Chronic ankle instability affects learning rate during repeated proprioception testing.
1. To determine whether individuals with chronic ankle instability (CAI) have lower proprioception sensitivity scores from a test on the Active Movement Extent Discrimination Apparatus (AMEDA). 2. To determine whether individuals with CAI can improve proprioception sensitivity scores with repeated active movement testing using the AMEDA. 3. To assess the test-retest reliability of the AMEDA. A cohort study comparing those with CAI or healthy ankles. University clinical laboratory. 61 healthy university students, 36 with CAI, 25 with stable ankles. A 2-way ANOVA was conducted to compare performance of CAI and stable ankle groups, over 3 test repetitions on the AMEDA. The reliability intra-class correlation coefficient (ICC) was obtained for test repetitions. The scores improved in both groups when the AMEDA test was repeated (p = <0.001). The rates of improvement in proprioception test scores differed, with the CAI group showing a slower learning rate than the stable ankle group (p = 0.047). The ICC for the whole group across the three trials was 0.80 (95% CI = 0.69 to 0.87, p = <0.001). CAI participants improve their proprioception scores more slowly upon repeated AMEDA testing, suggesting differences in learning strategies.


Improving satisfaction with postoperative pain management for patients with persistent pain: a preoperative pain medicine consultation intervention.
Preoperative pain medicine consultations with opioid-tolerant patients allow for an accurate medication history, patient involvement in the postoperative plan, and realistic goal setting. The purpose of this quality improvement project was to increase attendance at preoperative pain consultations, thereby increasing patient satisfaction. Retrospective chart reviews identified patients who had a preoperative pain consultation ordered from May through July 2016. Patient interviews determined reasons for not attending appointments, involvement in goal setting, engagement in pain management planning, and satisfaction with postoperative pain management. Retrospective chart reviews and interviews were conducted after the intervention (May-July 2017). Scheduling changes increased attendance at preoperative pain consultations by 14 percentage points (50% vs 64%). Those who attended consultations were more involved in goal setting and decisions and were more satisfied. Preoperative pain consultations with opioid-tolerant patients can increase satisfaction through realistic goal setting and involvement in the pain management plan.


Therapeutic aspects of kinesiogenic paroxysmal choreoathetosis and familial paroxysmal choreoathetosis of the Mount and Reback type.
Six generations of a family with paroxysmal choreoathetosis of the Mount and Reback type were studied. Neurological investigation and follow-up of the symptoms were possible for four generations, in which 15 members suffered from the disease. The attacks could be provoked by alcohol and intensified by caffeine or emotional excitement. Phenytoin, primidone and carbamazepine had no therapeutic effect. Treatment with L-dopa could provoke the choreoathetosis. Haloperidol was the most effective treatment and valproic acid was also able to reduce drastically the frequency and intensity of the attacks. Three patients with sporadic kinesiogenic, paroxysmal choreoathetosis were also studied, whose choreoathetosis was induced by movement. Treatment with carbamazepine or phenytoin was effective, but haloperidol increased the severity of the choreoathetoid attacks.


Hypertension, use of antihypertensive medications, and risk of epithelial ovarian cancer.
Few studies have examined the associations of hypertension and antihypertensive medications with ovarian cancer. In particular, beta-blockers, one of the most commonly prescribed medications to treat hypertension, may reduce ovarian cancer risk by inhibiting beta-adrenergic signaling. We prospectively followed 90,384 women in the Nurses' Health Study (NHS) between 1988-2012 and 113,121 NHSII participants between 1989-2011. Hypertension and use of antihypertensive medications were self-reported biennially. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We documented 948 ovarian cancer cases during follow-up. Similar results were observed in the two cohorts. While hypertension was not associated with ovarian cancer risk (Pooled HR = 1.01; 95% CI = 0.88, 1.16), current use of any antihypertensive medication was associated with slightly increased risk compared to never users (Pooled HR = 1.18; 95% CI: 1.02, 1.37). This increased risk was primarily due to use of thiazide diuretics (Pooled HR = 1.37; 95% CI: 1.13, 1.68). No associations were observed for beta-blockers or angiotensin-converting-enzyme inhibitors. Calcium channel blockers (CCBs) were associated with suggestively reduced risk (NHS HR = 0.73; 95% CI: 0.53, 1.01), after adjusting for all antihypertensive medications. Associations were similar among hypertensive women and stronger for longer use of thiazide diuretics and CCBs. In conclusion, our results provided no evidence that beta-blockers were associated with reduced ovarian cancer risk. In contrast, we observed an increased risk for use of thiazide diuretics that should be confirmed in other studies.


Predicting geogenic groundwater fluoride contamination throughout China.
Endemic fluorosis exists in almost all provinces of China. The long-term ingestion of groundwater containing high concentrations of fluoride is one of the main causes of fluorosis. We used artificial neural network to model the relationship between groundwater fluoride concentrations from throughout China and environmental variables such as climatic, geological. and soil parameters as proxy predictors. The results show that the accuracy and area under the receiver operating characteristic curve of the model in the test dataset are 80.5% and 0.86%, respectively, and climatic variables are the most effective predictors. Based on the artificial neural network model, a nationwide prediction risk map of fluoride concentrations exceeding 1.5 mg/L with a 0.5 × 0.5 arc minutes resolution was generated. The high risk areas are mainly located in western provinces of Xinjiang, Tibet, Qinghai, and Sichuan, and the northern provinces of Inner Mongolia, Hebei and Shandong. The total number of people estimated to be potentially at risk of fluorosis due to the use of untreated high fluoride groundwater as drinking water is about 89 million, or 6% of the population. The high fluoride groundwater risk map helps the authorities to prioritize areas requiring mitigation measures and thus facilitates the implementation of water improvement and defluoridation projects.


Biodegradation of 4-chlorophenol by acclimated and unacclimated activated sludge--evaluation of biokinetic coefficients.
Unacclimated and acclimated activated sludges were examined for their ability to degrade 4-CP (4-chlorophenol) in the presence and absence of a readily growing substrate using aerobic batch reactors. The effects of 4-CP on the micro (specific growth rate), COD removal efficiency, Y (yield coefficient), and q (specific substrate utilization rate) were investigated. It was observed that the toxicity of 4-CP on the culture decreased remarkably after acclimation. For example, the IC(50) value on the basis of micro was found to increase from 130 to 218 mg/L with the acclimation of the culture. Although an increase in 4-CP concentration up to 300 mg/L has no adverse effect on the COD removal efficiency of the acclimated culture, a considerable decrease was observed in the case of an unacclimated culture. Although 4-CP removal was not observed with an unacclimated culture, almost complete removal was achieved with the acclimated culture, up to 300 mg/L. The Haldane kinetic model adequately predicted the biodegradation of 4-CP and the kinetic constants obtained were q(m)=41.17 mg/(gMLVSSh), K(s)=1.104 mg/L, and K(i)=194.4 mg/L. The degradation of 4-CP led to formation of 5-chloro-2-hydroxymuconic semialdehyde, which was further metabolized, indicating complete degradation of 4-CP via a meta-cleavage pathway.


Pancreatic islet isolation variables in non-human primates (rhesus macaques).
Non-human primates (NHPs) are important preclinical models for pancreatic islet transplantation (PIT) because of their close phylogenetic and immunological relationship with humans. However, low availability of NHP tissue, long learning curves and prohibitive expenses constrain the consistency of isolated NHP islets for PIT studies. To advance preclinical studies, we attempted to identify key variables that consistently influence the quantity and quality of NHP islets. Seventy-two consecutive pancreatic islet isolations from rhesus macaques were reviewed retrospectively. A scaled down, semi-automated islet isolation method was used, and monkeys with streptozotocin-induced diabetes, weighing 3-7 kg, served as recipients for allotransplantation. We analysed the effects of 22 independent variables grouped as donor factors, surgical factors and isolation technique factors. Islet yields, success of isolation and transplantation results were used as quantitative and qualitative outcomes. In the multivariate analysis, variables that significantly affected islet yield were the type of monkey, pancreas preservation, enzyme lot and volume of enzyme delivered. The variables associated with successful isolation were the enzyme lot and volume delivered. The transplant result was correlated with pancreas preservation, enzyme lot, endotoxin levels and COBE collection method. Islet quantity and quality are highly variable between isolations. The data reviewed suggest that future NHP isolations should use bilayer preservation, infuse more than 80 ml of Liberase into the pancreas, collect non-fractioned tissue from the COBE, and strictly monitor for infection.


Cardiorespiratory, tissue oxygen and hepatic NADH responses to graded hypoxia.
To assess cardiorespiratory, tissue oxygen and hepatic nicotine adenine dinucleotide hydride (NADH) responses to graded hypoxia. Prospective, controlled, randomized study. University laboratory. 18 anaesthetised Sprague-Dawley rats spontaneously breathing either 21% (controls), 12.5% or 10% inspired oxygen concentrations (6 rats per group). All animals in the 21 and 12.5% O2 groups survived the 3-h study period, compared to only 1 in the 10% O2 group. In this latter group, mean arterial pressure and renal blood flow fell immediately with hypoxaemia, whereas aortic blood flow was maintained until the preterminal stages. Critical cellular hypoxia was suggested by an increasingly severe base deficit, an initial rise then a preterminal fall in hepatic NADH intensity and premature death in all but 1 animal. Hepatic NADH fluorescence intensity was unchanged in control animals but showed a progressive rise in the 12.5% O2 group, accompanied by a small though static increase in arterial base deficit. No significant differences were seen in arterial and tissue partial pressure of oxygen between the 12.5 and 10% O2 groups. This study demonstrates major differences in cardiorespiratory, hepatic NADH and outcome responses to small variations in the degree of hypoxic hypoxia. The fall in NADH fluorescence intensity presages impending death and is likely to reflect failure of cellular metabolic processes.


Fabrication of Gold Nanoparticles/Graphene-PDDA Nanohybrids for Bio-detection by SERS Nanotechnology.
In this research, graphene nanosheets were functionalized with cationic poly (diallyldimethylammonium chloride) (PDDA) and citrate-capped gold nanoparticles (AuNPs) for surface-enhanced Raman scattering (SERS) bio-detection application. AuNPs were synthesized by the traditional citrate thermal reduction method and then adsorbed onto graphene-PDDA nanohybrid sheets with electrostatic interaction. The nanohybrids were subject to characterization including X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential, and X-ray photoelectron spectroscopy (XPS). The results showed that the diameter of AuNPs is about 15-20 nm immobilized on the graphene-PDDA sheets, and the zeta potential of various AuNPs/graphene-PDDA ratio is 7.7-38.4 mV. Furthermore, the resulting nanohybrids of AuNPs/graphene-PDDA were used for SERS detection of small molecules (adenine) and microorganisms (Staphylococcus aureus), by varying the ratios between AuNPs and graphene-PDDA. AuNPs/graphene-PDDA in the ratio of AuNPs/graphene-PDDA = 4:1 exhibited the strongest SERS signal in SERS detection of adenine and S. aureus. Thus, it is promising in the application of rapid and label-free bio-detection of bacteria or tumor cells.


