Early-life socioeconomic status and malocclusion in adolescents and young adults in Uruguay.
This study aims to estimate orthodontic treatment need among 15-24 year-old individuals in Montevideo, Uruguay, and the association of occlusal traits with demographic, clinical and socioeconomic factors, considering a life course approach. A cross-sectional study using data from the First National Oral Health Survey in Uruguay was conducted. A two-stage cluster procedure was used to select a sample of 278 individuals in Montevideo. Household interviews and oral examinations were performed by six dentists. Dental Aesthetic (DAI) and Decayed Missing and Filled Teeth Indices (DMFT) were used to assess orthodontic treatment need and dental caries, respectively. Early life and current socioeconomic factors were obtained from the interview. Ordinal logistic regression was used to model the DAI index. Prevalence of definite malocclusion was 20.6%, followed by severe (8.2%) and very severe (7.6%). In the adjusted analysis, individuals with untreated dental caries (OR = 1.11; 95%CI: 1.03-1.20) and those who reported a lower socioeconomic level at 6 years of age (OR = 5.52; 95%CI: 1.06-28.62) had a higher chance of being a worse case of malocclusion. Current socioeconomic position was not associated with orthodontic treatment need. Individuals aged 22-24 years (OR = 1.59; 95%CI: 1.05-2.41) had a lower chance than those aged 14-17. This study shows that orthodontic treatment need is relatively high in Uruguayan adolescents and young adults. There is a potential relationship between early life socioeconomic status and the occurrence of malocclusion in adolescents and young adults under a life course approach.


Voxel-based gray and white matter morphometry correlates of hallucinations in schizophrenia: The superior temporal gyrus does not stand alone.
Auditory verbal hallucinations (AVH) in schizophrenia (SZ) have been proposed to result from abnormal local, interregional and interhemispheric integration of brain signals in regions involved in language production and perception. This abnormal functional integration may find its base in morphological abnormalities. Structurally, AVHs have been frequently linked to abnormal morphology of the superior temporal gyrus (STG), but only a few studies investigated the relation of hallucination presence with both whole-brain gray matter (GM) and white matter (WM) morphometry. Using a unified voxel-based morphometry-DARTEL approach, we investigated correlates of AVH presence in 51 schizophrenia patients (20 non-hallucinating [SZ -], 31 hallucinating [SZ +]), and included 51 age and sex matched healthy participants. Effects are reported at p < .05 FWE corrected. Patients showed lower GM volume of the left STG than controls, irrespective of AVH presence. In addition, SZ + showed lower GM volume of the left inferior frontal and right parahippocampal gyrus, and higher WM volume of the left postcentral and superior parietal lobule than controls. Finally, volume of the putamen was lower in SZ + compared to SZ -. No effects on corpus callosum morphometry were observed. Delusion severity, general positive and negative symptomatology illness duration, and medication status could not explain the results. Results suggest that STG GM abnormalities underlie the general susceptibility to experience psychotic symptoms and that additional abnormalities in a network of medial temporal, ventrolateral, putaminal, and parietal regions related to verbal memory and speech production may specifically increase the likelihood of experiencing AVH. Future studies should clarify the meaning of morphometry abnormalities for functional interregional communication.


Glenohumeral chondrolysis after shoulder arthroscopy with thermal capsulorrhaphy.
Glenohumeral chondrolysis is a rare but devastating complication that can occur after shoulder arthroscopy and thermal capsulorrhaphy. We retrospectively reviewed the medical records and imaging studies of 8 patients in whom glenohumeral chondrolysis developed after shoulder arthroscopy in which thermal energy was used. Of the 8 patients, 5 had previous thermal capsulorrhaphy for the diagnosis of instability. Two patients were diagnosed with instability with associated labral tears and underwent labral repair with thermal capsular shrinkage. One patient was diagnosed with a labral tear and underwent labral debridement with an extensive glenohumeral synovectomy via a thermal probe. No patients had evidence of chondral damage at their index arthroscopy, and none received postoperative pain pumps. In all patients, radiographic evidence of chondrolysis developed and repeat arthroscopy was performed to confirm the diagnosis. Open surgical stabilization has not been known to have this complication, and it is speculated that heating of the joint fluid at the time of arthroscopy from any source plays a role in cartilage death. Further studies are warranted to determine whether adequate outflow during shoulder arthroscopy where the fluid volume is relatively small will aid in avoiding complications associated with the use of heat sources.


Living with liver flukes: Does migration matter?
Migration is typically thought to be an evolved trait driven by responses to forage or predation, but recent studies have demonstrated avoidance of parasitism can also affect success of migratory tactics within a population. We evaluated hypotheses of how migration alters parasite exposure in a partially migratory elk (Cervus canadensis) population in and adjacent to Banff National Park, Alberta, Canada. Equal numbers of elk remain year-round on the winter range or migrate to summer range. We quantified diversity and abundance of parasites in faecal elk pellets, and prevalence (number of infected individuals) and intensity (egg counts) of giant liver fluke eggs (Fascioloides magna) in faeces across migratory tactics. We tested whether giant liver fluke intensity in faeces was affected by elk use of wetlands, elevation, forage biomass, and elk concentration in the previous summer. We rejected the "migratory escape" hypothesis that suggests migration allowed elk to escape parasite exposure because migrant elk had the highest richness and evenness of parasite groups. We also rejected the hypothesis that prevalence was highest at highest summer densities because higher-density resident elk had the lowest diversity and giant liver fluke egg presence and intensity. Instead, the high prevalence and intensity of giant liver flukes in migrants was consistent with both the hypothesis of "environmental tracking", because elk that migrated earlier may expose themselves to favourable parasite conditions, and with the "environmental sampling" hypothesis, because giant liver fluke intensity increased with increased exposure to secondary host habitat (i.e., wetland). Our results indicate that differential exposure of different migratory tactics that leave the winter range has a greater influence on parasites than the concentration of elk that reside on the winter range year-round.


Amoebic meningo-encephalitis due to a free-living amoeba. A case report.
A 47-year-old man developed an undiagnosed encephalitic illness and died within 12 days. Autopsy showed focal granulomatous lesions associated with a necrotizing vasculitis. Light microscopy revealed the presence of free-living amoebae morphologically resembling Acanthamoeba species. The pathology of this form of meningo-encephalitis is contrasted with that caused by Naegleria fowleri infection, and attention is drawn to its existence within the RSA.


Profile, outcome and predictors of mortality of abdomino-pelvic trauma patients in a tertiary intensive care unit in Saudi Arabia.
The Kingdom of Saudi Arabia (KSA) is one of countries with the world's highest number of deaths per 100,000 populations from road traffic accidents (RTAs). Numerous trauma victims sustain abdomino-pelvic injuries, which are associated with considerable morbidity and mortality. The purpose of this study was to describe profile, outcomes and predictors of mortality of patients with abdomino-pelvic trauma admitted to the intensive care unit (ICU) in a tertiary care trauma centre in Riyadh, KSA. This was a retrospective analysis of prospectively collected ICU database. All consecutive patients older than 14 years with abdomino-pelvic trauma from March 1999 to June 2013 were included. The followings were extracted: demographics, injury severity, mechanism and type of injury, associated injuries, use of vasopressors and mechanical ventilation, and worst laboratory results in the first 24h. The primary outcome was hospital mortality. We compared profile and outcomes between survivors and non-survivors and reported predictors of mortality. Of the 11,374 trauma patients who were admitted to the hospital during the study period, 2120 (18.6%) patients had abdomino-pelvic injuries, out of which 702 (33.1%) patients were admitted to the ICU. The mean age was 30.7 (SD 14.4) years and the majority was male (89.5%). RTA was the most common cause of abdomino-pelvic trauma (70.4%). Pelvis (46.2%), liver (25.8%), and spleen (23.1%) were the most frequently injured organs; and chest (55.6%), head (41.9%), and lower extremities (27.5%) were the most commonly associated injuries. Mechanical ventilation was required in 89.6% with a mean duration of 9.1 (SD 9.2) days and emergency surgery was performed in 45.0% of the patients with prolonged ICU and hospital length of stay (10.8 [SD 10.8], 56.9 [SD 96.7] days; respectively). Of the 702 patients with abdomino-pelvic trauma, 115 (16.4%) patients did not survive. Associated head trauma and retroperitoneal haematoma, higher level of lactic acid on admission and ISS, and advanced age were potential risk factors for hospital mortality. Abdomino-pelvic injuries are common in trauma patients, affecting mainly young male victims, and are associated with significant morbidity and mortality, and resource utilisation.


Mammalian target of rapamycin complex 2 (mTORC2) is a critical determinant of bladder cancer invasion.
Bladder cancer is the fourth most common cause of cancer in males in the United States. Invasive behavior is a major determinant of prognosis. In this study, we identified mammalian target of rapamycin complex 2 (mTORC2) as a central regulator of bladder cancer cell migration and invasion. mTORC2 activity was assessed by the extent of phosphorylation of Ser473 in AKT and determined to be approximately 5-fold higher in specimens of invasive human bladder cancer as opposed to non-invasive human bladder cancer. The immortalized malignant bladder cell lines, UMUC-3, J82 and T24 demonstrated higher baseline mTORC2 activity relative to the benign bladder papilloma-derived cell line RT4 and the normal urothelial cell line HU1. The malignant bladder cancer cells also demonstrated increased migration in transwell and denudation assays, increased invasion of matrigel, and increased capacity to invade human bladder specimens. Gene silencing of rictor, a critical component of mTORC2, substantially inhibited bladder cancer cell migration and invasion. This was accompanied by a significant decrease in Rac1 activation and paxillin phosphorylation. These studies identify mTORC2 as a major target for neutralizing bladder cancer invasion.


Hoarding, hermitage, and the law: why we love the collyer brothers.
Interest in hoarding behavior has intensified, as it works its way through DSM-V deliberations and treatment models. Meanwhile, both documentarians and fiction writers have embraced accounts of individuals with disposophobia and romanticized versions of the Collyer brothers, the Hermits of Harlem. In this article, I examine the range of media and professional attention given to hoarders and their problems and then focus on a potential role for forensic mental health professionals. The psycholegal problems of hoarders include health and zoning code violations that evolve into criminal charges, civil commitment, questions of animal cruelty, landlord-tenant disputes, divorce and custody evaluations, testamentary capacity, and child-neglect charges.


