TuLeD (Tupían lexical database): introducing a database of a South American language family.
The last two decades witnessed a rapid growth of publicly accessible online language resources. This has allowed for valuable data on lesser known languages to become available. Such resources provide linguists with opportunities for advancing their research. Yet despite the proliferation of lexical and morphological databases, the ca. 456 languages spoken in South America are poorly represented, particularly the Tupían family, which is the largest on the continent. This paper therefore introduces and discusses TuLeD, a lexical database exclusively devoted to a South American language family. It provides a comprehensive list of lexical items presented in a unified transcription for all languages with cognacy assignment and relevant (cultural or linguistic) notes. One of the main goals of TuLeD is to become a full-fledged database and a benchmark for linguistic studies on South American languages in general and the Tupían family in particular.


Theoretical study of the infrared frequencies of crystalline methyl acetate under interstellar medium conditions.
Identification of methyl acetate in the interstellar medium (ISM) and its spectroscopic studies have prompted us to investigate the structure of crystalline methyl acetate using numerical calculations. Here, we present a theoretical study of the structure of crystalline methyl acetate and its isotopologues and compare the calculated infrared (IR) spectra with the available experimental data. The optimized structure and vibrational properties were calculated using SIESTA software at 0 K. In the optimization process, the Perdew-Burke-Ernzerhof functional and conjugate gradient methods were used with double zeta polarization basis functions. After optimization of the periodic structure, the vibrational frequencies and normal modes were calculated within the harmonic approximation. Using the calculated results, we refine the mode assignments of experimental work on crystalline methyl acetate and determine the low frequency modes (below 650 cm(-1)). To investigate the accuracy of the pseudopotential and confirm the IR frequencies, we performed molecular calculations using a periodic model of methyl acetate and its isotopologues using SIESTA and compared them with results obtained from Gaussian 09 (all electron method) calculations. Finally, we assigned the vibrational modes of crystalline CD3-COO-CH3 and CH3-COO-CD3, for which experimental data are not available in the crystalline phase under ISM conditions. For all of the calculation methods, the IR vibrational modes of molecular and crystalline methyl acetate and its isotopologues were in good agreement with the available experimental data and predict the unavailable values.


Early and midterm results after open and endovascular repair of ruptured abdominal aortic aneurysms in a comparative analysis.
To compare early and midterm results of open versus endovascular aortic repair of ruptured abdominal aneurysms (rAAA). A retrospective analysis was performed of 58 consecutive patients with rAAA who were treated with open or endovascular aneurysm repair (EVAR) at a single center between January 2000 and December 2005. Patients without definitive signs of rupture (symptomatic patients) were excluded from the study. Twenty-nine patients (21 men; median age 71 years) were treated using endovascular techniques (EVAR group) and 29 (28 men; median age 71 years) with open repair (OR group). The hemodynamic status at the time of admission was evaluated with respect to blood pressure, pulse rate, and hemoglobin level to reduce selection bias. Patients underwent follow-up by clinical examination and computed tomography. The 30-day mortality rate was 31% (9/29) in each group (p = 1.0); the morbidity rates also did not differ between groups [16 (55.2%) EVAR vs. 18 (62.1%) OR; p = 0.9]. There was 1 (3.4%) primary conversion in the EVAR group and 7 (24.1%) endoleaks [3 (10.3%) primary; 4 (13.8%) secondary]. There was no difference between the groups with regard to intensive care unit stay (4 days for EVAR vs. 3 days for OR, p = 0.98) or total hospital stay (9 days for EVAR vs. 12 days for OR, p = 0.69). After a mean follow-up of 40.25 months (range 1-70), the midterm mortality rates did not differ [5 (17.2%) EVAR vs. 3 (10.3%) OR, p = 0.41]. EVAR of rAAAs is feasible, with equal early and midterm mortality rates compared to open repair. When a defined patient selection is used for rupture, including hemodynamic status, there is no evidence of a better outcome with EVAR in emergency cases.


Problems and complications of burn shock resuscitation.
The problems and complications of the fluid resuscitation phase of the treatment of major thermal burns are many and varied. Emphasis has been placed on the most important organ system responses commonly observed in the first week after injury. The efficacy of treatment and the lack of available treatment are outlined. The mechanical complications occurring from poorly selected and monitored fluid administration sites, complications of monitoring, problems of constrictive edema (usually in the extremities), airway problems, respiratory care, and innumerable other technical aspects were purposely omitted. While these problems and complications are extremely important and occur commonly in our experience, they are in the realm of technical performance of good emergency and intensive care medicine and their optimal management does not affect the problems and complications of the residual organ systems.


The effectiveness of simethicone in improving visibility during colonoscopy: a double-blind randomized study.
The effect of simethicone in improving visibility during colonoscopy was randomly studied in 97 patients receiving either simethicone (N = 49) or placebo (N = 48) in a colon lavage solution. Visibility was assessed by the amount of bubbles and the degree of haziness noted during colonoscopy. The degree of bubbles was scored on a scale of 0 to 3, and haziness was scored on a scale of 0 to 2. Patients receiving simethicone had significantly less bubbles (p less than 0.001) and less haziness (p less than 0.01) in the colon when compared to placebo-treated patients. These data indicate that the addition of simethicone to the colonic lavage solution results in improved colonic visibility and may result in technically easier and more accurate colonoscopy.


Distortion of β-globin chain of hemoglobin alters the pathway of erythrocytic glucose metabolism through band 3 protein.
Band 3 is a transmembrane protein of erythrocytes and its cytosolic part regulates glucose metabolism to proceed along the pentose phosphate pathway (PPP) or glycolytic pathway by binding with the central cavity of the β chain of deoxygenated hemoglobin and with some glycolytic enzymes competitively. In β thalassemia major and hemoglobin (Hb)Eβ thalassemia, β chain is either absent or distorted and glucose metabolism may be disturbed. We estimated adenosine triphosphate (ATP), glucose 6-phosphate dehydrogenase (G6PD) and aldolase activity in oxygenated and deoxygenated state of erythrocytes of β major, HbEβ thalassemia and normal controls to understand the hypothesis that major glucose metabolism within the erythrocytes of these diseases may proceed through the PPP. Fifty of each group of patients and 52 normal controls were included. Patients' blood was collected 1 month prior to blood transfusion. G6PD and aldolase were estimated using a commercial kit. ATP was measured by spectrophotometric method. Significantly low levels of erythrocytic ATP and higher levels of G6PD were found in two groups of patients. Aldolase level in deoxygenated hemolysate was significantly higher than oxygenated hemolysate in normal controls but no significant change was noticed in both types of thalassemic patients. In β thalassemia major and HbEβ thalassemia due to distortion of β chain, binding of deoxygenated hemoglobin with band 3 is inhibited and thus traffic control of glycolytic pathway is disturbed and shifted towards PPP.


A case of solitary intraductal papilloma of the breast coexisting with ductal carcinoma in situ (DCIS).
A 54-year-old woman was referred to this institution because of spontaneous bloody discharge from the nipple of her left breast in July 2003. Physical examination revealed no mass, but minimal pressure on the mammary gland exuded a bloody discharge from the nipple. No lymph node swelling was recognized in the axillary or subclavicular regions. Mammography and magnetic resonance imaging revealed mastopathy. Ultrasonography on the immersion method demonstrated a dilated duct with an irregular, solid, hypoechoic mass immediately behind the nipple. Fine-needle aspiration cytology showed the mass to be an intraductal tumor. Carcinoembryonic antigen (CEA) concentration of the nipple discharge was 400 ng/ml. Preoperatively, she was diagnosed as intraductal solitary papilloma, and endoscope-assisted microdochectomy was carried out under general anesthesia. The tumor was 10.5-10.6 mm in diameter and had developed from the posterior wall of the duct adjacent to the nipple. The tumor contained a small solid area in which a two-cell layer of epithelium was missing, and thus solitary papilloma coexisting with ductal carcinoma in situ (DCIS) was diagnosed. Solitary intraductal papilloma coexisting with carcinoma is rare; cases of DCIS are exceptionally rare. Follow-up for 3 years has revealed no evidence of recurrence.


Modeling of ionic relaxation around a biomembrane disk.
A simplified Brownian dynamics model and the corresponding software implementation have been developed for the simulation of electrolyte dynamics on the mesoscopic scale. In addition to direct control simulations, the model system has been verified by a quantitative comparison with the Debye-Hückel theory. As a first application, the model was used to simulate ionic relaxation processes following abrupt intramembrane charge rearrangements in the case of a disk shaped membrane. In addition to its general implications, the obtained properties of the relaxation kinetics confirm the assumptions of the theory of the so-called suspension method, a technique capable of tracing molecular charge motions of membrane proteins in three dimensions.


Testing Longitudinal Relationships between Internet Addiction and Well-Being in Hong Kong Adolescents: Cross-Lagged Analyses Based on three Waves of Data.
Using a panel design, this study examined the prospective relationships between Internet addiction and life satisfaction as well as hopelessness in a representative sample of Hong Kong adolescents. Starting from 2009/10 academic year, 3328 Secondary 1 students in 28 secondary schools in Hong Kong participated in this longitudinal study (Mean age = 12.59 years; SD = 0.74 years). All participants responded to a questionnaire that includes the Internet Addiction Test, Life Satisfaction Scale, and Hopelessness Scale on a yearly basis. Cross-lagged analyses based on three waves of data collected during three junior adolescent years showed that Internet addiction measured at Time 1 predicted poor life satisfaction and hopelessness at Time 2, but not vice versa. Similarly, Internet addiction at Time 2 predicted low life satisfaction at Time 3, and the cross-lagged effects of life satisfaction and hopelessness on Internet addiction from Time 2 to Time 3 remained non-significant. The findings support the thesis that poor personal well-being in adolescents is the consequence rather than the cause of Internet addictive behaviors. To improve quality of life and prevent suicidality in adolescents, strategies that help reduce addictive behaviors related to the Internet should be considered.


Passive particle agglutination test for screening of Treponema Pallidum antibodies in blood bank routine.
In most laboratories and blood banks, the TP.PA test has replaced the TPHA test for the screening of Treponema pallidum antibodies. In this study we show that the 1:20 serum dilution should be used to discriminate between negative and positive samples instead of the recommended 1:40 dilution, thus increasing sensitivity without a significant loss of specificity.