Quality control of bacterial mRNA decoding and decay.
Studies in eukaryotes and prokaryotes have revealed that gene expression is not only controlled through altering the rate of transcription but also through varying rates of translation and mRNA decay. Indeed, the expression level of a protein is strongly affected by the steady state level of its mRNA. RNA decay can, along with transcription, play an important role in regulating gene expression by fine-tuning the steady state level of a given transcript and affecting its subsequent decoding during translation. Alterations in mRNA stability can in turn have dramatic effects on cell physiology and as a consequence the fitness and survival of the organism. Recent evidence suggests that mRNA decay can be regulated in response to environmental cues in order to enable the organism to adapt to its changing surroundings. Bacteria have evolved unique post transcriptional control mechanisms to enact such adaptive responses through: 1) general mRNA decay, 2) differential mRNA degradation using small non-coding RNAs (sRNAs), and 3) selective mRNA degradation using the tmRNA quality control system. Here, we review our current understanding of these molecular mechanisms, gleaned primarily from studies of the model gram negative organism Escherichia coli, that regulate the stability and degradation of normal and defective transcripts.


[Activity of elastase and its inhibitors in arterial tissues and blood serum under experimental arterio-atherosclerosis].
The role of the elastolytic system serum and arterial tissues in pathogenesis of vascular pathology was investigated on rabbits in experimental arterio-atherosclerosis. Activation of proteolytic enzymes, in particular elastase, sharp alteration capacity of inhibitors in arterial wall both at Menckeberg arteriosclerosis and atherosclerosis, permits to assume, that in the basis these different pathologic processes can lie general mechanisms, which will be realized through disturbance of the elastolytic system balance in blood vessels.


Patient mutations alter ATRX targeting to PML nuclear bodies.
ATRX is a SWI/SNF-like chromatin remodeling protein mutated in several X-linked mental retardation syndromes. Gene inactivation studies in mice demonstrate that ATRX is an essential protein and suggest that patient mutations likely retain partial activity. ATRX associates with the nuclear matrix, pericentromeric heterochromatin, and promyelocytic leukemia nuclear bodies (PML-NBs) in a speckled nuclear staining pattern. Here, we used GFP-ATRX fusion proteins to identify the specific domains of ATRX necessary for subnuclear targeting and the effect of patient mutations on this localization. We identified two functional nuclear localization signals (NLSs) and two domains that target ATRX to nuclear speckles. One of the latter domains is responsible for targeting ATRX to PML-NBs. Surprisingly, this domain encompassed motifs IV-VI of the SNF2 domain suggesting that in addition to chromatin remodeling, it may also have a role in subnuclear targeting. More importantly, four different patient mutations within this domain resulted in an approximately 80% reduction in the number of transfected cells with ATRX nuclear speckles and PML colocalization. These results demonstrate that patient mutations have a dramatic effect on subnuclear targeting to PML-NBs. Moreover, these findings support the hypothesis that ATRX patient mutations represent functional hypomorphs and suggest that loss of proper targeting to PML-NBs is an important contributor to the pathogenesis of the ATR-X syndrome.


Modeling the Spatial Distribution of Xylella fastidiosa: A Nonstationary Approach with Dispersal Barriers.
Spatial species distribution models often assume isotropy and stationarity, implying that spatial dependence is direction-invariant and uniform throughout the study area. However, these assumptions are violated when dispersal barriers are present. Despite this, the issue of nonstationarity has been little explored in the context of plant health. The objective of this study was to evaluate the influence of barriers in the distribution of Xylella fastidiosa in the demarcated area in Alicante, Spain. Occurrence data from 2018 were analyzed through spatial Bayesian hierarchical models. The stationary model, illustrating a scenario without control interventions or geographical features, was compared with three nonstationary models: a model with mountains as physical barriers, and two models with a continuous and discontinuous perimeter barrier representing hypothetical control interventions. In the stationary model, the posterior mean of the spatial range, as the distance where two observations are uncorrelated, was 4,030 m 95% credible interval (2,907 to 5,564). This distance can be used to define the buffer zone in the demarcated area. The predicted probability of X. fastidiosa presence in the area outside the barrier was 0.46 with the stationary model, whereas it was reduced to 0.29 and 0.36 with the continuous and discontinuous barrier models, respectively. Differences between the discontinuous and continuous barrier models showed that breaks, where no control interventions were implemented, resulted in a higher predicted probability of X. fastidiosa presence in the areas with low sampling intensity. These results may help authorities prioritize the areas for surveillance and disease control.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.


Cytotoxic scalarane-type sesterterpenes from the Saudi Red Sea sponge Hyrtios erectus.
The CHCl3/MeOH extract of the marine sponge Hyrtios erectus showed cytotoxicity against three cancer cell lines HepG2, A549, and PC-3 with IC50 0.055, 0.044, and 0.023 μg/ml, respectively. The CH2Cl2 soluble fraction afforded three scalarane sesterterpenes (1-3) along with a cholestane derivative (4) and an indole alkaloid (5). Chemical structures were established by spectroscopic techniques and comparison with data reported in the literature. Scalarinol (1) was found as a new metabolite, while heteronemin (2) and 12-O-deacetyl-19-deoxyscalarin (3) are known compounds. 1-3 exhibited cytotoxic activity against the cancer cell lines with IC50 values ranging from 14 to 230 μM. The molecular affinity to the DNA was employed as marker to examine the proposed mechanism of cytotoxic activities. Compound 2, with IC50 28 μg/ml, displayed the highest affinity to the DNA.


Partial trisomy 13q22-qter associated to leukoencephalopathy and late onset generalised epilepsy.
The partial trisomy 13q.22 is an uncommon chromosomopathy. We present a case with a partial trisomic component 13q22 and a monosomic component 5p15 from paternal origin. This patient developed early menopause and major neurological disorders as leukoencephalopathy, late onset generalised epilepsy and stroke. She also had fatty acids disturbances and their potential relation to the neurological disorders and early menopause is discussed. The presented case illustrates the phenotype of 13q22-qter in adult age and reaffirms the importance of studying the karyotype of any patient with seizures or leukoencephalopathy particularly when there are associated other clinical features including stroke at a young age, fatty acids disturbances, microcephaly, hypotelorism, short neck, hemangiomata, short fingers or distal swell in thumbs.


Adjunctive clindamycin for cellulitis: a clinical trial comparing flucloxacillin with or without clindamycin for the treatment of limb cellulitis.
To compare flucloxacillin with clindamycin to flucloxacillin alone for the treatment of limb cellulitis. Parallel, double-blinded, randomised controlled trial. Emergency department attendances and general practice referrals within 20 hospitals in England. Flucloxacillin, at a minimum of 500 mg 4 times per day for 5 days, with clindamycin 300 mg 4 times per day for 2 days given orally versus flucloxacillin given alone. The primary outcome was improvement at day 5. This was defined as being afebrile with either a reduction in affected skin surface temperature or a reduction in the circumference of the affected area. Secondary outcomes included resolution of systemic features, resolution of inflammatory markers, recovery of renal function, reduction in the affected area, decrease in pain, return to work or normal activities and the absence of increased side effects. 410 patients were included in the trial. No significant difference was seen in improvement at day 5 for flucloxacillin with clindamycin (136/156, 87%) versus flucloxacillin alone (140/172, 81%)-OR 1.55 (95% CI 0.81 to 3.01), p=0.174. There was a significant difference in the number of patients with diarrhoea at day 5 in the flucloxacillin with clindamycin allocation (34/160, 22%) versus flucloxacillin alone (16/176, 9%)-OR 2.7 (95% CI 1.41 to 5.07), p=0.002. There was no clinically significant difference in any secondary outcome measures. There was no significant difference in the number of patients stating that they had returned to normal activities at the day 30 interview in the flucloxacillin with clindamycin allocation (99/121, 82%) versus flucloxacillin alone (104/129, 81%)-adjusted OR 0.90 (95% CI 0.44 to 1.84). The addition of a short course of clindamycin to flucloxacillin early on in limb cellulitis does not improve outcome. The addition of clindamycin doubles the likelihood of diarrhoea within the first few days. NCT01876628, Results.


Levels of translatable mRNA coding for rat liver glucokinase.
Changes in the level of translatable mRNA coding for glucokinase under different physiological conditions were determined using a reticulocyte lysate translation system and immunoprecipitation. Poly(A+) RNA isolated from livers of rats fed a high carbohydrate diet displayed a 10-fold increase in glucokinase template activity when compared to starved rats. Livers from streptozotocin-induced diabetic rats had only 9% of the glucokinase template activity displayed by controls. Administration of insulin to diabetic rats produced an increase in the level of mRNA coding for glucokinase within 20 min and reached a maximum 13-fold increase 1 h following insulin treatment. Under all experimental conditions examined, changes in the level of glucokinase mRNA were accompanied by similar changes in direction and magnitude of enzyme activity and the relative rate of synthesis of the enzyme in vivo. In addition, the developmental appearance of glucokinase activity at the 16th day following birth was accompanied by a corresponding increase in the amount of glucokinase mRNA. Thus, it appears that dietary, hormonal, and developmental changes in the activity of glucokinase arise as the result of changes in the amount of functional mRNA coding for the enzyme.


Effective detection of fetal sex using circulating fetal DNA in first-trimester maternal plasma.
The aim of this study was to develop a simple and effective method for noninvasively detecting fetal sex using circulating fetal DNA from first-trimester maternal plasma. A study was conducted with maternal plasma collected from 203 women between 5 and 12 wk of gestation. The presence of circulating fetal DNA was confirmed by a quantitative methylation-specific polymerase chain reaction of the unmethylated-PDE9A gene (U-PDE9A). Multiplex real-time PCR was used to simultaneously quantify the amount of DYS14 and GAPDH in maternal plasma. The results were confirmed by phenotype at birth. Pregnancy outcomes and U-PDE9A concentrations were obtained in all cases, including 99 male-bearing and 104 female-bearing participants. At equivalent specificity (100%), the false-negative rate was 9.1% for DYS14 quantification cycle, 7.1% for DYS14 concentration, and 0.0% for the concentration ratio of DYS14/GAPDH, respectively. In male-bearing participants, DYS14, U-PDE9A, and GAPDH concentrations were significantly lower in the false-negative case than in correct case (P<0.001 in all). Moreover, DYS14, U-PDE9A, and GAPDH concentrations showed significantly positive associations with each other (P≤0.001 in all). The ratio of DYS14/GAPDH in maternal plasma was an effective biomarker for noninvasive fetal sex detection during the first trimester, indicating that it could be useful for clinical application.


