-methyltransferase (INMT), in human and several other mammalian tissues. Subsequently, multiple hypotheses for the physiological role of endogenous DMT have emerged, from proposed immunomodulatory functions to an emphasis on the overlap between the mental states generated by exogenous DMT and naturally occurring altered states of consciousness; e.g., schizophrenia. However, no clear relationship between endogenous DMT and naturally occurring altered states of consciousness has yet been established from in vivo assays of DMT in bodily fluids. The advent of genetic screening has afforded the capability to link alterations in the sequence of specific genes to behavioral and molecular phenotypes via expression of identified single nucleotide polymorphisms (SNPs) in cell and animal models. As SNPs in INMT may impact endogenous DMT synthesis and levels via changes in INMT expression and/or INMT structure and function, these combined genetic and biochemical approaches circumvent the limitations of assaying DMT in bodily fluids and may augment data from prior in vitro and in vivo work. Therefore, all reported SNPs in INMT were amassed from genetic and biochemical literature and genomic databases to consolidate a blueprint for future studies aimed at elucidating whether DMT plays a physiological role.


The usefulness of x-ray computed tomography for the diagnosis of myocardial infarction.
Conventional and enhanced computed tomographic (CT) examinations were performed in 103 patients with myocardial infarction for evaluation of the diagnostic usefulness of CT. After intravenous bolus injection of contrast material, an initial filling defect and late enhancement of the infarcted myocardium appeared on the cardiac CT images. These two findings were direct evidence of myocardial infarction; the former was found mostly in the patient with recent myocardial infarctions, and the latter was recognized both in those with recent and those with "remote" infarctions. Wall thinning at the site of infarction was found by enhanced CT mostly in patients with anteroseptal or extensive anterior infarctions, and was rarely found in patients with inferoposterior infarctions. Left ventricular aneurysms and ventricular thrombi were found by enhanced CT in 39 and 23 of the 103 subjects, respectively, and the sensitivity of CT in detecting intracardiac thrombi was higher than that of two-dimensional echocardiography. Calcification of the myocardium and pericardial effusion associated with myocardial infarction were also detected by conventional nonenhanced CT. Thus, cardiac CT was found to be a useful test in evaluating patients with myocardial infarction.


Comparative analysis of free radical scavenging potential of several fruit peel extracts by in vitro methods.
We studied the radical scavenging potential of several fruit peel extracts using various standard chemical and biochemical in vitro methods. Peel extracts of C. sinensis (CS), P. granatum (PG), M. paradisiaca (MP), C. vulgaris (CV), C. melo (CM), M. indica (MI), and C. papaya (CP) were used in the present study and butylated hydroxyl anisole (BHA) was used as a standard. Marked 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity was observed with 25 μg/mL of CS and MP and 50 μg/mL of PG, while all the studied doses of CP were found to be pro-oxidative. β-Carotene bleaching revealed a higher singlet oxygen scavenging potential of all the peel extracts except MI. High NO-radical scavenging activity was observed at 25 μg/mL of PG and MP. Inhibition test of H2O2-induced LPO in erythrocytes or in liver tissue showed that all the peels tested were effective on peroxy-radicals at one or other doses. The present study revealed the radical scavenging activity of the test peel extracts in a manner that was dose- and radical/methodspecific. Therefore, evaluation of the efficacy of herbal extracts should be carried out using different methods and not merely a single in vitro method.


Investigation of Atrial Vortices Using a Novel Right Heart Model and Possible Implications for Atrial Thrombus Formation.
The main aim of this paper is to characterize vortical flow structures in the healthy human right atrium, their impact on wall shear stresses and possible implications for atrial thrombus formation. 3D Particle Tracking Velocimetry is applied to a novel anatomically accurate compliant silicone right heart model to study the phase averaged and fluctuating flow velocity within the right atrium, inferior vena cava and superior vena cava under physiological conditions. We identify the development of two vortex rings in the bulk of the right atrium during the atrial filling phase leading to a rinsing effect at the atrial wall which break down during ventricular filling. We show that the vortex ring formation affects the hemodynamics of the atrial flow by a strong correlation (ρ = 0.7) between the vortical structures and local wall shear stresses. Low wall shear stress regions are associated with absence of the coherent vortical structures which might be potential risk regions for atrial thrombus formation. We discuss possible implications for atrial thrombus formation in different regions of the right atrium.


Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women.
Concerns have been raised over possible adverse effects of prophylactic antiretroviral therapy (ART) on the fetus and newborn. We analyzed data relating to uninfected children enrolled in the European Collaborative Study and investigated the association between ART exposure, perinatal problems, and major adverse health events later in life. Median length of follow-up was 2.2 (0-15.9) years. Of the 2414 uninfected children, 687 (28%) were exposed to ART in all three periods (antenatal, intrapartum, and neonatal). Of the 1008 infants exposed to ART at any time, 906 (90%) were exposed antenatally, 840 (83%) neonatally, and 750 (74%) both antenatally and neonatally. ART exposure was not significantly associated with pattern or prevalence of congenital abnormalities or low birth weight. In multivariate analysis, prematurity was associated with exposure to combination therapy without a protease inhibitor (PI) (OR = 2.66; 95% CI: 1.52-4.67) and with a PI (OR = 4.14; 95% CI: 2.36-7.23). ART exposure was associated with anemia in early life ( <.001). There was no evidence of an association with clinical manifestations suggestive of mitochondrial abnormalities. The absence of serious adverse events in this large cohort of uninfected children exposed to prophylactic ART in the short to medium term is reassuring.


Ultrasound Markers of Carotid Atherosclerosis and Cognition: The Northern Manhattan Study.
Ultrasound markers of carotid atherosclerosis may be related to cognitive status. We hypothesized that individuals with greater carotid intima-media thickness (cIMT) and carotid plaque burden would exhibit worse cognition. One thousand one hundred sixty-six stroke-free participants from the NOMAS (Northern Manhattan Study) underwent carotid ultrasound and neuropsychological examination. Among them, 826 underwent a second neuropsychological examination an average of 5 years later. cIMT and plaque were assessed by a standardized B-mode ultrasound imaging and reading protocol. We used multivariable linear regression to examine cIMT, carotid plaque presence, and carotid plaque area as correlates of domain-specific neuropsychological Z scores cross-sectionally and over time. We also investigated possible effect modification by APOE ε4 allele, age, and race/ethnicity. Participants had a mean (SD) age of 70 (9) years and were 60% women, 66% Hispanic, 15% white, and 18% black. Those with greater cIMT exhibited worse episodic memory after adjustment for demographics and vascular risk factors (β=-0.60; P=0.04). APOE ε4 carriers with greater cIMT exhibited worse episodic memory (β=-1.31; P=0.04), semantic memory (β=-1.45; P=0.01), and processing speed (β=-1.21; P=0.03). Participants with greater cIMT at baseline did not exhibit significantly greater cognitive decline after adjustment. APOE ε4noncarriers with greater cIMT exhibited greater declines in executive function (β=-0.98; P=0.06). Carotid plaque burden was not significantly associated with cognition at baseline or over time. Subclinical carotid atherosclerosis was associated with worse cognition among those at higher risk for Alzheimer disease. Interventions targeting early stages of atherosclerosis may modify cognitive aging.