A randomized long-term trial of tacrolimus/sirolimus versus tacrolimums/mycophenolate versus cyclosporine/sirolimus in renal transplantation: three-year analysis.
We report three-year (interim) effects of combining sirolimus (Siro) vs. mycophenolate mofetil (MMF) as adjunctive therapy with calcineurin inhibitors (CI) in renal transplantation in the three different CI-based regimens. Between May 2000 and December 2001, 150 recipients of deceased donor (DD) and living donor (LD) kidney transplants were randomized into three groups (n=50/group): Group A (Tacro/Siro), Group B (Tacro/MMF) and Group C (CsA/Siro). This report details drug dosing and monitoring, protocol discontinuance, biopsy-proven rejection, graft failure, other adverse events, and death at 36 months postoperatively. Actual patient and graft survival respectively in Group A was 90% and 82%, in Group B was 92% and 88%, and in Group C was 96% and 88% (not significant). Biopsy-confirmed acute rejection incidents showed a trend in favor of Group B (10%) vs. Group A (26%) and Group C (20%) combined (P=0.07). The geometric mean */SE serum creatinine concentration and arithmetic mean +/- SE Cockroft-Gault creatinine clearance calculations, respectively, were 1.39*/1.1 and 72.8+/-4.3 for Group A, 1.36*/1.1 and 72.1+/-4.1 for Group B, and 1.60*/1.1 and 61.8+/-3.8 for Group C, a statistically favorable difference for Group B over Group C (P=0.04). There was also less de novo development of posttransplant diabetes mellitus and lipid disorders in Group B vs. A and C (P<0.04). This three-year (interim) analysis has indicated a trend towards better graft function, fewer endocrine disorders, and fewer acute rejection episodes comparing adjunctive MMF and Tacro vs. Siro and Tacro or Siro and CsA, in the dosages used.


Pancreas transplantation in nonuremic, type I diabetic recipients.
Between July 1978 and January 1988, 111 of 210 pancreas transplants were in nonuremic, nonkidney (NUNK) recipients in whom complications of diabetes were judged more serious than the potential side effects of antirejection therapy. In all NUNK cases, the 1-year patient survival rate (PSR) and graft survival rate (GSR) were 90% and 39%. Since November 1984, 1-year PSR and GSR for 62 NUNK recipients of pancreas transplants alone (PTA) were 93% and 48%, compared to 89% and 37% for 28 pancreas transplants after (PAK) and 89% and 73% for 20 simultaneous (SPK) with a kidney transplant. The 1-year GSR for 1984-88 technically successful (TS) PTA cases (n = 47) was 63%, versus 75% for PAK (n = 13) and 86% for SPK (n = 17) cases. The 1-year GSRs, by technique and source for 1984-88 PTA cases, were 58% for bladder-drained cadaver (n = 30), 51% for enteric-drained related (n = 32), and 29% for enteric-drained cadaver (n = 17) donor transplants, and 75% (n = 24), 77% (n = 16), and 38% (n = 13) for the corresponding TS cases. Of NUNK recipients, 35 have had grafts function for more than 1 year and all but 3 were treated with cyclosporine (CsA). In the CsA-treated recipients, serum creatinine increased and creatinine clearances decreased by a magnitude of 40% during the first 6 months but thereafter remained stable in all but 2 patients. In the patients with functioning grafts studied at 1 year, retinopathy remained stable in 59% and progressed in 41% of the eyes (n = 39). Motor nerve conduction velocities were significantly increased and muscle action potentials remained stable in 24 patients with functioning grafts studied at 1 year, while in 14 patients in whom transplants failed there was a significant decrease in evoked muscle action potentials. A sustained euglycemic, insulin-independent state can be established in nonuremic, nonkidney diabetic recipients of pancreas transplants alone, with a beneficial effect on neuropathy, lack of an immediate benefit on advanced retinopathy, and an effect on nephropathy compounded by the influence of CsA on renal function.


Comparing spinal blockade effectiveness and maternal hemodynamics using 25 gauge and 29 gauge spinal needles with the same volumetric flow rate in patients undergoing caesarean section.
Spinal needles with different diameters can be used to prevent side effects in patients undergoing spinal anaesthesia. However, the velocity of local anaesthetic changes through the spinal needle depending on the diameter of it. Local anaesthetic injection velocity has been reported to be associated with the spinal block level. We aimed to compare spinal needles of different diameters with the same local anaesthetic volumetric flow rate in terms of spinal blockade and hemodynamics in obstetric patients. Eighty-four patients received spinal anaesthesia by either a 25G needle or 29G with the same volumetric flow rate. Block levels, adverse effects, ephedrine given and a success rate of spinal anaesthesia were significantly higher in 25G than in 29G (p < .05). Athough the use of 29G was associated with a low level of block, a sufficient block level was generated for caesarean section. Furthermore, in spite of the technical difficulty, use of 29G was accompanied by a decreased incidence of maternal hypotension, bradycardia and a lowered ephedrine administration. Impact statement Local spinal anaesthetic injections at faster flows cause turbulent flow leading to lower anaesthesia concentrations. The control of spinal anaesthesia levels has some difficulties due to anatomical repositioning, especially in pregnant patients. Also, it can cause frequent hemodynamic complications including hypotension and bradycardia, complications that may also have inadvertent effects on foetus. In this study, we showed that smaller diameter spinal needles provided safer spinal anaesthesia levels and a lower incidence of hemodynamic complications.


Investigating potential interactions between envelope following responses elicited simultaneously by different vowel formants.
Envelope following responses (EFRs) evoked by the periodicity of voicing in vowels are elicited at the fundamental frequency of voice (f0), irrespective of the harmonics that initiate it. One approach of improving the frequency specificity of vowel stimuli without increasing test-time is by altering the f0 selectively in one or more formants. The harmonics contributing to an EFR can then be differentiated by the unique f0 at which the EFRs are elicited. The advantages of using such an approach would be increased frequency specificity and efficiency, given that multiple EFRs can be evaluated in a certain test-time. However, multiple EFRs elicited simultaneously could interact and lead to altered amplitudes and outcomes. To this end, the present study aimed to evaluate: (i) if simultaneous recording of two EFRs, one elicited by harmonics in the first formant (F1) and one elicited by harmonics in the second and higher formants (F2+), leads to attenuation or enhancement of EFR amplitude, and (ii) if simultaneous measurement of two EFRs affects its accuracy and anticipated efficiency. In a group of 22 young adults with normal hearing, EFRs were elicited by F1 and F2+ bands of /u/, /a/ and /i/ when F1 and F2+ were presented independently (individual), when F1 and F2+ were presented simultaneously (dual), and when F1 or F2+ was presented with spectrally matched Gaussian noise of the other (noise). Repeated-measures analysis of variance indicated no significant group differences in EFR amplitudes between any of the conditions, suggesting minimal between-EFR interactions. Between-participant variability was evident, however, significant changes were evident only in a third of the participants for the stimulus /u/ F1. For the majority of stimuli, the change between individual and dual conditions was positively correlated with the change between individual and noise conditions, suggesting that interaction-based changes in EFR amplitude, when present, were likely due to the restriction of cochlear regions of excitation in the presence of a competing stimulus. The amplitude of residual noise was significantly higher in the dual or noise relative to the individual conditions, although the mean differences were very small (<3 nV). F-test-based detection of EFRs, commonly used to determine the presence of an EFR, did not vary across conditions. Further, neither the mean reduction in EFR amplitude nor the mean increase in noise amplitude in dual relative to individual conditions was large enough to alter the anticipated gain in efficiency of simultaneous EFR recordings. Together, results suggest that the approach of simultaneously recording two vowel-evoked EFRs from different formants for improved frequency-specificity does not alter test accuracy and is more time-efficient than evaluating EFRs to each formant individually.


Sulphate reduction and vertical distribution of sulphate-reducing bacteria quantified by rRNA slot-blot hybridization in a coastal marine sediment.
In the past, enumeration of sulphate-reducing bacteria (SRB) by cultivation-based methods generally contradicted measurements of sulphate reduction, suggesting unrealistically high respiration rates per cell. Here, we report evidence that quantification of SRB rRNA by slot-blot hybridization is a valuable tool for a more realistic assessment of SRB abundance in the natural environment. The distribution of SRB was investigated in a coastal marine sediment by hybridization of membrane-immobilized rRNA with oligonucleotide probes. As represented by general probe-target groups, SRB rRNA contributed between 18% and 25% to the prokaryotic rRNA pool. The dominant SRB were related to complete oxidizing genera (Desulphococcus, Desulphosarcina and Desulphobacterium), while Desulphobacter could not be detected. The vertical profile and quantity of rRNA from SRB was compared with sulphate reduction rates (SRR) measured with 35SO4(2-) tracer in whole-core incubations. While SRB abundance was highest near the surface, peaking at around 1.5 cm, measured sulphate reduction rates were lowest in this region. A second peak of SRB rRNA was observed at the transition zone from oxidized to reduced sediment, directly above the sulphate reduction maximum. Cell numbers calculated by converting the relative contribution of SRB rRNA to the percentage of DAPI-stained cells indicated a population size for SRB of 2.4-6.1 x 10(8) cells cm(-3) wet sediment. Cellular sulphate reduction rates calculated on the basis of these estimated cell numbers were between 0.01 and 0.09 fmol SO4(2-) cell(-1) day(-1), which is below the rates that have been determined for pure cultures (0.2-50 fmol SO4(2-) cell(-1) day(-1)) growing exponentially at nearoptimal temperature with a surplus of substrates.


Contact tracing along with epidemiological and clinical characteristics of Novel corona virus 2019 in prisoners of Camp Jail, Lahore - A prospective case ascertaining study.
Prisons are reported as hub for communicable disease, as the closed environment, overcrowding, poor hygienic conditions facilitate the disease transmission. This study was conducted to describe contact tracing to identify, educate and manage COVID-19 in camp jail Lahore and to describe clinical and epidemiological features of disease in prisoners. After diagnosis of primary case of COVID-19 on 24th March, 2020 in camp jail, 527 suspected cases were identified through contact tracing. The health department-initiated case identification through contact tracing, isolation of confirmed and suspected cases, and quarantine of exposed persons and establishment of 100 bedded hospital in jail for infection prevention and control and treatment. Baseline characteristics of primary case and secondary cases were described along with the secondary attack rate of infection. Mean age of secondary cases was 36.9(11.5) years with mean stay of 14.9(13.6) months. Two third of the prisoners were from Punjab. 11 % were illiterate and almost half were under metric. 527 prisoners were labelled as suspected cases through contact tracing and 59 out of 527 suspected prisoners tested COVID positive through RT-PCR with few reporting mild respiratory symptoms. Fifty five out of 59 tested negatives on day-5 and all have uneventful recovery by day-21. Secondary attack rate was 11%. In order to prevent Covid-19 outbreaks, proactive containment and comprehensive contact tracing to identify monitor and manage cases and contacts, in incarcerated facilities like prisons is a public health solution to prevent and control large scale epidemic. Active monitoring for infected patients, and implementing timely infection prevention and control measures are mandatory for highly infectious Covid-19 in this vulnerable population.