Neutrophil Gelatinase--Associated Lipocalin and Cystatin C Are Sensitive Markers of Renal Injury in Patients With Multiple Myeloma.
Renal impairment is a common complication of patients with multiple myeloma (MM). We aimed to evaluate the clinical significance of 2 newly discovered biomarkers of renal injury, cystatin C (CysC), a protein reflecting glomerular filtration rate, and neutrophil gelatinase-associated lipocalin (NGAL), a protein reflecting tubular injuries. We studied 64 patients with newly diagnosed myeloma: 16 with asymptomatic (smoldering) MM and 48 with symptomatic myeloma; 8 patients with monoclonal gammopathy of undetermined significance (MGUS); and 20 healthy control subjects. Along with common blood and urine chemistry determinations, measurements of CysC, NGAL, β2-microglobulin, high-sensitivity C-reactive protein, and interleukin 6 were performed. We found that only patients with symptomatic MM had increased levels of CysC compared to controls (P < .01); that serum NGAL levels were elevated in all patients compared to controls P < .001; that NGAL strongly correlated with both estimation of glomerular filtration rate (eGFR) (CysC) and eGFR (Modification of Diet in Renal Disease [MDRD] formula) (r = 0.616, P < .0001; and r = -0.371, P < .01, respectively); that CysC showed strong correlation with eGFR (r = -0.782, P < .001) and with the International Scoring System (ISS) (more pronounced in patients with ISS-3); and that receiver operating characteristic curve analysis showed that NGAL values of > 50.5 μg/L have a 80.8% sensitivity and 86.4% specificity for eGFR < 60 mL/min (area under the curve = 0.764). These findings suggest that both NGAL and CysC are very sensitive markers that reflect renal impairment in newly diagnosed patients with MM. The high levels of NGAL in asymptomatic patients and in MGUS patients support the hypothesis of the presence of renal damage in these patients early in the course of their disease and may reveal NGAL to be an early marker that predicts the presence of renal impairment in MM.


Effect of interferon on integrity of vaccinia virus and ribosomal RNA in infected cells.
The state of vaccinia and ribosomal RNAs in IFN-treated, vaccinia virus-infected mouse L cells grown in suspension is examined. In these cells a drastic inhibition (approximately 90%) of both viral and cellular protein synthesis occurs after virus infection of IFN-treated cells. The findings show that (1) primary transcription of vaccinia virus is not impaired by IFN, but is rather enhanced; (2) viral RNAs produced in IFN-treated, infected cells are predominantly of the early class; (3) these viral RNAs can be translated in a cell-free protein-synthesizing system; (4) in IFN-treated, infected cells there is extensive cleavage of 28 and 18 S rRNA at early times post infection, resulting in a characteristic cleavage pattern; (5) cleavage of rRNA is viral RNA dependent. The results indicate that in this virus-cell system the IFN-mediated inhibition of vaccinia and cellular protein synthesis is correlated with an alteration in ribosomal integrity.


Exposure to formaldehyde and glutardialdehyde in operating theatres.
The disinfection of operating theatres and adjoining areas is carried out with chemical disinfectants containing not only formaldehyde but also glutardialdehyde. The cleaning staff is therefore unavoidably exposed to these two substances. Adequate and correct evaluation of staff exposure must be based on exact quantification of these aldehydes in room air. The statutory MAK-levels of 0.5 ppm (formaldehyde) and 0.2 ppm (glutardialdehyde) call for highly sensitive and specific analytical methods for monitoring exposure that should be suited for personal measuring as well. Since previous methods have failed to meet these requirements, we have adapted a newly developed method for the specific measurement of formaldehyde and other aldehydes and ketones for the personal monitoring of formaldehyde and glutardialdehyde. Detailed personal measurings over whole shifts and of short-term peaks have yielded the following results: During routine disinfection activities in operating theatres using low concentrations of disinfectants, the limits prescribed by MAK can be respected. Disinfections to prevent notifiable infectious diseases in accordance with the Federal Epidemic Law (Bundesseuchengesetz) involving the use of higher disinfectant concentrations are liable to exceed the MAK limits for formaldehyde and glutardialdehyde. If for reasons of hygiene this excess exposure cannot be avoided, effective protection of the cleaning staff from unacceptably high concentrations of these substances can be ensured only by providing personal protective outfits.


Histological features in western patients with idiopathic non-cirrhotic portal hypertension.
In the western world, idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease. This study aimed to investigate the histopathological features in western INCPH patients and to assess pathological differences between liver specimens of INCPH with and without HIV. Biopsies of 70 INCPH patients (of which 15 were HIV-infected) were compared to 23 patients with non-cirrhotic portal vein thrombosis (PVT), which served as a control group for non-cirrhotic portal hypertension. Phlebosclerosis, nodular regeneration (NR), sinusoidal dilatation, paraportal shunting vessels, perisinusoidal fibrosis and portal tract remnants were the most prevalent morphological features of INCPH. There were significant (P < 0.01) morphological differences between INCPH and PVT liver specimens with regard to portal tract remnants (46% versus 0%), phlebosclerosis (95% versus 65%), portal vein dilatation (34% versus 78%) and NR (56% versus 22%). The degree of NR correlated with the severity of phlebosclerosis (P < 0.01). NR was seen more frequently in the HIV-INCPH group, compared to the non-HIV-infected patients (P < 0.001). Portal tract remnants, phlebosclerosis and nodular regeneration are typical features of INCPH. Sinusoidal dilatation, paraportal shunting vessels and increased portal and parenchymal vessels might represent pressure-related morphological signs of portal hypertension. Finally, more nodular regeneration was observed in HIV-associated INCPH.


Medical problems in whitewater sports.
Overall, whitewater sports are relatively free of serious medical problems, with submersion accidents, trauma, and overuse syndromes being the most commonly encountered afflictions. Various infectious diseases and environmental exposure problems may occur, but serious illness or injury from such causes is infrequent. Nonetheless, the growing popularity of whitewater sports, along with increasing attempts by less experienced persons to navigate more difficult rivers, underscores the need for physicians to be aware of the medical problems likely to be encountered in these activities so that they may appropriately counsel and prepare persons for these invigorating yet potentially dangerous pastimes.


Leiomyosarcoma of prostate.
Leiomyosarcoma of the prostate is a rare tumor with no established protocol of treatment in the literature. We report a case with peculiar clinical presentation and androgen receptor content supporting the origin of the tumor. The potential advantage of hormonal manipulation during progression of the disease is suggested.


Evidence for the presence of mobile charges in the cell membrane of Valonia utricularis.
Charge-pulse relaxation studies were performed on cells of the giant marine alga Valonia utricularis with microelectrodes inserted into the vacuole. If the cell was charged by short pulses of 200 ns duration, the decay of the initial membrane voltage could be described by two relaxation processes at normal pH (8.2). The fast exponential relaxation had a time constant of approximately 100 microseconds whereas the the time constant of the slow relaxation ranged between 2 and 15 ms. The ratio of the two amplitudes varied between 10 and 20 and was found to be independent of the initial voltage, up to 400 mV. In contrast to the time constants, the amplitude ratio was a function of the duration of the charge pulse. As the pulse length was increased to 10 ms, the fast relaxation disappeared. A change in pH of the natural sea water from 8.2 to 4 resulted in the disappearance of both exponential processes and the appearance of one single exponential with a 1-ms time constant over the whole pulse-length range. The analysis of the data in terms of a two-membrane model leads to unusual values and a pH-dependence of the specific capacitances (0.6 and 6 microF cm-2) of the two membranes, which can be treated as two serial circuits of a capacitor and a resistor in parallel. The charge-pulse and the current-clamp data are consistent with the assumption that the cell membrane of V. utricularis contains mobile charges with a total surface concentration of approximately 4 pmol cm-2. These charges cross the membrane barrier with a translocation rate constant around 500 s-1 and become neutralized at low pH. From our experimental results it cannot be completely excluded that the tonoplast has also a high specific resistance. But in this case it has to be assumed that the tonoplast and plasmalemma have very similar electrical properties and contain both mobile charges, so that the two membranes appear as a single membrane. Experiments on artificial lipid bilayer membranes in the presence of the lipophilic ion dipicrylamine, support our mobile charge concept for the cell membrane of V. utricularis.


Estradiol Modulates Neural and Behavioral Arousal in Women With Posttraumatic Stress Disorder During a Fear Learning and Extinction Task.
Fear responding in posttraumatic stress disorder (PTSD) is sexually heterogeneous and varies with hormonal fluctuations throughout the menstrual cycle. While research suggests that estrogen levels affect PTSD symptoms among women, there is a dearth of research on modulatory effects of estrogen on fear responding among women with PTSD, and neural outcome measures are lacking. A sample of 42 women with PTSD underwent 2 consecutive alternating blocks of fear conditioning and extinction training, during which a CS+ conditioned stimulus, but not a CS-, predicted the occurrence of an electric shock in an acquisition context but not in an extinction context. Assayed saliva determined estradiol levels. Skin conductance response and whole-brain voxelwise activity during functional magnetic resonance imaging were outcome variables in linear mixed-effects models, with estradiol level, PTSD severity, and task contrasts as predictors. Skin conductance response exhibited a significant estradiol × PTSD severity × habituation interaction (t = 3.180, p = .002), such that PTSD severity was correlated with increased arousal responding between training blocks among women with lower estradiol (t = -3.985, p < .001) but not higher estradiol (t = 0.550, p = .583). Voxelwise activity also demonstrated an identical three-way interaction within dorsomedial prefrontal cortex and anterior insula clusters. The skin conductance response and imaging interactions between PTSD severity and estradiol were not specific to conditioned stimulus type or context. Estradiol moderated the relationship between PTSD severity and arousal response habituation between fear conditioning and extinction training sessions, such that high estradiol protected against the negative impact of severe PTSD symptoms on fear habituation. These findings suggest that estrogen enhances habituation among women with severe PTSD, potentially influencing the efficacy of extinction-based therapies.