Early veterinary history in the United States of America.
Those involved in the early history of veterinary medicine in the United States of America provided valuable services and an excellent foundation for later development of the profession. Even though the farriers and cowleeches had little knowledge, and occasionally less ethics, most performed as best they could. Certainly, the medical profession contributed greatly to the success of the American veterinary profession. Furthermore, the influence of British veterinarians and their publications added much to improving the profession. Perhaps the greatest accomplishment for the betterment of the profession was the establishment of the United States Veterinary Medical Association. Once the practicing veterinarians in the United States became organized and concerned, the profession appeared to develop rapidly providing both educational opportunities and pride in veterinary medicine.


[All that neurologist would like to know about sensitivity, specificity and predictive values].
The aim of the diagnostic process is to establish the prevalence or probability of a disease given a clinical picture. A diagnostic test could be considered as every piece of information obtained from a patient. Diagnostic test can be done throughout technical devices, medical examinations or questionnaire. The diagnostic test offers information that allows us to classify patients according a different probability to be sick. The operative validity of a test can be done in terms of diagnostic accuracy. It means the ability to truly classify a patient in the right clinical situation. Diagnostic accuracy is the quality of the information provided by a test (sensitivity, specificity). Diagnostic usefulness is the practical value of the provided information. The predictive value of a diagnostic test depends on its accuracy and the prevalence of the disease in the setting where the diagnostic process is to be made. Decision making with the information provided by the test implies to consider the consequences of the false result.


The adolescent with simple or corrected congenital heart disease.
An ever-increasing number of congenital heart disease patients are surviving into and beyond adolescence. Despite the encouraging cardiac results, with the vast majority asymptomatic and requiring no medication and having few, if any, limitations, there are many challenges for this patient population. They are likely to find obstacles to attaining education, social development, health and life insurance, and employment. Most of these obstacles are attributable to the stresses upon children with congenital heart disease and their families, and the prejudices of a society that knows little about congenital heart disease. Practitioners caring for these young people must be familiar with these issues and knowledgeable about the facts of individual cases, so that they may anticipate needs and offer support to their patients in their progress toward adulthood.


Influence of cytostatics on some platelet functions in vitro. V. Hydroxyurea.
Hydroxyurea added to citrated platelet-rich plasma in vitro did not influence the aggregation of the platelets, their adhesion to glass, their release of aggregating activity, platelet factor 4 or availability of platelet factor 3. Neither did it have any effect on the uptake of 14C-serotonin, the reptilase clot retraction or the coagulation system.


Evaluating factors influencing customers' intention to eat Korean cuisine "Samgyeopsal" in the Philippines: A structural equation model forest classifier approach.
Samgyeopsal has become a widely popular cuisine in the Philippines since 2014. The rise of Samgyeopsal is evident worldwide as it is available in countries such as the United States, Northern, and Southern Asia. This study aimed to explore the intention to eat Samgyeopsal during the COVID-19 pandemic utilizing structural equation modeling and random forest classifier. With a total of 1014 responses collected online, the result showed that utilitarian and hedonic motivation, Korean influence, and attitude led to very high actual behavior in east Samgyeopsal in the Philippines. Moreover, subjective norm, perceived behavioral control, and intention led to significant results influencing intention to actual behavior. Lastly, the COVID-19 safety protocol showed the least significant result. This study is the first study that evaluated the intention of consumers to eat Samgyeopsal in the Philippines during the COVID-19 pandemic. The results of this study would be beneficial to Korean BBQ restaurateurs and the further development of their marketing strategies even in other countries. Finally, the model construct of this study can be extended and applied in evaluating the consumers' eating intention toward other varieties of food or cuisines worldwide.


Vitamin C as a Modulator of the Response to Cancer Therapy.
Ascorbic acid (vitamin C) has been gaining attention as a potential treatment for human malignancies. Various experimental studies have shown the ability of pharmacological doses of vitamin C alone or in combinations with clinically used drugs to exert beneficial effects in various models of human cancers. Cytotoxicity of high doses of vitamin C in cancer cells appears to be related to excessive reactive oxygen species generation and the resulting suppression of the energy production via glycolysis. A hallmark of cancer cells is a strongly upregulated aerobic glycolysis, which elevates its relative importance as a source of ATP (Adenosine 5'-triphosphate). Aerobic glycolysis is maintained by a highly increased uptake of glucose, which is made possible by the upregulated expression of its transporters, such as GLUT-1, GLUT-3, and GLUT-4. These proteins can also transport the oxidized form of vitamin C, dehydroascorbate, permitting its preferential uptake by cancer cells with the subsequent depletion of critical cellular reducers as a result of ascorbate formation. Ascorbate also has a potential to affect other aspects of cancer cell metabolism due to its ability to promote reduction of iron(III) to iron(II) in numerous cellular metalloenzymes. Among iron-dependent dioxygenases, important targets for stimulation by vitamin C in cancer include prolyl hydroxylases targeting the hypoxia-inducible factors HIF-1/HIF-2 and histone and DNA demethylases. Altered metabolism of cancer cells by vitamin C can be beneficial by itself and promote activity of specific drugs.


[Metastatic Crohn's disease involving the penile foreskin].
To describe the case of the patient with history of Crohn's disease presenting metastatic extension to the penile foreskin. Circumcision was carried out and the skin was sent to the pathology department. Pathologic study of the specimen showed an ulcerated granuloma without caseum, typically associated with metastatic Crohn's disease. After one year of follow-up there is no evidence of recurrence. Crohn's disease is a disease of unknown origin, the main characteristic of which is the development of non necrotizing granulomas that may involved not only the gastrointestinal tract. When the extraintestinal involvement is not produced by continuity we call it metastatic disease. Such metastases may be found in the genitourinary tract, and other sites. This involvement may include lithiasis, amyloidosis, ... and the presence of lesions in the genital skin, as in our case.


[Clinical importance of determination of lipid peroxidation of erythrocyte membrane in children with mucoviscidosis].
The intensity of membranous red blood cell metabolism (lipid peroxidation /LPO/ and malonic dialdehyde /MDA/ metabolism) was examined in children suffering from mucoviscidosis depending on the gravity of the clinical manifestations of the disease. The membranopathological processes accompanied by different disorders of membranous metabolism, depending on the patient's status gravity and the intensity of inflammation in the respiratory organs were revealed. Based on the disagreement between different parameters that characterize LPO of red blood cells and MDA metabolism the conclusion is drawn that in children with mucoviscidosis, the metabolic processes occurring at the level of cellular membranes are not balanced. The data obtained point to the necessity of an individual approach to the use of membranoprotectors in multimodality treatment of children with mucoviscidosis together with the control over the treatment efficacy on the basis of a dynamic follow-up of membranous LPO with the aid of the method employed in the work.


Pregnenolone sulphate-independent inhibition of TRPM3 channels by progesterone.
Transient Receptor Potential Melastatin 3 (TRPM3) is a widely expressed calcium-permeable non-selective cation channel that is stimulated by high concentrations of nifedipine or by physiological steroids that include pregnenolone sulphate. Here we sought to identify steroids that inhibit TRPM3. Channel activity was studied using calcium-measurement and patch-clamp techniques. Progesterone (0.01-10μM) suppressed TRPM3 activity evoked by pregnenolone sulphate. Progesterone metabolites and 17β-oestradiol were also inhibitory but the effects were relatively small. Dihydrotestosterone was an inhibitor at concentrations higher than 1μM. Corticosteroids lacked effect. Overlay assays indicated that pregnenolone sulphate, progesterone and dihydrotestosterone bound to TRPM3. In contrast to dihydrotestosterone, progesterone inhibited nifedipine-evoked TRPM3 activity or activity in the absence of an exogenous activator, suggesting a pregnenolone sulphate-independent mechanism of action. Dihydrotestosterone, like a non-steroid look-alike compound, acted as a competitive antagonist at the pregnenolone sulphate binding site. Progesterone inhibited endogenous TRPM3 in vascular smooth muscle cells. Relevance of TRPM3 or the progesterone effect to ovarian cells, which have been suggested to express TRPM3, was not identified. The data further define a chemical framework for competition with pregnenolone sulphate at TRPM3 and expand knowledge of steroid interactions with TRPM3, suggesting direct steroid binding and pregnenolone sulphate-independent inhibition by progesterone.


