The effects of cognitive behavioral therapy in women with polycystic ovary syndrome: A meta-analysis.
Cognitive behavioral therapy (CBT) has well-characterized benefits in alleviating diseases associated with depression, anxiety, and obesity, resulting in a marked improvement in the patient's quality of life. There are some studies regarding the effects of CBT on patients with polycystic ovary syndrome (PCOS). However, there is still no report of a meta-analysis for systematic assessment. This study aimed to evaluate the effectiveness of CBT in improving weight loss, anxiety, depression, life quality, compliance, and pregnancy outcomes in patients with PCOS. Studies regarding CBT related to PCOS in PubMed, Cochrane library, Embase, ClinicalTrials.gov, CNKI, and WANFANG DATA were searched for up to 19 November 2020. A random-effects model was used to perform a meta-analysis. Eight trials regarding CBT compared with lifestyle modification and routine treatments were included. No differences in depression (SMD -1.11; 95% CI -2.28, 0.07; P > 0.05), body mass index (BMI) (SMD 0.88; 95% CI -0.94, 2.71; P > 0.05), or overall life quality (SMD 1.24; 95% CI -0.44, 2.92; P > 0.05) were evident between CBT and control groups; however, anxiety (SMD -1.12; 95% CI -2.1, -0.13; P < 0.05) and quality of life in hirsutism (SMD 0.92; 95% CI 0.48, 1.35; P < 0.05) were significantly improved. For secondary outcomes, both patient compliance and pregnancy rate were improved, but no significant change in pregnancy loss rate was identified. CBT exhibited obvious advantages in the alleviation of anxiety, improvement of quality of life in hirsutism, and increase of compliance and pregnancy rate in patients with PCOS. Larger and higher-quality randomized controlled trials are needed to clarify the role of CBT in PCOS. [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021225856].


The impact of extended bed rest on the musculoskeletal system in the critical care environment.
Prolonged immobility is harmful with rapid reductions in muscle mass, bone mineral density and impairment in other body systems evident within the first week of bed rest which is further exacerbated in individuals with critical illness. Our understanding of the aetiology and secondary consequences of prolonged immobilization in the critically ill is improving with recent and ongoing research to establish the cause, effect, and best treatment options. This review aims to describe the current literature on bed rest models for examining immobilization-induced changes in the musculoskeletal system and pathophysiology of immobilisation in critical illness including examination of intracellular signalling processes involved. Finally, the review examines the current barriers to early activity and mobilization and potential rehabilitation strategies, which are being, investigated which may reverse the effects of prolonged bed rest. Addressing the deleterious effects of immobilization is a major step in treatment and prevention of the public health issue, that is, critical illness survivorship.


Ethanol induces cell-cycle activity and reduces stem cell diversity to alter both regenerative capacity and differentiation potential of cerebral cortical neuroepithelial precursors.
The fetal cortical neuroepithelium is a mosaic of distinct progenitor populations that elaborate diverse cellular fates. Ethanol induces apoptosis and interferes with the survival of differentiating neurons. However, we know little about ethanol's effects on neuronal progenitors. We therefore exposed neurosphere cultures from fetal rat cerebral cortex, to varying ethanol concentrations, to examine the impact of ethanol on stem cell fate. Ethanol promoted cell cycle progression, increased neurosphere number and increased diversity in neurosphere size, without inducing apoptosis. Unlike controls, dissociated cortical progenitors exposed to ethanol exhibited morphological evidence for asymmetric cell division, and cells derived from ethanol pre-treated neurospheres exhibited decreased proliferation capacity. Ethanol significantly reduced the numbers of cells expressing the stem cell markers CD117, CD133, Sca-1 and ABCG2, without decreasing nestin expression. Furthermore, ethanol-induced neurosphere proliferation was not accompanied by a commensurate increase in telomerase activity. Finally, cells derived from ethanol-pretreated neurospheres exhibited decreased differentiation in response to retinoic acid. The reduction in stem cell number along with a transient ethanol-driven increase in cell proliferation, suggests that ethanol promotes stem to blast cell maturation, ultimately depleting the reserve proliferation capacity of neuroepithelial cells. However, the lack of a concomitant change in telomerase activity suggests that neuroepithelial maturation is accompanied by an increased potential for genomic instability. Finally, the cellular phenotype that emerges from ethanol pre-treated, stem cell depleted neurospheres is refractory to additional differentiation stimuli, suggesting that ethanol exposure ablates or delays subsequent neuronal differentiation.