Liver Fat Content and Body Fat Distribution in Youths with Excess Adiposity.
This study had two main objectives: To examine the association between body fat distribution and non-alcoholic fatty liver disease (NAFLD) and liver fat content, and to determine whether the relationship between NAFLD and regional body fat distribution, with respect to liver fat content in youths with excess adiposity, is independent of cardiorespiratory fitness (CRF) and a healthy diet. Liver fat content (controlled attenuation parameter (CAP)), body fat distribution (body mass index (BMI) z-score, waist circumference, waist-to-height ratio, fat mass/height, body fat percentage, total fat mass, android-to-gynoid fat mass ratio, visceral adipose tissue (VAT), and lean mass index, determined by dual-energy X-ray absorptiometry (DXA)), CRF (20-m shuttle-run test), and healthy diet (adherence to the Mediterranean diet by KIDMED questionnaire) were measured in 126 adolescents (66% girls) aged between 11 and 17 years. Participants were assigned to two groups according to the presence or absence of hepatic steatosis (CAP values ≥225 dB/m or <225 dB/m of liver fat, respectively). Considering the similar total fat values for the two groups (>30% by DXA), youths with NAFLD had higher fat distribution parameters than those without NAFLD, regardless of sex, age, puberty stage, lean mass index, CRF, and healthy diet (p < 0.01). In the non-NAFLD group, the association between hepatic fat and fat distribution parameters presented a similar pattern, although the association was statistically insignificant after adjusting for a potential confounding variable (ps > 0.05), except for the case of VAT. Body fat distribution parameters were higher in youths with NAFLD compared to those without NAFLD. Additionally, body fat distribution showed a significant association with liver fat content as assessed by CAP in youths with NAFLD independent of CRF and adherence to the Mediterranean diet, supporting the notion that upper body fat distribution might play a pivotal role in the development of NAFLD in adolescents. These results may have implications for the clinical management of youths with excess adiposity given the high prevalence of NAFLD in children and young adults.


Polymer-Ligated Nanocrystals Enabled by Nonlinear Block Copolymer Nanoreactors: Synthesis, Properties, and Applications.
The past several decades have witnessed substantial advances in synthesis and self-assembly of inorganic nanocrystals (NCs) due largely to their size- and shape-dependent properties for use in optics, optoelectronics, catalysis, energy conversion and storage, nanotechnology, and biomedical applications. Among various routes to NCs, the nonlinear block copolymer (BCP) nanoreactor technique has recently emerged as a general yet robust strategy for crafting a rich diversity of NCs of interest with precisely controlled dimensions, compositions, architectures, and surface chemistry. It is notable that nonlinear BCPs are unimolecular micelles, where each block copolymer arm of nonlinear BCP is covalently connected to a central core or polymer backbone. As such, their structures are static and stable, representing a class of functional polymers with complex architecture for directing the synthesis of NCs. In this review, recent progress in synthesizing NCs by capitalizing on two sets of nonlinear BCPs as nanoreactors are discussed. They are star-shaped BCPs for producing 0D spherical nanoparticles, including plain, hollow, and core-shell nanoparticles, and bottlebrush-like BCPs for creating 1D plain and core/shell nanorods (and nanowires) as well as nanotubes. As the surface of these NCs is intimately tethered with the outer blocks of nonlinear BCPs used, they can thus be regarded as polymer-ligated NCs (i.e., hairy NCs). First, the rational design and synthesis of nonlinear BCPs via controlled/living radical polymerizations is introduced. Subsequently, their use as the NC-directing nanoreactors to yield monodisperse nanoparticles and nanorods with judiciously engineered dimensions, compositions, and surface chemistry is examined. Afterward, the intriguing properties of such polymer-ligated NCs, which are found to depend sensitively on their sizes, architectures, and functionalities of surface polymer hairs, are highlighted. Some practical applications of these polymer-ligated NCs for energy conversion and storage and drug delivery are then discussed. Finally, challenges and opportunities in this rapidly evolving field are presented.


Accumulation of GAS5 in exosomes is a marker of apoptosis induction.
Long non-coding RNAs (lncRNAs) are key regulatory molecules in many fundamental cellular processes and their deregulation is assumed to contribute to carcinogenesis. Exosomal lncRNAs are thought to be involved in the dissemination of cell signals to control local cellular microenvironments. In the current study, exosomal expression of growth arrest specific 5 (GAS5), an inhibitor of cell proliferation and promoter of apoptosis, was evaluated in apoptotic processes initiated by different mechanisms. Therefore, MCF-7 and MDA-MB-231 breast cancer cells were treated with Taxol (2 and 10 nM) and bleomycin (2 and 10 ng/ml) for 24 h. Following cell viability determination and measurement of apoptosis, cellular and exosomal expression levels of GAS5 were investigated using a quantitative polymerase chain reaction assay. The findings indicate that Taxol is more toxic than bleomycin at the indicated doses and the effect was more evident in the MCF-7 cells. Despite varying toxicity rates, comparable levels of apoptotic nucleosomes were measured between Taxol- and bleomycin-treated cells. Upon drug treatment, cellular expression levels of GAS rose (≤1.5-fold) in the two cell lines. It appears that even a small increase in cellular expression leads to exosomal enrichment, as the accumulation of GAS5 in exosomes was marked in the MCF-7 cells (≤5.8-fold). Compared with the MCF-7 cells, the extent of GAS5 enrichment in the exosomes secreted from MDA-MB-231 cells was moderate (≤1.9-fold), potentially as a result of reduced cell death. The present study indicates that GAS5 accumulation in exosomes is a prevalent event in apoptotic processes that are initiated by different mechanisms.


Facial nerve palsy-an unusual complication after evacuation of a subdural haematoma or hygroma in children.
This paper reports and discusses on the possible etiology of postoperative contralateral facial nerve palsy after uneventful evacuation of a subdural haematoma or hygroma after mild head trauma in two children with pre-existing middle cranial fossa subarachnoid cysts. Two 14- and 15-year-old boys had prolonged headaches after mild head injuries. CT showed a right-sided middle cranial fossa arachnoid cyst in each patient. In one patient, an ipsilateral subdural haematoma was identified, and in the other, bilateral hygromas were identified. Exacerbation of symptoms required emergency evacuation of the subdural haematoma in the first child, and bilateral external drainage of the hygroma in the other child. In both children the late postoperative period was complicated by peripheral facial nerve palsies contralateral to the arachnoid cyst. Facial nerve palsy may be a complication of hygroma or haematoma drainage. The etiology is not clear; traction of the facial nerve due to displacement of the brainstem may be the most likely explanation.


Inhibition of phosphodiesterase-4 (PDE4) activity triggers luminal apoptosis and AKT dephosphorylation in a 3-D colonic-crypt model.
We previously established a three-dimensional (3-D) colonic crypt model using HKe3 cells which are human colorectal cancer (CRC) HCT116 cells with a disruption in oncogenic KRAS, and revealed the crucial roles of oncogenic KRAS both in inhibition of apoptosis and in disruption of cell polarity; however, the molecular mechanism of KRAS-induced these 3-D specific biological changes remains to be elucidated. Among the genes that were upregulated by oncogenic KRAS in this model, we focused on the phosphodiesterase 4B (PDE4B) of which expression levels were found to be higher in clinical tumor samples from CRC patients in comparison to those from healthy control in the public datasets of gene expression analysis. PDE4B2 was specifically overexpressed among other PDE4 isoforms, and re-expression of oncogenic KRAS in HKe3 cells resulted in PDE4B overexpression. Furthermore, the inhibition of PDE4 catalytic activity using rolipram reverted the disorganization of HCT116 cells into the normal physiologic state of the epithelial cell polarity by inducing the apical assembly of ZO-1 (a tight junction marker) and E-cadherin (an adherens junction marker) and by increasing the activity of caspase-3 (an apoptosis marker) in luminal cavities. Notably, rolipram reduced the AKT phosphorylation, which is known to be associated with the disruption of luminal cavity formation and CRC development. Similar results were also obtained using PDE4B2-shRNAs. In addition, increased expression of PDE4B mRNA was found to be correlated with relapsed CRC in a public datasets of gene expression analysis. These results collectively suggested that PDE4B is upregulated by oncogenic KRAS, and also that the inhibition of PDE4 catalytic activity can induce both epithelial cell polarity and luminal apoptosis in CRC, thus highlighting the utility of our 3-D culture (3 DC) model for the KRAS-induced development of CRC in 3-D microenvironment. Indeed, using this model, we found that PDE4B is a promising candidate for a therapeutic target as well as prognostic molecular marker in CRC. Further elucidation of the signaling network of PDE4B2 in 3 DC would provide a better understanding of CRC in vivo.


Prenatal diagnosis of cystic fibrosis in a highly heterogeneous population.
Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasian populations. The Spanish CF population is highly heterogeneous, with more than 70 different mutations causing CF. Since the CFTR gene was cloned, we have performed 81 prenatal diagnoses for 74 couples. Sixty-nine cases had a high risk (1/4) for CF and 12 presented a lower risk (1/240). Direct analysis was possible in 36 cases (44.4 per cent); it was necessary to combine mutation analysis with polymorphic markers in 24 cases (29.6 per cent); mutation analysis and microvillar enzymatic (MVE) analysis were combined in five cases (6.1 per cent); and in 16 cases (19.8 per cent), only indirect analysis was possible. Nine different mutations were detected in this series of families: 621 + 1G -> T, delta F508, 1609delCA, G542X, G551D, 1949del84, R1162X, W1282X, and N1303K. Another ten mutations were identified in these samples after prenatal diagnosis (1811 + 1.6kbA -> G, 711 + 1G -> T, 2869insG, G85E, 2176insC, delta I507, 3272-26A -> G, Q890X, R1066C, and 4005 + 1G -> A). Our current strategy for molecular diagnosis of CF in the Spanish population is based, as a first step, on direct analysis for the two most frequent mutations (delta F508 and G542X) and indirect analysis using the intragenic markers IVS8CA, IVS17BTA, and IVS17BCA. The second step consists of screening for the mutations already associated with the CFTR microsatellite haplotypes. The third step is a specific search for unknown mutations. While actual diagnostic methods are not automatic and robust enough for heterogeneous populations, the diagnostic strategy outlined provides rapid, accurate, and reliable prenatal diagnosis for the majority of couples.