[Peripheral fundus changes in subjects with healthy eyes (pilots)].
Over a period of one year in 1980 2451 pilots between 25 and 41 years of age and 674 pilot recruits between 18 and 24 years of age were examined ophthalmologically. All the subjects tested had a visual acuity of 20/20 or better. Of this population, 16% wore glasses with refractive powers ranging up to +4.0 to -1.5 D. Fundus examination revealed microaneurysms in 8%, chorioretinal scars in 6%, paving-stones in 5%, pigmented nevi of the choroid in 4.2% and hypertrophies of the retinal pigment epithelium in 1.3%. White without pressure was seen in 11%. The incidence of formations predisposing to retinal breaks (lattice degeneration and snail tracks 9.1%, round retinal holes 1.5%) was comparable to that of other populations examined by other authors.


Vaccinia virus recombinant expressing herpes simplex virus type 1 glycoprotein D prevents latent herpes in mice.
In humans, herpes simplex virus causes a primary infection and then often a latent ganglionic infection that persists for life. Because these latent infections can recur periodically, vaccines are needed that can protect against both primary and latent herpes simplex infections. Infectious vaccinia virus recombinants that contain the herpes simplex virus type 1 (HSV-1) glycoprotein D gene under control of defined early or late vaccinia virus promoters were constructed. Tissue culture cells infected with these recombinant viruses synthesized a glycosylated protein that had the same mass (60,000 daltons) as the glycoprotein D produced by HSV-1. Immunization of mice with one of these recombinant viruses by intradermal, subcutaneous, or intraperitoneal routes resulted in the production of antibodies that neutralized HSV-1 and protected the mice against subsequent lethal challenge with HSV-1 or HSV-2. Immunization with the recombinant virus also protected the majority of the mice against the development of a latent HSV-1 infection of the trigeminal ganglia. This is the first demonstration that a genetically engineered vaccine can prevent the development of latency.


Mitochondrial Dysfunction is a Key Pathway that Links Saturated Fat Intake to the Development and Progression of NAFLD.
Non-Alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and is characterized by fat accumulation in the liver. Hypercaloric diets generally increase hepatic fat accumulation, whereas hypocaloric diets decrease liver fat content. In addition, there is evidence to suggest that moderate amounts of unsaturated fatty acids seems to be protective for the development of a fatty liver, while consumption of saturated fatty acids (SFA) appears to predispose toward hepatic steatosis. Recent studies highlight a key role for mitochondrial dysfunction in the development and progression of NAFLD. It is proposed that changes in mitochondrial structure and function are key mechanisms by which SFA lead to the development and progression of NAFLD. In this review, it is described how SFA intake is associated with liver steatosis and decreases the efficiency of the respiratory transport chain. This results in the production of reactive oxygen species and damage to nearby structures, eventually leading to inflammation, apoptosis, and scarring of the liver. Furthermore, studies demonstrating that SFA intake affects the composition of mitochondrial membranes are presented, and this process accelerates the progression of NAFLD. It is likely that events are intertwined and reinforce each other, leading to a constant deterioration in health.


Suppression of peripheral sympathetic activity underlies protease-activated receptor 2-mediated hypotension.
Protease-activated receptor (PAR)-2 is expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although some reports have suggested involvement of a neurogenic mechanism in PAR-2-induced hypotension, the accurate mechanism remains to be elucidated. To examine this possibility, we investigated the effect of PAR-2 activation on smooth muscle contraction evoked by electrical field stimulation (EFS) in the superior mesenteric artery. In the present study, PAR-2 agonists suppressed neurogenic contractions evoked by EFS in endothelium-denuded superior mesenteric arterial strips but did not affect contraction elicited by the external application of noradrenaline (NA). However, thrombin, a potent PAR-1 agonist, had no effect on EFS-evoked contraction. Additionally, ω-conotoxin GVIA (CgTx), a selective N-type Ca(2+) channel (ICa-N) blocker, significantly inhibited EFS-evoked contraction, and this blockade almost completely occluded the suppression of EFS-evoked contraction by PAR-2 agonists. Finally, PAR-2 agonists suppressed the EFS-evoked overflow of NA in endothelium-denuded rat superior mesenteric arterial strips and this suppression was nearly completely occluded by ω-CgTx. These results suggest that activation of PAR-2 may suppress peripheral sympathetic outflow by modulating activity of ICa-N which are located in peripheral sympathetic nerve terminals, which results in PAR-2-induced hypotension.


Spontaneous formation of nanosized unilamellar polyion complex vesicles with tunable size and properties.
Fabrication of monodispersed, submicrometer-sized vesicles (nanosomes) that form through self-assembly possessing a thin and permeable membrane remains a significant challenge. Conventional fabrication of nanosomes through self-assembly of amphiphilic molecules often requires cumbersome processes using organic solvents combined with physical procedures (e.g., sonication, thermal treatment, and membrane filtration) to obtain unilamellar structures with a controlled size distribution. Herein, we report the first example of spontaneously formed submicrometer-sized unilamellar polyion complex vesicles (Nano-PICsomes) via self-assembly of a pair of oppositely charged PEG block aniomer and homocatiomer in an aqueous medium. Detailed dynamic light scattering and transmission electron microscopic analysis revealed that vesicle sizes can be controlled in the range of 100-400 nm with a narrow size distribution, simply by changing the total polymer concentration. Also, each Nano-PICsome was composed of a uniform single PIC membrane, the thickness of which is around 10-15 nm, regardless of its size. Fluorescence correlation spectroscopy measurement verified that Nano-PICsomes were able to encapsulate water-soluble fluorescent macromolecules in the inner water phase and release them slowly into the exterior. Moreover, cross-linking of the vesicle membrane allows tuning of permeability, enhancement in stability under physiological conditions, and preservation of size and structure even after freeze-drying and centrifugation treatment. Finally, Nano-PICsomes showed a long circulation time in the bloodstream of mice. Precise control of the particle size and structure of hollow capsules through simple aqueous self-assembly and easy modification of their properties by cross-linking is quite novel and fascinating in terms of ecological, low-cost, and low-energy fabrication processes as well as the potential utility in the biomedical arena.


PEI fluorination reduces toxicity and promotes liver-targeted siRNA delivery.
Polyethyleneimine (PEI) has been extensively investigated as an efficient carrier for nucleic acid delivery. Yet, it suffers from a high toxicity profile that hinders clinical translation. Fluorination has proven to be a valid approach to reduce the cytotoxicity of PEI and improve the in vitro siRNA delivery potency. Hydrophobicity and lipophobicity can be controllably introduced into the side chains of PEI. However, the effect of fluorination on siRNA delivery in vivo, particularly the biodistribution of siRNA polyplex nanoparticles with fluorinated PEIs, has not been extensively explored. Here, we introduce two series of fluorinated PEIs via amidation with ethyl trifluoroacetate and perfluorobutyryl chloride. Fluorination substantially improved the performance of PEI for siRNA delivery by reducing the cytotoxicity to MDA-MB-231 cells. Importantly, fluorinated PEI enabled the major accumulation of siRNA polyplex nanoparticles in the liver while non-fluorinated PEI delivered siRNA nanoparticles mainly to the lungs after intravenous administration to mice. It is envisioned that fluorination may be an important general strategy for lowering toxicity of cationic polymers, and that the fluorination-induced alteration of biodistribution may be applicable for improved delivery to different organs. Graphical abstract.