[Reducing the risk of blood-transmitted infections of HIV, hepatitis B or C virus in a teaching hospital in Amsterdam--evaluation of a protocol for needlestick accidents among hospital staff during the period 1997-2001].
To evaluate a protocol for hospital staff aimed at reducing their risk of exposure to blood-transmitted infections. Prospective. In August 1997 a protocol was introduced to the Onze Lieve Vrouwe Gasthuis Hospital in Amsterdam, with procedures to be followed after percutaneous or mucocutaneous blood contact in which there was a chance of transmission of hepatitis B (HBV) or C (HCV), as well as guidelines for the prescription of post-exposure prophylaxis (PEP) after accidents with an HIV risk. In the period 1 August 1997-30 June 2001 data were collected from registration forms that reported accidents and the ensuing events. A total of 403 accidents were reported by 138 (34.2%) physicians, 135 (33.5%) ward nurses, 46 (11.4%) operation assistants, 30 (7.4%) co-assistants, 21 (5.2%) analysts and 33 (8.2%) persons with another position. There was a constant increase in the number of reports over the period. The seroprevalence of the source patients was: 6.9% (25/360) HIV, 8.1% (6/74) HBV and 6.3% (23/363) HCV. PEP was prescribed on 46 occasions: 15 times for an HIV positive source and 31 times for what was initially an unknown HIV source. Following the introduction of a rapid HIV test in September 1999, there was a reduction in the number of unnecessary PEP prescriptions from 4 in 1997, 7 in 1998 and 16 in 1999 to 3 in 2000 and 1 in 2001. All 15 persons who were correctly started on a PEP treatment took the medication for a period of 28 days despite many side effects. No seroconversions were established during the follow-up period of 6 months.


Decrease in cyclosporin-mediated prostacyclin production in renal versus carotid arteries: a mechanism for cyclosporin-induced hypertension.
Although the mechanism of cyclosporin (CsA)-induced hypertension is unknown, it has been shown to inhibit prostacyclin (PGI2) production directly, which may be a factor. We determined whether CsA had a differential effect on PGI2 production from the carotid artery (CA) and internal jugular vein (JV) compared to that from the renal artery (RA) and vein (RV) as a possible contributing factor to renovascular hypertension based upon the ability of organs to regulate their own blood flow according to local circumstances. The neck and renal vessels were removed from anesthetized adult female dogs (N = 8) and placed in a stimulation chamber, with Cell I being control (Hepes buffer), Cell II containing 0.3 mg/ml CsA, and Cell III containing CsA and 25 microM arachidonic acid (AA). Following serial stimulation periods, the supernatant was evaluated for PGI2 production by radioimmunoassay. PGI2 production from CA was significantly higher than that from RA following control and AA stimulation, 1474 +/- 382 pg/cm2-min vs 733 +/- 173 pg/cm2-min (P less than 0.05) and 2236 +/- 347 vs 1090 +/- 217 (P less than 0.01), respectively. CsA-induced PGI2 production from the carotid arteries was significantly greater than that from the renal arteries, 2944 +/- 586 vs 1003 +/- 235 (P less than 0.005). However, stimulation with AA following CsA resulted in sustained PGI2 production in both arteries that was similar to stimulation with CsA alone, 3014 +/- 600 vs 2944 +/- 586 for the carotids and 1278 +/- 280 vs 1003 +/- 235 for the renal arteries.(ABSTRACT TRUNCATED AT 250 WORDS)


The chromosome fiber: evidence for an ordered superstructure of nucleosomes.
Chromosome fibers isolated from lymphocyte nuclei and prepared for electron microscopy by techniques designed to preserve their native structure have a distinctly knobby appearance, suggesting that DNA and protein are not distributed evenly along the fiber axis. Individual knobs (superbeads) are arranged in tandem and have an average diameter of about 200 A. Mild nuclease digestion of isolated nuclei releases apparent monomer superbeads that are composed of nucleohistone particles with the properties of nucleosomes. The kinetics of digestion indicate that the superbead is a discrete structural unit containing, on the average, about eight nucleosomes.


A fluorometric paper-based sensor array for the discrimination of heavy-metal ions.
A fluorometric paper-based sensor array has been developed for the sensitive and convenient determination of seven heavy-metal ions at their wastewater discharge standard concentrations. Combining with nine cross-reactive BODIPY fluorescent indicators and array technologies-based pattern-recognition, we have obtained the discrimination capability of seven different heavy-metal ions at their wastewater discharge standard concentrations. After the immobilization of indicators and the enrichment of analytes, identification of the heavy-metal ions was readily acquired using a standard chemometric approach. Clear differentiation among heavy-metal ions as a function of concentration was also achieved, even down to 10(-7)M. A semi-quantitative estimation of the heavy-metal ion concentration was obtained by comparing color changes with a set of known concentrations. The sensor array was tentatively investigated in spiked tap water and sea water, and showed possible feasibility for real sample testing.