Prompt Hole Extraction Suppresses V5+ Dissolution and Sustains Large-Area BiVO4 Photoanodes for Over 2100 h Water Oxidation.
Nanostructured bismuth vanadate (BiVO4) is at the forefront of emerging photoanodes in photoelectrochemical tandem devices for solar water splitting owing to the suitable band edge position and efficient charge separation capability. However, the (photo)chemical corrosion involving V5+ dissolution limits the long-term stability of BiVO4. Herein, guided by DFT calculations, we introduce an ALD-derived NiOx catalyst layer on BiVO4 to stabilize the surface Bi-O bonds, facilitate hole extraction, and thus suppress the V5+ dissolution. At the same time, the ALD NiOx catalyst layer could efficiently suppress the surface recombination and accelerate the surface OER kinetics, boosting the half-cell applied bias photon-to-current efficiency of BiVO4 to 2.05%, as well as a fill factor of 47.1%. By adding trace NaVO3 to the electrolyte, the NiOx/BiVO4 photoanode with an illumination area of 10.5 cm2 shows a record operational stability of more than 2100 h.


Atorvastatin causes regression of endometriotic implants in a rat model.
Endometriotic implants were induced surgically in female Wistar albino rats, which were randomly divided into three groups. The rats in group I (n=10) and group II (n=9) were given 2.5 mg/kg/day intraperitoneal and oral atorvastatin, respectively, for 28 days. Group III (n=9) was given no medication (control). The mean volume and weight of explants in group I were significantly lower (both P < 0.05) compared with group III. Histopathological score of the implants was significantly lower in groups I and II, when compared with group III (P < 0.01 and P < 0.05, respectively). There were significant reductions in explant concentrations of vascular endothelial growth factor and matrix metalloproteinase 9 in group I (P < 0.01 and P < 0.001, respectively) and group II (both P < 0.01) compared with group III while staining due to tissue inhibitor of metalloproteinase 2 was significantly higher in group I (P < 0.01) and group II (P < 0.01) compared with group III. Moreover, explant concentration of superoxide dismutase was significantly increased in groups I and II compared with group III (both P < 0.05). In conclusion, atorvastatin causes significant regression of endometriotic implants in rats. Moreover, intraperitoneal atorvastatin seems to be more effective than oral atorvastatin.


[Effects of T-type calcium channel blockers on spontaneous meiotic maturation of mouse ovarian oocytes in vitro].
We studied the effects of blockers of the T-type Ca2+ channels on resumption of meiosis and spontaneous meiotic maturation of murine ovarial oocytes in vitro. We found that the efficiency of suppression of oocyte maturation by blockers of the Ca2+ channels increases in the following succession: amiloride hydrochloride, mebifradil, NiCl2. It is supposed that there is a possibility to use blockers of the T-type Ca2+ channels for creation of new combined intrauterine contraceptives.


Delineation of the cis-acting element mediating EBNA-2 transactivation of latent infection membrane protein expression.
To delineate the cis-acting element through which EBNA-2 transactivates latent membrane protein 1 (LMP1), we assayed the effect of EBNA-2 on the activity of LMP1 promoter upstream deletion mutants in the context of the LMP1 or heterologous promoters controlling chloramphenicol acetyltransferase (CAT) reporter gene expression in Epstein-Barr virus-negative Burkitt lymphoma cells. Assays of progressive 5' deletions of the LMP1 promoter revealed low constitutive and at least eightfold EBNA-2-stimulated activity from -512 to +40 (-512/+40), -334/+40, and -234/+40 LMP1CAT plasmids. More extensive 5'-deleted -205/+40, -155/+40, and -147/+40 LMP1CAT plasmids also had low constitutive activity but were not EBNA-2 responsive. The most 5'-deleted -55/+40 LMP1CAT plasmid had moderate constitutive activity and was not EBNA-2 inducible. Either orientation of the -334/+40 LMP1 sequence conferred EBNA-2 responsiveness when positioned upstream of an enhancerless simian virus 40 or herpes simplex virus thymidine kinase (TK) promoter. EBNA-2 and the cis-acting LMP1 DNA were both required to increase TK promoter-initiated mRNA, indicating that the EBNA-2 effect is at the transcriptional level. Further deletion analysis of the EBNA-2-responsive cis-acting element defined a -234/-92 LMP1 DNA fragment which conveyed EBNA-2 responsiveness to the herpes simplex virus TK promoter. The 5' 30 bp between -234 and -205 were essential for EBNA-2 responsiveness. Thus, these experiments define a 142-bp cis-acting element which is sufficient for conveying EBNA-2 responsiveness and an essential 30-bp component of that element. The role of this element in LMP1 and LMP2B expression and its possible role in LMP2A expression are discussed.


Synergistic analgesic effect of morphine and tramadol in non‑sensitized and morphine‑sensitized mice: an isobolographic study.
Morphine and tramadol are the opioid analgesic drugs acting via activation of μ‑opioid receptors. It is important to understand which mechanism (synergistic or additive anti‑nociceptive activity) induced potent anti‑nociceptive effect by co‑administration of morphine and tramadol. Identification of new strategies that can potentiate analgesic effects of opioids will be good therapeutic approaches for pain relief. To this aim, male mice were cannulated in the left ventricle by a stereotaxic instrument. A tail‑flick test was used to record the pain threshold. The results revealed that intracerebroventricularly injection of morphine induced an anti‑nociceptive effect in non‑sensitized and morphine‑sensitized mice. We found that infusion of tramadol produced an anti‑nociceptive response in non‑sensitized mice, whereas tramadol in doses of 0.5 and 1 μg/mouse induced analgesia in morphine‑sensitized mice. Co‑injection of a non‑effective dose of tramadol or morphine (0.25 μg/mouse) with different doses of morphine or tramadol (0.25, 0.5, and 1 μg/mouse) respectively potentiated the analgesic effect of the previous drug. An isobolographic analysis of data was performed, indicating a synergistic interaction between morphine and tramadol in non‑sensitized and morphine‑sensitized mice. Our data indicated that both morphine and tramadol elicit more anti‑nociceptive response in morphine sensitized mice; there is a synergistic effect between morphine and tramadol upon induction of analgesic effect in non‑sensitized and morphine‑sensitized mice.


Year-round grazing to counteract effects of atmospheric nitrogen deposition may aggravate these effects.
Excessive nitrogen input in natural ecosystems is a major threat to biodiversity. A coastal dune area near Amsterdam in the Netherlands suffers from high atmospheric nitrogen deposition affecting sensitive habitats such as fixed coastal dunes with herbaceous vegetation ('grey dunes'). To mitigate its effect year round grazing was applied from 2007 until 2012. In winter, when natural food supply is low, the cattle received supplementary hay that caused additional inputs of nitrogen. Estimates based on nitrogen contents of hay, as well as of manure, showed the input through winter feeding (c. 3-14 kg N ha(-1).y(-1)) is in the same order of magnitude as both the actual deposition (c. 17 kg N ha(-1).y(-1)) and the critical load for a number of herbaceous habitat types (10-15 kg N ha(-1).y(-1)). Locally, the effect of winter feeding adds to the effect of nitrogen redistribution within the area caused by the cattle's terrain usage. We conclude that winter feeding may aggravate effects of atmospheric nitrogen deposition.


Prognostic significance of cyclooxygenase-2 and response to chemotherapy in invasive ductal breast carcinoma patients by real time surface plasmon resonance analysis.
Cyclooxygenase-2 (COX-2), an inducible enzyme, has been implicated in the progression and angiogenesis of breast cancer. The aim of the study is to quantify the concentration of COX-2 and its association with clinico-pathological parameters and response to treatment in patients with invasive ductal carcinoma receiving both neo-adjuvant and adjuvant chemotherapy. The level of COX-2 was estimated using a novel biosensor-based surface plasmon resonance technique in serum of 84 patients with breast cancer (48 patients of neo-adjuvant chemotherapy and 36 patients of adjuvant chemotherapy) and 40 age- and gender-matched normal individuals. A significant increase in COX-2 level was observed in patients compared with normal individuals (p>0.0001). The COX-2 level in serum was found to be significantly higher in patients with lymph node involvement (p<0.0061). 68% (33/48) of the patients receiving neo-adjuvant chemotherapy showed significantly (p<0.0025) reduced COX-2 levels. This study shows significant decrease of COX-2 level in patients with breast cancer treated with both neo-adjuvant and adjuvant chemotherapy. Estimation of COX-2 level in serum may serve as a tumor biomarker in patients with breast cancer.


Quantum statistical corrections to dynamic nuclear magnetic resonance
A quantum statistical treatment of the chemical exchange between molecular eigenstates or conformations revealed previously unsuspected dynamic terms in the spin Hamiltonian operator that describes fast exchange. These terms resulted from the effect of nuclear spin on rotational and vibrational relaxation. With the traditional theory, an interpretation of new carbon-13 nuclear magnetic resonance measurements of the chemical shift of methylcyclohexane in solution showed fast-exchange equilibrium constants that were inconsistent with the slow-exchange free-energy difference and were spread over a range of 30 percent for the various carbon-13 positions. Modeling of the new terms indicated that they have the correct magnitude and temperature dependence to reconcile these inconsistencies.


No effect of resveratrol supplementation after 6 months on insulin sensitivity in overweight adults: a randomized trial.
Effects of resveratrol on metabolic health have been studied in several short-term human clinical trials, with conflicting results. Next to dose, the duration of the clinical trials may explain the lack of effect in some studies, but long-term studies are still limited. The objective of this study was to investigate the effects of 6-mo resveratrol supplementation on metabolic health outcome parameters. Forty-one overweight men and women (BMI: 27-35 kg/m2; aged 40-70 y) completed the study. In this parallel-group, double-blind clinical trial, participants were randomized to receive either 150 mg/d of resveratrol (n = 20) or placebo (n = 21) for 6 mo. The primary outcome of the study was insulin sensitivity, using the Matsuda index. Secondary outcome measures were intrahepatic lipid (IHL) content, body composition, resting energy metabolism, blood pressure, plasma markers, physical performance, quality of life, and quality of sleep. Postintervention differences between the resveratrol and placebo arms were evaluated by ANCOVA adjusting for corresponding preintervention variables. Preintervention, no differences were observed between the 2 treatment arms. Insulin sensitivity was not affected after 6 mo of resveratrol treatment (adjusted mean Matsuda index: 5.18 ± 0.35 in the resveratrol arm compared with 5.50 ± 0.34 in the placebo arm), although there was a significant difference in postintervention glycated hemoglobin (HbA1c) between the arms (P = 0.007). The adjusted means showed that postintervention HbA1c was lower on resveratrol (35.8 ± 0.43 mmol/mol) compared with placebo (37.6 ± 0.44 mmol/mol). No postintervention differences were found in IHL, body composition, blood pressure, energy metabolism, physical performance, or quality of life and sleep between treatment arms. After 6 mo of resveratrol supplementation, insulin sensitivity was unaffected in the resveratrol arm compared with the placebo arm. Nonetheless, HbA1c was lower in overweight men and women in the resveratrol arm. This trial was registered at Clinicaltrials.gov as NCT02565979.