The effect of HPV infection on a couple's relationship: a qualitative study in Taiwan.
The purpose of this study is to explore the effect of human papillomavirus (HPV) on the sexual lives of women and their partners. Twenty oncogenic or high-risk HPV infected cases were collected via purposive sampling. At a tertiary medical center in Taipei, 20 women underwent a 2-hour in-depth interview. The content of each interview was analyzed qualitatively regarding (1) effect of HPV infection on a couple's relationship; (2) effect of HPV infection on sexual life; (3) partner support and social support; (4) myths about love and marriage; and (5) sexual myths. The better a couple's relationship, the less these patients struggled to confront the issue (HPV infection). Most patients urged partners to have check-ups and advised friends about Pap smear tests. Couple relationships were generally not affected by HPV infection, unlike their sexual lifestyles. Most patients fulfilled the traditional Chinese female role of maintaining the relationship. However, due to the physical and psychosocial discomfort of treatment and fear of infection, some had no desire for sex, while others lessened their sex frequency. Most patients received very little support from their partner, family, and friends. The relationship quality was affected by marital and sexual myths held by patients. Cervical HPV infection has a negative effect on women's sexual relationships. Thus, more attention from health care providers is required.


HIV type 1 chemokine receptor usage in mother-to-child transmission.
To investigate the role of the HIV-1 phenotype in mother-to-child HIV-1 transmission, we evaluated coreceptor usage and replication kinetics in chemokine receptor-expressing U87MG.CD4 cells of primary isolates from 32 HIV-1-infected mothers of Italian origin, none under preventive antiretroviral therapy, and from their infected infants. Five of 15 mothers of infected children and 2 of 17 mothers of uninfected children harbored viruses able to use CXCR4 as coreceptor. However, all isolates used CCR5, alone or in association with CXCR4. The replicative capacity in coreceptor-expressing cells of the viral isolates did not differ between the two groups of mothers. All mothers with an R5 virus transmitted a virus with the same coreceptor usage, whereas those four with a multitropic virus transmitted such a virus in one case. Although the presence of a mixed viral population was documented in the mothers, we did not observe transmission solely of X4 viruses. Interestingly, the only child infected with a multitropic virus carried a defective CCR5 allele. Analysis of the env V3 region of the provirus from this child revealed infection with multiple viral variants with a predominance of R5-type over X4-type sequences. These findings show that CCR5 usage of a viral isolate is not a discriminating risk factor for vertical transmission. Furthermore, X4 viruses can be transmitted to the newborn, although less frequently. In particular, we document the transmission of multiple viral variants with different coreceptor usage in a Delta32 CCR5 heterozygous child, and demonstrate that the heterozygous genotype per se does not contribute to the restriction of R5-type virus spread.


Decision quality instrument for treatment of hip and knee osteoarthritis: a psychometric evaluation.
A high quality decision requires that patients who meet clinical criteria for surgery are informed about the options (including non-surgical alternatives) and receive treatments that match their goals. The aim of this study was to evaluate the psychometric properties and clinical sensibility of a patient self report instrument, to measure the quality of decisions about total joint replacement for knee or hip osteoarthritis. The performance of the Hip/Knee Osteoarthritis Decision Quality Instrument (HK-DQI) was evaluated in two samples: (1) a cross-sectional mail survey with 489 patients and 77 providers (study 1); and (2) a randomized controlled trial of a patient decision aid with 138 osteoarthritis patients considering total joint replacement (study 2). The HK-DQI results in two scores. Knowledge items are summed to create a total knowledge score, and a set of goals and concerns are used in a logistic regression model to develop a concordance score. The concordance score measures the proportion of patients whose treatment matched their goals. Hypotheses related to acceptability, feasibility, reliability and validity of the knowledge and concordance scores were examined. In study 1, the HK-DQI was completed by 382 patients (79%) and 45 providers (58%), and in study 2 by 127 patients (92%), with low rates of missing data. The DQI-knowledge score was reproducible (ICC = 0.81) and demonstrated discriminant validity (68% decision aid vs. 54% control, and 78% providers vs. 61% patients) and content validity. The concordance score demonstrated predictive validity, as patients whose treatments were concordant with their goals had more confidence and less regret with their decision compared to those who did not. The HK-DQI is feasible and acceptable to patients. It can be used to assess whether patients with osteoarthritis are making informed decisions about surgery that are concordant with their goals.


High-Frequency Jet Ventilation in Pediatric Acute Respiratory Failure.
High-frequency jet ventilation (HFJV) is primarily used in premature neonates; however, its use in pediatric patients with acute respiratory failure has been reported. The objective of this study was to evaluate HFJV use in the pediatric critical care setting. We hypothesized that HFJV would be associated with improvements in oxygenation and ventilation. Medical records of all patients who received HFJV in the pediatric ICU of a quaternary care center between 2014 and 2018 were retrospectively reviewed. Premature infants who had not been discharged home were excluded, as were those in whom HFJV was started while on extracorporeal membrane oxygenation. Data on demographics, pulmonary mechanics, gas exchange, and outcomes were extracted and analyzed using chi-square testing for categorical variables, nonparametric testing for continuous variables, and a linear effects model to evaluate gas exchange over time. A total of 35 subjects (median age = 2.9 months, median weight = 5.2 kg) were included. Prior to HFJV initiation, median (interquartile range) oxygenation index (OI) was 11.3 (7.2-16.9), [Formula: see text] = 133 (91.3-190.0), pH = 7.18 (7.11-7.27), [Formula: see text] = 64 (52-87) mm Hg, and [Formula: see text] = 74 (64-125) mm Hg. For subjects still on HFJV (n = 25), there was no significant change in OI, [Formula: see text], or [Formula: see text] at 4-6 h after initiation, whereas pH increased (P = .001) and [Formula: see text] decreased (P = .001). For those remaining on HFJV for > 72 h (n = 12), the linear effects model revealed no differences over 72 h for OI, [Formula: see text], [Formula: see text], or mean airway pressure, but there was a decrease in [Formula: see text] while pH and [Formula: see text] increased. There were 9 (26%) subjects who did not survive, and nonsurvivors had higher Pediatric Index of Mortality 2 scores (P = .01), were more likely to be immunocompromised (P = .01), were less likely to have a documented infection (P = .02), and had lower airway resistance (P = .02). HFJV was associated with improved ventilation among subjects able to remain on HFJV but had no significant effect on oxygenation.