The effect of iron on Chilean Alexandrium catenella growth and paralytic shellfish toxin production as related to algal blooms.
The dinoflagellate Alexandrium catenella is a well-known paralytic shellfish toxin producer that forms harmful algal blooms (HABs) worldwide. Blooms of this species have repeatedly brought severe ecological and economic impacts to Chile, especially in the southern region, where the shellfish and salmon industries are world-famous. The mechanisms of such HABs have been intensively studied but are still unclear. Nutrient overloading is one of the often-discussed drivers for HABs. The present study used the A. catenella strain isolated from southern Chile to investigate how iron conditions could affect their growth and toxin production as related to HAB. Our results showed that an optimum concentration of iron was pivotal for proper A. catenella growth. Thus, while excess iron exerted a toxic effect, low iron media led to iron insufficiency and growth inhibition. In addition, the study shows that the degree of paralytic shellfish toxin production by A. catenella varied depending on the iron concentration in the culture media. The A. catenella strain from southern Chile produced GTX1-4 exclusively in the fmol cell-1 scale. Based on these findings, we suggest that including iron and paralytic shellfish toxin measurements in the fields can improve the current HAB monitoring and contribute to an understanding of A. catenella bloom dynamics in Chile.


Chromogenic Multiplex Immunohistochemistry Reveals Modulation of the Immune Microenvironment Associated with Survival in Elderly Patients with Lung Adenocarcinoma.
With underrepresentation of elderly patients with lung adenocarcinoma (LADC) in anti-PD-1/PD-L1 clinical trials, better understanding of the interplay of PD-L1 and tumor-associated immune cells (TAICs) could assist clinicians in stratifying these patients for immunotherapy. One hundred and one patients with LADCs, stratified by age, were included for analysis of PD-L1 expression and density of TAICs expressing CD4, CD8, and CD33, by using multiplex chromogenic immunohistochemistry (IHC) assays and automated digital quantification. The CD4⁺/CD8⁺ ratio was significantly higher in elderly patients. In patients <75 years, the density of CD4⁺, CD8⁺, and PD-L1 in TAICs showed a positive significant correlation with PD-L1 expression in tumor cells (TCs), while a lower correlation was observed in the elderly population. In the latter, a high CD4⁺/CD8⁺ ratio, and combined PD-L1 expression ≥1% TCs with a low CD8⁺ density, low CD33⁺ density, and a high CD4⁺ density correlated to worse overall survival. We identified differences according to age in the CD4⁺/CD8⁺ ratio and in correlation between PD-L1 expression and the density of TAICs in LADC patients. Distinct groups of tumor microenvironments had an impact on the OS of elderly patients with LADC.


Mosquito biology: Scents and selectability.
Malaria-transmitting mosquitoes are skilled human hunters, selectively choosing their prey based on a complex array of sensory cues. A new study unveils a distinct pattern of preference for human-associated olfactory cues that underlies the selective behavior of these mosquitoes.


N-Acetylcysteine supplementation for the prevention of atrial fibrillation after cardiac surgery: a meta-analysis of eight randomized controlled trials.
Atrial fibrillation is the most common type of arrhythmia after cardiac surgery. An increasing body of evidence demonstrates that oxidative stress plays a pivotal role in the pathophysiology of atrial fibrillation. N-acetylcysteine (NAC) is a free radical scavenger, and may attenuate this pathophysiologic response and reduce the incidence of postoperative AF (POAF). However, it is unclear whether NAC could effectively prevent POAF. Therefore, this meta-analysis aims to assess the efficacy of NAC supplementation on the prevention of POAF. Medline and Embase were systematically reviewed for studies published up to November 2011, in which NAC was compared with controls for adult patients undergoing cardiac surgery. Outcome measures comprised the incidence of POAF and hospital length of stay (LOS). The meta-analysis was performed with the fixed-effect model or random-effect model according to the heterogeneity. Eight randomized trials incorporating 578 patients provided the best evidence and were included in this meta-analysis. NAC supplementation significantly reduced the incidence of POAF (OR 0.62, 95% CI 0.41 to 0.93; P = 0.021) compared with controls, but had no effect on LOS (WMD -0.07, 95% CI -0.42 to 0.28; P = 0.703). The prophylactic NAC supplementation may effectively reduce the incidence of POAF. However, the overall quality of current studies is poor and further research should focus on adequately powered randomized controlled trials with POAF incidence as a primary outcome measure.