Binding of myosin I to membrane lipids.
The single-headed myosins called myosin-I were first isolated from the protozoan Acanthamoeba and subsequently identified in other cells. We previously reported evidence that myosin-I is responsible for the movement of membranes, extracted from Acanthamoeba, along actin filaments in vitro. Here we show for the first time that myosin-I can bind directly to NaOH-extracted membranes isolated from Acanthamoeba and to vesicles of pure lipids with an affinity sufficient for extensive binding in the cell. Membrane-bound myosin-I may provide a mechanism for many cellular movements previously thought to involve filamentous myosin-II.


Fertility after ectopic pregnancy in relation to background factors and surgical treatment.
To study the importance of certain background factors and surgical treatment, the obstetric outcome in 205 women consecutively treated for ectopic pregnancy was analyzed by means of questionnaires 4 to 5.5 years after surgery. The response rate was 83.4% and, among women desiring pregnancy (n = 112), the total pregnancy rate was 75.9% and the delivery rate 53.6%. The total incidence of repeat ectopics was 27.3%, and the proportion of women who had a repeat ectopic pregnancy but no delivery was 20.5%. Six of seven women having an ectopic pregnancy with a copper intrauterine contraceptive device in situ had a normal delivery during the follow-up period. The subsequent fertility among nonresponders appeared lower than among responding women. A number of background factors present at the time of surgery were correlated to subsequent infertility, e.g., history of infertility and previous abdominal surgery. Conversely, there was no correlation between the fertility outcome and the type of operative procedure.


Neutralization of heparin by prothrombin activation products.
The neutralization of heparin by active site blocked meizothrombin and thrombin, prothrombin fragment 1.2, fragment 1 and fragment 2 was probed by the heparin-dependent factor Xa inactivation by antithrombin III (AT III). Meizothrombin had no effect on the inactivation of factor Xa, whereas thrombin had an inhibitory effect (IC50 = 700 nM). After factor Xa catalyzed cleavage of meizothrombin, the resulting products, prothrombin fragment 1.2 plus thrombin, did not show any heparin neutralizing properties. However, after isolation of the reaction products, both thrombin and prothrombin fragment 1.2 exhibited heparin neutralizing properties in the factor Xa inactivation reaction. The IC50-values were 700 nM and 100 nM, respectively. Prothrombin fragment 1, when present at 125 nM, caused a 50% reduction of the heparin-dependent rate of inactivation of factor Xa and prothrombin fragment 2 had no effect at all. From this we conclude that, in addition to the thrombin part of the prothrombin molecule, the fragment 1 region also exhibits a rather high affinity for heparin.


Basidiobolomycosis in Togo: clinico-pathological study of a series of 12 presumed cases.
The purpose of our study was to describe the histological diagnosed of the Basidiobolomycosis cases from 1990 to 2017 (28 years) in the only Pathology Anatomy Laboratory in Togo. A total of 12 cases of suspected Basidiobolomycosis have been identified. The sex ratio (M/F) was 2. The average age of the patients was 24.8 ± 1.6 years. Six patients (6/12) had a pathological history: HIV infection (n = 4 cases) and tuberculosis (n = 2 cases). The clinical manifestations were localized to pure skin (n = 9 cases), skin and mucous digestive (n = 2 cases) and disseminated (n = 1 cases). Direct mycological examination and culture in 4 patients was positive in 3 patients. The samples examined consisted of 11 cutaneous biopsies measuring 1-3 cm and a biopsy of the intestinal mucosa. Histology showed granulomatous inflammation of the dermohypodermal site with numerous giant cells associated with eosinophilic polynuclear cells, in which there are 5-7 mm non-septate, irregular mycelial filaments. Patients were treated with ketoconazole at a dose of 10 mg/kg daily. The progression of the patients' condition was favorable after 4 weeks of treatment with a regression of the closets size. Patients were completely healed after 8 weeks of treatment, without recurrence after 6 months. No deaths have been recorded.


[The pancreas as target organ for hepatitis B virus--immunohistological detection of HBsAg in pancreatic carcinoma and chronic pancreatitis].
In a retrospective study pancreatic tissue specimens from 199 patients who had had pancreas surgery were tested for the presence of HBsAg. HBsAg could be demonstrated in two patients with chronic pancreatitis, in five patients with pancreas carcinoma and in one asymptomatic HBsAg carrier by use of the immunoperoxidase method. Demonstration of HBsAg in acinus epithelia and the small ductules supports the hypothesis, that virus particles can be produced and secreted by pancreatic tissue. The incidence of HBsAg in pancreas carcinoma (7% of cases investigated) is higher than can be explained by coincidence, thus there may be a certain association. These findings and data reported in the literature, showing that acute necrotizing pancreatitis can be caused by hepatitis virus, may lead to the conclusion, that in patients suffering from acute pancreatitis with unknown etiology serological virus diagnostics should be done.


Wafer-Scale Uniform Carbon Nanotube Transistors for Ultrasensitive and Label-Free Detection of Disease Biomarkers.
Carbon nanotube (CNT) field-effect transistor (FET)-based biosensors have shown great potential for ultrasensitive biomarker detection, but challenges remain, which include unsatisfactory sensitivity, difficulty in stable functionalization, incompatibility with scalable fabrication, and nonuniform performance. Here, we describe ultrasensitive, label-free, and stable FET biosensors built on polymer-sorted high-purity semiconducting CNT films with wafer-scale fabrication and high uniformity. With a floating gate (FG) structure using an ultrathin Y2O3 high-κ dielectric layer, the CNT FET biosensors show amplified response and improved sensitivity compared with those sensors without Y2O3, which is attributed to the chemical gate-coupling effect dominating the sensor response. The CNT FG-FETs are modified to selectively detect specific disease biomarkers, namely, DNA sequences and microvesicles, with theoretical record detection limits as low as 60 aM and 6 particles/mL, respectively. Furthermore, the biosensors exhibit highly uniform performance over the 4 in. wafer as well as superior bias stress stability. The FG CNT FET biosensors could be extended as a universal biosensor platform for the ultrasensitive detection of multiple biological molecules and applied in highly integrated and multiplexed all CNT-FET-based sensor architectures.


Marked increase in high density lipoproteins in mountaineers.
Apoprotein-AI concentrations were measured in whole blood in 13 male mountaineers before, during and after a strenuous climb of 8 weeks' duration. The AI concentration almost doubled in 3 weeks and remained elevated at that level for the full period of the climb. This study demonstrates the rapid rate at which high density lipoproteins can rise and the very high levels (148 +/- 29 mg/dl in whole blood) that can be reached. The rise can be attributed at least in part to exercise though other factors such as exposure to cold, hypoxia and mental stress might also have contributed.


High growth hormone serum partially protects mice against Trypanosoma cruzi infection.
Chagas disease (CD) is one of the most devasting parasitic diseases in the Americas, affecting 7-8 million people worldwide. In vitro and in vivo experiments have demonstrated that growth hormone (GH) serum levels decrease as CD progresses. Interestingly, inactivating mutations in the GH receptor in humans result in Laron syndrome (LS), a clinical entity characterized by increased serum levels of GH and decreased insulin growth factor-1 (IGF-1). The largest cohort of LS subjects lives in the southern provinces of Ecuador. Remarkably, no clinical CD cases have been reported in these individuals despite living in highly endemic areas. In the current ex vivo study, we employed serum from GHR-/- mice, also known as LS mice (a model of GH resistance with high GH and low IGF-1 levels), and serum from bovine GH (bGH) transgenic mice (high GH and IGF-1), to test the effect on Trypanosoma cruzi infection. We infected mouse fibroblast L-cells with T. cruzi (etiological CD infectious agent) and treated them with serum from each mouse type. Treatment with GHR-/- serum (LS mice) significantly decreased L-cell infection by 28% compared with 48% from control wild-type mouse serum (WT). Treatment with bGH mouse serum significantly decreased infection of cells by 41% compared with 54% from WT controls. Our results suggest that high GH and low IGF-1 in blood circulation, as typically seen in LS individuals, confer partial protection against T. cruzi infection. This study is the first to report decreased T. cruzi infection using serum collected from two modified mouse lines with altered GH action (GHR-/- and bGH).


Prediction of permanent hypoparathyroidism by parathyroid hormone and serum calcium 24 h after thyroidectomy.
To assess the value of 24-hour intact parathyroid hormone (iPTH), serum calcium, and decreases in both were evaluated against preoperative values (iPTH and serum calcium decline) and used to determine the existence of permanent hypoparathyroidism (pHPP) after total thyroidectomy (TT). The clinical data of patients who underwent total thyroidectomy in our hospital between September 2014 and July 2015 were retrospectively analyzed. There were 42 cases with normal parathyroid function, 58 cases with temporary HPP, and 10 cases with pHPP. When iPTH and serum calcium were administered at 24 h after surgery, iPTH decline and calcium decline differed significantly among the three groups above (P < .01). The accuracy and positive predictive value of 24 h iPTH for pHPP were higher than any one of the others. The sensitivity, specificity, false positive rate, and accuracy were 100%, 95%, 33.33%, and 94.45%, respectively. The AUC was 0.982 when 24-hour iPTH was equal to or <3.15 pg/mL. The use of blood calcium equal to or <2.03 mmol/L (8.12 mg/dL) pointed to a diagnosis of pHPP, with a sensitivity of 100%, specificity of 63%, false positive rate of 78.72%, and accuracy of 66.36%. Measurement of the postoperative 24-h intact parathyroid hormone and serum calcium concentration can predict the occurrence of permanent hypoparathyroidism and the former is more advantageous. Postoperative 24-h intact parathyroid hormone equal to or <3.15 pg/mL is a reliable index, and it is suitable for the prediction of postoperative permanent hypoparathyroidism.


Case-fatality study of workers and residents with radiographic asbestos disease in Libby, Montana.
Vermiculite ore from Libby, Montana contains on average 24% of a mixture of toxic and carcinogenic amphibole asbestiform fibers. These comprise primarily winchite (84%), with smaller quantities of richterite (11%) and tremolite (6%), which are together referred to as Libby amphibole (LA). A total of 1883 individuals who were occupationally and/or environmentally exposed to LA and were diagnosed with asbestos-related pleuropulmonary disease (ARPPD) following participation in communitywide screening programs supported by the Agency for Toxic Substances and Disease Registry (ATSDR) and followed up at the Center for Asbestos Related Disease (CARD) between 2000 and 2010. There were 203 deaths of patients with sufficient records and radiographs. Best clinical and radiologic evidence was used to determine the cause of death, which was compared with death certificates. Asbestos-related mortality was 55% (n = 112) in this series of 203 patients. Of the 203 deaths, 34 (17%) were from asbestos-related malignancy, 75 (37%) were from parenchymal asbestosis, often with pleural fibrosis, and 3 (1.5%) were from respiratory failure secondary to pleural thickening. Asbestos is the leading cause of mortality following both occupational and nonoccupational exposure to LA in those with asbestos-related disease.