Enhanced production of γ-amino acid 3-amino-4-hydroxybenzoic acid by recombinant Corynebacterium glutamicum under oxygen limitation.
Bio-based aromatic compounds are of great interest to the industry, as commercial production of aromatic compounds depends exclusively on the unsustainable use of fossil resources or extraction from plant resources. γ-amino acid 3-amino-4-hydroxybenzoic acid (3,4-AHBA) serves as a precursor for thermostable bioplastics. Under aerobic conditions, a recombinant Corynebacterium glutamicum strain KT01 expressing griH and griI genes derived from Streptomyces griseus produced 3,4-AHBA with large amounts of amino acids as by-products. The specific productivity of 3,4-AHBA increased with decreasing levels of dissolved oxygen (DO) and was eightfold higher under oxygen limitation (DO = 0 ppm) than under aerobic conditions (DO ≥ 2.6 ppm). Metabolic profiles during 3,4-AHBA production were compared at three different DO levels (0, 2.6, and 5.3 ppm) using the DO-stat method. Results of the metabolome analysis revealed metabolic shifts in both the central metabolic pathway and amino acid metabolism at a DO of < 33% saturated oxygen. Based on this metabolome analysis, metabolic pathways were rationally designed for oxygen limitation. An ldh deletion mutant, with the loss of lactate dehydrogenase, exhibited 3.7-fold higher specific productivity of 3,4-AHBA at DO = 0 ppm as compared to the parent strain KT01 and produced 5.6 g/L 3,4-AHBA in a glucose fed-batch culture. Our results revealed changes in the metabolic state in response to DO concentration and provided insights into oxygen supply during fermentation and the rational design of metabolic pathways for improved production of related amino acids and their derivatives.


Dawn of antioxidants and immune modulators to stop HIV-progression and boost the immune system in HIV/AIDS patients: An updated comprehensive and critical review.
In the last two decades, human immunodeficiency virus (HIV), the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS), is one of the leading causes of morbidity and mortality, worldwide. Providing the optimum management of HIV/AIDS is a major challenge in the 21st century. Since, HIV-infected persons have an extended lifespan due to the development of effective antiretroviral therapies, malnutrition is becoming central factors of long-term survivors. The nutrition status of AIDS patients has a significant influence on the maintenance and optimal effectiveness of the immune system. Micronutrient therapy in combination with allopathic treatments can extend and improve the quality and quantity of life in individuals infected with HIV/AIDS. HIV infection is thought to lead to augmented oxidative stress which may in turn lead to faster development of HIV disease. Hence, antioxidants might have a significant role in the treatment of HIV/AIDS. An additional approach to treating HIV infection is fortifying the immune response of infected people. Immune modulators help to activate and boost the normal immune function. The present review first describes the boon of antioxidants (especially Vitamin A) and immune modulators (cytolin, resveratrol, murabutide, setarud, tucaresol, AVR118, Immunitin (HE2000), reticulose, and interleukin-7) in the treatment of HIV/AIDS. Then, providing a comparatively succinct outline on updated patents study on antioxidants and immune modulators to treat HIV/AIDS will be discussed.


Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten-year experience in a Brazilian center.
To characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. Observational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age=36 months, 25-75 IQR=10-108; males=810) submitted to the TfIEF test during the period were reviewed. Fifty-one individuals (3%) had an altered TfIEF pattern (5±2.8 cases/year; median age=24 months, 25-75 IQR=11-57 months; males=27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia=4; hereditary fructose intolerance=4; peroxisomal diseases=2; PMM2-CDG=2; MPDU1-CDG=1; SLC35A2-CDG=1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. The data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.


A modified lead attenuation method to determine the fast neutron sensitivity kU of a photon dosemeter.
Various lead attenuation techniques to determine the fast neutron sensitivity kU of a photon dosemeter are reviewed and a modified method is proposed to determine the kU value of a commercially available Geiger--Müller detector. The dependence on the 'effective' photon energy of the gamma-component of the mixed n--gamma field is illustrated and the most probable photon energy is deduced from measurements outside the radiation field. Using the relevant photon mass attenuation coefficient, measurements carried out with a well-collimated neutron beam at the MRC Cyclotron, Hammersmith Hospital, London, show that the Dg component contributes 2.41 +/- 0.13% to the total radiation field. Using a detector with a PTFE sleeve in the place of a Perspex sleeve, highly consistent results are obtained and the enhancement of the kU value by the Perspex is demonstrated. The neutron sensitivities of two MX 163 GM detectors with Perspex and PTFE sleeves were respectively determined as 0.73 +/- 0.07% and 0.98 +/- 0.14%.


Gracilin-Derivatives as Lead Compounds for Anti-inflammatory Effects.
Gracilins are diterpenes derivative, isolated from the marine sponge Spongionella gracilis. Natural gracilins and synthetic derivatives have shown antioxidant, immunosuppressive, and neuroprotective capacities related to the affinity for cyclophilins. The aim of this work was to study anti-inflammatory and immunosuppressive pathways modulated by gracilin L and two synthetic analogues, compound 1 and 2, on a cellular model of inflammation. In this way, the murine BV2 microglia cell line was used. To carry out the experiments, microglia cells were pre-treated with compounds for 1 h and then stimulated with lipopolysaccharide for 24 h to determine reactive oxygen species production, mitochondrial membrane potential, the release of nitric oxide, interleukin-6 and tumor necrosis factor-α and the expression of Nuclear factor-erythroid 2-related factor 2, Nuclear Factor-κB, the inducible nitric oxide synthase, and the cyclophilin A. Finally, a co-culture of neuron SH-SY5Y and microglia BV2 cells was used to check the neuroprotective effect of these compounds. Cyclosporine A was used as a control of effect. The compounds were able to decrease inflammatory mediators, the expression of inflammatory target proteins as well as they activated anti-oxidative mechanism upon inflammatory conditions. For this reason, natural and synthetic gracilins could be interesting for developing anti-inflammatory drugs.


The Effect of Smoking on Corneal Biomechanics.
To determine the effect of smoking on corneal biomechanical behavior. The medical records of consecutive patients that presented to the ophthalmology department were reviewed. History of smoking and ophthalmological examination findings were recorded. The smoking group met the following criteria: a clear history of and present smoking habit, negative history of corneal disease and surgery, ocular response analyzer measurement at the time of examination, and a waveform score ≥3.7. Nonsmokers (never smoked or quit smoking ≥6 months earlier) that met the same criteria constituted the control group. Corneal biomechanical parameters were measured using ocular response analyzer. Data were analyzed using Pearson's χ2 test, Mann-Whitney U test, and Spearman's correlation coefficient. The smoking group included 166 eyes of 166 patients with a mean age of 38.7 ± 11.95 years, and the control group consisted of 170 eyes of 170 patients with a mean age of 38.40 ± 12.2 years. Mean cumulative smoking dose in the smoking group was 9.59 ± 11.87 pack-years (0.04- 75.00). There was no significant correlation between cumulative smoking dose and corneal hysteresis and corneal resistance factor (P = 0.382 and 0.074, respectively). There were no significant differences in corneal hysteresis or the corneal resistance factor between the two groups (P > 0.05). There was no significant difference in corneal hysteresis between those in the smoking group aged 18-44 years and those aged 45-64 years (P = 0.258), whereas in the control group mean corneal hysteresis was significantly lower in the 45-64 year olds than in the 18-44 year olds (P = 0.034). Although there was no significant difference in corneal biomechanics between smoking and control groups, the decrease in corneal hysteresis with aging was less apparent in the smoking group, which may be due to the potential changes in the cornea's microstructure induced by smoking during aging and the effect of smoking in aged corneal tissue viscosity.


Handgrip strength predicts length of hospital stay in an abdominal surgical setting: the role of frailty beyond age.
Chronological age per se cannot be considered a prognostic risk factor for outcomes after elective surgery, whereas frailty could be. A simple and easy-to-get marker for frailty, such as handgrip strength (HGS), may support the surgeon in decision for an adequate healthcare plan. The aims of this study were to: (1) determine the prevalence of frailty in an abdominal surgery setting independent of age; (2) evaluate the predictive validity of HGS for the length of hospital stay (LOS). This is a retrospective study conducted in subjects who underwent abdominal surgical procedures. Only subjects with complete cognitive, functional, nutritional assessments and available measurement of HGS at admission were included. A final cohort of 108 patients were enrolled in the study. Subjects had a mean age of 67.8 ± 15.8 years (age range 19-93 years old) and were mostly men. According to Fried's criteria, 17 (15.7%, 4F/13 M) were fit, 58 (23.7%; 24F/34 M) were pre-frail and 33 (30.6%; 20F/13 M) were frail. As expected, HGS significantly differed between groups having frail lower values as compared with pre-frail and fit persons (fit: 32.99 ± 10.34 kg; pre-frail: 27.49 ± 10.35 kg; frail: 15.96 ± 9.52 kg, p < 0.0001). A final regression analysis showed that HGS was significantly and inversely associated with LOS (p = 0.020) independent of multiple covariates, including age. Most of the population undergoing abdominal surgery is pre-frail or frail. The measurement of handgrip strength is simple and inexpensive, and provides prognostic information for surgical outcomes. Muscle strength, as measured by handgrip dynamometry, is a strong predictor of LOS in a surgical setting.


Quantitative autoradiography of alpha 2 agonist binding sites in the spontaneously hypertensive rat brain.
The relative binding of the alpha 2 agonist [3H]para-aminoclonidine ([3H]PAC) was examined in discrete regions of the spontaneously hypertensive (SHR) and WKY normotensive rat brains by quantitative autoradiography. Substantially less binding was noted in various brain nuclei known to influence cardiovascular function when comparing the SHR to WKY rat brains. These areas included the nucleus of the solitary tract, dorsal motor nucleus of the vagus, locus coeruleus and paraventricular nucleus of the hypothalamus. This difference in binding was also noted in the bed nucleus of the stria terminalis and the nucleus reuniens of the thalamus. Other brain areas which are not believed to be directly involved in central cardiovascular control such as the cerebral cortex, dorsal lateral geniculate and hippocampus exhibited no significant difference in binding between the two strains. Scatchard analysis of [3H]PAC binding indicated that the difference in binding may be due to a selective loss of the high affinity alpha 2 agonist sites in the SHR. These results indicate that a selective loss of alpha 2 receptors in discrete brain cardiovascular control regions of the SHR may contribute to the elevated blood pressure seen in this strain.