Percutaneous aortic balloon valvuloplasty in octogenarians: morbidity and mortality.
To examine the morbidity, mortality, and hospital course of an elderly patient sample (mean age, 86 years; 95% CI, 84 to 87) having percutaneous aortic balloon valvuloplasty. Retrospective consecutive case series before and after balloon valvuloplasty. Tertiary care referral hospital. Consecutive sample of 26 patients aged 80 years or older with symptomatic aortic stenosis referred for balloon valvuloplasty from July 1987 to July 1988. Percutaneous aortic balloon valvuloplasty reduced the transvalvular gradient from 59 (95% CI, 51 to 67) to 31 mm Hg (95% CI, 26 to 35; P less than 0.0001) and increased aortic valve area from 0.45 (95% CI, 0.38 to 0.51) to 0.67 cm2 (95% CI, 0.58 to 0.76; P less than 0.0001). The mean length of hospital stay for the entire study population was 11.2 days (95% CI, 7.3 to 15.2) at a total hospital charge per patient of $29,600 (95% CI, 21,050 to 38,150). For patients having procedural complications (11 complications in 8 patients), surgical procedures, or cardiogenic shock, the mean hospital stay increased to 16.2 days (95% CI, 6.2 to 26.2; P less than 0.05) and the hospital charge increased to $44,400 (95% CI, 24,280 to 64,520; P less than 0.01). Two patients who presented with cardiogenic shock died, and 1 patient had an aortic valve replacement before discharge. Four patients were recently discharged (less than 1 month) and follow-up was obtained in the remaining 19 patients at 6.1 months (95% CI, 4.1 to 8.1). Five more patients, including the remaining patient who presented with cardiogenic shock, died after discharge for an overall mortality of 32%. Twelve of the remaining fourteen patients had fewer symptoms and improved an average of 1.1 New York Heart Association classes (95% CI, 0.7 to 1.4; P less than 0.0001). Percutaneous aortic balloon valvuloplasty in patients 80 years and older improves hemodynamics and symptoms of heart failure during short-term follow-up in most patients, but overall mortality is high in this elderly patient population. Hospital charges and length of stay were much higher in patients with complications or coexisting medical illnesses. Valvuloplasty is a reasonable alternative treatment for patients with aortic stenosis who require palliative treatment of symptoms and have high surgical risk.


Early discontinuation but not the timing of adjuvant therapy affects survival of patients with high-risk colorectal cancer: a population-based study.
Adjuvant therapy results in significant improvement in survival of patients with high-risk colorectal cancer. Little is known about the significance of timing and early discontinuation of adjuvant treatment in such patients. Our study aims to determine the prognostic impact of timing and completion of adjuvant therapy in patients with high-risk colorectal cancer. Medical records of patients with stage III colon and stage II/III rectal cancer diagnosed between 1993 and 2000 in the province of Saskatchewan were reviewed. Cox proportional hazards models were used to analyze the impact of timing and completion of adjuvant therapy on survival. Six hundred sixty-three eligible patients with a median age of 66 years were identified. Sixty-five percent patients received adjuvant <56 days after surgery and 79% patients completed planned treatment. Median follow-up was 54.6 months. Five-year disease-free survival and overall survival of patients who received adjuvant therapy <56 days after surgery was 54.6% and 59.5%, respectively, compared with 51.9% and 57.1%, respectively, of patients who received therapy ≥56 days after surgery (P = NS). The five-year disease disease-free survival and overall survival of patients who completed planned treatment was 56.7% and 62.3%, respectively, compared with 42.1% and 45%, respectively, of patients who required early treatment discontinuation (P < .0001). On multivariate analysis, age ≥65 years, T4 tumor, grade 3 cancer, node-positive disease, rectal tumor, and early treatment discontinuation were identified as poor prognostic factors. Although time to adjuvant therapy following surgical resection did not impact the outcomes, failure to complete planned therapy was associated with adverse prognosis.


Metapopulation epidemic models with a universal mobility pattern on interconnected networks.
The global pandemic of the coronavirus disease 2019 (COVID-19) exemplifies the influence of human mobility on epidemic spreading. A framework called the movement-interaction-return (MIR) model is a model to study the impact of human mobility on epidemic spreading. In this paper, we investigate epidemic spreading in interconnected metapopulation networks. Specifically, we incorporate the human mobility pattern called the radiation model into the MIR model. As a result, the proposed model is more realistic in comparison to the original MIR model. We use the tensorial framework to develop Markovian equations that describe the dynamics of the proposed model on interconnected metapopulation networks. Then we derive the corresponding epidemic thresholds by converting tensors into matrices. Comprehensive numerical simulations confirm our analysis.


Ring artifact correction in gamma-ray process tomography imaging.
Ring artifacts have been studied for X-ray based Computed Tomography (CT) systems but not on γ-ray based in-situ applications. This paper discusses application of recently proposed automatic ring artifact reduction method (Yoon et al., 2016) on previously obtained experimental projection data from a γ-ray based Industrial Process Tomography (IPT) system for a prototype catalytic column. Studies include qualitative and quantitative evaluation of the method. It is observed that ring artifacts are suppressed without loss of significant information in γ-ray PT images.


Higher buccal mtDNA content is associated with residential surrounding green in a panel study of primary school children.
Mitochondria are known to respond to environmental stressors but whether green space is associated with mitochondrial abundance is unexplored. Furthermore, as exposures may affect health from early life onwards, we here evaluate if residential green space is associated with mitochondria DNA content (mtDNAc) in children. In primary schoolchildren (COGNAC study), between 2012 and 2014, buccal mtDNAc was repeatedly (three times) assessed using qPCR. Surrounding low (<3m), high (≥3m) and total (sum of low and high) green space within different radii (100m-1000m) from the residence and distance to the nearest large green space (>0.5ha) were estimated using a remote sensing derived map. Given the repeated measures design, we applied a mixed-effects model with school and subject as random effect while adjusting for a priori chosen fixed covariates. mtDNAc was assessed in 246 children with a total of 436 measurements (mean age 10.3 years). Within a 1000m radius around the residential address, an IQR increment in low (11.0%), high (9.5%), and total (13.9%) green space was associated with a respectively 15.2% (95% CI: 7.2%-23.7%), 10.8% (95% CI: 4.5%-17.5%), and 13.4% (95% CI: 7.4%-19.7%) higher mtDNAc. Conversely, an IQR increment (11.6%) in agricultural area in the same radius was associated with a -3.4% (95% CI: 6.7% to -0.1%) lower mtDNAc. Finally, a doubling in distance to large green space was associated with a -5.2% (95% CI: 7.9 to -2.4%) lower mtDNAc. To our knowledge, this is the first study evaluating associations between residential surrounding green space and mtDNAc in children. Our results showed that green space was associated with a higher mtDNAc in children, which indicates the importance of the early life environment. To what extent these findings contribute to later life health effects should be further examined.