Impact of Affordable Care Act-related insurance expansion policies on mortality and access to post-discharge care for trauma patients: an analysis of the National Trauma Data Bank.
Uninsured trauma patients have worse outcomes and worse access to post-discharge care that is critically important for recovery after injury. Little is known regarding the impact of the insurance coverage expansion policies of the Affordable Care Act (ACA), most notably state-level Medicaid expansion, on trauma patients. In this study, we examine the national impact of these policies on payer mix, inpatient mortality, and access to post-acute care for trauma patients. We used the 2011-2016 National Trauma Data Bank to evaluate for changes in insurance coverage among trauma patients 18-64 years old. Our pre-/post-expansion models defined 2011-2013 as the pre-policy period, 2015-2016 as the post-policy period, and 2014 as a washout year. To evaluate for policy-associated changes in inpatient mortality and discharge disposition among the policy-eligible sample, we leveraged multivariable linear regression techniques to adjust for year-to-year variation in patient demographics, injury characteristics, and facility traits. We then examined the relationship between the magnitude of facility-level reductions in uninsured patients and access to post-acute care after policy implementation. We identified 1,656,469 patients meeting inclusion criteria between 2011 and 2016. The pre-policy uninsured rate of 23.4% fell by 5.9 percentage-points after coverage expansion (p < 0.001), with a corresponding 7.5 percentage-point increase in Medicaid coverage (p < 0.001). After policy implementation, there were no significant changes in inpatient mortality. However, there was a >30% relative increase in discharge to a post-acute care facility and a similar increase in discharge with home health services (p < 0.001 for both). The greatest gains in access to post-acute services were seen among facilities with the greatest reductions in their uninsured rate (p = 0.003). ACA-related coverage expansion policies, most notably Medicaid expansion, were associated with a >25% reduction in the uninsured rate among non-elderly adult trauma patients. Although no immediate impact on inpatient mortality was seen, insurance coverage expansion was associated with a higher proportion of patients receiving critically important post-discharge care. Epidemiological, level III.


Real-time full-spectral imaging and affinity measurements from 50 microfluidic channels using nanohole surface plasmon resonance.
With recent advances in high-throughput proteomics and systems biology, there is a growing demand for new instruments that can precisely quantify a wide range of receptor-ligand binding kinetics in a high-throughput fashion. Here we demonstrate a surface plasmon resonance (SPR) imaging spectroscopy instrument capable of simultaneously extracting binding kinetics and affinities from 50 parallel microfluidic channels. The instrument utilizes large-area (~ cm(2)) metallic nanohole arrays as SPR sensing substrates and combines a broadband light source, a high-resolution imaging spectrometer and a low-noise CCD camera to extract spectral information from every channel in real time with a refractive index resolution of 7.7 × 10(-6) refractive index units. To demonstrate the utility of our instrument for quantifying a wide range of biomolecular interactions, each parallel microfluidic channel is coated with a biomimetic supported lipid membrane containing ganglioside (GM1) receptors. The binding kinetics of cholera toxin b (CTX-b) to GM1 are then measured in a single experiment from 50 channels. By combining the highly parallel microfluidic device with large-area periodic nanohole array chips, our SPR imaging spectrometer system enables high-throughput, label-free, real-time SPR biosensing, and its full-spectral imaging capability combined with nanohole arrays could enable integration of SPR imaging with concurrent surface-enhanced Raman spectroscopy.


Tobacco use among a population of women attending cervical cancer screening programs in primary health care clinics in South Africa: a cross-sectional study.
we determined the prevalence, patterns and factors associated with tobacco use among women presenting for cervical cancer screening in primary health care clinics in Gauteng province, South Africa. this study utilized data from an ongoing cross-sectional study commenced in September 2018, in which 749 participants had responded to an interviewer-administered semi-structured questionnaire on socio-demographics, HIV status, tobacco use, family planning methods, sexual and cervical cancer screening behaviours. Data were entered into the web-based research electronic data capture (REDCap). We performed descriptive data analysis and included multivariate logistic regression. We considered a p-value < 0.05 statistically significant. participants´ median age was 38 years (interquartile range: 31-38) with 43.9% (328) reporting being HIV-positive. The prevalence of ever and current tobacco use were 24.3% (182/749) and 17.1% (128/749) respectively. In multivariable logistic regression, participants who self-identified as racial ethnicity other than Black African and those who were HIV positive and not on antiretroviral treatment, had increased odds of reporting current tobacco use ((adjusted odds ratio (AOR)= 5.6, 95% CI: 3.2-9.8) and (AOR= 8.2, 95% CI: 2.0-34.1) respectively). current tobacco use is common among women attending cervical cancer screening programs in primary health care clinics in Gauteng Province. Furthermore, study findings suggest the need to integrate tobacco cessation treatments into women´s health and HIV treatment programs.


Anti-diabetic effect of a traditional Chinese medicine formula.
An anti-diabetic TCM formula consisting of Schizandra chinensis Baill. (SC), Coptis chinensis (CC), Psidium guajava L. leaves (PG) and Morus alba L. leaves (MA) was developed based on its α-glucosidase, DPP-4 and AGE inhibitory activities in vitro using response surface methodology (RSM). Then, the in vivo study was carried out to confirm the anti-diabetic function of the formula. RSM results showed that the optimum anti-diabetic TCM formula is the combination SC (3000 μg mL(-1)), CC (80 μg mL(-1)), PG (374.56 μg mL(-1)) and MA (480 μg mL(-1)). For the in vivo study, insulin resistant mice were induced by high-fat/high-sucrose (HF/HS) feeding for 6 weeks. Administration of the developed formula significantly decreased non-fasting blood glucose in the HF/HS diet mice. Moreover, the formula decreased blood glucose levels in the insulin tolerance test. These results indicated that the anti-diabetic mechanism of the formula might be due to decreased insulin resistance. The serum fructosamine level in the high dose group was significantly lower than the HF/HS and normal control groups, indicating that the formula could improve middle term glucose levels and reduce the risk of complications. The contents of berberine and 1-deoxynojirimycin in the formula were 4.7 ± 0.4 and 77.1 ± 1.1 μg mL(-1), respectively. These two compounds can be used as indicators for quality control during production.


Closing the gap between single-unit and neural population codes: Insights from deep learning in face recognition.
Single-unit responses and population codes differ in the "read-out" information they provide about high-level visual representations. Diverging local and global read-outs can be difficult to reconcile with in vivo methods. To bridge this gap, we studied the relationship between single-unit and ensemble codes for identity, gender, and viewpoint, using a deep convolutional neural network (DCNN) trained for face recognition. Analogous to the primate visual system, DCNNs develop representations that generalize over image variation, while retaining subject (e.g., gender) and image (e.g., viewpoint) information. At the unit level, we measured the number of single units needed to predict attributes (identity, gender, viewpoint) and the predictive value of individual units for each attribute. Identification was remarkably accurate using random samples of only 3% of the network's output units, and all units had substantial identity-predicting power. Cross-unit responses were minimally correlated, indicating that single units code non-redundant identity cues. Gender and viewpoint classification required large-scale pooling of units-individual units had weak predictive power. At the ensemble level, principal component analysis of face representations showed that identity, gender, and viewpoint separated into high-dimensional subspaces, ordered by explained variance. Unit-based directions in the representational space were compared with the directions associated with the attributes. Identity, gender, and viewpoint contributed to all individual unit responses, undercutting a neural tuning analogy. Instead, single-unit responses carry superimposed, distributed codes for face identity, gender, and viewpoint. This undermines confidence in the interpretation of neural representations from unit response profiles for both DCNNs and, by analogy, high-level vision.


Semisupervised Ordinal Regression Based on Empirical Risk Minimization.
Ordinal regression is aimed at predicting an ordinal class label. In this letter, we consider its semisupervised formulation, in which we have unlabeled data along with ordinal-labeled data to train an ordinal regressor. There are several metrics to evaluate the performance of ordinal regression, such as the mean absolute error, mean zero-one error, and mean squared error. However, the existing studies do not take the evaluation metric into account, restrict model choice, and have no theoretical guarantee. To overcome these problems, we propose a novel generic framework for semisupervised ordinal regression based on the empirical risk minimization principle that is applicable to optimizing all of the metrics mentioned above. In addition, our framework has flexible choices of models, surrogate losses, and optimization algorithms without the common geometric assumption on unlabeled data such as the cluster assumption or manifold assumption. We provide an estimation error bound to show that our risk estimator is consistent. Finally, we conduct experiments to show the usefulness of our framework.