Excision and Primary Anastomosis for Bulbar Urethral Strictures Improves Functional Outcomes and Quality of Life: A Prospective Analysis from a Single Centre.
Excision and primary anastomotic (EPA) urethroplasty remains the gold standard definitive treatment for short urethral stricture disease. For patients, postoperative erectile function and quality of life are the main goals of the surgery. Patient-reported outcome measures (PROMs) are therefore of major importance. The objective of this study was to prospectively analyse functional outcomes and patient satisfaction. We prospectively evaluated 47 patients before and after EPA from August 2009 until February 2017. The first follow-up visit occurred after a median of 2.2 months (n = 47/47), with the second and third follow-ups occurring at a median of 8.5 months (n = 38/47) and 20.2 months (n = 31/47). Before surgery and at each follow-up visit, the patients received five questionnaires: the International Prostate Symptom Score (IPSS), the International Prostate Symptom Score with the Quality of Life (IPSS-QOL) score, the Urogenital Distress Inventory Short Form (UDI-6) score, the International Index of Erectile Function-5 (IIEF-5) score, and the ICIQ-Lower Urinary Tract Symptoms Quality of Life (ICIQ-LUTS-QOL) score. Surgery was performed in all cases using the same standardized EPA technique. Voiding symptoms, erectile dysfunction, and quality of life were analysed using paired sample t-tests, with a multiple-testing Bonferroni correction. Any requirement for instrumentation after surgery was considered treatment failure. Patients with mild or no baseline erectile dysfunction showed significant decline in erectile function at first follow-up (mean IIEF-5 of 23.27 [standard deviation; SD: 2.60] vs. 13.91 [SD: 7.50]; p=0.002), but this had recovered completely at the third follow-up (IIEF-5: 23.25 [SD: 1.91]; p=0.659). Clinically significant improvements were noted in IPSS, IPSS-QOL-score, UDI-6-score, and ICIQ-LUTS-QOL-score at the first follow-up (p<0.0001). These improvements remained significant at the second and third follow-ups (p<0.0001) for all PROMs. Three of the patients experienced stricture recurrence. The main limitations of this study were incomplete questionnaires, loss to follow-up, and low number of patients. EPA results in an initial decline in erectile function, but full recovery occurred at a median of 20 months. Voiding improved significantly, and a major improvement in quality of life was noted, which persisted for up to 20 months after surgery. This study showed the importance of patient-reported outcome measures in indicating the actual outcome of urethral stricture disease surgery.


Child Mouthing of Feces and Fomites and Animal Contact are Associated with Diarrhea and Impaired Growth Among Young Children in the Democratic Republic of the Congo: A Prospective Cohort Study (REDUCE Program).
To identify exposure pathways to fecal pathogens that are significant contributors to diarrheal diseases and impaired growth in young children, and to evaluate scalable interventions to reduce fecal contamination from these pathways. Reducing Enteropathy, Undernutrition, and Contamination in the Environment (REDUCE) was a prospective cohort study of 370 children <5 years of age was conducted in Walungu Territory, South Kivu, Democratic Republic of the Congo. Child mouthing behaviors were assessed through caregiver reports and 5-hour structured observations. Caregiver reports of child contact with animals and child diarrhea were also obtained. Anthropometric measurements were collected at baseline and at a 6-month follow-up. Children observed putting soil in their mouth during structured observation at baseline had a significantly higher odds of diarrhea at the 6-month follow-up (OR, 1.79; 95% CI, 1.04 to 3.07). Children observed mouthing feces during structured observation had a significant reduction in height-for-age z-score (HAZ) from baseline to the 6-month follow-up (ΔHAZ, -0.69; 95% CI, -1.34 to -0.04). A significant reduction in HAZ was also observed for children with caregiver reports of touching guinea pigs (-0.33; 95% CI, -0.58 to -0.08) and rabbits (-0.34; 95% CI, -0.64 to -0.04) and children with feces in their sleeping space during unannounced spot checks (-0.41; 95% CI, -0.74 to -0.09). These findings emphasize the urgent need for infant water, sanitation, and hygiene interventions targeting child mouthing behaviors, fecal contamination in child living spaces, and child contact with domestic animals to reduce exposure to fecal pathogens among susceptible populations.


Reassessment of carotid intima-media thickness by standard deviation score in children and adolescents after Kawasaki disease.
Previous studies that used carotid ultrasound have been largely conflicting in regards to whether or not patients after Kawasaki disease (KD) have a greater carotid intima-media thickness (CIMT) than controls. To test the hypothesis that there are significant differences between the values of CIMT expressed as absolute values and standard deviation scores (SDS) in children and adolescents after KD and controls, we reviewed 12 published articles regarding CIMT on KD patients and controls. The mean ± SD of absolute CIMT (mm) in the KD patients and controls obtained from each article was transformed to SDS (CIMT-SDS) using age-specific reference values established by Jourdan et al. (J: n = 247) and our own data (N: n = 175), and the results among these 12 articles were compared between the two groups and the references for comparison of racial disparities. There were no significant differences in mean absolute CIMT and mean CIMT-SDS for J between KD patients and controls (0.46 ± 0.06 mm vs. 0.44 ± 0.04 mm, p = 0.133, and 1.80 ± 0.84 vs. 1.25 ± 0.12, p = 0.159, respectively). However, there were significant differences in mean CIMT-SDS for N between KD patients and controls (0.60 ± 0.71 vs. 0.01 ± 0.65, p = 0.042). When we assessed the nine articles on Asian subjects, the difference of CIMT-SDS between the two groups was invariably significant only for N (p = 0.015). Compared with the reference values, CIMT-SDS of controls was within the normal range at a rate of 41.6 % for J and 91.6 % for N. These results indicate that age- and race-specific reference values for CIMT are mandatory for performing accurate assessment of the vascular status in healthy children and adolescents, particularly in those after KD considered at increased long-term cardiovascular risk.


If You Can See It, You Can Be It: Perceptions of Diversity in Surgery Among Under-Represented Minority High School Students.
Increasing racial and ethnic diversity in the surgical workforce is essential to improving outcomes for marginalized communities. To address the persistent shortage of under-represented minority (URM) surgeons, this study assessed the impact of providing early exposure to the field of surgery on URM high school students' perceptions of pursuing surgical careers. The Association of Women Surgeons organized a pilot 3-hour "Day in the Life" virtual event geared toward URM high school students involving suturing/knot-tying, case conferences, and mentoring activities. Pre- and post-event survey results from 65 participants showed that students became more familiar with surgery (p < 0.001) and perceived the field as more diverse (p = 0.017). Over 70% felt capable of becoming surgeons themselves and over 80% were interested in learning more and gaining mentorship. Our programming provides a model for future initiatives aimed at strengthening the pipeline of URM surgeons.


The National Register of infants with congenital hypothyroidism detected by neonatal screening in Italy.
Neonatal screening for congenital hypothyroidism began in Italy in 1977 and then progressively developed covering 94% of live births in 1991. The National Register of infants with congenital hypothyroidism was established in 1987 as a project of the Health Ministry. The results of the Register provided valuable epidemiological information about congenital hypothyroidism in Italy and evidenced some aspects in the screening organization which had to be improved. Discussion of Register data during annual national meetings has recently allowed an improvement of the screening program with particular regard to the beginning of therapy with L-thyroxine and its dose.


Synthesis and binding affinities of fluoroalkylated raloxifenes.
Three fluoroalkylated derivatives (1-3) of the selective estrogen receptor modulator (SERM), raloxifene, have been synthesized. The key step in the synthesis is the C-C bond formation of benzo[b]thiophene and a substituted phenyl group (ring C) using a Stille reaction. The in vitro binding affinities of the substituted raloxifenes 1-3 are 45, 60, 89%, respectively, relative to the affinity of estradiol, which is higher than the affinity of raloxifene itself (25%). When labeled with the positron-emitting radionuclide, these compounds might be useful as PET imaging agents for estrogen receptor-positive breast tumors.


Serum antibody to poliovirus in patients in a mental deficiency hospital, with particular reference to Down's syndrome.
Neutralization tests for poliovirus antibodies were carried out on 74 patients in an adult mental deficiency hospital: 37 patients with Down's syndrome and 37 non-Down's mental defectives. The distribution of antibody titres to poliovirus types 1, 2 and 3 did not differ significantly between the two groups. Most patients had antibody to at least one poliovirus type but less than a third had antibodies at a titre of 1/8 or greater to all three types. The low level of poliovirus immunity in this population may be of epidemiological importance.


Predictors of abnormality in thallium myocardial perfusion scans for type 2 diabetes.
Type 2 diabetes mellitus (T2DM) increases coronary artery disease (CAD) risk. In this study, we used T2DM clinical variables to predict abnormality in thallium-201 myocardial perfusion scans (Th-201 scans). These clinical variables were summed stress score (SSS), summed rest score, and summed difference score (SDS), with data obtained from 368 male and 428 female participants with T2DM. Multiple linear regression results were as follows. In male participants, body mass index (BMI) and creatinine (Cr) were associated with SSS (β = 0.224, p < 0.001; β = 0.140, p = 0.022, respectively), and only BMI was associated with SDS (β = 0.174, p = 0.004). In female participants, BMI and high-density lipoprotein cholesterol level were associated with SSS (β = 0.240, p < 0.001; β = - 0.120, p = 0.048, respectively), and only BMI was correlated with SDS (β = 0.123, p = 0.031). Our multivariate logistic regression indicated that in male and female participants, BMI was the only independent indicator of high SSS (SSS ≥ 9). In this study, we demonstrated that male patients have a higher SSS and SDS than female patients do in Th-201 scans for T2DM in a Chinese population. For male and female patients, BMI was the strongest predictor of abnormality in Th-201 scans. Our results can help clinicians identify patients with T2DM at high risk of CAD.


High levels of metals/metalloids in blood and urine of residents living in the area affected by the dam failing in Barra Longa, District, Brazil: A preliminary human biomonitoring study.
Fundão mining tailings dam in Mariana District has collapsed in 2015 and caused the biggest environmental disaster in Brazil. Barra Longa District had its urban area invaded by toxic sludge and its population was extensively exposed to it. Blood and urine samples were collected from 11 residents, focused on investigating the presence of metals at the end of an exploratory health study in 507 inhabitants in 2016. Results have shown increased levels of aluminum, arsenic, cadmium, cooper, lead, manganese and nickel, and zinc defficiency in their body, as well as clinical outcomes.