Esthetic outcome for implant therapy of a maxillary lateral incisor using prefabricated titanium and customized zirconia abutments: 4-year clinical reports.
The reported clinical scenarios presented two patients, one managed with a prefabricated abutment and the other with a customized abutment, and both patients were pleased with the outcome. However, from a professional viewpoint, the esthetic outcome using the custom zirconia abutment was superior to that using the prefabricated titanium abutment.


The ALERT model of care for the assessment and personalized management of patients with lymphoedema.
This study documents the development and evaluation of a comprehensive multidisciplinary model for the assessment and personalized care of patients with lymphoedema. The Australian Lymphoedema Education Research and Treatment (ALERT) programme originated as an advanced clinic for patients considering surgery for lymphoedema. The programme commenced liposuction surgery in May 2012 and then introduced lymph node transfer in 2013 and lymphovenous anastomosis (LVA) in 2016. An outpatient conservative treatment clinic was established in 2016. ALERT commenced investigations with indocyanine green (ICG) lymphography in late 2015, leading to the creation of a diagnostic assessment clinic offering ICG in 2017. Since 2012, 1200 new patients have been referred to ALERT for assessment of lymphoedema for a total of 5043 episodes of care. The introduction of ICG lymphography in 2015 initially allowed better screening for LVA, but is now used not only to guide surgical options, but also as a diagnostic tool and to guide manual lymphatic drainage massage. The total number of new patients who attended the surgical assessment clinic to December 2018 was 477, with 162 patients (34·0 per cent) undergoing surgery. The ALERT programme has developed a multidisciplinary model of care for personalized lymphoedema treatment options based on clinical, imaging and ICG lymphography. Patients are selected for surgery based on several individual factors.


Living with Congenital Aortic Stenosis: Exercise Restriction, Patterns of Adherence, and Quality of Life.
Modern consensus panel guidelines recommend restriction from most organized sports for patients with moderate or severe aortic stenosis (AS). However, there is little published data on how frequently physicians deviate from guidelines, how well patients adhere to exercise restrictions, or the effect of restriction on patient-reported quality of life. In this study, we surveyed 93 subjects with AS and their cardiologists regarding participation in organized sports, physical activity, weightlifting, and exercise restriction. Subjects completed the pediatric quality of life inventory (PedsQL) and the pediatric cardiac quality of life inventory (PCQLI). We found that subjects with severe AS (n = 3) were commonly, but not universally, restricted from organized sports (n = 2, 66%). Subjects with moderate AS (n = 40) were rarely restricted from organized sports (n = 6, 17%). No physician-specific characteristics were associated with increased likelihood of recommending exercise restriction. Subjects were more likely to be restricted if they were older (16 years vs. 13 years, p 0.02) and had moderate versus mild AS (p 0.013). PCQLI scores for teens and young adults with AS (age 13-25) were lower than a comparison group of patients with mild congenital heart disease. For all age groups, the PedsQL social functioning score was lower for subjects with exercise restriction (p 0.052). In summary, cardiologists apply consensus guidelines leniently when restricting patients with moderate/severe AS from organized sports and weightlifting. Patients with AS routinely adhere to exercise restriction recommendations. Children and young adults with AS and exercise restriction have lower QOL scores in the social functioning domain.


Preliminary observations on the suppression of nocturnal plasma melatonin levels by short-term administration of diazepam in humans.
Several studies suggest that GABAergic mechanisms may be involved in the modulation of melatonin secretion. However, conflicting results have been reported in animal studies; in humans the issue has not been widely investigated. In the present study, using a double-blind design, six healthy men received orally, at midnight, 10 mg of diazepam, a GABAergic agent, or placebo, on two different occasions 1 week apart. Blood samples were collected, in the dark, immediately before the drug administration, and at 12:30, 1, 2, 3, and 4 AM. Serum melatonin was measured by a radioimmunological method with [125I]melatonin as a tracer. Two-way ANOVA with repeated measurements disclosed a significant effect for treatment (P less than 0.01), for time (P less than 0.0004), and for treatment X time interaction (P less than 0.05). Following diazepam administration, serum melatonin levels observed at 2, 3, and 4 AM were significantly lower than the corresponding values following placebo (P less than 0.002 at 2 and 4 AM; P less than 0.03 at 3 AM [Students' paired t test]). These results show that nocturnal blood melatonin levels may be suppressed by the acute administration of a GABAergic agent, suggesting that GABA may be involved in the modulation of pineal activity in man.