A systematic review of the effect of gastric pouch and/or gastrojejunostomy (stoma) size on weight loss outcomes with Roux-en-Y gastric bypass.
The effect of the gastric pouch or Gastrojejunostomy (GJ or stoma) size on weight loss outcomes after Roux-en-Y gastric bypass (RYGB) is unclear with studies reporting conflicting results. The purpose of this systematic review was to determine the impact of the gastric pouch or stoma size on weight loss outcomes with RYGB. An online search of PubMed was carried out to identify all articles evaluating the effect of the gastric pouch and/or gastric stoma size at the time of surgery on outcomes associated with RYGB. Quality and heterogeneity of data precluded a meta-analysis. So a systematic review was performed without a meta-analysis. This review found a total of 14 studies (two of which were randomised) evaluating the effect of pouch sizes on weight loss outcomes after RYGB. Nine of these studies did not find any significant association between pouch size and weight loss outcomes whereas five studies found larger pouches to be associated with poorer weight loss outcomes. No study found larger pouches to be associated with better weight loss outcomes. Out of the ten studies (one of which was randomised) that evaluated the effect of stoma size on weight loss outcomes after RYGB, six studies did not show any significant effect of stoma size on weight loss outcomes and four found larger stoma sizes to be associated with significantly poorer weight loss outcomes. No study found larger stoma to be associated with better weight loss outcomes. This review finds that a larger pouch or stoma size may be associated with adverse weight loss outcomes but the quality of data does not allow us to precisely determine optimum pouch or stoma size with RYGB. There is a need for more randomised data comparing long-term weight loss outcomes with pouches or stoma of different sizes.


Painful fat syndrome in a male patient.
Painful fat syndrome or lipoedema is a distinct clinical condition, characterised by bilateral and symmetrical enlargement of the upper and lower leg with tenderness, but excluding the feet. Lipoedema occurs almost exclusively in females, and no male patient has been reported in the literature published in English. We report on an extremely rare presentation of lipoedema in a male patient. A thorough study based on the case history, physical manifestations, and magnetic resonance imaging (MRI) provided valuable clues for a differential diagnosis. Conservative treatment using weight reduction, compression-stocking application, and diuretic therapy was not effective. Tumescent liposuction with postoperative pressure garments provided a satisfactory treatment.


Effect of enzymatic hydrolysis on the functional, antioxidant, and angiotensin I-converting enzyme (ACE) inhibitory properties of whole horse gram flour.
Horse gram hydrolysate (HGH) with different degree of hydrolysis (DH) (20, 25, 35, 40, and 45%) was prepared from whole horse gram flour using alcalase. The amino acid composition of HGH showed the presence of essential amino acids. The alcalase hydrolysis (DH ≥ 20%) increased protein solubility with a notable difference in the pH range of 3-5 (p < 0.05). The emulsifying activity and stability of HGH improved with increase in pH, especially at DH ≥ 25% (p < 0.05). With increase in DH, the foaming properties reduced while the antioxidant and angiotensin I-converting enzyme inhibitory activities increased. Sensory evaluation showed no significant difference (p > 0.05) in preference between control soup and soup mixed with HGH. Thus, these results suggest the possibility of HGH to be used as an appropriate functional ingredient with different food applications including in management of oxidative stress as well as in controlling hypertension .


Low intensity galvanic vestibulo-ocular reflex in normal subjects.
An electrical stimulation in man applied between the two mastoids could facilitate the distinction between labyrinthine and retrolabyrinthine lesions by stimulating directly the primary vestibular afferences. However, for this test to be really effective in current medical practice, the results obtained in normal subjects must be symmetrical and reproducible one day to another. The ocular responses induced by a constant electrical stimulation of 2.5 mA, applied between the two mastoids for 30 s (electrically evoked vestibulo-ocular reflex [EVOR]), in one direction and the other, were quantified in ten healthy subjects. Each subject was studied in two different sessions separated by 1 week. Horizontal eye movements were recorded in darkness by an infrared light reflection eye-tracking system. Slow-phase velocity and nystagmus frequency were about 20% higher when the cathode was on the right mastoid than when it was on the left mastoid. This directional preponderance (DP) displayed large individual differences between the two sessions. The reproducibility of the reflectivity (mean of right and left EVOR) was high (r about 0.8). The weak reproducibility of the DP makes the EVOR at weak intensity inadequate to evaluate unilateral vestibular hypofunction. On the other hand, because of the high reproducibility of reflectivity, the EVOR should be effective in detecting bilateral vestibular hypofunction. Moreover, because of the weak intensity of stimulation, no local anaesthesia is needed so the manoeuvre is easy to repeat in case of chronic diseases.


Detección de Nuevas Tecnologías Sanitarias Para Mejorar el Control Metabólico de Pacientes Con Diabetes Tipo 2 Atendidos en el Programa de Salud Cardiovascular de Chile.
In Chile, > 900,000 people with type 2 diabetes mellitus (DM2) are controlled in the Cardiovascular Health Program (PSCV). Even though the PSCV includes a set of interventions for the control of patients with DM2, the results are still insufficient, generating a high human, economic, and social cost. This study aimed to identify and select new health technologies for the control of patients with DM2 not currently incorporated into the PSCV to be proposed as candidates for an economic evaluation in the Chilean context. For the identification of new health technologies, consultations with key informants and an umbrella review of updated scientific evidence were used as sources of information. In a second step, selection among those technologies was conducted based on the effectiveness of the intervention, target population, nature of the intervention, and international evidence of cost-effectiveness antecedents. Key informants identified 12 candidate health technologies not currently incorporated into the PSCV. From the umbrella review, an additional 9 health technologies were identified that were not identified by the key informants. Of the 21 new health technologies identified, finally 8 health technologies were selected (structured group education, pedometer use, periodontal treatment, cognitive-behavioral therapy, telemonitoring, sitagliptin, canagliflozin, and insulin degludec). The health technologies detected have a high potential to be studied through economic evaluations that allow guiding decision making around improving the health outcomes of patients with DM2 in Chile.


Neonatal cystitis alters mechanisms of stress-induced visceral hypersensitivity in rats.
In rodent models, conditioning with acute footshock (AFS) has been demonstrated to produce bladder hypersensitivity which is more robust when rats, tested as adults, had also been pretreated with neonatal bladder inflammation (NBI). The spinal neurochemical mechanisms of pro-nociceptive processes in rats pretreated with NBI are not fully known and so the present study administered intrathecal (IT) opioid (naloxone) and NMDA receptor (MK-801) antagonists to determine whether these receptors' actions had been altered by NBI. Female Sprague-Dawley rat pups were intravesically pretreated on postnatal days P14-P16 with a 1% zymosan solution or with control procedures and then raised to adulthood (12-15 weeks of age). Bladder hypersensitivity was induced through use of an AFS paradigm. Visceromotor responses (VMRs; abdominal muscle contractions) to graded, air pressure-controlled urinary bladder distension were used as nociceptive endpoints. Immediately following AFS pretreatments, rats were anesthetized and surgically prepared. Pharmacological antagonists were administered via an IT catheter onto the lumbosacral spinal cord and VMRs determined 15 min later. Administration of IT naloxone hydrochloride (10 μg) to rats which had been pretreated only with AFS resulted in VMRs that were more robust than VMRs in similarly pretreated rats that received IT normal saline. In contrast, IT naloxone had no significant effect on rats that had been pretreated with both NBI&AFS, although MK-801 was inhibitory. These effects of IT naloxone suggest the presence of inhibitory influences in normal rats that are absent in rats pretreated with NBI. Absence of inhibitory influences produced by AFS was also demonstrated in rats pretreated with NBI&AFS using measures of thermal paw withdrawal latency (PWL): rats pretreated with only AFS had longer PWLs than rats pretreated with both NBI&AFS. Together, a reduction in anti-nociceptive mechanisms coupled with pro-nociceptive NMDA-linked mechanisms results in more robust nociceptive responses to distension in rats which had experienced NBI.


Glucocorticoid resistance is a dominant trait in hybrids between cytolytic T-lymphocyte lines and AKR thymomas.
By screening several cytolytic T-lymphocyte lines, AKR thymomas, and CTL X AKR thymoma hybrids from two different crosses for their sensitivity to the glucocorticoid (GC) analog dexamethasone (dex), we have found that CTL lines and cytolytically active, IL-2-dependent (CTL-like) hybrids are resistant to the cytostatic or cytolytic effects of dex; AKR thymomas and thymoma-like hybrids (cytolytically inactive, IL-2-independent), however, are sensitive to these effects of the drug. The GC resistance behaves like a dominant trait in these crosses. Although they are resistant to GC, the CTL lines and the CTL-like hybrids do contain functional hormone receptors and macrophage-activating factor (MAF) release by the CTL lines and CTL-like hybrids is inhibited by dex.


Citric acid: emerging applications of key biotechnology industrial product.
Owing to new biotechnological production units mostly located in China, global supply of citric acid in the course of the last two decades rose from less than 0.5 to more than 2 million tonnes becoming the single largest chemical obtained via biomass fermentation and the most widely employed organic acid. Critically reviewing selected research achievements and production trends, we identify the reasons for which this polycarboxylic acid will become a key chemical in the emerging bioeconomy.Graphical abstractPalermo's Fabbrica Chimica Italiana Goldenberg today. In 1930 it was Europe's largest citric acid plant (photo courtesy of Aldo Ferrande).


The evolution and nursing history of a general intensive care unit (1962-1983).
In this paper we have reviewed the origin and evolution of Whiston Hospital's General Intensive Care Unit (ICU) from its humble beginnings as an offshoot of a general ward in the early 1960s. The length of service of the senior nursing staff over a period of 21 years was also calculated. The average duration of service was 16.5 years--a figure which significantly surpassed those quoted in the literature. In addition, we have outlined the development of nurse training in intensive care as well as the role of the nurses in research in the ICU. The question as to whether later college-based training was superior to the previous hospital-based course remained unanswered.