Assay and the levels of 2-5A-synthetase in lymphocytes of patients with viral, bacterial and autoimmune diseases.
The level of 2-5A-synthetase in extracts of peripheral blood lymphocytes was estimated by the capacity of the enzyme to synthesize 2-5A in the presence of ATP. The 2-5A was then purified on a small column of DEAE-cellulose. Here we show that under or experimental conditions, the amount of 2-5A formed is proportional to the level of the enzyme. The concentration of 2-5A (nmol of AMP/10(6) lymphocytes) in an assay therefore reflects the level of the enzyme. Enhanced levels of 2-5A synthetase were observed in the lymphocytes of patients with viral and bacterial infections. In most of the cases studied, these enhanced levels of the enzyme decreased during the course of infection parallel to recovery. Thus, the level of 2-5A synthetase may indicate the state of the disease and its evolution during the period of treatment; furthermore, it may be a useful marker in monitoring the return to a normal physiological condition. In addition to patients with viral and bacterial infections, enhanced levels of 2-5A synthetase were observed in patients suffering from autoimmune diseases. In five patients studied here, the enhanced levels of 2-5A synthetase remained high at different periods during the course of the disease. These results suggest the presence of circulating interferon throughout the disease.


Pediatric prescription pick-up rates after ED visits.
To determine the compliance rate in filling outpatient medication prescriptions written upon discharge from the emergency department (ED). Emergency department records of children during a 3-month period were examined along with pharmacy claim data obtained in cooperation with the largest insurance carrier in the community (private and Medicaid). Pharmacy claim data were used to validate the prescription pick-up date. Overall, 65% of high-urgency prescriptions were filled. The prescription pick-up rate in the 0-to 3-year age group (75%) was significantly higher than in the rest of the cohort (55%) ( P < .001). Children with private insurance were more likely to fill their prescriptions (68%) compared to children with Medicaid insurance (57%) ( P = .03). This study demonstrates that filling a prescription after discharge from an ED represents a substantial barrier to medication compliance.


Iatrogenic keratoconus as a complication of radial keratotomy.
A 47-year-old man with a family history of keratoconus had uneventful bilateral radial keratotomy (RK) with astigmatic keratotomy (AK) enhancements 12 years earlier. He noticed a gradual onset of blurry vision with progressively increasing myopic shift. Visual acuity remained poor even with spectacles or soft contact lenses. Slitlamp examination revealed 16 well-healed RK scars and 2 AK scars with marked corneal steepening inferiorly in an area of astigmatic enhancement in the left eye but an otherwise normal fellow eye with 16 well-healed RK scars. He subsequently had penetrating keratoplasty for decreased vision not correctable by rigid gas-permeable contact lenses. Microscopic examination of the corneal button showed findings consistent with keratoconus. This case represents the first documented incidence of corneal ectasia as a complication of primary RK.


Nucleus rostrolateralis: an expansion of the epithalamus in some actinopterygii.
The diencephalic nucleus rostrolateralis (RL) in the African butterfly fish (Pantodon buchholzi) is a brain nucleus identified in fewer than a dozen of the ∼25,000 species of actinopterygian fishes. Located in the rostrolateral diencephalon, this nucleus in Pantodon receives direct and indirect visual input from the superior visual field. Its lack of precedent or consistent phylogenetic expression creates a difficulty in interpreting the functional role of this nucleus within the visual system. By tracing experiments, RL was found to be afferent to nucleus interpeduncularis (IP) and the target of cells from the subpallium of the telencephalon. RL is a component of a descending telencephalic pathway involved in at least one behavior at the intersection of limbic and somatic activities--feeding. The parallelism between the ventral telencephalon--RL--IP and the limbic/striatal--habenula--IP pathway (the dorsal diencephalic conduction system, DDCS) suggests that RL is a component within the DDCS. Moreover, the hodological connections of RL suggest that RL is likely a hypertrophy of the lateral habenula.


Extension of the four-stranded intercalated cytosine motif by adenine.adenine base pairing in the crystal structure of d(CCCAAT).
The crystal structure of d(CCCAAT), refined at 2.0 A resolution, shows a four stranded molecule in which two parallel duplexes intercalate with opposite polarity, using cytosine.protonated cytosine base pairs. The intercalation motif in this structure is extended by adenine.adenine base pairs. Two topologically distinct broad grooves are found in the lath-like central part of the molecule with the phosphate groups on one side bent over towards each other, stabilized by bridging water molecules. At the 3' ends, two arrangements of intermolecular A.A.T base triplets are found, involving both asymmetric and symmetric A.A base pairs joined to thymine residues by Watson-Crick and reverse Hoogsteen base pairing, respectively.


lncRNAs HIF1A-AS2 facilitates the up-regulation of HIF-1α by sponging to miR-153-3p, whereby promoting angiogenesis in HUVECs in hypoxia.
Angiogenesis serves as an important protective mechanism against ischemic stroke, because angiogenesis promotes the generation of collateral circulation and consequently improves the blood supply to cerebral infraction areas. Long noncoding RNAs (lncRNAs), which can act as a competing endogenous RNA, mediate protein-coding gene expression by sponging miRNA. Based on previous studies, the present study hypothesized that lncRNAs HIF1A-AS2 by sponging to miR-153-3p might regulate expression of HIF-1α and its down-stream targets, thereby influencing angiogenesis in hypoxia. Permanent middle cerebral artery occlusion (pMCAO) model was established in SD rats to explore the association between angiogenesis and expression profiles of miR-153-3p and HIF-1α in infraction areas. The effect of HIF1A-AS2 on angiogenesis was investigated in an in vitro study by using human umbilical vein endothelial cells (HUVECs). Results showed that angiogenesis was induced during pMCAO. pMCAO decreased miR-153-3p RNA level in infraction areas, but increased protein levels of HIF-1α, VEGFA and Notch1. HIF1A-AS2 was up-regulated in HUVECs in hypoxia. Luciferase reporter assay indicated that HIF1A-AS2 serves as a 'sponge' to miR-153-3p, which decreased the post-transcriptional silencing of HIF-1α by miR-153-3p. This function of HIF1A-AS2 facilitated the activation of HIF-1α/VEGFA/Notch1 cascades, by which HUVECs viability, migration ability and tube formation were promoted. These results suggest an enhanced angiogenesis in HUVECs. In short, HIF1A-AS2 facilitates the up-regulation of HIF-1α by sponging to miR-153-3p, whereby promoting angiogenesis in HUVECs in hypoxia. The present study revealed an important mechanism for understanding angiogenesis in hypoxia, thus laid theoretical basis for developing new strategy for the treatment of ischemic stroke.


Electrically switchable metallic polymer nanoantennas.
Electrical switching of a metal-to-insulator transition would provide a building block for integrated electro-optically active plasmonics. In this work, we realize plasmonic nanoantennas from metallic polymers, which show well-pronounced localized plasmon resonances in their metallic state. As a result of the electrochemically driven optical metal-to-insulator transition of the polymer, the plasmonic resonances can be electrically switched fully off and back on at video-rate frequencies of up to 30 hertz by applying alternating voltages of only ±1 volt. With the use of this concept, we demonstrate electrically switchable beam-steering metasurfaces with a 100% contrast ratio in transmission. Our approach will help to realize ultrahigh efficiency plasmonic-based integrated active optical devices, including high-resolution augmented and virtual reality technologies.


Transformation of highly marbled meats under various cooking processes.
Cooking induces modifications in meat structure and composition, affecting its sensory and nutritional properties. These changes depend on the cooking method and meat characteristics. In the present study, beef were cooked in three different ways-grilling, boiling, and sous-vide cooking-with two endpoint temperatures, 55 °C and 77 °C, to better understand the general impact of cooking on the structure of fatty meat. Light microscopy was used to visualize muscle, connective, and adipose tissues. After cooking, muscle fibers were more compact, which can be attributed to perimysium shrinkage and water transfer, for all cooking processes except grilling at 55 °C. The cross-sectional area of muscle fibers was not impacted by cooking, regardless of the temperature or cooking method. Connective tissue between adipocytes was affected by cooking at 77 °C, but not at 55 °C. Despite the cooking method used, cooking to well-done (77 °C) clearly affected the structure of the perimysium of beef, possibly because of collagen denaturation.


Patients' views of pay for performance in primary care: a qualitative study.
Many countries use pay-for-performance schemes to reward family practices financially for achieving quality indicators. The views of patients on pay for performance remain largely unexplored. To gain the views of family practice patients on the United Kingdom pay-for-performance Quality and Outcomes Framework (QOF). Interviews with 52 patients were conducted in 15 family practices across England. All patients had at least one long-term condition that had been diagnosed before the introduction of the QOF in 2004. Semi-structured interviews analysed using open explorative thematic coding. Few patients had heard of the QOF or had noticed changes to the structure or process of their care. However, where they were noted, changes to consultations such as increased use of computers and health checks initiated by the GP or practice nurse were seen as good practice. The majority of patients were surprised to hear their practice received bonuses for doing 'simple things'. Some patients also raised concerns over potential unintended consequences of pay-for-performance frameworks, such as a reduced focus on non-incentivised areas. This study adds a unique patient perspective to the debate around the impact of pay-for-performance schemes and consequences on patient care. Patients' views, experiences, and concerns about pay for performance mostly chime with previously described opinions of primary care staff. Patient surprise and concern around incentivising basic processes of care shows how patient views are vital when monitoring and evaluating a scheme that is designed to improve patient care.


Nerve growth factor receptor immunohistochemistry has a limited additional value to diagnose Hirschsprung's disease.
The diagnosis of Hirschsprung's disease (HSCR) is based on the histopathological evaluation of rectal suction biopsies (RSB), using haematoxylin and eosin (H&E) stains and acetylcholinesterase (AChE) histochemistry. The use of different immunohistochemical markers, such as nerve growth factor receptor (NGFR), has been suggested to facilitate the diagnosis of HSCR. The aim of this study was to evaluate the addition of NGFR immunohistochemistry to diagnose HSCR. RSB from 23 HSCR patients and 16 patients investigated for, but not diagnosed with, HSCR were retrospectively reviewed. The histopathology report supported or did not support the diagnosis of HSCR. In patients with HSCR, the primary biopsies confirmed the diagnosis in 21 of 23 cases with H&E staining, in 16 of 23 cases with AChE histochemistry, and in 8 of 23 cases with NGFR immunohistochemistry. Due to inadequate biopsies or equivocal interpretation, the biopsies were repeated in seven of the patients with HSCR and two patients underwent biopsies a third time. In the 16 patients investigated for but not diagnosed with HSCR, the three tests were normal in all cases. We conclude that NGFR immunohistochemistry has limited additional value to diagnose HSCR.