Time-dependent observer errors in pulmonary nodule detection.
The work was carried out to investigate differences in visual search characteristics between groups of observers with different levels of experience in the task of pulmonary nodule detection in chest radiology and we report here on these differences in respect of time related decisions. Volunteer observers were divided into three groups depending on their level of expertise. There were eight radiologists, eight radiographers and eight novices. Their task was to detect pulmonary nodules in a test bank of 120 digitized posteroanterior (PA) chest radiographs. Five of the eight radiographers were tested twice: once before and once after a 6-month training programme in interpretation of the adult chest radiograph. During each test session the observers' eye movements were tracked. Data on the observers' decisions through Alternate Free Response Operating Characteristic (AFROC) methodology were correlated to their eye-movement and fixation patterns. True negative decisions from all observers were associated with shorter fixation times than false negative decisions. No correct negative decisions were made after fixations exceeding 3 s.


Extensions to the likelihood maximization approach for finding reaction coordinates.
This paper extends our previous work on obtaining reaction coordinates from aimless shooting and likelihood maximization. We introduce a simplified version of aimless shooting and a half-trajectory likelihood score based on the committor probability. Additionally, we analyze and compare the absolute log-likelihood score for perfect and approximate reaction coordinates. We also compare the aimless shooting and likelihood maximization approach to the earlier genetic neural network (GNN) approach of Ma and Dinner [J. Phys. Chem. B 109, 6769 (2005)]. For a fixed number of total trajectories in the GNN approach, the accuracy of the transition state ensemble decreases as the number of trajectories per committor probability estimate increases. This quantitatively demonstrates the benefit of individual committor probability realizations over committor probability estimates. Furthermore, when the least squares score of the GNN approach is applied to individual committor probability realizations, the likelihood score still provides a better approximation to the true transition state surface. Finally, the polymorph transition in terephthalic acid demonstrates that the new half-trajectory likelihood scheme estimates the transition state location more accurately than likelihood schemes based on the probability of being on a transition path.


Gene expression profiling of MYC-driven tumor signatures in porcine liver stem cells by transcriptome sequencing.
To identify the genes induced and regulated by the MYC protein in generating tumors from liver stem cells. In this study, we have used an immortal porcine liver stem cell line, PICM-19, to study the role of c-MYC in hepatocarcinogenesis. PICM-19 cells were converted into cancer cells (PICM-19-CSCs) by overexpressing human MYC. To identify MYC-driven differential gene expression, transcriptome sequencing was carried out by RNA sequencing, and genes identified by this method were validated using real-time PCR. In vivo tumorigenicity studies were then conducted by injecting PICM-19-CSCs into the flanks of immunodeficient mice. Our results showed that MYC-overexpressing PICM-19 stem cells formed tumors in immunodeficient mice demonstrating that a single oncogene was sufficient to convert them into cancer cells (PICM-19-CSCs). By using comparative bioinformatics analyses, we have determined that > 1000 genes were differentially expressed between PICM-19 and PICM-19-CSCs. Gene ontology analysis further showed that the MYC-induced, altered gene expression was primarily associated with various cellular processes, such as metabolism, cell adhesion, growth and proliferation, cell cycle, inflammation and tumorigenesis. Interestingly, six genes expressed by PICM-19 cells (CDO1, C22orf39, DKK2, ENPEP, GPX6, SRPX2) were completely silenced after MYC-induction in PICM-19-CSCs, suggesting that the absence of these genes may be critical for inducing tumorigenesis. MYC-driven genes may serve as promising candidates for the development of hepatocellular carcinoma therapeutics that would not have deleterious effects on other cell types in the liver.


Functional analysis of multiple AUG codons in the transcripts of the STA2 glucoamylase gene from Saccharomyces cerevisiae.
A scanning ribosome will usually initiate translation as soon as it encounters the first favourable AUG codon and only a few eukaryotic transcripts have more complex arrangements. These relatively few complex transcripts are normally characterized by structural features such as multiple AUGs and significant secondary structure. However, the functional relevance of these features has rarely been established. We present here a study of the functional significance of the multiple AUGs in the leader of STA2 transcripts of the budding yeast Saccharomyces cerevisiae, and extrapolate, where applicable, these results to a co-regulated gene, MUC1. The STA2 gene (a representative member of the polymorphic STA1-3 gene family), encodes an extracellular glucoamylase, and is evolutionarily linked to, and transcriptionally co-regulated with, the MUC1 gene, which encodes a mucin-like protein essential for pseudohyphal/invasive growth and cell-adhesion in S. cerevisiae. Each of these genes contains a putative upstream ORF, while STA2 has two additional in-frame AUG codons 5' to the major cistron. We show that utilization of the alternative translational start-sites of STA2 results in glucoamylases that differ at their N-termini, which are associated with differences in their localization patterns. Analysis of mutants revealed the presence of a putative secretion-enhancing signal that might prove to be relevant to the alternative targeting mechanism recently uncovered in S. cerevisiae. We show that a short up-stream ORF present in the leaders of STA1-3 and MUC1 is probably bypassed by a process of leaky scanning.


Variability in the metabolism of proguanil to the active metabolite cycloguanil in healthy Kenyan adults.
Extensive metabolizers (EM) and poor metabolizers (PM) of the malaria chemoprophylactic drug proguanil have been identified by measuring the proguanil/cycloguanil ratio in urine following a single dose of the pro-drug. The pharmacokinetic characteristics of proguanil were similar in 8 EM and 8 PM subjects, but there were significant differences between the 2 groups with respect to cycloguanil pharmacokinetics. In none of the PM subjects could cycloguanil be detected in whole blood samples at any time after proguanil dosage. Plasma cycloguanil was measureable in only 2 of 8 PM subjects, despite an analytical sensitivity in the high-performance liquid chromatographic assay of 1 ng/ml cycloguanil. A comparatively high proportion of Black Kenyan adults appear to metabolize proguanil poorly, possibly because they lack the specific mixed function oxidase which will accept proguanil as substrate.


Eosinophil Peroxidase Catalyzed Protein Carbamylation Participates in Asthma.
The biochemical mechanisms through which eosinophils contribute to asthma pathogenesis are unclear. Here we show eosinophil peroxidase (EPO), an abundant granule protein released by activated eosinophils, contributes to characteristic asthma-related phenotypes through oxidative posttranslational modification (PTM) of proteins in asthmatic airways through a process called carbamylation. Using a combination of studies we now show EPO uses plasma levels of the pseudohalide thiocyanate (SCN-) as substrate to catalyze protein carbamylation, as monitored by PTM of protein lysine residues into Nϵ-carbamyllysine (homocitrulline), and contributes to the pathophysiological sequelae of eosinophil activation. Studies using EPO-deficient mice confirm EPO serves as a major enzymatic source for protein carbamylation during eosinophilic inflammatory models, including aeroallergen challenge. Clinical studies similarly revealed significant enrichment in carbamylation of airway proteins recovered from atopic asthmatics versus healthy controls in response to segmental allergen challenge. Protein-bound homocitrulline is shown to be co-localized with EPO within human asthmatic airways. Moreover, pathophysiologically relevant levels of carbamylated protein either incubated with cultured human airway epithelial cells in vitro, or provided as an aerosolized exposure in non-sensitized mice, induced multiple asthma-associated phenotypes including induction of mucin, Th2 cytokines, IFNγ, TGFβ, and epithelial cell apoptosis. Studies with scavenger receptor-A1 null mice reveal reduced IL-13 generation following exposure to aerosolized carbamylated protein, but no changes in other asthma-related phenotypes. In summary, EPO-mediated protein carbamylation is promoted during allergen-induced asthma exacerbation, and can both modulate immune responses and trigger a cascade of many of the inflammatory signals present in asthma.


UNDERSTANDING THE VITAL DETERMINANTS SHAPING LEARNERS' PHYSICAL ACTIVITYAND PSYCHOEMOTIONAL WELLBEING IN THE COVID-19 PERIOD.
The Corona Virus (COV-19) epidemic significantly affected the educational environment, requiring a quick transition to distance and blended learning methods. This extraordinary disruption had an incredible impact on pupil's levels of physical activity (PA), psycho-emotional health (PEH) and engagement with academic material. The research aims to examine the vital determinants that influenced various areas of learners' lives during CoV-19. The purpose of this 600-person study was to collect data on the subjects' overall health and PA levels for the CoV-19 pandemic. The SPSS application was used to process the questionnaire's collected data. The information given reveals the respondents' degree of PA throughout the quarantine. According to the breakdown, 15% indicated low levels of PA, 39% reported medium levels and 46% reported high levels. The data show that, despite the respondents' different levels of PA, little PA predominated for most of them. The limitations of distance learning throughout quarantine and the prevalent recommendation of leaving residence for necessary reasons were blamed for this tendency. There were fewer prospects for higher-intensity PA due to these circumstances.


RFX2 is a potential transcriptional regulatory factor for histone H1t and other genes expressed during the meiotic phase of spermatogenesis.
H1t is a novel linker histone variant synthesized in mid- to late pachytene spermatocytes. Its regulatory region is of interest because developmentally specific expression has been impressed on an otherwise ubiquitously expressed promoter. Using competitive band-shift assays and specific antisera, we have now shown that the H1t-60 CCTAGG palindrome motif region binds members of the RFX family of transcriptional regulators. The testis-specific binding complex contains RFX2, probably as a homodimer. Other DNA-protein complexes obtained from testis as well as somatic organs contain RFX1, primarily as a heterodimer. Western blots confirmed that RFX2 expression is greatly enhanced in adult testis and that RFX2 is equally prominent in highly enriched populations of late pachytene spermatocytes and round spermatids. Immunohistochemistry carried out on mouse testis showed that RFX2 is strongly expressed in pachytene spermatocytes, remains high in early round spermatids, and declines only in advance of nuclear condensation. Maximum expression correlates well with the appearance of H1t. In contrast, RFX1 immunoreactivity in germ cells was only detected in late round spermatids. RFX-specific band complexes were also identified for both the mouse lamin C2 and Sgy promoters, using either testis nuclear extracts or in vitro-synthesized RFX2. These results call attention to RFX2 as a transcription factor with obvious potential for the regulation of gene expression during meiosis and the early development of spermatids.


Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes.
Blood samples from closely monitored patients at the Veterans Administration Hospital in Houston, Texas, were collected, coded, and sent to Microbiological Associates over an 8-month period. Lymphocytes were isolated and cryopreserved at -190 degrees. Lymphocyte samples were simultaneously thawed, phytohemagglutinin activated, and analyzed for benz(a)anthracene-induced aryl hydrocarbon hydroxylase (AHH) levels, [3H]thymidine incorporation, and reduced nicotinamide adenine dinucleotide-dependent cytochrome b5 (cytochrome c) reductase activity. Determinations were made at both 96 and 120 hr in culture, and peak activities were compared among a total of 51 individuals who expressed such lesions as squamous cell carcinomas (22%), adenocarcinomas (14%), oat cell carcinomas (6%), chronic obstructive pulmonary disease (22%), and other nonmalignant diseases. Of the 14 highest AHH/cytochrome c activities observed, all were found in patients with primary lung cancer. Mean AHH/cytochrome c activities were 0.89 for lung cancer patients (a total of 21) and 0.47 for noncancer patients (a total of 30) (p less than 0.001). No relationship was observed between AHH/cytochrome c activity and age of patient, numbers of cigarettes smoked, family history of cancer, location or histological type of tumor, or level of phytohemagglutinin blastogenesis ([3H]thymidine cpm/cytochrome c). Whether the higher AHH levels are the cause or the result of the primary lung cancer remains to be determined.


Role of ultrasound screening for gallbladder disease in pretransplant patients.
There is no uniform data regarding prophylactic cholecystectomy in patients undergoing renal transplantation with gallbladder disease. Data analyses suggest that posttransplant patients on cyclosporine have a higher incidence of gallbladder calcifications compared with nonimmunosuppressed patients. Laparoscopic cholecystectomy is a relatively safe procedure in modern-day surgery. Taking these facts into consideration, we attempted to compare risks and complications associated with gallbladder disease and eventual cholecystectomy in pretransplant versus posttransplant patients. Between June 1999 and December 2005, 210 renal transplants were performed at our institution. One hundred four patients who had transplants before April 2003 were not screened for gallbladder disease and nine of these patients developed gallbladder disease. These patients form our control group. One hundred six patients who had transplants after April 2003 had pretransplant screening for gallbladder disease and 11 patients were identified with gallbladder disease. These patients form our study group. Nine patients who developed gallbladder disease after renal transplant underwent laparoscopic cholecystectomy with three resulting morbidities (33%), two graft losses (22%), and one mortality (11%). There was one mortality (11%) in this group. One patient in the study group died of acute gallstone pancreatitis. Of the 11 patients who were found to have gallbladder disease on screening, nine patients underwent laparoscopic cholecystectomy with one morbidity and no mortality or graft loss. Given the relative rarity of the critical events in this study (morbidity, mortality, and graft loss), the definitive statistical value of prescreening for gallbladder disease cannot be established. However, our results are suggestive of clinical value and thus we tentatively recommend ultrasound screening for gallbladder disease for all pretransplant patients and laparoscopic cholecystectomy for those identified to have gallbladder disease.


Inferring gene regulatory networks from time series data using the minimum description length principle.
A central question in reverse engineering of genetic networks consists in determining the dependencies and regulating relationships among genes. This paper addresses the problem of inferring genetic regulatory networks from time-series gene-expression profiles. By adopting a probabilistic modeling framework compatible with the family of models represented by dynamic Bayesian networks and probabilistic Boolean networks, this paper proposes a network inference algorithm to recover not only the direct gene connectivity but also the regulating orientations. Based on the minimum description length principle, a novel network inference algorithm is proposed that greatly shrinks the search space for graphical solutions and achieves a good trade-off between modeling complexity and data fitting. Simulation results show that the algorithm achieves good performance in the case of synthetic networks. Compared with existing state-of-the-art results in the literature, the proposed algorithm exceptionally excels in efficiency, accuracy, robustness and scalability. Given a time-series dataset for Drosophila melanogaster, the paper proposes a genetic regulatory network involved in Drosophila's muscle development. Available from the authors upon request.


The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma.
The pathology of traumatic brain injury (TBI) is characterized by the decreased capacity of neurons to metabolize energy and sustain synaptic function, likely resulting in cognitive and emotional disorders. Based on the broad nature of the pathology, we have assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of concussive injury on important aspects of neuronal function and cognition. Fluid percussion injury (FPI) or sham injury was performed, and rats were then maintained on a diet high in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF), synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in FPI rats. It is known that BDNF facilitates synaptic transmission and learning ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting metabolic homeostasis, DHA may help the injured brain by providing resistance to oxidative stress. Furthermore, DHA normalized levels of calcium-independent phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane homeostasis and function after FPI. The overall results emphasize the potential of dietary DHA to counteract broad and fundamental aspects of TBI pathology that may translate into preserved cognitive capacity.


The Role of S100B Protein at 24 Hours of Postnatal Age as Early Indicator of Brain Damage and Prognostic Parameter of Perinatal Asphyxia.
Introduction. S100B protein is a cytosolic calcium-binding protein with a molecular weight of 21 kDa, which is present in various cells and concentrated mainly in the glial cells, which play a vital role in the maintenance of cellular homeostasis in the central nervous system. It is possible that increased S100B protein level might be considered as sensitive and specific indicator to predict early brain damage. Aim. To investigate the prognostic value of serum S100B protein in neonates with perinatal asphyxia (PA) at 24 hours of postnatal age. Methods. A systematic review was performed. Inclusion criteria were studies including data of neonates with PA, monitored with serum S100B, and with neurodevelopmental follow-up of at least 2 weeks. The period of bibliographic search was until January 2017. The consulted databases were MEDLINE, PsycINFO, and Embase. A combination of the following subject headings and keywords was adapted for each electronic database: "perinatal asphyxia," "hypoxic ischemic encephalopathy," "hypoxia-ischemia, brain," and "S100B." Meta-Disc1.4 software was used. Results. From the 1620 articles initially identified, 6 were finally included and reviewed. The overall diagnostic sensitivity of serum S100B was 0.80 (95% confidence interval [CI] = 0.68-0.88) and the specificity was 0.79 (95% CI = 0.70-0.87). But there was lower predictability value, that is, the positive likelihood ratio was only 3.26 (95% CI 1.74-6.12) and the negative likelihood ratio was 0.32 (95% CI = 0.20-0.5). The diagnostic odds ratio was 12.40 (95% CI = 4.66-33.0). Conclusion. Increased serum S100B level at 24 hours of postnatal life can demonstrate brain damage, but it should not be the only one used to predict PA outcome.


Body composition parameters in systemic sclerosis-a systematic review and meta-analysis.
The aim of this systematic review and meta-analysis was to summarize current evidence regarding body composition (BC) in systemic sclerosis (SSc) in order to gain new insights and improve clinical care in the context of the nutritional status of SSc patients. Search engines for databases Web of Science, PubMed, Scopus and Cochrane Library were searched on 4th of January 2023. Studies were included if they provided data regarding BC obtained by dual-energy X-ray absorptiometry (DXA) or bioelectrical impedance analysis (BIA) in patients with SSc and healthy controls (HC). The study design criteria for inclusion were cohort and observational studies. The risk of bias assessment was performed using the Newcastle-Ottawa scale. For meta-analysis, mean difference with a 95% confidence interval was obtained and all results were depicted as forest plots. The number of retrieved publications was 593, of which 9 were included in a random-effects meta-analysis totalling 489 SSc patients and 404 HC. Overall, significantly lower body mass index, lean mass (LM), fat mass (FM) and phase angle values were found in SSc patients when compared with HC. Furthermore, FM and LM were significantly lower in SSc patients when DXA method applied, whereas the same parameters were comparable between two groups of participants when BIA was applied. Altered BC is characteristic of SSc patients indicating the need for regular nutritional status assessment in order to improve the quality of life and clinical care of patients with SSc.


Ischemic injury activates PTHrP and PTH1R expression in human ventricular cardiomyocytes.
The PTHrP/PTH1R signalling system induces calciotropic and myorelaxant effects on the vascular system and plays critical roles in the development of the cardiovascular system. In animal models, PTHrP exerts important effects on heart rate and contractility, particularly under ischemic conditions, while, in human hearts, the expression of PTHrP by cardiomyocytes remains to be defined in both normal and ischemic conditions. The present study has been conducted on 101 autoptical cases and confirmed on nine explanted hearts in order to analyze the expression of the PTHrP/PTH1R system by ventricular myocardium in respect to morphological aspects of the myocardial ischemic damage, myofiber hypertrophy and disarray, coronarosclerosis, age and sex. Immunohistochemistry showed positive cytoplasmic immunostaining for both PTHrP and PTH1R in ventricular cardiomyocytes. The expression levels of the PTHrP/PTH1R system resulted significantly increased (P = 0.0008 and P < 0.0001, respectively) in association with the myocardial ischemic damage and the presence of cardiomyocyte hypertrophy (P = 0.02 and P = 0.009 respectively). Conversely, increased expression levels of PTHrP alone were observed in myofiber disarray (P = 0.04), whereas PTH1R was augmented in coronarosclerosis (P = 0.004) and age (P = 0.001). Taken together, these results demonstrate that human ventricular cardiomyocytes express PTHrP and PTH1R and suggest that the activation of the PTHrP/PTH1R system could represent an aspect of the embryonic gene program typically reactivated by the myocardium when subjected to ischemia and/or hypertrophy.