Tactile motion biases visual motion perception in binocular rivalry.
There is an ongoing debate whether or not multisensory interactions require awareness of the sensory signals. Static visual and tactile stimuli have been shown to influence each other even in the absence of visual awareness. However, it is unclear if this finding generalizes to dynamic contexts. In the present study, we presented visual and tactile motion stimuli and induced fluctuations of visual awareness by means of binocular rivalry: two gratings which drifted in opposite directions were displayed, one to each eye. One visual motion stimulus dominated and reached awareness while the other visual stimulus was suppressed from awareness. Tactile motion stimuli were presented at random time points during the visual stimulation. The motion direction of a tactile stimulus always matched the direction of one of the concurrently presented visual stimuli. The visual gratings were differently tinted, and participants reported the color of the currently seen stimulus. Tactile motion delayed perceptual switches that ended dominance periods of congruently moving visual stimuli compared to switches during visual-only stimulation. In addition, tactile motion fostered the return to dominance of suppressed, congruently moving visual stimuli, but only if the tactile motion started at a late stage of the ongoing visual suppression period. At later stages, perceptual suppression is typically decreasing. These results suggest that visual awareness facilitates but does not gate multisensory interactions between visual and tactile motion signals.


Students teaching students: A survey of a medical student led surgical skills workshop - A prospective cohort study.
Surgical skills training is a recognized vital component of medical education, yet a standardized curriculum does not exist. Early opportunities for skills development and mentorship may increase student interest in pursuing surgery. We evaluated the effects of a student-led, faculty-supervised suture clinic on student comfort level with basic surgical skills and interest in surgery. A cohort survey study of 103 second-year medical students participating in a surgical skills course was performed between the years 2016-2018. Upon completion of the course, we assessed their comfort level with performing six basic skills as well as their interest in pursuing surgery based on pre- and post-course surveys. Mean age was 25 years and 50.5% were female. Most students (61.2%) had no prior suturing experience. Upon completion of the course, there was a significant improvement (p = < 0.0001) in comfort level for each of the six skills. Most students (81%) reported an increased interest in surgery. Early implementation of a basic skills workshop can augment student comfort level and promote an interest in surgery. Peer student mentors can effectively lead the workshop and minimize the time commitment needed by surgical faculty. This can serve as a new direction in medical education and an avenue for further studies to analyze the longitudinal effects of the curriculum on career choice and success in surgical residency.


Distribution of laminins in the basement membranes of the upper gastrointestinal tract and Barrett's oesophagus.
Barrett's oesophagus predisposes to oesophageal adenocarcinoma. In vitro, laminin, a component of the epithelial basement membrane (BM), is important in regulation of cell differentiation. There is limited information on the distribution of laminin chains in the upper gastrointestinal tract (GIT) and none in Barrett's oesophagus. This study aimed to investigate qualitatively the distribution of laminins in the normal upper GIT mucosa and Barrett's oesophagus in order to understand the role of laminins in metaplasia. Immunoperoxidase staining for laminin chains alpha1, alpha2, alpha3, alpha5, beta1, beta2, beta3, gamma1, and gamma2 was performed on frozen endoscopic squamous and Barrett's oesophageal biopsies and surgical resection specimens from squamous oesophagus (in resection specimens for oesophageal cancer), and in oesophageal and gastric biopsies from control subjects. alpha1 laminin was expressed in the BM of submucosal glands and ducts in squamous oesophagus and Brunner's glands in the duodenum, but not in Barrett's oesophagus or elsewhere in the upper GIT. alpha2 laminin chain was expressed in a granular distribution in the BM of squamous epithelium. In columnar epithelium, including Barrett's oesophagus, alpha2 laminin chain was expressed continuously in the BM of glands and deeper pits, but expression was reduced and granular in the surface epithelial BM. beta2 laminin was continuous in squamous epithelial BM, but in Barrett's and cardia, gastric body, and duodenum, it was expressed faintly in the surface but continuously in the BM of glands and deeper pits. The constituents of laminin-5 were continuously expressed in the BM of squamous epithelium, but in the cardia, gastric body, duodenum, and Barrett's, they were expressed only in the BM of surface epithelium, with a sharp decline in the glandular and deeper pit BM. Site-specific distribution of the alpha2 and beta2 laminin chains may therefore have an important role in Barrett's metaplasia. However, the absence of alpha1 laminin in Barrett's mucosa suggests that this is unlikely to play an important role in columnar metaplasia.