FAPI PET Signal in Hibernoma Reflects FAP Expression in Tumor Vasculature Cells.
A 43-year-old man with a growing mass in the right groin, concerned for liposarcoma, underwent MRI and 68 Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT before surgery. Fibroblast activation protein inhibitor PET/CT demonstrated increased uptake (SUV max , 3.2) predominantly in the solid portion, where MRI showed gadolinium enhancement. The patient subsequently underwent surgery and was diagnosed with hibernoma. The immunohistochemistry of the tumor revealed the fibroblast activation protein expression in the fibrovascular network and myofibroblastic cells of the tumor. This case suggests that the FAPI uptake can be affected by the vascular cells, and thus, a careful interpretation of the FAPI PET signal may be needed.


Casting Light on Intracellular Tracking of a New Functional Graphene-Based MicroRNA Delivery System by FLIM and Raman Imaging.
The theranostic ability of a new fluorescently labeled cationic cyclodextrin-graphene nanoplatform (GCD@Ada-Rhod) was investigated by studying its intracellular trafficking and its ability to deliver plasmid DNA and microRNA. The nanoplatform was synthesized by both covalent and supramolecular approaches, and its chemical structure, morphology, and colloidal behavior were investigated by TGA, TEM, spectroscopic analysis such as UV-vis, fluorescence emission, DLS, and ζ-potential measurements. The cellular internalization of GCD@Ada-Rhod and its perinuclear localization were assessed by FLIM, Raman imaging, and fluorescence microscopy. Biological experiments with pCMS-EGFP and miRNA-15a evidenced the excellent capability of GCD@Ada-Rhod to deliver both pDNA and microRNA without significant cytotoxicity. The biological results evidenced an unforeseen caveolae-mediated endocytosis internalization pathway (generally expected for particles <200 nm), despite the fact that the GCD@Ada-Rhod size is about 400 nm (by DLS and TEM data). We supposed that the internalization pathway was driven by physical-chemical features of GCD@Ada-Rhod, and the caveolae-mediated uptake enhanced the transfection efficiency, avoiding the lysosomal acid degradation. The cellular effects of internalized miRNA-15a on the oncogene protein BCL-2 were investigated at two different concentrations (N/P = 10 and 5), and a reduction of the BCL-2 level was detected at a low concentration (i.e., N/P = 10). miRNA-15a is considered an ideal cancer therapy molecule due to its activity on multiple transcription factors, and the elucidation of the correlation between the concentration of delivered miRNA-15a and the down-/up-regulation of the BCL-2 level, documented for the first time in this work, could be an important contribution to guide its clinical application.


Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.
High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPARα, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM(®)). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. The cytochrome P450 (CYP) 2D6 phenotype explained 52% of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28% higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26% with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response. Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment.


Clinical estimation of gestational age: rules for avoiding preterm delivery.
Reliable knowledge of the duration of pregnancy prior to birth is often of crucial importance in making obstetric care decisions. Laboratory methods for estimating fetal maturity have received considerable attention, but the usefulness of historical information has only rarely been addressed. In order to examine the value of clinical estimators of fetal gestational age (GA) in 690 pregnancies, the correlations of menstrual history (LMP), first unamplified audible fetal heart tones (FFH), and quickening (Q), with GA, based on the modified Dubowitz examination at birth, were examined. Evaluation of each of the data sets used alone reveals that in order to be 90% certain that an infant will be mature at delivery (greater than or equal to 38 weeks), a reliable LMP must have been noted for 42 weeks prior to birth, the FFH heard for 21 weeks, and Q felt for 25 weeks. These findings suggest that carefully obtained historical and physical examination information remains a cornerstone of appropriate obstetric care.


Another niche for Notch.
The Notch signaling pathway patterns the developing nephron along the proximal-distal axis during renal development. In an adult acute tubular necrosis model, Kobayashi et al. now show expression of many Notch components and the activation of Notch target genes, suggesting a critical function for Notch in regenerating proximal tubules.


[Construction of human mucosa oral epithelial cell lines overexpressing telomerase reverse transcriptase gene mediated by lentivirus].
To construct a cell line of oral mucosa epithelial cells that stably express human telomerase reverse transcriptase (hTERT) by lentiviral vectors, approaches for the establishment of stable and efficient immortalized oral mucosa epithelial cell lines were explored. Whole RNA was extracted from 293T cells. The hTERT gene was amplified by polymerase chain reaction (PCR) and cloned into the lentiviral vector as pLVX-puro-hTERT. The lentivirus particles were successfully packaged and used to infect primary oral epithelial cells. The positive cell clones were selected by puromycin. Finally, the expression of hTERT was examined by real-time fluorescent quantitative PCR (qRT-PCR) and Western blot analysis. The sequencing results confirmed the construction of the recombinant lentivirus pLVX-puro-hTERT. The morphology of infected cells was similar to that of normal oral mucosal epithelial cells, with a cobble stone-like appearance. The qRT-PCR and Western blot results showed that hTERT was overexpressed in infected cells compared with the normal group (P<0.05). The oral epithelial cell line with stable expression of hTERT was successfully established by the lentivirus, which provides an experimental basis for the establishment of a highly efficient and stable oral epithelial immortalized cell line.


Acetylcholinesterase decrease in the optic lobe after unilateral eye deprivation.
Unilateral eye enucleation in a teleost and a turtle results in progressive AChE decrease in the optic lobe controlateral to the extirpated eye. The final difference reaches 15% in teleost and more than 20% in turtle. No drastic differences in localization, but a rearrangement of histochemical pattern, due to the degeneration of retinal fibres, is noticed.


Cyclooxygenase enzymes in allergic inflammation and asthma.
The cyclooxygenase enzyme system produces eicosanoids which mediate many important physiological and pathological functions. Experimental and clinical data suggest a role for this enzyme system in the pathogenesis of allergic inflammation and asthma. This article focuses on the function of this pathway in the lung, reviews evidence implicating the involvement of this pathway in asthma and allergic airway inflammation, and discusses implications for the treatment of asthmatics with cyclooxygenase inhibitors.


Outbreak of cutaneous leishmaniasis in Silti woreda, Ethiopia: risk factor assessment and causative agent identification.
An outbreak of skin lesions was reported in June 2005 in the district of Silti woreda, 150 km south of Addis Ababa, by the Christian Children's Fund (CCF) and confirmed to be cutaneous leishmaniasis (CL) by our group from the Armauer Hansen Research Institute in July 2005. A house-to-house survey of 1907 residents in three kebeles of Silti woreda conducted in April 2006 showed a prevalence of 4.8%. RFLP analysis of the internal transcribed spacer RNA (ITS1) showed that Leishmania aethiopica was the causative agent. In the survey, it was found that the age group 11-20 years was the most affected. Environmental factors such as proximity of the house to the gorge where hyraxes reside, presence of the plants Adhatoda schimperiana and Acacia spp. in the compound and sharing the same room with domestic animals were significantly associated with developing CL. The prevalence of active disease was higher in Kibet town (10.4%) compared to the rural kebeles. The identified risk factors of CL in the area need further study. The appearance of leishmaniasis in Silti, which was not known to be endemic for the disease, underlines the need to initiate a leishmaniasis control program in Ethiopia to limit its expansion.


Beyond the redox imbalance: Oxidative stress contributes to an impaired GLUT3 modulation in Huntington's disease.
Failure in energy metabolism and oxidative damage are associated with Huntington's disease (HD). Ascorbic acid released during synaptic activity inhibits use of neuronal glucose, favouring lactate uptake to sustain brain activity. Here, we observe a decreased expression of GLUT3 in STHdhQ111 cells (HD cells) and R6/2 mice (HD mice). Localisation of GLUT3 is decreased at the plasma membrane in HD cells affecting the modulation of glucose uptake by ascorbic acid. An ascorbic acid analogue without antioxidant activity is able to inhibit glucose uptake in HD cells. The impaired modulation of glucose uptake by ascorbic acid is directly related to ROS levels indicating that oxidative stress sequesters the ability of ascorbic acid to modulate glucose utilisation. Therefore, in HD, a decrease in GLUT3 localisation at the plasma membrane would contribute to an altered neuronal glucose uptake during resting periods while redox imbalance should contribute to metabolic failure during synaptic activity.


Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. 1. Neuronal cytoplasmic inclusions.
Neuronal alterations in five cases of multiple system atrophy (MSA) were investigated histologically, immunocytochemically and ultrastructurally. Argentophilic neuronal cytoplasmic inclusions (NCIs) were observed in all cases. They were distributed, in order of decreasing frequency, in the pontine nucleus, striatum, subiculum, amygdala, hippocampus, dentate fascia, substantia nigra and inferior olivary nucleus. Anti-ubiquitin antibodies visualized many thickened neurites in the degenerating gray matter as well as NCIs. Some NCIs were also recognized by anti-phosphorylated neurofilament antibodies. Ultrastructurally, NCIs consisted of a meshwork of granule-associated filaments, the diameter ranging from 18 to 28 nm, that were mixed with neurofilaments. The granule-associated filaments were also present in the axoplasm of myelinated fibers. Our studies demonstrate widespread distribution of NCIs in the central nervous system of MSA. The same pathological process that forms the granule-associated filaments in axons may also be responsible for the formation of ubiquitin-positive thickened neurites. These axonal alterations, as well as neuronal perikaryal changes, may play an important role in the impaired neuronal function in MSA.


[Quality of life and its association with the severity of fecal incontinence].
Wexner's score is widely used to assess the severity of fecal incontinence (FI). The 36-item short form health survey (SF-36) and the Fecal Incontinence Quality of Life Scale (FIQLS), a disease-specific scale, are instruments measuring quality of life that have been validated into Spanish. To evaluate quality of life in patients with FI by using the FIQL and SF-36 scales to correlate the results with the Wexner's score. Wexner's score, SF-36 and FIQLS were completed by 73 patients. The cut-off point for severity, as previously published, was 9 (Wexner's score <9=mild FI; Wexner's score ≥9=severe FI). the scores for all SF-36 sub-scales were lower in patients with FI than in the healthy Spanish population (p<0.001). The mental component of the SF-36 correlated with the subscales of «behavior» and «embarrassment» of the FIQLS (p<0.05). Wexner's score correlated with all the domains of the FIQLS (p<0.01). The results for all the domains of the FIQLS were lower for the Wexner ≥ 9 group than for the Wexner <9 group (p<0.001). There was no significant correlation between Wexner's score and the SF-36. Age, urge and daily FI, comorbidity and anorectal surgery worsened different aspects of quality of life measured by the FIQLS. quality of life measured by the SF-36 and FIQLS was substantially impaired in patients with FI. The severity of FI correlated with FIQLS. Other factors such as age, type and frequency of FI should be considered when evaluating quality of life.