Specific Features of Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.
Primary sclerosing cholangitis (PSC) is a chronic and progressive disease of the biliary tract. PSC is strongly associated with inflammatory bowel disease (IBD), mainly with ulcerative colitis, and most PSC patients have underlying IBD. The pathophysiological interactions between IBD and PSC are unclear, although it seems that the patients with IBD and PSC have a distinct phenotype. IBD with coexisting PSC is more extensive and is characterized by milder activity compared to IBD alone. The coexistence of PSC increases the risk for colorectal cancer in IBD patients and lifelong annual surveillance colonoscopy is recommended. Also, liver transplantation (LT) for PSC may affect the course of IBD. In addition, the management of IBD after LT includes many specific problems. On the other hand, the effect of IBD on the natural history of PSC appears to be milder. However, IBD may increase the risk of postsurgical complications after LT and is a risk factor for recurrent PSC after LT. Overall, the coexistence of IBD with PSC changes the management, natural history and prognosis of both diseases.


[Endoscopic Anatomy of the Inferior Orbital Fissure-Müller's Muscle Structural Unit at the Medial Sellar Orbital Junction and its surgical relevance]
Diseases of the orbit represent a surgical challenge, particularly those compromising the orbital apex. Optimal surgical access should provide the best possible exposure, allowing to identify certain key anatomical structures, called landmarks. Describe the endoscopic anatomy of the structural unit formed by the Inferior Orbital Fissure (IOF) and the Müller's muscle (MM) at the orbital apex (OA), thus generating a new endoscopic anatomical landmark. A bone-descriptive analysis of the IOF in dry craniums, was followed by dissection and endoscopic study of six heads (twelve sides), colored and fixed in formaldehyde. In ten dry craniums (twenty sides), distances and angles of OA foramina were measured (optic foramen [OF] and foramen rotundum [FR]). Statistical analysis was performed with SPSS 17.0 statistical software (SPSS, Inc. Chicago, IL). The structural unit IOF-MM was identified in all endoscopic dissections, verifying its intimate relationship with the OA. From the morpho-metric standpoint, OF and FR were found at an average distance of 65.19 mm and 60.16 mm, respectively. The average angle of the OF was 13.32 degrees, whereas the one for FR was 19.31 degrees. We found a significant correlation between OF and FR only on the left side (left hemi-crane) (Kendall Tau b 0.69, p=0.006). There were no anatomical or morphological differences between both sides. The unit IOF-MM is a constant anatomical landmark, useful and safe under endoscopic technique, which allows the recognition of the OA and its contiguous areas.


Biopterin derivatives in normal and phenylketonuric patients after oral loads of L-phenylalanine, L-tyrosine, and L-tryptophan.
Plasma biopterin derivatives studied in 10 normal and 21 phenylketonuric children showed a significantly high concentration in the latter group. Biopterin derivatives correlated with plasma phenylalanine concentration, but in normal adults given an oral phenylalanine load the rate of increase with phenylalanine differed from that in phenylketonuric patients. A patient with hyperphenylalaninaemia, not due to phenylketonuria, had an abnormal biopterin derivatives response to phenylalanine distinct from that of patients with classical phenylketonuria. This may be a useful investigation to differentiate some variants of phenylketonuria.


Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group.
The etiology of familial hemophagocytic lymphohistiocytosis (FHL), which is characterized by fever, hepatosplenomegaly, pancytopenia, and coagulopathy, remains unknown. We analyzed 43 FHL patients, all with affected siblings, in 18 families who were identified during the period 1986-1995 in Japan. The presence of consanguinity was evident in two families (11%). The majority of families lived in western Japan, where the frequency of consanguineous marriage is high. The incidence of FHL was significantly higher in the western island, Kyushu, than in other areas. The segregation ratio calculated for these families was 0.35 by the Weinberg proband method, showing the autosomal-recessive inheritance of the disease. Since the diagnosis of an FHL patient without affected siblings (sporadic case) is quite difficult, we calculated the possible number of sporadic cases; approximately 122 patients could be identified as sporadic FHL cases during the same period in Japan. Most of the clinical and laboratory findings were not distinguishable from those of other types of lymphohistiocytosis. However, atypical lymphoid cells with azurophilic granules in peripheral blood were observed in half of the patients at diagnosis, suggesting the clinical importance of this parameter for early diagnosis. Despite intensive therapy, the prognosis of FHL was extremely poor; but 4 of the 8 patients who have survived had received bone marrow transplantation (BMT), indicating the effectiveness of BMT for this disorder. The distribution of FHL in areas of highly frequent consanguineous marriage and the segregation analysis indicated a genetic factor in FHL. The identification of the genes for FHL is expected to contribute to a cure for this disorder, and might also enable FHL carrier detection and donor selection for BMT.


Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients.
Few options are available for cytomegalovirus (CMV) treatment in transplant recipients resistant, refractory, or intolerant to approved agents. Letermovir (LET) is approved for prophylaxis in hematopoietic cell transplant (HCT) recipients, but little is known about efficacy in CMV infection. We conducted an observational study to determine the patterns of use and outcome of LET treatment of CMV infection in transplant recipients. Patients who received LET for treatment of CMV infection were identified at 13 transplant centers. Demographic and outcome data were collected. Twenty-seven solid organ and 21 HCT recipients (one dual) from 13 medical centers were included. Forty-five of 47 (94%) were treated with other agents prior to LET, and 57% had a history of prior CMV disease. Seventy-seven percent were intolerant to other antivirals; 32% were started on LET because of resistance concerns. Among 37 patients with viral load < 1000 international units (IU)/ml at LET initiation, two experienced >1 log rise in viral load by week 12, and no deaths were attributed to CMV. Ten patients had viral load > 1000 IU/ml at LET initiation, and six of 10 (60%) had a CMV viral load < 1000 IU/ml at completion of therapy or last known value. LET was discontinued in two patients for an adverse event. Patients treated with LET with viral load < 1000 IU/ml had good virologic outcomes. Outcomes were mixed when LET was initiated at higher viral loads. Further studies on combination therapy or alternative LET dosing are needed.


Clostridium difficile: the anaerobe that made the grade.
Unlike other anaerobic bacteria of clinical importance, Clostridium difficile has managed to enter into the realm of public awareness. Following the trail blazed by methicillin-resistant Staphylococcus aureus (MRSA), C. difficile has made the transition from being an obscure anaerobic bacterium, mainly of interest to specialist anaerobic microbiologists, to that of an infamous "superbug" responsible for outbreaks of hospital-acquired infection that commonly result in serious disease and death. This report picks out key moments, particularly in the UK, which tracked the rise in both the public and political awareness of this organism.