Aortic stiffness and calcification in men in a population-based international study.
Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aortic calcification in middle-aged general population remains unknown although studies in patients with end-stage renal disease or elderly subjects suggest that aortic calcification is an important determinant of aortic stiffness. The goal of this study was to examine the association of aortic calcification and stiffness in multi-ethnic population-based samples of relatively young men. We examined the association in 906 men aged 40-49 (81 Black Americans, 276 Japanese Americans, 258 White Americans and 291 Koreans). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer. Aortic calcification from aortic arch to iliac bifurcation was evaluated using electron-beam computed tomography. Aortic calcium score was calculated and was categorized into four groups: zero (n=303), 1-100 (n=411), 101-300 (n=110), and 401+ (n=82). Aortic calcification category had a significant positive association with cfPWV after adjusting for age, race, and mean arterial pressure (mean (standard error) of cfPWV (cm/s) from the lowest to highest categories: 836 (10), 850 (9), 877 (17) and 941 (19), P for trend <0.001). The significant positive association remained after further adjusting for other cardiovascular risk factors. The significant positive association was also observed in each race group. The results suggest that aortic calcification can be one mechanism for aortic stiffness and that the association of aortic calcification with stiffness starts as early as the 40s.


Effects of 90- and 30-min naps or a 120-min nap on alertness and performance: reanalysis of an existing pilot study.
The aim of this study was to investigate alertness and cognitive performance immediately after and until the end of the night shift after taking a 120-min monophasic nap (One-nap) or a split 90-min and 30-min nap (Two-nap) during a 16-h simulated night shift, and the relationship between sleep quality and both alertness and performance. This study was performed in 41 females. Among them, 15 participants were included in the No-nap group, 14 in the One-nap group (22:00-00:00), and 12 in the Two-nap group (22:30-00:00 and 02:30-03:00). Participants were tested every hour from 16:00 to 09:00 for performance on the Uchida-Kraepelin test, as well as for subjective feelings of fatigue and drowsiness, body temperature, and heart rate variability. The shorter the sleep latency, the worse the alertness immediately after the 90-min nap. The 120-min and 30-min naps also revealed that prolonged total sleep time led to increased fatigue and drowsiness upon awakening. From 04:00 to 09:00, in the No-nap and One-nap groups, fatigue was higher than in the Two-nap group. The One-nap and Two-nap groups did not show improved morning performance. These results suggest that a split nap might improve drowsiness and fatigue during a long night shift.


How intravenous nitroglycerine transit time from bag-to-bloodstream can be affected by infusion technique: a simulation study.
To measure the possible delays in intravenous nitroglycerine administration. This was a simulation study of sham intravenous nitroglycerine using a standard nitroglycerine titration protocol. Variables studied were (i) common cannulae/needles, (ii) infusion accessories and (iii) presence of a parallel intravenous saline carrier line (or drive line) infusing at 30 mL/h. Outcomes were (i) delay from bag-to-bloodstream arrival and (ii) the dosage showing on the infusion pump when the sham drug first exits the cannula (aka the 'presumed initial dosage'). There was a statistically significant difference in both (i) time-to-bloodstream arrival and (ii) the dosage showing on the infusion pump as the sham first exits the cannula with (i) different cannulae, (ii) different accessories and (iii) presence of a carrier line. The bag-to-bloodstream time varied 10-fold: 197-2062 s. The 'presumed initial dosage' varied sixfold: 5-30 µg/min. Adding the medication to an already flowing carrier line reduced the time for the sham to exit the cannula fourfold: from 2062 to 469 s. Despite limitations, this study outlines the importance of cannula type, infusion accessories and carrier lines. Larger cannulae and greater priming volumes substantially delay drug delivery, whereas carrier lines/drive lines substantially accelerate drug delivery. Our study also shows how patients could be exposed to clinical delays, as well as incorrect presumptions about drug dosage. Guidelines, and education efforts, should highlight the clinical importance of factors that affect bag-to-bloodstream time.


RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth.
An acute inflammatory response needs to be properly regulated to promote the elimination of pathogens and prevent the risk of tumorigenesis, but the relevant regulatory mechanism has not been fully elucidated. Here, we report that Ras guanine nucleotide-releasing protein 1 (RasGRP1) is a bifunctional regulator that promotes acute inflammation and inhibits inflammation-associated cancer. At the mRNA level, Rasgrp1 activates the inflammatory response by functioning as a competing endogenous RNA to specifically promote IL-6 expression by sponging let-7a. In vivo overexpression of the Rasgrp1 3' untranslated region enhances lipopolysaccharide-induced systemic inflammation and dextran sulphate sodium-induced colitis in Il6+/+ mice but not in Il6-/- mice. At the protein level, RasGRP1 overexpression significantly inhibits the tumour-promoting effect of IL-6 in hepatocellular carcinoma progenitor cell-like spheroids. Examination of the EGFR signalling pathway shows that RasGRP1 inhibits inflammation-associated cancer cell growth by disrupting the EGFR-SOS1-Ras-AKT signalling pathway. Tumour patients with high RasGRP1 expression have better clinical outcomes than those with low RasGRP1 expression. Considering that acute inflammation rarely leads to tumorigenesis, this study suggests that RasGRP1 may be an important bifunctional regulator of the acute inflammatory response and tumour growth.


5-Enolpyruvylshikimate-3-phosphate synthase: determination of the protonation state of active site residues by the semiempirical method.
EPSP synthase (EPSPS) catalyzes the addition of shikimate-3-phosphate (S3P) and phosphoenolpyruvate (PEP) to form a tetrahedral intermediate (TI) that is converted to 5-enolpyruvylshikimate-3-phosphate (EPSP) and inorganic phosphate. A semiempirical molecular modeling study of the EPSPS active site containing the TI was implemented for the assignment of the protonation states of four basic residues, Lys22, Lys340, His385, and Lys411, based on the evaluation of 16 different protonation states and comparison of the resulting energy minimized heavy atoms coordinates with available X-ray crystallographic data of the D313A mutant of EPSPS. The results, employing both gas phase and continuum solvent models, are indicative that after the TI formation the histidine residue is most probably in neutral form (N(epsilon)-protonated) and the lysine residues are in protonated form, which suggests that none of the presently proposed assignments of aminoacid residues involved in the reaction mechanism could be completely correct. The protonated state of Lys22 in the presence of the TI supports the proposal that this residue is a general acid catalyst for TI breakdown. Modeling of the native enzyme active site suggests that Asp313 residue has only minor effects on the definition of the TI position inside the active site. Hydrogen-bonds distances suggest that, in order to act as a base, Asp313 needs the intermediacy of a hydroxyl group of the TI for effecting the attack on the TI methyl group in the elimination step leading to EPSP, as suggested previously in the literature.


A multivariate method for meta-analysis and comparison of diagnostic tests.
We present here an extension of the classic bivariate random effects meta-analysis for the log-transformed sensitivity and specificity that can be applied for two or more diagnostic tests. The advantage of this method is that a closed-form expression is derived for the calculation of the within-studies covariances. The method allows the direct calculation of sensitivity and specificity, as well as, the diagnostic odds ratio, the area under curve and the parameters of the summary receiver operator's characteristic curve, along with the means for a formal comparison of these quantities for different tests. There is no need for individual patient data or the simultaneous evaluation of both diagnostic tests in all studies. The method is simple and fast; it can be extended for several diagnostic tests and can be fitted in nearly all statistical packages. The method was evaluated in simulations and applied in a meta-analysis for the comparison of anti-cyclic citrullinated peptide antibody and rheumatoid factor for discriminating patients with rheumatoid arthritis, with encouraging results. Simulations suggest that the method is robust and more powerful compared with the standard bivariate approach that ignores the correlation between tests. Copyright © 2016 John Wiley & Sons, Ltd.


LNC942 promoting METTL14-mediated m6A methylation in breast cancer cell proliferation and progression.
Increasing evidence supports that long noncoding RNAs (lncRNAs) act as master regulators involved in tumorigenesis and development at the N6-methyladenine (m6A) epigenetic modification level. However, the underlying regulatory mechanism in breast cancer (BRCA) remains elusive. Here, we unveil that LINC00942 (LNC942) exerts its functions as an oncogene in promoting METTL14-mediated m6A methylation and regulating the expression and stability of its target genes CXCR4 and CYP1B1 in BRCA initiation and progression. Specifically, LNC942 and METTL14 were significantly upregulated accompanied with the upregulation of m6A levels in BRCA cells and our included BRCA cohorts (n = 150). Functionally, LNC942 elicits potent oncogenic effects on promoting cell proliferation and colony formation and inhibiting cell apoptosis, subsequently elevating METTL14-mediated m6A methylation levels and its associated mRNA stability and protein expression of CXCR4 and CYP1B1 in BRCA cells. Mechanistically, LNC942 directly recruits METTL14 protein by harboring the specific recognize sequence (+176-+265), thereby stabilized the expression of downstream targets of LNC942 including CXCR4 and CYP1B1 through posttranscriptional m6A methylation modification in vitro and in vivo. Therefore, our results uncover a novel LNC942-METTL14-CXCR4/CYP1B1 signaling axis, which provides new targets and crosstalk m6A epigenetic modification mechanism for BRCA prevention and treatment.


Isoferritins in normal leucocytes.
Monocytes, lymphocytes and polymorphs were separated from the peripheral blood of normal human subjects. Ferritin concentrations were determined with antibodies to both human spleen and heart ferritins. The heart type ferritin concentration in monocytes was 38.4 +/- 21.6 fg/cell (mean +/- SD), in lymphocytes 8.6 +/- 6.6 fg/cell and in polymorphs 3.2 +/- 2.4 fg/cell. Spleen type ferritin concentrations (fg/cell) were 15.6 +/- 7.0 in monocytes, 6.6 +/- 5.7 in lymphocytes and 7.0 +/- 4.6 in polymorphs. The mean heart/spleen ferritin ratios were 2.8/1 for monocytes, 2.0/1 for lymphocytes and 0.6/1 for polymorphs. The cell extracts were also subjected to anion exchange chromatography. Heart type ferritin eluted at a higher chloride ion concentration than spleen type ferritin. Both H and L subunits were synthesized by mononuclear cells when incubated with 3H-leucine. Human leucocytes contain a wide range of isoferritins and ferritin concentrations may be considerably underestimated in conventional assays for serum ferritin which employ antibodies to liver or spleen ferritin.


The impact of engineered nanomaterials on the environment: Release mechanism, toxicity, transformation, and remediation.
The presence and longevity of nanomaterials in the ecosystem, as well as their properties, account for environmental toxicity. When nanomaterials in terrestrial and aquatic systems are exposed to the prevailing environmental conditions, they undergo various transformations such as dissociation, dissolution, and aggregation, which affects the food chain. The toxicity of nanomaterials is influenced by a variety of factors, including environmental factors and its physico-chemical characteristics. Bioaccumulation, biotransformation, and biomagnification are the mechanisms that have been identified for determining the fate of nanomaterials. The route taken by nanomaterials to reach living cells provides us with information about their toxicity profile. This review discusses the recent advances in the transport, transformation, and fate of nanomaterials after they are released into the environment. The review also discusses how nanoparticles affect lower trophic organisms through direct contact, the impact of nanoparticles on higher trophic organisms, and the possible options for remediation.