A profile of travelers--an analysis from a large swiss travel clinic.
Globally, the Swiss have one of the highest proportions of the population traveling to tropical and subtropical countries. Large travel clinics serve an increasing number of customers with specific pre-travel needs including uncommon destinations and preexisting medical conditions. This study aims to identify health characteristics and travel patterns of travelers seeking advice in the largest Swiss travel clinic so that tailored advice can be delivered. A descriptive analysis was performed on pre-travel visits between July 2010 and August 2012 at the Travel Clinic of the Institute of Social and Preventive Medicine, University of Zurich, Switzerland. A total of 22,584 travelers sought pre-travel advice. Tourism was the main reason for travel (17,875, 81.5%), followed by visiting friends and relatives (VFRs; 1,715, 7.8%), traveling for business (1,223, 5.6%), and "other reasons" (ie, volunteer work, pilgrimage, study abroad, and emigration; 1,112, 5.1%). The main travel destination was Thailand. In the VFR group, the highest proportions of traveling children (258, 15.1%) and of pregnant or breastfeeding women (23, 3.9%) were observed. Mental disorders were more prominent in VFRs (93, 5.4%) and in travel for "other reasons" (63, 5.7%). The latter stayed for the longest periods abroad; 272 (24.9%) stayed longer than 6 months. VFR travelers received the highest percentage of yellow fever vaccinations (523, 30.5%); in contrast, rabies (269, 24.2%) and typhoid vaccinations (279, 25.1%) were given more often to the "other travel reasons" group. New insights into the characteristics of a selected and large population of Swiss international travelers results in improved understanding of the special needs of an increasingly diverse population and, thus, in targeted preventive advice and interventions.


Pazopanib in Metastatic Renal Cancer: A "Real-World" Experience at National Cancer Institute "Fondazione G. Pascale".
Pazopanib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma. The present study analyzed the outcomes of pazopanib in first-line treatment of mRCC, in a single Italian cancer center. In the light of the retrospective, observational nature and the unselected population, our experience can be defined a "real-world" study. The medical records of 38 mRCC patients treated with front-line pazopanib were retrospectively reviewed and analyzed. The progression free survival (PFS) and the overall survival (OS) were the primary endpoints, while secondary objectives included objective response rate (ORR), disease control rate (DCR), and treatment tolerability. Pazopanib achieved a median PFS (mPFS) of 12.7 months (95% CI, 6.9-18.5 months). The median OS (mOS) was 26.2 months (95% CI, 12.6-39.9 months); the observed ORR and DCR were 30.3 and 72.7%, respectively, with a median duration of response of 11 weeks. mPFS appeared not to be influenced by number of co-morbidities (< 3 vs. ≥3), gender, Fuhrman grade and age. Conversely, the ORR and the DCR positively affect the mPFS (HR = 0.05 [95% CI, 0.05-0.55], p = 0.01; HR = 0.10 [95% CI, 0.02-0.43], p = 0.002, respectively). A worse outcome was associated with a lower mPFS in patients with liver metastases (p = 0.2) and with a high tumor burden (number of metastatic sites < 6 vs. ≥6) (p = 0.08). Worst OS was observed in patients aged ≥70 years old (HR = 6.91 [95% CI, 1.49-31.91], p = 0.01). The treatment was well-tolerated: no grade 4 adverse events, nor discontinuation due to toxicities was reported. Grade 3 hypertension affected positively the OS reaching the statistical significance (HR = 0.22 [95% CI, 0.05-0.8], p = 0.03). Thyroid dysfunction (hypo and hyperthyroidism) seems to correlate with better outcome in terms of a longer mPFS (HR = 0.12 [95% CI, 0.02-0.78], p = 0.02). Our results are consistent with those reported in prospective phase III trials and the published retrospective "real world" experiences. This analysis confirms the safety and efficacy of pazopanib in first-line setting, both in frail patients with multiple co-morbidities and Karnofsky PS < 80% and in younger, healthier patients with a number of metastatic sites < 6.


Intelligent automated control of life support systems using proportional representations.
Effective automatic control of Advanced Life Support Systems (ALSS) is a crucial component of space exploration. An ALSS is a coupled dynamical system which can be extremely sensitive and difficult to predict. As a result, such systems can be difficult to control using deliberative and deterministic methods. We investigate the performance of two machine learning algorithms, a genetic algorithm (GA) and a stochastic hill-climber (SH), on the problem of learning how to control an ALSS, and compare the impact of two different types of problem representations on the performance of both algorithms. We perform experiments on three ALSS optimization problems using five strategies with multiple variations of a proportional representation for a total of 120 experiments. Results indicate that although a proportional representation can effectively boost GA performance, it does not necessarily have the same effect on other algorithms such as SH. Results also support previous conclusions that multivector control strategies are an effective method for control of coupled dynamical systems.


Characterization of four mammalian numb protein isoforms. Identification of cytoplasmic and membrane-associated variants of the phosphotyrosine binding domain.
Numb is a membrane-associated, phosphotyrosine binding (PTB) domain-containing protein that functions as an intrinsic determinant of cell fate during Drosophila development. We have identified four isoforms of mammalian Numb with predicted molecular masses of 65, 66, 71, and 72 kDa that are generated by alternative splicing of the Numb mRNA. The different isoforms result from the presence of two sequence inserts within the PTB domain and the central region of the protein. The endogenous expression pattern of these isoforms, examined using specific antisera, varied in different tissues and cell lines. In addition, differentiation of P19 cells with retinoic acid leads to the specific loss of expression of the 71- and 72-kDa Numb proteins, suggesting that the expression of certain forms of Numb protein is regulated in a cell type-specific manner. Expression of Numb proteins fused to green fluorescent protein revealed that the form of the PTB domain with the alternatively spliced insert constitutively associated with the plasma membrane in polarized Madin-Darby canine kidney cells. In contrast, the isoform without the insert was cytoplasmic, suggesting that different PTB domain isoforms may regulate the subcellular localization of Numb proteins. The membrane localization may be due, in part, to differential affinity for acidic phospholipids. The distinct expression and localization patterns of the different mammalian Numb isoforms suggest that they have distinct functional properties.


Drug distribution transients in solution and suspension-based pressurised metered dose inhaler sprays.
This paper presents in situ time-resolved drug mass fraction measurements in pressurised metered dose inhaler (PMDI) sprays, using a novel combination of synchrotron X-ray fluorescence and scattering. Equivalent suspension and solution formulations of ipratropium bromide in HFA-134a propellant were considered. Measurements were made both inside the expansion chamber behind the nozzle orifice, and in the first few millimeters of the spray where droplet and particle formation occur. We observed a consistent spike in drug mass fraction at the beginning of the spray when the first fluid exits the nozzle orifice. Approximately 20% of the total delivered dose exits the nozzle in the first 0.1 s of the spray. The drug mass fraction in the droplets immediately upon exiting the nozzle peaked at approximately 50% of the canister mass fraction, asymptoting to approximately 20% of the canister concentration. The effect is due to a change in the drug mass fraction inside the droplets, rather than changes in droplet size or distribution. The transient was found to originate inside the expansion chamber. We propose that this effect may be a major contributor to low delivery efficiency in PMDIs, and have important implications for oropharyngeal deposition and inhalation technique. This highlights the importance of expansion chamber and nozzle design on the structure of PMDI sprays, and indicates areas of focus that may lead to improvement in drug delivery outcomes.


Recurrent laryngeal nerve monitoring during esophagectomy and mediastinal lymph node dissection.
Patients who undergo surgery to the esophagus and lungs are in jeopardy of recurrent laryngeal nerve (RLN) damage during the procedure. This study was designed to investigate the feasibility of intraoperative monitoring of the RLN for single-lung ventilation esophagus and lung surgery. Twelve consecutive patients booked for esophagus or lung surgery were included in this prospective, observational study. Six patients underwent transthoracic esophagectomy for carcinoma of the esophagogastric junction or lower esophagus, five had a lobectomy, and one underwent a pneumonectomy for lung carcinoma. Intraoperative, noninvasive RLN identification and monitoring was performed unilaterally (n = 8) or bilaterally (n = 4) using a handheld stimulator and a laryngeal surface electrode. The correct functioning of the nerve monitoring system was tested directly at the vagus nerve. Diagnosis of postoperative RLN paralysis was performed using indirect laryngoscopy. During the surgical procedures, we monitored a nerve signal in all 12 patients. In one patient with lower esophagus carcinoma, a nerve signal could be detected only on one side. Postoperative indirect laryngoscopy showed normal vocal cord movement in all patients. Intraoperative RLN identification and monitoring during single-lung ventilation surgery is technically feasible, easy, and reliable. The introduction of standardized RLN monitoring during this type of surgery may reduce the incidence of permanent RLN paralysis.


The fate of endoleaks after endovascular aneurysm repair and the impact of oral anticoagulation on their persistence.
The impact of anticoagulation on late endoleaks after endovascular aneurysm repair (EVAR) is unclear despite multiple investigators studying the relationship. The purpose of this study was to determine if long-term anticoagulation impacted the development of late endoleaks and if specific anticoagulants were more likely to exacerbate the development of endoleaks. Using the Society for Vascular Surgery Vascular Quality Initiative database, patients undergoing EVAR between 2003 and 2019 for abdominal aortic aneurysms were evaluated. Patients were divided into two groups: those without a late endoleak and those with a late endoleak. Bivariate analysis was performed to assess preoperative, intraoperative, postoperative, and long-term follow-up variables. A multivariable analysis was done to determine associations of independent variables with late endoleaks. Patients were further subcategorized based on anticoagulation status before and after EVAR, specific type of anticoagulation, and the presence of an index endoleaks (diagnosed at the time of EVAR) to determine the subsequent frequency of late endoleaks. A total of 29,783 patients were analyzed with 2169 (7.3%) having a late endoleak identified. Several risk factors were related to late endoleaks, including anticoagulation before and after EVAR (odds ratio [OR], 4.23; 95% confidence interval [CI], 2.57-6.96; P < .001), anticoagulation after EVAR (OR, 1.88; 95% CI, 1.43-2.49; P < .001), and index endoleak (OR, 1.45; 95% CI, 1.26-1.66; P < .001). The frequency of late endoleaks in patients anticoagulated before and after EVAR and after EVAR as compared with those never anticoagulated was 16.89% and 14.40% vs 6.95%, respectively (both P > .001). No difference in late endoleaks were noted for patients treated with warfarin and novel oral anticoagulants. The most common type of index and late endoleak identified was type II, but patients with type I, type II, and type IV index endoleaks were more commonly found to have type I, type II, and type IV late endoleaks, respectively. The frequency of late endoleaks in patients with both an index endoleak and anticoagulation after EVAR was 20.42% as compared with patients with only anticoagulation after EVAR (14.63%; P = .0015) and with patients with index endoleaks not anticoagulated (10.06%; P < .00001). Late endoleaks were more common in patients treated with anticoagulation after EVAR. No difference in late endoleak frequency was detected between anticoagulation with warfarin and novel oral anticoagulants. Patients on anticoagulation and those with an index endoleak were at a higher risk of having a late endoleak.