Dynamical equations for high-order structure functions, and a comparison of a mean-field theory with experiments in three-dimensional turbulence.
Two recent papers [V. Yakhot, Phys. Rev. E 63, 026307, (2001) and R. J. Hill, J. Fluid Mech. 434, 379, (2001)] derive, through two different approaches that have the Navier-Stokes equations as the common starting point, a set of dynamic equations for structure functions of arbitrary order in turbulence. These equations are not closed. Yakhot proposed a "mean-field theory" to close the equations for locally isotropic turbulence, and obtained scaling exponents of structure functions and expressions for the peak in the probability density function of transverse velocity increments, and for its behavior for intermediate amplitudes. At high Reynolds numbers, some relevant experimental data on pressure gradient and dissipation terms are presented that are needed to provide closure, as well as on other aspects predicted by the theory. Comparison between the theory and the data shows varying levels of agreement, and reveals gaps inherent to the implementation of the theory.


Effect of diethylstilbestrol on polyamine metabolism in hamster epididymis.
To investigate the effect of diethylstilbestrol (DES), one of the most potent endocrine disruptors, on the metabolism of polyamines in hamster epididymis. Male golden hamsters of 7-week-old were kept under a light and dark cycle of 14 h and 10 h for 1 week to stimulate maximally the gonadal function. DES was injected subcutaneously at doses of 0.01 mg . kg(-1) . day(-1), 0.1 mg . kg(-1) . day(-1) and 1 mg . kg(-1) . day(-1) for one week. DES treatment caused a significant decrease in the weight of epididymis. The activity of epididymal ornithine decarboxylase (ODC) increased 1 day after DES treatment, kept at a high level for 4 days and then decreased to nearly normal level at day 7. The activity of spermidine/spermine N1-acetyltransferase (SSAT) also increased transiently after DES treatment. The contents of putrescine, spermidine, spermine and N(1)-acetylspermidine were increased 1 day approximately 4 days after DES treatment and restored to normal at day 7. All these changes showed a marked difference between the caput and the cauda. The polyamine biosynthesis in the hamster epididymis can be affected by DES, a xenoestrogen. DES may probably affect polyamine metabolism in the epididymis by regulating the rate-limiting enzymes involved in the polyamine biosynthesis.


Alterations in DNA repair gene expression and their possible regulation in rat-liver regeneration.
Rapidly proliferating tissue may require enhanced DNA repair capacity in order to avoid fixation of promutagenic DNA lesions to mutations. Partial hepatectomy (PH) triggers cell proliferation during liver regeneration (LR). However, little is known on how DNA repair genes change and how they are regulated at the transcriptional level during LR. In the present study, the Rat Genome 230 2.0 array was used to detect the expression profiles of DNA repair genes during LR, and differential expression of selected genes was confirmed by real-time RT-PCR. 69 DNA repair genes were found to be associated with LR, more than half of which distributed in a cluster characterized by a gradual increase at 24-72h and then returning to normal. The expression of base excision repair- and transcription-coupled repair-related genes was enhanced in the early and intermediate phases of LR, whereas the expression of genes related to HR, NHEJ and DNA cross-link repair, as well as DNA polymerases and related accessory factors, and editing or processing nucleases, were mainly enhanced in the intermediate phase. The expression changes of genes in DNA damage response were complicated throughout the whole LR. Our data also suggest that the expression of most DNA repair genes may be regulated by the cell cycle during LR.


Predictive Capability of HPV and Pap Tests in Screening for Cervical Cancer over a Three-Year Follow-up.
To compare the predictive capability of HPV and Pap smear tests for screening pre-cancerous lesions of the cervix over a three-year follow-up, in a population of users of the Brazilian National Health System (SUS). This is a retrospective cohort study of 2,032 women with satisfactory results for Pap smear and HPV tests using second-generation hybrid capture, made in a previous study. We followed them for 36 months with data obtained from medical records, the Cervix Cancer Information System (SISCOLO), and the Mortality Information System (SIM). The outcome was a histological diagnosis of cervical intraepithelial neoplasia grade 2 or more advanced lesions (CIN2+). We constructed progression curves of the baseline test results for the period, using the Kaplan-Meier method, and estimated sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios for each test. A total of 1,440 women had at least one test during follow-up. Progression curves of the baseline test results indicated differences in capability to detect CIN2+ (p < 0.001) with significantly greater capability when both tests were abnormal, followed by only a positive HPV test. The HPV test was more sensitive than the Pap smear (88.7% and 73.6%, respectively; p < 0.05) and had a better negative likelihood ratio (0.13 and 0.30, respectively). Specificity and positive likelihood ratio of the tests were similar. These findings corroborate the importance of HPV test as a primary cervical cancer screening.


Protective effects of gastrodin on lead-induced synaptic plasticity deficits in rat hippocampus.
Lead is a well-known toxin in the environment that causes severe damage to the nervous system. Gastrodin is the main bioactive component of Tian ma ( GASTRODIA ELATA Bl.), which is a traditional herbal medicine widely used in eastern Asia. Increasing lines of evidence show that gastrodin has diverse effects, especially neuroprotective effects. In the present study, we investigated whether gastrodin supplementation can rescue impairments of synaptic plasticity produced by developmental lead exposure. We examined three electrophysiological parameters of synaptic plasticity: input/output (I/O) function, paired-pulse facilitation (PPF), and long-term potentiation (LTP) of field excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 region of rats on postnatal day 22 (P22). Our results showed that lead exposure significantly impaired synaptic plasticity in the hippocampal CA1 region and that gastrodin can effectively rescue these lead-induced impairments. Therefore, gastrodin may have potential therapeutic value for lead-induced impairments during human developmental stages.


Neural network modelling of Cryptosporidium and Giardia concentrations in the Delaware River, USA.
Artificial neural networks are brain-like structures used in mathematical modelling that excel in pattern recognition. In this research, a simple feed-forward artificial neural network, trained by error back-propagation algorithm, was used as a tool to relate peak Cryptosporidium and Giardia concentrations with other biological, chemical and physical parameters in surface water. Multiple water quality parameters at a water treatment plant intake on the Delaware River, New Jersey, USA, collected in 1996, were provided to the authors for recognition analysis. Water samples were classified as "background" and "above background" based on the concentration of full and empty oocysts and cysts of Cryptosporidium and Giardia. The results of this preliminary effort were encouraging. Parameters significant to the identification of each protozoa were identified, eight for Cryptosporidium and seven for Giardia by a stepwise elimination technique. Data withheld from the model training was used to validate the trained models and evaluate the most effective internal architecture. In both cases, the best prediction performance was found when the number of internal nodes was twice that of the input parameters in single hidden-layer architecture. Predictions for the classification of the verification data set resulted in no false-negatives (mis-prediction of above background protozoa concentrations) when the models were optimally trained.


Ovarian sensitivity index can be used as a more sensitive indicator than follicular output rate to predict IVF/ICSI outcomes in patients of normal expected ovarian response stimulated with GnRH antagonist protocol.
This retrospective study was performed to investigate the predictive power of the Ovarian Sensitivity Index (OSI) for IVF/ICSI outcomes in infertile patients who were of normal expected ovarian response. A total of 912 infertile patients who underwent GnRH antagonist protocol between January 2017 to August 2019 at the Medical Center for Human Reproduction, Beijing Chao-Yang Hospital were included. All patients completed the full oocyte retrieval cycle and either had a live birth or had no embryos left. OSI was significantly lower in patients with a live birth (196.0 ± 120.4 in the live birth group vs 276.4 ± 235.7 in the non-live birth group, p < 0.001) while follicular output rate (FORT, defined as the ratio of pre-ovulatory follicle count on hCG day x 100/small antral follicle count at baseline) showed no significant difference. Patients were divided into low, average and high OSI groups and analysed in tertiles. From the low to the high OSI group, the cumulative live birth rate (CLBR) decreased dramatically (72.7 vs 67.2 vs 54.8%, p < 0.001). Multivariate regression analysis showed that OSI was an independent factor affecting CLBR (OR: 0.996, 95%CI: 0.995-0.998, p < 0.001) in our study population. In conclusion, OSI can be used as an independent indicator to distinguish fecundity in infertile patients with normal expected ovarian response and is probably more sensitive than FORT.