SETD8 potentiates constitutive ERK1/2 activation via epigenetically silencing DUSP10 expression in pancreatic cancer.
Constitutive ERK1/2 activation has been frequently observed in pancreatic adenocarcinoma (PDAC). How ERK1/2 activation status been potentiated and maintained by epigenetic mechanisms has seldom been discussed in PDAC. In this study, we first examined the expression status of p-ERK1/2 in PDAC tissues by immunohistochemical staining and then screened possible epigenetic factors that displayed different expression status between p-ERK1/2 high and low groups by RNA profiling, and found that SETD8 displayed an increased expressional pattern in p-ERK1/2high patient group. Then the impact of SETD8 on the proliferation of PDAC cells were investigated on the basis of gain or loss-of-function assays. RNA sequencing assays were performed to screen potential SETD8 downstream targets that contribute to ERK1/2 activation. Mass spectrometry and transcriptional analysis, including dual-luciferase assay and chromatin immunoprecipitation assay (ChIP), were used to explore the molecular mechanisms that governing SETD8-mediated ERK1/2 activation. In vitro cell line studies and in vivo xenograft mouse model studies indicated that SETD8 promoted cell proliferation and increased tumor formation capacity of PDAC cell lines. Mechanism explorations uncovered that SETD8 suppressed the expression of DUSP10, which was responsible for dephosphorylation of ERK1/2. Mass spectrometry and transcriptional analysis results demonstrated that STAT3 interacted with SETD8 and recruited SETD8 to the promoter region of DUSP10, leading to epigenetic silencing of DUSP10 and the resultant activation of ERK1/2. In conclusion, SETD8 interacts with STAT3 on DUSP10 promoter region and epigenetically silences DUSP10 expression. Decreased DUSP10 expression in PDAC potentiates activation of ERK1/2 phosphorylation, resulting in unfavorable prognosis of PDAC.


Development of the Hand Assessment for Infants: evidence of internal scale validity.
The aim of this study was to develop a descriptive and evaluative assessment of upper limb function for infants aged 3 to 12 months and to investigate its internal scale validity for use with infants at risk of unilateral cerebral palsy. The concepts of the test items and scoring criteria were developed. Internal scale validity and aspects of reliability were investigated on the basis of 156 assessments of infants at 3 to 12 months corrected age (mean 7.2mo, SD 2.5) with signs of asymmetric hand use. Rasch measurement model analysis and non-parametric statistics were used. The new test, the Hand Assessment for Infants (HAI), consists of 12 unimanual and five bimanual items, each scored on a 3-point rating scale. It demonstrated a unidimensional construct and good fit to the Rasch model requirements. The excellent person reliability enabled person separation to six significant ability strata. The HAI produced an interval-level measure of bilateral hand use as well as unimanual scores of each hand, allowing a quantification of possible asymmetry expressed as an asymmetry index. The HAI can be considered a valid assessment tool for measuring bilateral hand use and quantifying side difference between hands among infants at risk of developing unilateral cerebral palsy. The Hand Assessment for Infants (HAI) measures the use of both hands and quantifies a possible asymmetry of hand use. HAI is valid for infants at 3 to 12 months corrected age at risk of unilateral cerebral palsy.


A prospective study comparing vertical banded gastroplasty versus laparoscopic adjustable gastric banding in the treatment of morbid and super-obesity.
We present our prospective comparative study on 60 patients subjected to two types of gastric restrictive procedures, i.e. Vertical Banded Gastroplasty (VBG) and Laparoscopic Adjustable Gastric Banding (LAGB) at King Abdul Aziz University Hospital, Jeddah, Saudi Arabia. The aim of our study was to compare weight reduction after both procedures. Thirty patients had VBG and thirty had LAGB based upon informed consents. The age, sex and preoperative weight and BMI were comparable in both groups. Excess weight loss of 87% was achieved in the VBG group while only 50% was noticed in the LAGB group at 6 months postoperatively.


Mesalamine and azathioprine modulate junctional complexes and restore epithelial barrier function in intestinal inflammation.
Disruption of mucosal structure and barrier function contribute to the pathogenesis of inflammatory bowel disease (IBD). Efficacy of therapy in IBD is based on endoscopic mucosal healing, which occurs by a dynamic interplay of epithelial cell regeneration, migration and differentiation. Both mesalamine (5-ASA) and azathioprine (AZTP) promote this process through mechanisms not clearly understood. We examined molecular pathways implicated in epithelial barrier function that were altered by 5-ASA and AZTP. Paracellular permeability induced by inflammatory mediators was mitigated by both compounds through restoration of cellular anchoring complexes. 5-ASA and AZTP induced rearrangement and membranous localization of junctional proteins and modulated genes involved in tight junctions. Intestinal organoids from wildtype-mice treated with TNF-α and IL-10- deficient-mice displayed impaired epithelial barrier with loss of membranous E-cadherin and reduced Desmoglein-2 expression. These effects were counteracted by 5-ASA and AZTP. Unlike AZTP that exhibited antiproliferative effects, 5-ASA promoted wound healing in colon epithelial cells. Both affected cellular senescence, cell cycle distribution and restricted cells in G1 or S phase without inducing apoptosis. This study provides mechanistic evidence that molecular actions of 5-ASA and AZTP on intestinal epithelia are fundamental in the resolution of barrier dysfunction.


Zeise's salt as powerful platinating agent for proteins investigated by top-down-mass spectrometry.
Metallodrugs have become an integral part of modern medicinal chemistry with platinum drugs as anti-cancer agents being well-known examples. The historically interesting compound Zeise's salt, potassium trichlorido(ethene)platinate(II) has scarcely been investigated in this context yet. This study is geared towards shedding light on the biological reactivity of this platinum complex. Mass Spectrometry tools were used to obtain a deeper understanding of its interactions with biomolecules on the molecular level. Angiotensin I and Ubiquitin were chosen as model systems. Comparison to Cisplatin show that Zeise's salt is more reactive towards nucleophilic sites in proteins. Our data indicate that the ethylene ligand remains on the platinum when coordinated to a nitrogen donor in the biomolecule and therefore offers a linkage for the introduction of further functionality. When attached to sulfur donors in the biomolecule, platinum(II) provides a site for the formation of crosslinks and loops in the biomolecules by losing all four of its initial ligands.


Childhood maltreatment and adult mental disorders - the prevalence of different types of maltreatment and associations with age of onset and severity of symptoms.
Childhood maltreatment (CM) is a risk factor for numerous mental disorders. However, the specificity of CM types in mental disorders is still being discussed. The present study examined the prevalence of five CM types in patients with schizophrenia/schizoaffective disorder (SZ; n = 107), bipolar disorder (BD; n = 103), depression (MDD; n = 604; with the two subgroups Persistent Depressive Disorder (PDD) and non-chronic MDD), and in healthy controls (HC; n = 715). Additionally, associations between CM types, symptom severity, and age of onset were investigated. The prevalence of all CM types was higher in the patient groups compared to HC. Emotional neglect, emotional abuse, and physical neglect were reported most frequently in all groups. Notably, patients with PDD reported more CM of all types than patients with non-chronic MDD. The severity of depression was associated with emotional abuse and neglect; anxiety with emotional abuse, emotional neglect, and sexual abuse; positive SZ symptoms with physical neglect; negative symptoms with emotional and physical neglect; and mania with sexual abuse and physical neglect. CM was associated with a younger age of onset in MDD and BD. The high prevalence of CM in patients with severe mental disorders highlights the importance of considering this issue in the treatment of such patients.


Course, risk factors, and prognostic factors in elderly primary care patients with mild depression: a two-year observational study.
The aim of this study was to observe course, risk factors, and prognostic factors in a primary care cohort aged > 60 with mild to moderate depression during two-year follow-up. Observational study. Primary care. During an 11-month period all (n = 302) consecutive patients aged 60 and above attending a primary care centre in Gothenburg, Sweden were screened by a nurse for depressive symptoms with the Primary Care Evaluation of Mental Disorders, Patient Questionnaire (PRIME-MD PQ) and the Montgomery-Åsberg Depression Rating Scale, self-rated version (MADRS-S) and by a GP with a patient-centred consultation model. In the second step, the GPs diagnosed depression in screen-positives by use of the PRIME-MD Clinical Evaluation Guide (PRIME-MD CEG). All patients with mild to moderate depression were followed up for two years to assess course with several MADRS-S score assessments. Main outcome measures. Risk factors, prognostic factors, and symptoms at baseline and after two years were tested with logistic regression, using the DSM-IV and MADRS-S (cut-off > 13) respectively. Course patterns were observed and described. A total of 54 patients were diagnosed with depression. Follow-up revealed declining median MADRS-S scores and three course patterns: remitting, stable, and fluctuating. History of depression, significant life events, lacking leisure activities, and use of sedatives were risk factors for depression, all previously known. An important finding was that lacking leisure activities also increased the risk of depressive symptoms after two years (odds ratio 12, confidence interval 1.1-136). It is desirable to identify elderly individuals with less severe depression. Three course patterns were observed; this finding requires further study of the clinical characteristics related to the different patterns. Awareness of risk factors may facilitate identification of those at highest risk of poor prognosis.


ODC1 inhibits the inflammatory response and ROS-induced apoptosis in macrophages.
Macrophage activation plays a critical role in the innate immune response. Ornithine decarboxylase (ODC1) metabolizes l-ornithine to polyamines and is the rate-limiting enzyme involved in the metabolism of polyamines, which are reportedly involved in cell differentiation, proliferation, and migration. However, the function of ODC1 in immune cells and especially in macrophages, as well as its underlying molecular mechanism, remains unclear. This study revealed the potential ODC1 function and mechanism associated with the lipopolysaccharide (LPS)-, Bacillus Calmette-Guerin (BCG)-, or carbon tetrachloride (CCl4)-induced inflammatory response in macrophages. We found significant upregulation of ODC1 in macrophages following LPS simulation and ODC1-specific suppression of proinflammatory cytokine secretion from macrophages upon stimulation with LPS, BCG and CCl4, respectively, suggesting a role as a common control element of the inflammatory response. Western blotting for nuclear factor-κB and mitogen-activated protein kinases revealed significant inhibition of phosphorylation of multiple transcription factors following ODC1 overexpression in macrophages. Moreover, ODC1 inhibited reactive oxygen species-induced and caspase-dependent apoptosis highlighted by decreased caspase-3 and -9 expression following ODC1 upregulation. These findings indicated that ODC1 was involved in attenuating the inflammatory response upon stimulation of macrophages, making it a potential therapeutic target for inflammatory diseases.