Juxtacortical lesions are associated with seizures in cerebral small vessel disease.
Small vessel cerebrovascular disease (SVCD) can manifest with epileptic seizures and transient ischemic attacks (TIA). This study was designed to test if the extent and spatial distribution of SVCD differs in patients with focal impaired awareness seizures (FIAS) from patients with TIA. This is a retrospective single-center case-control study of elderly patients at a high cardiovascular risk. 118 patients with FIAS (cases) were compared to a matched control group of 118 patients with TIA. The extent and spatial distribution of white matter hyperintensities (WMH) characteristic for SVCD and medial temporal lobe atrophy were analyzed on magnetic resonance imaging (MRI) obtained at admission. The Fazekas, Wahlund, and Scheltens scales were used for grading. Juxtacortical small lesions were analyzed separately. FIAS patients were observed to have more extensive WMH (p < 0.001) and more pronounced medial temporal lobe atrophy (p < 0.001) than TIA patients. WMH in FIAS patients were predominantly localized in supratentorial white matter compared to TIA patients (p < 0.001). Juxtacortical hyperintensities were far more common in FIAS patients than in TIA patients (80.5% vs. 22.0%; p < 0.001). Multivariate analysis revealed juxtacortical small lesions as strong independent predictor (OR, 95% CI 12.8, 6.7-24.3) and medial temporal lobe atrophy as further independent predictor of FIAS (3.1, 1.3-7.1). Juxtacortical small lesions and to a smaller extent medial temporal lobe atrophy are associated with epileptic seizures in elderly patients at a high cardiovascular risk. This observation may provide a structural explanation for epilepsy in SVCD. Juxtacortical small lesions in SVCD should be considered a structural cause for epilepsy and promote anticonvulsive therapy after a first seizure.


Predictors of adverse short-term outcomes in late preterm infants.
Infants born between 34 weeks and 36 weeks and 6 days of gestation are defined as late preterm infants (LPIs), and they account for approximately 74% of all premature births. Preterm birth (PB) remains the leading cause of infant mortality and morbidity worldwide. To analyse short-term morbidity and mortality and identify predictors of adverse outcomes in late preterm infants. In this retrospective study, we evaluated adverse short-term outcomes of LPIs admitted to the Intensive Care Unit (ICU), Clinic for Children's Diseases, University Clinical Center Tuzla, between 01.01.2020 and 31.12.2022. The analysed data included sex, gestational age, parity, birth weight, Apgar score (i.e., assessment of vitality at birth in the first and fifth minutes after birth), and length of hospitalization in NICU, as well as short-term outcome data. Maternal risk factors we observed were: age of mother, parity, maternal morbidity during pregnancy, complications and treatment during pregnancy. LPIs with major anatomic malformations were excluded from the study. Logistic regression analysis was used to identify risk factors for neonatal morbidity among LPIs. We analysed data from 154 late preterm newborns, most of whom were male (60%), delivered by caesarean Sect. (68.2%) and from nulliparous mothers (63.6%). Respiratory complications were the most common outcome among all subgroups, followed by CNS morbidity, infections and jaundice requiring phototherapy. The rate of almost all of the complications in the late-preterm group decreased as gestational age increased from 34 to 36 weeks. Birth weight (OR: 1,2; 95% CI: 0,9 - 2,3; p = 0,0313) and male sex (OR: 2,5; 95% CI: 1,1-5,4; p = 0,0204) were significantly and independently associated with an increased risk for respiratory morbidity, and gestational weeks and male sex were associated with infectious morbidity. None of the risk factors analysed herein were predictors of CNS morbidity in LPIs. A younger gestational age at birth is associated with a greater risk of short-term complications among LPIs, thus highlighting the need for increased knowledge about the epidemiology of these late preterm births. Understanding the risks of late preterm birth is critical to optimizing clinical decision-making, enhancing the cost-effectiveness of endeavours to delay delivery during the late preterm period, and reducing neonatal morbidity.


Repeated exposure to acrolein vapour: subacute studies in hamsters, rats and rabbits.
The subacute inhalation toxicity of acrolein was examined in 4 groups of 20 hamsters, 12 rats and 4 rabbits each, exposed repeatedly to acrolein vapour at concentrations of 0, 0.4, 1.4 and 4.9 ppm (6 h/day, 5 days/week) for a 13-week period. The most important effects found at the highest level included mortality in rats, ocular and nasal irritation, growth depression and histopathological changes of the respiratory tract in each of the animal species exposed. The aberrations in the airways consisted of destruction and hyper- and metaplasia of the lining epithelium accompanied by inflammatory alterations. Rats appeared to be the most susceptible of the species examined and showed treatment-related abnormalities even at 0.4 ppm, whereas this exposure level was found to be a no-toxic effect level in both hamsters and rabbits.


Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.