Case management for patients with chronic systolic heart failure in primary care: the HICMan exploratory randomised controlled trial.
Chronic (systolic) heart failure (CHF) represents a clinical syndrome with high individual and societal burden of disease. Multifaceted interventions like case management are seen as promising ways of improving patient outcomes, but lack a robust evidence base, especially for primary care. The aim of the study was to explore the effectiveness of a new model of CHF case management conducted by doctors' assistants (DAs, equivalent to a nursing role) and supported by general practitioners (GPs). This patient-randomised controlled trial (phase II) included 31 DAs and employing GPs from 29 small office-based practices in Germany. Patients with CHF received either case management (n = 99) consisting of telephone monitoring and home visits or usual care (n = 100) for 12 months. We obtained clinical data, health care utilisation data, and patient-reported data on generic and disease-specific quality of life (QoL, SF-36 and KCCQ), CHF self-care (EHFScBS) and on quality of care (PACIC-5A). To compare between groups at follow-up, we performed analyses of covariance and logistic regression models. Baseline measurement showed high guideline adherence to evidence-based pharmacotherapy and good patient self-care: Patients received angiotensin converting enzyme inhibitors (or angiotensin-2 receptor antagonists) in 93.8% and 95%, and betablockers in 72.2% and 84%, and received both in combination in 68% and 80% of cases respectively. EHFScBS scores (SD) were 25.4 (8.4) and 25.0 (7.1). KCCQ overall summary scores (SD) were 65.4 (22.6) and 64.7 (22.7). We found low hospital admission and mortality rates. EHFScBS scores (-3.6 [-5.7;-1.6]) and PACIC and 5A scores (both 0.5, [0.3;0.7/0.8]) improved in favour of CM but QoL scores showed no significant group differences (Physical/Mental SF-36 summary scores/KCCQ-os [95%CI]: -0.3 [-3.0;2.5]/-0.1 [-3.4;3.1]/1.7 [-3.0;6.4]). In this sample, with little room for improvement regarding evidence-based pharmacotherapy and CHF self-care, case management showed no improved health outcomes or health care utilisation. However, case management significantly improved performance and key intermediate outcomes. Our study provides evidence for the feasibility of the case management model. ISRCTN30822978.


Treatment of complicated urinary tract infections with the long acting cephalosporin, ceftriaxone.
Ceftriaxone, a new broad spectrum cephalosporin with a long biological half-life has been used on a single intravenous daily dosage regimen over a five day period to treat complicated urinary tract infection. Bacteriological analysis of urine up to six weeks after such treatment, indicated that ceftriaxone was successful in 13 out of 15 cases treated compared with two out of 15 cases treated with cefuroxime given three times daily over the five day treatment period.


Obesity and gastro-esophageal acid reflux: physiopathological mechanisms and role of gastric bariatric surgery.
Controversial findings about the relationships between obesity and gastro-esophageal reflux have been reported, as well as about the effects of weight loss and bariatric surgery on reflux. The aims of this study were to evaluate esophageal motility and gastro-esophageal acid circadian patterns in obese patients and to test the effects of vertical banded gastroplasty (VBG) on these parameters. 14 obese subjects (BMI 36-53 kg/m2), 4 men, 10 women, 27-61 years old, admitted for elective bariatric surgery, underwent clinical evaluation, upper endoscopy, esophageal manometry and gastroesophageal pH monitoring. Evaluations were repeated 6 to 12 months after gastric surgery that consisted of a VBG (7 patients), accompanied in the other 7 patients with an anti-reflux procedure (fundoplication). Manometric and pH-metric findings in the obese patients were compared with a normal-weight control group before and after the two different surgical treatments. Gastro-esophageal reflux was significantly more frequent in obese (57.1%) than in control group (7.1%). Esophageal motility in obese subjects was not different from controls. After VBG alone, we found a reduction in basal lower esophageal sphincter (LES) pressure and an increase of acid reflux. When VBG was accompanied by fundoplication, basal LES pressure increased and acid reflux frequency decreased. Obesity is associated with gastroesophageal reflux. VBG reduced weight, but not gastro-esophageal acid reflux. Therefore, in our population, this operation cannot be considered as an antireflux procedure.


[The role of genes of renin-angiotensin system in the development of adverse outcomes of treatment in severe intraventricular hemorrhages in premature infants].
Introduction: Intraventricular hemorrhage (IVH) causes increased morbidity and mortality in premature infants and is associated with adverse neurological outcomes. The aim of the research is to confirm the role of genes of renin-angiotensin system in the development of adverse outcomes of treatment of severe IVC in preterm. Materials and methods: A prospective study was conducted, which included 58 premature infants (average birth weight 1016.8 ± 52.59 g, gestational age 26.96 ±0.33 weeks), who were treated at medical institutions in Poltava region during 2012-2015. I/D polymorphism of ACE gene, A/C polymorphism of AGT2R1 gene and 4a/b polymorphism of the eNOS gene were studied. The distribution of the genotype was compared between groups using the χ2 analysis. Results: Out of 58 children enrolled in the study, 33 (56.9%) of infants developed ventricular dilatation, which in 8 (13.8%) of the newborns progressed to hydrocephalus. Thirty-four (58.6%) infants with severe IVHs died. The average (median) time of death of infants was 10.6 days. Among children who died, a combination of genotypes ID & DD of the gene ACE +4ab & 4AA of the eNOS gene was found significantly more often than in children who survived, and at the border of statistical significance - the isolated genotype 4ab & 4 aa of the eNOS gene. The combination of genotype ID+DD of the ACE gene and the AC + CC genotype of the AGTR1 gene was significantly more frequent among children with ventricular dilatation than in children without it. The weight at birth have negative correlation trends with lethal outcomes and do not have with ventricular dilatation and hydrocephalus. Conclusions: Lethal outcomes in children with IVH are associated with weight at birth, as well as the presence of a combination of genotypes ID+DD of the ACE gene and 4ab+4aa of the eNOS gene.


Redistributing energy flow and polarization of a focused azimuthally polarized beam with rotationally symmetric sector-shaped obstacles.
The redistribution of transversal energy flow and polarization in the focal field are represented by obstructing an azimuthally polarized beam with rotationally symmetric sector-shaped obstacles. Several energy flow rings that can finally transport the absorptive particles into fixed locations are formed in the focal plane. Furthermore, the local polarization state of the focal field is also modified by use of the rotationally symmetric obstacles. This kind of energy flow may have wide applications in optical trapping and manipulation.


Overcoming the limited availability of human milk oligosaccharides: challenges and opportunities for research and application.
Human milk oligosaccharides (HMOs) are complex sugars highly abundant in human milk but currently not present in infant formula. Rapidly accumulating evidence from in vitro and in vivo studies, combined with epidemiological associations and correlations, suggests that HMOs benefit infants through multiple mechanisms and in a variety of clinical contexts. Until recently, however, research on HMOs has been limited by an insufficient availability of HMOs. Most HMOs are found uniquely in human milk, and thus far it has been prohibitively tedious and expensive to isolate and synthesize them. This article reviews new strategies to overcome this lack of availability by generating HMOs through chemoenzymatic synthesis, microbial metabolic engineering, and isolation from human donor milk or dairy streams. Each approach has its advantages and comes with its own challenges, but combining the different methods and acknowledging their limitations creates new opportunities for research and application with the goal of improving maternal and infant health.


Implementation of the guided reading approach with elementary school deaf students.
The researchers investigated the effects of the Guided Reading approach (Fountas & Pinnell, 1996) on the reading development of elementary school deaf students over a period of 2 school years. A single-subject experimental research designed was used. Qualitative analyses of observations of instruction and interviews with the teachers were conducted to determine fidelity to the Guided Reading protocol. Visual display of graphed Running Records scores during the 2-year implementation showed that all students improved during intervention, all participants except the oldest group experienced a drop in scores from the end of one school year to the beginning of the next, and that it took months for most students to regain their previous year's scores; some had not done so even by the end of fall term.


Comparison of Clinical Outcomes in Patients Undergoing Coronary Intervention with Drug-Eluting Stents or Bare-Metal Stents: A Nationwide Population Study.
The aim of this propensity score-matched cohort study was to investigate the prognostic impacts of drug-eluting stents (DES) and bare-metal stents (BMS) in patients undergoing percutaneous coronary intervention (PCI). We conducted a retrospective cohort study based on the National Health Insurance program. Patients who had undergone coronary stenting between Jan. 2007 and Dec. 2008 were recruited and monitored until the end of 2010. Subjects with either BMS or DES were matched 2:1 by propensity score, which adjusted for age, sex, stent number and Charlson comorbidity index (CCI). The Kaplan-Meier method and Cox regression models were used for prognostic analyses. Among a total of 966 patients with a mean age of 66 years, 644 subjects had BMS and 322 subjects had DES. The incidence of myocardial infarction (MI) and death were significantly lower in the DES group as compared with the BMS group for the three-year follow-up duration. With adjustments for age, sex, premium-based monthly salary, levels of hospital care, stent number, CCI, medications, and acute coronary syndrome presentation in the index hospitalization, use of DES rather than BMS was associated with reduced adverse coronary events (hazard ratio and 95% confidence interval: 0.55, 0.38-0.81 in the whole population, and 0.44, 0.26-0.73 in the subgroup patients with stable coronary artery disease). Implantation of DES was related to better outcomes than for BMS, in terms of reducing MI and mortality after PCI. The survival benefit for patients with DES was even greater in patients with stable coronary artery disease.


Extracellular matrix in multicellular aggregates acts as a pressure sensor controlling cell proliferation and motility.
Imposed deformations play an important role in morphogenesis and tissue homeostasis, both in normal and pathological conditions. To perceive mechanical perturbations of different types and magnitudes, tissues need appropriate detectors, with a compliance that matches the perturbation amplitude. By comparing results of selective osmotic compressions of CT26 mouse cells within multicellular aggregates and global aggregate compressions, we show that global compressions have a strong impact on the aggregates growth and internal cell motility, while selective compressions of same magnitude have almost no effect. Both compressions alter the volume of individual cells in the same way over a shor-timescale, but, by draining the water out of the extracellular matrix, the global one imposes a residual compressive mechanical stress on the cells over a long-timescale, while the selective one does not. We conclude that the extracellular matrix is as a sensor that mechanically regulates cell proliferation and migration in a 3D environment.