Discrepancies between self and observer ratings of depression. The relationship to demographic, clinical and personality variables.
The observer-rated Hamilton depression scale (HamD) and the self-report Beck Depression Inventory (BDI) are among the most commonly used rating scales for depression, and both have well demonstrated reliability and validity. However, many depressed subjects have discrepant scores on these two assessment methods. The present study evaluated the ability of demographic, clinical and personality factors to account for the discrepancies observed between BDI and HamD ratings. The study group consisted of 94 SCID-diagnosed outpatients with a current major depressive disorder. Subjects were rated with the 21-item HamD and completed the BDI and the NEO-Five Factor Inventory. Younger age, higher educational attainment, and depressive subtype (atypical, non-melancholic) were predictive of higher BDI scores relative to HamD observer ratings. In addition, high neuroticism, low extraversion and low agreeableness were associated with higher endorsement of depressive symptoms on the BDI relative to the HamD. In general, these predictive variables showed a greater ability to explain discrepancies between self and observer ratings of psychological symptoms of depression compared to somatic symptoms of depression. The study does not determine which aspects of neuroticism and extraversion contribute to the observed BDI/HamD discrepancies. Depression ratings obtained with the BDI and HamD are frequently discordant and a number of patient characteristics robustly predict the discrepancy between these two rating methods. The value of multi-modal assessment in the conduct of research on depressive disorders is re-affirmed.


Biological variation in the biparietal diameter and its bearing on clinical ultrasonography.
Interpopulation differences in the term BPD and its relations to BW stress the need for each institution to analyze its own data. Variations in the BPD as a function of BW do not connote differences in the brain: body weight relationship, because the neurocrania of all term fetuses are not homomorphic. Differentiation of neurocranial form accounts for there being no consistent relationship between the BPD and calculated brain weight in interpopulation comparisons. The wide scatter of BPD and BW values in data from a single source challenges the wisdom of judging individual serial BPD readings by mean population values. Because the correlation between BW and the common indices of maternal size (stature, weight, and surface area) is too low (r = 0.27, 0.27, and 0.35, respectively) to provide a useful means of determining the fetal growth potential, each fetus should be used as its own control in serial cephalometry.


Basal cell skin cancer and the risk of second primary cancers: a cancer registry-based study in Lithuania.
The aim of this population-based cohort study was to determine the risk of second primary cancer in basal cell carcinoma (BCC) patients in Lithuania. This analysis was based on patients diagnosed with BCC in Lithuania between 1998 and 2007 and followed until 2011. Standardized incidence ratios for subsequent cancers as a ratio of observed number of cancer cases in people with previous BCC diagnosis to the expected number of cancer cases in the underlying general population were calculated. After diagnosis of BCC, 1442 new cases of selected cancers were diagnosed. Compared with the general population, the incidence of all new primaries combined after BCC was very close to expected. Statistically meaningful increase in developing subsequent cancer was obtained for Hodgkin's lymphoma, prostate cancer, and leukemia in men, and for cancers of the lip, lung, and breast in women. Risk of melanoma and thyroid cancer was significantly elevated in both sexes. Relative risk of cancer of the eye was increased although not significant. In our study, we found increased cancer risk for cancers related to sun exposure. In addition, increased risks were identified for Hodgkin's lymphoma, thyroid cancer, leukemia, prostate, and breast cancer in BCC patients.


Human umbilical cord blood cells transfected with VEGF and L(1)CAM do not differentiate into neurons but transform into vascular endothelial cells and secrete neuro-trophic factors to support neuro-genesis-a novel approach in stem cell therapy.
Genetically modified mono-nuclear cell fraction from human umbilical cord blood (HUCB) expressing human vascular endothelial growth factor (VEGF) and mouse neural L(1) cell adhesion molecule (L(1)CAM) were used for gene-stem cell therapy of transgenic (G)93(A) mice adopted as an animal amyotrophic lateral sclerosis (ALS) model. We generated non-viral plasmid constructs, expressing human VEGF(165) (pcDNA-VEGF) and mouse neural L(1) cell adhesion molecule (pcDNA-mL(1)CAM). Mono-nuclear fraction of HUCB cells were transiently transfected by electro-poration with a mixture of expression plasmids (pcDNA-VEGF+pcDNA-mL(1)CAM). Sixteen transgenic female and male mice were randomly assigned to three groups: (1) transplantation of genetically modified HUCB cells expressing L(1) and VEGF (n=6), (2) transplantation of un-transfected HUCB cells (n=5), and (3) control group (n=5). In first two experimental groups 1x10(6) cells were injected retro-orbitally in pre-symptomatic 22-25-week-old (G)93(A) mice. Our results demonstrate that HUCB cells successfully grafted into nervous tissue of ALS mice and survived for over 3 months. Therefore, genetically modified HUCB cells migrate in the spinal cord parenchyma, proliferate, but instead of transforming into nerve cells, they differentiate into endothelial cells forming new blood vessels. We propose that: (A) expression of mouse neural L(1)CAM is responsible for increased homing and subsequent proliferation of transplanted cells at the site of neuro-degeneration, (B) expression of human VEGF directs HUCB cell differentiation into endothelial cells, and (C) neuro-protective effect may stem from the delivery of various neuro-trophic factors from newly formed blood vessels.


Klotho sensitivity of the hERG channel.
Klotho, a hormone and enzyme, is a powerful regulator of ageing and life span. Klotho deficiency leads to cardiac arrythmia and sudden cardiac death. We thus explored whether klotho modifies cardiac K(+)-channel hERG. Current was determined utilizing dual electrode voltage clamp and hERG protein abundance utilizing immunohistochemistry and chemiluminescence in Xenopus oocytes expressing hERG with or without klotho. Coexpression of klotho increased cell membrane hERG-protein abundance and hERG current at any given voltage without significantly modifying the voltage required to activate the channel. The effect of klotho coexpression was mimicked by recombinant klotho protein and reversed by β-glucuronidase-inhibitor D-saccharic acid-1,4-lactone.


The development and ultrastructure of Plasmodium falciparum damaged in vitro by human "crisis" sera and by chloroquine.
P. falciparum malaria was cultured in vitro in the presence of sera from patients with cerebral malaria, meningitis and also after chloroquine administration. Intra-erythrocytic parasite damage was seen by light and electron microscopy. The significance of the results is discussed with relevance to non-specific immune mechanisms, and the damage induced by these mechanisms compared with that from chloroquine.


Imaging in situ protein-DNA interactions in the cell nucleus using FRET-FLIM.
Although the distribution of DNA-binding proteins inside the cell nucleus can be analyzed by immunolabeling or by tagging proteins with GFP, we cannot establish whether the protein is bound to DNA or not. Here, we describe a novel approach that allows imaging of the in situ interaction between a GFP-fusion protein and DNA in the cell nucleus, using fluorescence resonance energy transfer (FRET). We used fluorescence lifetime imaging microscopy (FLIM) as a reliable tool to detect protein in contact with DNA. The method was successfully applied to the DNA-binding proteins histone H2B and the glucocorticoid receptor and to the heterochromatin-associated proteins HP1alpha and HP1beta.


[Coronary artery bypass graft surgery in dialysis patient].
To determine the operative outcome of coronary artery bypass graft surgery (CABG) for severe coronary artery disease in long-term hemodialysis patients, we analyzed a group of 16 patients who underwent CABG over a ten-year period in our institution. Hospital mortality was 12.5% (2 of 16 patients). These two patients died of ischemic colitis and perioperative myocardial infarction, respectively. There were five late deaths: one patient died from myocardial infarction, one from uremia, one from gastro-intestinal bleeding, one from gastric cancer and one from unknown cause. There were four significant postoperative complications (morbidity 25%), consisted of one pulmonary tuberculosis, one sternal dehiscence secondary to mediastinitis, one mediastinal hematoma secondary to late bleeding from the LITA dissection area and one A-V shunt trouble. Graft patency rate within the first two months was 93% (30 to 42 in 13 patients). Hospital survivors experienced complete relief from angina. Actuarial survival was 68.8% at 3 years, 57.3% at 5 years and 28.6% at 7 years. This rate is not significantly different from the survival of all dialysis patients, but seems to be better than that of dialysis patients with not operated coronary artery disease. We concluded that CABG in dialysis patients can be accomplished with acceptable morbidity and mortality and effective relief of symptoms.


Utility of the STOP-Bang and Epworth scales and the neck-to-height ratio to detect severe obstructive apnea-hypopnea syndrome in severe obesity.
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is present in 80% of patients evaluated for bariatric surgery (BS). Extensive evaluation is not widely available, but treatment is mandatory for severe cases. The Snore, Tiredness, Observed apneas and Pressure - Body mass index, Age, Neck circumference and Gender (STOP-Bang) and Epworth questionnaires and neck-to-height ratio (NHtR) are accessible clinical tools to screen for sleep and metabolic disturbances, but their utility to detect severe OSAHS in patients with severe obesity has not been determined. To evaluate the cutoff point of those clinical tools that may predict severe OSAHS, confirmed by polysomnography in patients referred for BS. Tertiary referral center in Mexico City. We applied the STOP-Bang and Epworth questionnaires, evaluated anthropometric characteristics, and collected samples for arterial gasometry and metabolic parameters from 68 patients with severe obesity, who were then referred for polysomnography before their evaluation for BS. Of the 68 patients participating in the study, 67.7% were female, with a median age of 43 years (35-49 years) and a body mass index (BMI) of 45.5 kg/m2 (42.4-50.9 kg/m2; 28.3% had a BMI ≥ 50 kg/m2). A STOP-Bang cutoff >5 points had a sensitivity of 60% and specificity of 90% for detecting severe OSAHS (area under the curve [AUC] = .962); meanwhile, an NHtR >.25 had a sensitivity of 90% and specificity of 52.5% (AUC = .759). The Epworth scale score >11 points had a sensitivity of 57.1% and specificity of 83.3% (AUC = .802). Clinical data may be useful to detect severe sleep apnea in high-risk populations, allowing for rapid referral and better use of resources.