Demineralized bone implants.
There are three mechanisms of bone formation that underlie the use of the different types of implants. In osteogenesis, viable osteoblasts and preosteoblasts are transplanted from one part of the body to the site where new bone is needed; cancellous marrow grafts are an example of such osteogenic engraftment. In osteoconduction, the implant does not provide many viable cells but rather acts as a scaffolding for the ingrowth of new bone from the margins of the defect with the concurrent resorption of the implant; cortical bone grafts or banked bone segments are examples of this "creeping substitution." In osteoinduction, the implant stimulates the transformation of connective tissue to produce endochondral bone, even in extraskeletal sites; demineralized bone implants promote bone formation by osteoinduction. The physiology, cell biology, biochemistry, and endocrinologic regulation of induced osteogenesis are areas of active investigation. Fresh autogenous cancellous bone grafts are preferred for non-stress-bearing defects, but are often of limited availability for extensive procedures, especially in infants. Demineralized bone implants have been used successfully in certain types of craniomaxillofacial, orthopedic, periodontal, and hand reconstruction. Tissue transformation may become as important to reconstructive surgery as is tissue transplantation.


Voreloxin, formerly SNS-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models.
Voreloxin, formerly known as SNS-595 or AG-7352, is a novel naphthyridine analog currently under investigation for the treatment of ovarian and hematologic malignancies. Voreloxin mechanism of action includes DNA intercalation and inhibition of topoisomerase II that causes selective DNA damage. In this study, we describe the anti-proliferative activity of voreloxin in a wide range of in vitro and in vivo models of human cancers. The cytotoxicity of voreloxin in vitro was examined by MTT assay in 15 cell lines, including 4 drug-resistant lines. Activation of caspase in cell lines and tumors was evaluated by immunohistochemistry. Anti-tumor activity was assessed in 16 xenograft and 3 syngeneic tumor models in mice. Tumors were allowed to grow to approximately 150 mm(3) prior to treatment with voreloxin or comparator drugs. Activity of the anti-cancer agents was determined by calculating the inhibition rate (IR = [1 - (average tumor weight treated/average tumor weight control)] x 100%) and survival ratio (number surviving mice/number of mice per group at start of study) for each agent and dose and schedule tested. In vitro studies demonstrated voreloxin has broad anti-proliferative activity in 11 tumor cell lines, with IC(50) values ranging from 0.04 to 0.97 muM. Similar activity was observed in vitro in drug-resistant cell lines, including those that overexpress P-glycoprotein and have reduced topoisomerase levels. After a single intravenous dose, voreloxin concentrations in tumor were correlated with induction of the apoptosis marker caspase-3. The optimal dose and schedule was established using a KB nasopharyngeal carcinoma xenograft model. Administration of voreloxin at 20 mg/kg weekly for five doses effectively inhibited tumor growth (86%). Voreloxin demonstrated strong dose-dependent tumor growth inhibition (63-88%) in 10 of 11 solid tumor (breast, ovarian, colon, lung, gastric, and melanoma) xenograft models, 2 hematologic tumor xenograft models, 3 multidrug resistant tumor models and 3 murine syngeneic tumor models (Colon 26, Lewis Lung carcinoma, M5076 Ovarian Sarcoma). These data demonstrate that voreloxin is a broadly active anti-tumor agent in vitro and in vivo, with potent activity in aggressive and drug-resistant tumor models.


Predicting frictional aging from bulk relaxation measurements.
The coefficient of static friction between solids normally increases with the time they have remained in static contact before the measurement. This phenomenon, known as frictional aging, is at the origin of the difference between static and dynamic friction coefficients but has remained difficult to understand. It is usually attributed to a slow expansion of the area of atomic contact as the interface changes under pressure. This is however challenging to quantify as surfaces have roughness at all length scales. In addition, friction is not always proportional to the contact area. Here we show that the normalized stress relaxation of the surface asperities during frictional contact with a hard substrate is the same as that of the bulk material, regardless of the asperities' size or degree of compression. This result enables us to predict the frictional aging of rough interfaces based on the bulk material properties of two typical polymers: polypropylene and polytetrafluoroethylene.


Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory.
To describe results from genetic testing for cardiomyopathies in a national laboratory for genetic testing in Norway since 2003. Retrospective data collection from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Data from 4408 probands and 3008 relatives were available. Three probands had two variants, nine had incidental findings of variants not related to their cardiomyopathy diagnosis. Of the remaining 4396 probands, 65.1% were males, age at genetic testing was 50.9 (±18.1) years and 6.1% were under the age of 18. A likely pathogenic or pathogenic variant (216 different variants including 67 novel) was detected in 574 probands, corresponding to a hit-rate of genetic testing of 13.1% in total, 11.9% in hypertrophic, 14.1% in dilated, and 14.9% in arrhythmogenic right ventricular cardiomyopathy. Of the 3008 relatives, 47.6 % were males, age at genetic testing was 39.3 (±20.5) years, 17.9% were under the age of 18, and 43.2% were positive for the variant found in their family. Probands and relatives combined, 1/2809 persons in Norway were found to be heterozygous for a cardiomyopathy variant. Next Generation Sequencing provided more findings in dilated cardiomyopathy, especially in TTN accounting for 44.2% of all variants. Otherwise, the majority of variants were found in the classical sarcomeric and desmosomal genes. Genetic testing provided a genetic basis of the cardiomyopathy in 13.1% of probands, and subsequent family testing identified almost three times as many variant-positive relatives which could be offered preventive follow-up.


Fine-needle aspiration diagnosis of angiosarcoma of the spleen: a case report and review of the literature.
Primary angiosarcoma of the spleen is a very rare neoplasm with a poor prognosis. The definitive diagnosis is usually based on the histologic evaluation of the splenectomy specimen. We describe a case of angiosarcoma diagnosed by fine-needle aspiration cytology prior to splenectomy. A 69-year-old white woman presented with heterogeneous lesions in the spleen during a follow-up computed tomographic scan for a history of liposarcoma of the right buttock. A malignant endothelial neoplasm was diagnosed by fine-needle aspiration cytology using immunocytochemistry, and a splenectomy confirmed the presence of angiosarcoma. To our knowledge, this is the first well-documented and confirmed case of primary angiosarcoma of the spleen diagnosed by fine-needle aspiration cytology. This report emphasizes the value of fine-needle aspiration cytology as an important diagnostic tool in splenic neoplasms.


Quantification of immunoglobulins in respiratory tract secretions of the horse.
Lavage techniques were used to obtain secretions from the nasal cavity, trachea and bronchi of conscious horses. The techniques, which utilised fibreoptic endoscopy for recovery of tracheal and bronchial secretions, were well tolerated by the horses. The recovery rates of the lavaged fluids were acceptable, but were lowest for bronchial secretions, and there was minimal contamination by blood. The fluids were analysed for IgG and IgM by single radial immunodiffusion, and for IgA and albumin by rocket immunoelectrophoresis. Relative to albumin there was significantly more IgA and IgM, and significantly less IgG, in the nasal cavity than the trachea. IgA and IgM levels were greatest in the nasal cavity and decreased progressively to the bronchi, whereas IgG levels showed the reverse trend. The immunoglobulin: albumin ratios of secretions taken from many levels of the tract were significantly higher than those of serum, suggesting local production of immunoglobulin in the respiratory tract.


Synthesis of Functionalized [3], [4], [5] and [6]Dendralenes through Palladium-Catalyzed Cross-Couplings of Substituted Allenoates.
A mild method for the synthesis of highly functionalized [3]-[6]dendralenes is reported, representing a general strategy to diversely substituted higher homologues of the dendralenes. The methodology utilizes allenoates bearing various substitution patterns, along with a wide range of boron and alkenyl nucleophiles that couple under palladium catalysis leading to sp-, sp2 -, and sp3 -substituted arrays. Regioselective transformations of the newly formed unsymmetrical dendralene derivatives are demonstrated. The use of micellar catalysis, where water is the global reaction medium, and room temperature reaction conditions, highlights the green nature of this technology.


Packaging analysis of counterfeit medicines.
The authentication of the packaging represents an important step in the investigation of suspected counterfeits of pharmaceutical products. The visual comparison with a retained sample is the first step to detect a counterfeited packaging. Due to the improvement of technologies like printing, the emergence of counterfeits with a better appearance can be observed. Moreover counterfeits are nowadays often a combination of fake and genuine parts that have been manipulated. Authenticating each part of the product is important in the frame of the investigation to understand how the counterfeiters proceed, and which prevention measures should be taken. Lab instruments like spectrometers can help confirm counterfeits of packaging for packaging components on which visually, no difference with a reference would be observed. In this study several analytical tools were evaluated to help support the authentication of the primary and secondary packaging of one medicinal product as an example using seven reference materials and five counterfeits. In some cases, visual examination of the packaging already enabled to detect counterfeits of the studied features. Also the boxes, leaflets and vials have been analysed with Infrared (IR) spectroscopy, Raman microspectroscopy, X-ray fluorescence (XRF) spectroscopy, Scanning Electron Microscopy (SEM) and microcomputed tomography (microCT). According to the obtained results, IR and XRF could support the visual examination of the different packaging components. Despite the small amount of counterfeits, relevant links could also be detected between the studied cases based on the packaging characteristics.


Structural basis for conformational switching and GTP loading of the large G protein atlastin.
Atlastin, a member of the dynamin superfamily, is known to catalyse homotypic membrane fusion in the smooth endoplasmic reticulum (ER). Recent studies of atlastin have elucidated key features about its structure and function; however, several mechanistic details, including the catalytic mechanism and GTP hydrolysis-driven conformational changes, are yet to be determined. Here, we present the crystal structures of atlastin-1 bound to GDP·AlF(4)(-) and GppNHp, uncovering an intramolecular arginine finger that stimulates GTP hydrolysis when correctly oriented through rearrangements within the G domain. Utilizing Förster Resonance Energy Transfer, we describe nucleotide binding and hydrolysis-driven conformational changes in atlastin and their sequence. Furthermore, we discovered a nucleotide exchange mechanism that is intrinsic to atlastin's N-terminal domains. Our results indicate that the cytoplasmic domain of atlastin acts as a tether and homotypic interactions are timed by GTP binding and hydrolysis. Perturbation of these mechanisms may be implicated in a group of atlastin-associated hereditary neurodegenerative diseases.