Rapid diagnosis of ocular herpes simplex infections.
The Surecell herpes (HSV) test kit is a test for detecting the presence of herpes simplex viral antigen by means of a monoclonal antibody based immunoassay. The test has proved to be highly sensitive and specific in diagnosing genital, oral, and dermatological herpes infections. In this study, samples from patients with ocular keratitis were evaluated by tissue cultures and the Surecell test. The eyes of New Zealand rabbits were then inoculated with HSV type 1 acute keratitis, acute Staphylococcus keratitis, and HSV type 1 postkeratitis (healed corneas). Tear film samples collected from each eye with a cotton swab were evaluated by routine culture (A-549 monolayers) and by the Surecell test with and without prior placement of the swab in Hank's medium. The Surecell system had a 70% sensitivity and a 100% specificity in the detection of HSV antigen in ocular infections, and was shown to be a quick, efficient, and accurate method of testing for HSV antigen in humans. These results from humans and rabbits indicate that the Surecell test, which requires no special equipment, can be a useful in office adjunct in the clinical diagnosis of ocular herpes simplex.


Comparison of OCT angiography and indocyanine green angiographic findings with subtypes of polypoidal choroidal vasculopathy.
To compare the findings of optical coherence tomography angiography (OCTA) with indocyanine green angiography (ICGA) in polypoidal choroidal vasculopathy (PCV) that was divided into two types: polypoidal choroidal neovascularisation (CNV) and typical PCV (type 2 PCV). We studied a retrospective case series of 32 patients with treatment-naïve PCV (24 men, eight women; mean age 65.4 years). PCV was categorised into polypoidal CNV (type 1 PCV) and type 2 PCV based on ICGA findings. OCTA was performed using the RTVue XR Avanti. Macular cubes (3×3 or 6×6 mm) were acquired. To evaluate the locations of polyps and branched vessel networks (BVNs), we used B-mode scan. OCTA clearly depicted only 17% of the type 1 PCV polyps and 46% of the type 2 PCV polyps which were detectable by ICGA. All type 1 PCV polyps detectable by OCTA were located just beneath the retinal pigment epithelium (RPE). On the other hand, type 2 PCV polyps were detected in various locations. All BVNs of type 1 PCV were located between the RPE and Bruch's membrane on OCTA images. However, the BVNs in type 2 PCV were located mainly under the RPE, though some were located in the choroid. Polyps of type 1 PCV were more difficult to detect with OCTA than those of type 2 PCV. Polyps of type 1 PCV were located just beneath the RPE. The BVNs of type 1 PCV were located between the RPE and Bruch's membrane.


A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation.
Tripeptidyl peptidase 1 (TPP1) deficiency causes CLN2 disease, late infantile (or classic late infantile neuronal ceroid lipofuscinosis), a paediatric neurodegenerative disease of autosomal recessive inheritance. Patients suffer from blindness, ataxia, epilepsy and cognitive defects, with MRI indicating widespread brain atrophy, and profound neuron loss is evident within the retina and brain. Currently there are no effective therapies for this disease, which causes premature death in adolescence. Zebrafish have been successfully used to model a range of neurological and behavioural abnormalities. The aim of this study was to characterize the pathological and functional consequences of Tpp1 deficiency in zebrafish and to correlate these with human CLN2 disease, thereby providing a platform for drug discovery. Our data show that homozygous tpp1(sa0011) mutant (tpp1(sa0011)(-/-)) zebrafish display a severe, progressive, early onset neurodegenerative phenotype, characterized by a significantly small retina, a small head and curved body. The mutant zebrafish have significantly reduced median survival with death occurring 5 days post-fertilization. As in human patients with CLN2 disease, mutant zebrafish display storage of subunit c of mitochondrial ATP-synthase, hypertrophic lysosomes as well as localized apoptotic cell death in the retina, optic tectum and cerebellum. Further neuropathological phenotypes of these mutants provide novel insights into mechanisms of pathogenesis in CLN2 disease. Secondary neurogenesis in the retina, optic tectum and cerebellum is impaired and axon tracts within the spinal cord, optic nerve and the posterior commissure are disorganized, with the optic nerve failing to reach its target. This severe neurodegenerative phenotype eventually results in functional motor impairment, but this is preceded by a phase of hyperactivity that is consistent with seizures. Importantly, both of these locomotion phenotypes can be assayed in an automated manner suitable for high-throughput studies. Our study provides proof-of-principle that tpp1(sa0011)(-/-) mutants can utilize the advantages of zebrafish for understanding pathogenesis and drug discovery in CLN2 disease and other epilepsies.


Cortical bone vessel identification and quantification on contrast-enhanced MR images.
Cortical bone porosity is a major determinant of bone strength. Despite the biomechanical importance of cortical bone porosity, the biological drivers of cortical porosity are unknown. The content of cortical pore space can indicate pore expansion mechanisms; both of the primary components of pore space, vessels and adipocytes, have been implicated in pore expansion. Dynamic contrast-enhanced MRI (DCE-MRI) is widely used in vessel detection in cardiovascular studies, but has not been applied to visualize vessels within cortical bone. In this study, we have developed a multimodal DCE-MRI and high resolution peripheral QCT (HR-pQCT) acquisition and image processing pipeline to detect vessel-filled cortical bone pores. For this in vivo human study, 19 volunteers (10 males and 9 females; mean age =63±5) were recruited. Both distal and ultra-distal regions of the non-dominant tibia were imaged by HR-pQCT (82 µm nominal resolution) for bone structure segmentation and by 3T DCE-MRI (Gadavist; 9 min scan time; temporal resolution =30 sec; voxel size 230×230×500 µm3) for vessel visualization. The DCE-MRI was registered to the HR-pQCT volume and the voxels within the MRI cortical bone region were extracted. Features of the DCE data were calculated and voxels were categorized by a 2-stage hierarchical kmeans clustering algorithm to determine which voxels represent vessels. Vessel volume fraction (volume ratio of vessels to cortical bone), vessel density (average vessel count per cortical bone volume), and average vessel volume (mean volume of vessels) were calculated to quantify the status of vessel-filled pores in cortical bone. To examine spatial resolution and perform validation, a virtual phantom with 5 channel sizes and an applied pseudo enhancement curve was processed through the proposed image processing pipeline. Overlap volume ratio and Dice coefficient was calculated to measure the similarity between the detected vessel map and ground truth. In the human study, mean vessel volume fraction was 2.2%±1.0%, mean vessel density was 0.68±0.27 vessel/mm3, and mean average vessel volume was 0.032±0.012 mm3/vessel. Signal intensity for detected vessel voxels increased during the scan, while signal for non-vessel voxels within pores did not enhance. In the validation phantom, channels with diameter 250 µm or greater were detected successfully, with volume ratio equal to 1 and Dice coefficient above 0.6. Both statistics decreased dramatically for channel sizes less than 250 µm. We have a developed a multi-modal image acquisition and processing pipeline that successfully detects vessels within cortical bone pores. The performance of this technique degrades for vessel diameters below the in-plane spatial resolution of the DCE-MRI acquisition. This approach can be applied to investigate the biological systems associated with cortical pore expansion.