An unknown source of vitamin K1 in patients on total parenteral nutrition.
We found a level of 20.8 +/- 3.4 mug/dl of vitamin K1 (VK1) in Intralipid 20% and initiated a study based on the follow-up of children receiving total parenteral nutrition without any other exogenous VK1 intake than from Intralipid 20% (1 g/kg/day). This lipid administration was sufficient to cover the needs during a study period of 4 to 29 weeks.


Compassionate Use Program of Ipilimumab and Nivolumab in Intermediate or Poor Risk Metastatic Renal Cell Carcinoma: A Large Multicenter Italian Study.
This is a retrospective analysis on the safety and activity of compassionate Ipilimumab and Nivolumab (IPI-NIVO) administered to patients with metastatic Renal Cell Carcinoma (mRCC) with intermediate or poor International Metastatic RCC Database Consortium (IMDC) score as a first-line regimen. IPI was infused at 1 mg/kg in combination with Nivolumab 3 mg/kg every three weeks for four doses, followed by maintenance Nivolumab (240 or 480 mg flat dose every two or four weeks, respectively) until disease progression or unacceptable toxicity. A total of 324 patients started IPI-NIVO at 86 Italian centers. Median age was 62 years, 68.2% IMDC intermediate risk. Primary tumor had been removed in 65.1% of patients. Two hundred and twenty patients (67.9%) completed the four IPI-NIVO doses. Investigator-assessed overall response rate was 37.6% (2.8% complete). Twelve-month survival rate was 66.8%, median progression-free survival was 8.3 months. Grade 3 or 4 treatment-related adverse events occurred in 67 patients (26.9%). IMDC intermediate risk, nephrectomy, BMI ≥ 25 kg/m2, and steroid use for toxicities correlated with improved survival, while age < 70 years did not. IPI-NIVO combination is a feasible and effective regimen for the first-line treatment of intermediate-poor IMDC risk mRCC patients in routine clinical practice.


Activation of astrocytic lysosomal proteinases by factors released by mononuclear leukocytes.
Lysosomal proteinases are increased in the tissue lesions of experimental allergic encephalomyelitis and have been implicated in the degradation of myelin proteins. The cellular origins of the increased proteinases are not known but reactive astrocytes found in areas of increased activity are candidate cells. To evaluate the potential of astrocytes as the source of these proteinases, cathepsin B (CB) and cathepsin D (CD) levels were measured in lysates of cultured astrocytes from neonatal rats. Because astrocytes are activated by inflammatory mediators in demyelinating lesions the effect of activation on proteinase levels was examined. Culture supernatants from mononuclear leukocytes stimulated with either concanavalin A or phytohemagglutinin (PHA) induced significant increases in the astrocytic proteinases. Neither PHA alone, interleukin-1, interleukin-2, nor gamma-interferon induced significant increases. Fractions of the supernatant from PHA stimulated mononuclear leukocytes were tested and activity was found in fractions corresponding to a molecular weight of 45-50,000. These studies demonstrate that astrocytes contain significant amounts of CB and CD activity which can be increased by a factor or factors released by activated mononuclear leukocytes.


Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa.
The cephalosporin nitric oxide (NO)-donor prodrug DEA-C3D ('DiEthylAmin-Cephalosporin-3'-Diazeniumdiolate') has been shown to initiate the dispersal of biofilms formed by the Pseudomonas aeruginosa laboratory strain PAO1. In this study, we investigated whether DEA-C3D disperses biofilms formed by clinical cystic fibrosis (CF) isolates of P. aeruginosa and its effect in combination with two antipseudomonal antibiotics, tobramycin and colistin, in vitro. β-Lactamase-triggered release of NO from DEA-C3D was confirmed using a gas-phase chemiluminescence detector. MICs for P. aeruginosa clinical isolates were determined using the broth microdilution method. A crystal violet staining technique and confocal laser scanning microscopy were used to evaluate the effects of DEA-C3D on P. aeruginosa biofilms alone and in combination with tobramycin and colistin. DEA-C3D was confirmed to selectively release NO in response to contact with bacterial β-lactamase. Despite lacking direct, cephalosporin/β-lactam-based antibacterial activity, DEA-C3D was able to disperse biofilms formed by three P. aeruginosa clinical isolates. Confocal microscopy revealed that DEA-C3D in combination with tobramycin produces similar reductions in biofilm to DEA-C3D alone, whereas the combination with colistin causes near complete eradication of P. aeruginosa biofilms in vitro. DEA-C3D is effective in dispersing biofilms formed by multiple clinical isolates of P. aeruginosa and could hold promise as a new adjunctive therapy to patients with CF.


Optimizing combination rifampin therapy for staphylococcal osteoarticular infections.
Staphylococcus spp. causes more than half of all osteoarticular infections of native structures or implanted material. The ability of Staphylococcus spp. to persist within infected bone tissue and to produce a bacterial biofilm, most notably in infections of implanted material, can lead to treatment failures and microbiological relapses. Rifampin is a cornerstone of the treatment of staphylococcal osteoarticular infections, particularly those of implanted material. Rifampin is a bactericidal antibiotic that diffuses very well within bone tissue and bacterial biofilms. The mechanism of action is inhibition of bacterial DNA transcription to mRNA independently from bacterial division, which results in activity against even dormant Staphylococcus spp. organisms. However, the high risk of emergence of rifampin-resistant mutants requires the concomitant administration of another antibiotic. Several antibiotics are recommended in the French guidelines issued by the French-Speaking Society for Infectious Diseases (Société de Pathologie Infectieuse de Langue Française [SPILF]). Here, we discuss the results from in vitro, animal, and clinical studies that explain the advantages and drawbacks of each antibiotic used with rifampin to treat osteoarticular infections due to Staphylococcus spp.


Human milk nutrient fortifiers alter the developing gastrointestinal microbiota of very-low-birth-weight infants.
Nutrient fortifiers are added to human milk to support the development of very-low-birth-weight infants. Currently, bovine-milk-based fortifiers (BMBFs) are predominantly administered, with increasing interest in adopting human-milk-based fortifiers (HMBFs). Although beneficial for growth, their effects on the gastrointestinal microbiota are unclear. This triple-blind, randomized clinical trial (NCT02137473) tested how nutrient-enriching human milk with HMBF versus BMBF affects the gastrointestinal microbiota of infants born < 1,250 g during hospitalization. HMBF-fed infants (n = 63, n = 269 stools) showed lower microbial diversity, altered microbial community structure, and changes in predicted microbial functions compared with BMBF-fed infants (n = 56, n = 239 stools). HMBF-fed infants had higher relative and normalized abundances of unclassified Enterobacteriaceae and lower abundances of Clostridium sensu stricto. Post hoc analyses identified dose-dependent relationships between individual feed components (volumes of mother's milk, donor milk, and fortifiers) and the microbiota. These results highlight how nutrient fortifiers impact the microbiota of very-low-birth-weight infants during a critical developmental window.


Diabetic crises in children treated with small doses of intramuscular insulin.
A new regimen for the management of diabetic crises in children using small doses of intramuscular insulin and generous amounts of intravenous fluids has been devised. Insulin dosage was calculated from the patient's weight and was independent of the degree of hyperglycaemia. Minimum demands were made upon the laboratory.


Identification of Porcine Endogenous Retrovirus (PERV) packaging sequence and development of PERV packaging viral vector system.
Studies of the retroviruses have focused on the specific interaction of the nucleocapsid protein with a packaging signal in the viral RNA as important for this selectivity, but the packaging signal in porcine endogenous retrovirus (PERV) has not been defined. Herein, we identified and analyzed this packaging signal in PERV and found hairpin structures with conserved tetranucleotides in their loops and nucleocapsid recognition sequences; both of which are key elements in the viral packaging signal of MLV. We evaluated packaging efficiency of sequence variants isolated from viral and proviral integrated genomes. All viral packaging sequences (Ψ) were identical, while five distinct packaging sequences were identified from proviral sources. One proviral sequence (Ψ1) was identical to that of the viral Ψ and had the highest packaging efficiency. Three variants (Ψ2, Ψ3, Ψ4) maintained key elements of the viral packaging signal, but had nucleotide replacements and consequently demonstrated reduced packaging efficiency. Despite of the same overall hairpin structure, the proviral variant (Ψ5) had only one GACG sequence in the hairpin loop and showed the lowest packaging efficiency other than ∆Ψ, in which the essential packaging sequence was removed. This result, thus, defined the packaging sequences in PERV and emphasized the importance of nucleotide sequence and RNA structure in the determination of packaging efficiency. In addition, we demonstrate efficient infection and gene expression from the PERV based viral vector, which may serve as a novel alternative to current retroviral expression systems.


[Influence of a multiple intervention program for hand hygiene compliance in an ICU].
To assess compliance with hand hygiene (HH) in ICU workers before (P1) and after (P2) implementation of a HH promotion program and distribution of an alcoholic solution for HH, and to analyze factors independently associated to HH before and after patients care. Fifty hours of observational evaluation were carried out during each period of the study (P1 and P2); the number of opportunities for HH (before and after patients care) was registered. Educational program (6 months): poster campaign, educational meetings with staff about HH, and the provision of alcohol hand rubs. ICU in a secondary level hospital. Healthcare workers in the ICU. A quasi-experimental design was used to evaluate compliance with HH before and after implementation of the educational program. Dependent variable: HH compliance before-after patients care; independent variables that might be associated to compliance (including the educational program). In P1 there were 338 opportunities for HH both before and after patients care, versus 355 in P2 (before and after patients care). The hand-washing rate was significantly higher in P2 than in P1 (prior to patient care: 45.3% and 34.9%, respectively, and after patient care: 63% and 51.7%, respectively). In the multivariate analysis, the educational program, together with other variables, was significantly associated to HH before and after patients care. There was a significant increase in compliance with hand hygiene among the ICU personnel during the educational phase, both before and after patients care.


Reconstruction of the alar groove.
The obliteration of a well-defined alar groove is common after nasal alar reconstruction. A method is described that can be used at the time of reconstruction to ensure the continued definition of the groove or to restore it in cases where it has been obliterated. The technique is based on the natural tendency of the skin to tube itself. Cheek skin is advanced beneath the posterior free edge of the reconstructed ala so that this edge now comes into contact with an epidermal surface. As this edge now tends to tube itself, a natural alar groove is produced. This method has been used successfully in six cases.