Sheehan's syndrome with pancytopenia: a case report and review of the literature.
Sheehan's syndrome is defined by varying degrees of anterior pituitary deficiency due to postpartum ischemic necrosis of the pituitary gland after massive bleeding. It is a rare disorder in western countries and even in Tunisia. Hematologic abnormalities such as normochromic anemia have been reported in these patients. However, pancytopenia is rarely observed. We describe the case of a 48-year-old Tunisian woman with features of hypopituitarism. Laboratory tests showed pancytopenia that was completely reversed after adequate hormone replacement. Clinicians should consider the possibility of hypopituitarism as a cause of pancytopenia. This is an original case report that is of interest to hematologists, who should be aware of Sheehan's syndrome as a treatable etiology of pancytopenia for women.


A BCL2 promoter polymorphism rs2279115 is not associated with BCL2 protein expression or patient survival in breast cancer patients.
The B-cell CLL/lymphoma 2 (BCL2) gene family encodes pro- and anti-apoptotic proteins that are critical regulators of programmed cell death. Higher levels of BCL2 expression in breast tumours have been shown to be an independent prognostic factor for improved survival from breast cancer. The promoter single nucleotide polymorphism (SNP) rs2279115 has been associated with both BCL2 expression and patient survival. The aim of this study was to attempt to replicate these observations in a cohort of 1015 UK women with breast cancer, and to compare genotype frequencies in cases and controls. In this study, 1015 breast cancer cases and 1034 control subjects were genotyped for the rs2279115 SNP by 5' nuclease PCR. Paraffin embedded tumour tissue for 342 case subjects was assembled into tissue microarrays, and the level of expression of BCL2 was established by immunohistochemistry. Kaplan Meier survival curves and Cox Proportional Hazards models were used to examine the effect of genotype on patient survival. The effect of SNP genotype on tumour BCL2 protein levels and breast cancer susceptibility was assessed by logistic regression. In this study higher BCL2 expression was significantly associated with improved survival from breast cancer (p = 0.015), in keeping with previous reports. The SNP rs2279115 was not found to be associated with tumour expression of BCL2, (p = 0.77), and neither was it associated with case/control status (p = 0.25). There was no significant association between the SNP and overall survival (p = 0.75). In conclusion, we found that higher tumour BCL2 expression is associated with improved survival from breast cancer, in keeping with previous studies. However, in contrast to a previous report, the promoter SNP rs2279115 was not associated with BCL2 expression or overall survival from breast cancer.


Pediatric unilateral isolated choanal atresia is not associated with mandibular condyle hypoplasia.
We hypothesized that the ontogeny of unilateral isolated choanal atresia involves a field defect manifesting as ipsilateral mandibular condylar hypoplasia. The topic is important because the mechanism of the unilateral isolated choanal atresia is unknown. Retrospective self-controlled case series. We included 20 patients (2 males and 18 females, ages 2 weeks to 13 years) with unilateral isolated non-syndromic choanal atresia. We studied their high-resolution computed tomographic scans. Two otolaryngologists measured the largest cross-sectional area of the mandibular condyle in the axial plane perpendicular to the posterior border of each mandibular ramus independently. Statistical significance and inter-rater agreement were calculated with paired Wilcoxon rank sum test and Spearman's non-parametric correlation coefficient respectively. Cross-sectional areas of the condyles ipsilateral to the choanal atresia were not statistically different than those of the contralateral condyle (P = 0.27). Inter-observer agreement of condyle areas was excellent: Spearman's r = 0.85 on the right and r = 0.94 on the left. In this cohort of children with the rarity of isolated non-syndromic unilateral congenital choanal atresia, no associated mandibular condyle hypoplasia was found. The data suggest that the underlying ontogeny was unlikely attributable to a field defect.


Genetic scores of smoking behaviour in a Chinese population.
This study sought to structure a genetic score for smoking behaviour in a Chinese population. Single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) were evaluated in a community-representative sample (N = 3,553) of Beijing, China. The candidate SNPs were tested in four genetic models (dominance model, recessive model, heterogeneous codominant model and additive model), and 7 SNPs were selected to structure a genetic score. A total of 3,553 participants (1,477 males and 2,076 females) completed the survey. Using the unweighted score, we found that participants with a high genetic score had a 34% higher risk of trying smoking and a 43% higher risk of SI at ≤ 18 years of age after adjusting for age, gender, education, occupation, ethnicity, body mass index (BMI) and sports activity time. The unweighted genetic scores were chosen to best extrapolate and understand these results. Importantly, genetic score was significantly associated with smoking behaviour (smoking status and SI at ≤ 18 years of age). These results have the potential to guide relevant health education for individuals with high genetic scores and promote the process of smoking control to improve the health of the population.


Efficiency-Enhanced Scalable Organic Photovoltaics Using Roll-to-Roll Nanoimprint Lithography.
Invited for this month's cover is the group of Prof. Morten Madsen, University of Southern Denmark, together with Stensborg A/S and Dr. Shalev's group at the Ben-Gurion University of the Negev. The image shows the integration of Roll-to-Roll (R2R) light-management foils to enhance efficiency of R2R organic photovoltaics. The Full Paper itself is available at 10.1002/cssc.202101611.


Systematic design and testing of nested (RT-)PCR primers for specific amplification of mouse rearranged/expressed immunoglobulin variable region genes from small number of B cells.
The aim of this study was to develop a highly specific and sensitive (RT-)PCR capable of potentially amplifying the rearranged/expressed VH and VL gene belonging to any mouse immunoglobulin V gene family from a single or a small number of B cells. A database of germline immunoglobulin sequences was used to design 112 primers for a nested (RT-)PCR based strategy to cover all VH, VL, JH, JL, CH and CL gene families/genes from C57BL/6 and BALB/c mice. 93.7% of the primers had 4-fold or less, while 71.4% had no degeneracy. The proportions of germline V genes to which the primers bind with no, up to 1 and up to 2 mismatches are 59.7%, 84.1% and 94.9%, respectively. Most but not all V gene family specific primers designed allow amplification of full-length V genes. The nested primers permit PCR amplification of rearranged V genes belonging to all VH and VL gene families from splenocyte genomic DNA. The V gene family-specific nature of the primers was experimentally confirmed for randomly selected 6 VH and 6 Vkappa families, and all Vlambda genes. The broad V gene family coverage of our primer set was experimentally validated by amplifying the rearranged/expressed VH and VL genes from splenocytes and a panel of 38 hybridomas under conditions where primer mixes and genomic DNA or total RNA was used as starting template. We observed no or low-level cross-family priming. Pooled constant region specific primers allowed efficient RT-PCR amplification of H and L chain isotypes. The expressed VH and VL genes belonging to different V gene families RT-PCR amplified from a mixture of hybridomas in a representative manner. We successfully amplified the expressed VH and Vkappa gene from a single hybridoma cell by RT-PCR and from 10-15 microdissected B cells by genomic PCR. This, first of its kind, comprehensive set of highly sensitive and specific nested primers that provide broad V gene family coverage will open up new avenues and opportunities to study various aspects of mouse B cell biology.


Carbon Nanotubes Enabled Laser 3D Printing of High-Performance Titanium with Highly Concentrated Reinforcement.
Zero- to two-dimensional nanomaterials have been incorporated into metal-matrices to improve the strength of metals, but challengingly, high-volume-fraction nanomaterials are difficult to disperse uniformly in metal matrices, severely degrading the ductility of conventionally processed metals. Here, a considerably dense uniform dispersion of in situ formed nanoscale lamellar TiC reinforcement (16.1 wt %) in Ti matrix is achieved through laser-tailored 3D printing and complete reaction of Ti powder with a small amount (1.0 wt %) of carbon nanotubes (CNTs). An enhanced tensile strength of 912 MPa and an outstanding fracture elongation of 16% are simultaneously achieved for laser-printed components, showing a maximum 350% improvement in "product of strength and elongation" compared with conventional Ti. In situ nanoscale TiC reinforcement favors the formation of ultrafine equiaxed Ti grains and metallurgically coherent interface with minimal lattice misfit between TiC lamellae and Ti matrix. Our approach hopefully provides a feasible way to broaden structural applications of CNTs in load-bearing Ti-based engineering components via laser-tailored reorganization with Ti.


AIDS treatment advances and behavioral prevention setbacks: preliminary assessment of reduced perceived threat of HIV-AIDS.
Recent advances in AIDS treatment have brought renewed optimism for prolonging the lives of those infected with HIV. This article examined beliefs about how new treatments may reduce HIV transmission risk among 298 HIV-negative gay and bisexual men attending a gay pride festival. Results from an anonymous survey showed that men who practiced unprotected anal intercourse as the receptive partner (UAR intercourse) were younger, less well educated, and more likely to believe that it is safe to have UAR intercourse with an HIV-positive man who has an undetectable viral load and that new treatments for HIV relieve their worries about unsafe sex. As HIV treatments continue to advance, new challenges for HIV prevention will likely emerge.


The cytoplasmic N-terminal tail of Zika virus NS4A protein forms oligomers in the absence of detergent or lipids.
The non-structural (NS) NS4A protein in flaviviruses has three predicted transmembrane domains, is critical for virulence and participates in membrane morphogenesis. In Dengue virus (DENV), both hydrophylic N-terminal tail and its first transmembrane domain participate in the formation of oligomers which are important for pathogenicity. However, the relative importance of the N-terminal domain in oligomerization has been under debate. In particular, since in the absence of detergent or lipids, this domain (residues 1-48) in both DENV and Zika virus (ZIKV) NS4A, was found to be disordered. Recently, however, we reported preliminary data that showed that peptide ZIKV NS4A 4-58 adopts a defined secondary structure in aqueous solution and forms oligomers, signaling its importance for full length NS4A oligomerization. Herein we have performed detailed analytical ultracentrifugation experiments to further characterize the oligomerization of this peptide and also a shorter variant (residues 4-44). In both cases, sedimentation velocity produced a single species with concentration-dependent sedimentation coefficient, consistent with a fast equilibrium between at least two species. Combining sedimentation velocity and equilibrium experiments, data is best fitted to a monomer-dimer-trimer equilibrium. Possible models of NS4A oligomers obtained with AlphaFold-2 predict the stabilizing role for residues in this N-terminal domain, such as Arg20, Asn27, Ala44 and Glu50, all at highly conserved positions in flavivirus NS4A proteins. Our results are thus consistent with N-terminal domain interactions acting as one of the driving forces for NS4A homo-oligomerization.