Comparison of treatment persistence with different oral anticoagulants in patients with atrial fibrillation.
Oral anticoagugulants (OACs) effectively reduce the risk for ischemic stroke in patients with atrial fibrillation (AF), but undertreatment and poor persistence with treatment are important problems. NOACs now provide alternatives to warfarin. This study compares the persistence with presently available antithrombotic treatments in AF patients with a CHA2DS2VASc score ≥2. All first claims of either warfarin (n = 9969), dabigatran (n = 2701), rivaroxaban (n = 2074), apixaban (n = 1352), or aspirin (n = 4540) from April 2011 until December 2014, in individuals with non-valvular AF and CHA2DS2VASc scores of 2-9, were identified in the administrative health data register (VAL) of the Stockholm region (2.1 million inhabitants). Prescription claims were analyzed with and without multivariate analysis in relation to age, sex, prescriber category, prior OAC treatment, number of drugs, and death. The overall persistence with any OAC was 88.2% (CI 87.5-88.9) at 1 year and 82.9% (CI 81.8-83.9) at 2 years. After 1 year, the crude persistence was 85.0% (CI 84.2-85.9) with warfarin, 85.9% (CI 81.8-90.1) with apixaban, 74.4% (CI 72.3-76.5) with dabigatran, and 77.4% (CI 74.6-80.2) with rivaroxaban. Multivariate analysis confirmed significantly higher persistence with warfarin and apixaban than with dabigatran or rivaroxaban. The adherence (proportion of days covered >80%) was above 90% for all NOACs; significantly higher with rivaroxaban compared to dabigatran (p < 0.001), but not compared to apixaban (p = 0.14). After 2 years, the persistence with any anticoagulant treatment was high in patients with non-valvular AF. Our results indicate better persistence with warfarin and apixaban than with dabigatran or rivaroxaban in regular care.


Coxsackie B virus IgM in children at onset of type 1 (insulin-dependent) diabetes mellitus: evidence for IgM induction by a recent or current infection.
Thirty-five children with newly-diagnosed Type 1 (insulin-dependent) diabetes mellitus and their 47 siblings were investigated for the presence of IgM antibodies to Coxsackie B virus serotypes 1-5 (CBV 1-5) with the aid of mu-antibody-capture radioimmunoassays. When a high cut-off value was used, 16 (46%) diabetic children and 16 (34%) siblings showed CBV-IgM. Of the siblings of diabetic patients positive for CBV-IgM, 11 (44%) were CBV-IgM-positive; the corresponding figure for the siblings of negative patients was five (26%). With a lower cut-off value, leading to a "borderline titre", the frequency of IgM positivity increased in both the patients and siblings. When the borderline titres were included, the number of IgM-positive patients was 19 (54%) and the corresponding number of siblings was 29 (62%). Of the siblings of positive patients, 27 (93%) showed CBV-IgM, and of the siblings of the negative patients, two (11%) were CBV-IgM-positive. Sixteen (89%) siblings of IgM-negative patients remained negative. Regarding the serotypes of CBV to which IgM was directed, CBV 4 was most frequent, followed by serotypes CBV 3, CBV 2, CBV 5 and CBV 1. There was a striking similarity between the individual diabetic child and his or her sibling(s) concerning this specificity of IgM. It is concluded that within most families with a newly-diagnosed diabetic child positive for CBV-IgM the same serotype(s) of the virus circulates and that the intrafamilial spread of virus is considerable. The results strongly indicate that the IgM detected was CBV-specific and caused by a recent or current CBV infection.(ABSTRACT TRUNCATED AT 250 WORDS)


Women's preferences for vaginal antimicrobial contraceptives. II. Preferred characteristics according to women's age and socioeconomic status.
A study was carried out to identify characteristics that women would want for an idealized vaginal contraceptive, and the possible association of these characteristics with age and socioeconomic status. The study was done in Campinas, São Paulo State, Brazil. A total of 635 women were selected by age and socioeconomic status, using the "social network" technique. Almost half were adolescents (15-19 years old) and the rest were adults (20-45 years old). Half were of low socioeconomic status and the rest of medium-high status. The data were analyzed with SPSS-PC and EPI-INFO 6.0. Logistic regression and chi 2 were used for the analysis. Despite some differences found between age and socioeconomic status in regard to the characteristics desired for the idealized method, most of the participants expressed the same preferences. The results indicate that women would like the idealized method to be a cream, rather than a suppository, with no odor or flavor, to be colorless, to be placed in the vagina with an applicator well before coitus, and to offer protection against sexually transmitted diseases including AIDS.


Dietary fat and calcium intakes of menopausal women.
The purpose of this retrospective, descriptive study was to assess the baseline dietary intake of fat and calcium in a group of women attending a multidisciplinary menopause clinic. Dietary fat and calcium intakes of this group were determined with food-frequency questionnaires, food records, and dietary interviews. The dietary fat and calcium intakes of those patients who expressed concern of risk for cardiovascular disease or osteoporosis and those patients using herbal preparations were compared with those who did not. Of 75 women, the majority of patients exceeded the dietary fat recommendations and had insufficient intakes of calcium. Significantly fewer patients with an expressed concern of risk for cardiovascular disease exceeded the recommendation for total fat and saturated fat (p < 0.05). There was no significant difference in calcium intake between those with and those without an expressed concern of risk for osteoporosis or in the diets of patients who did or those who did not take herbal products. The large proportion of patients not meeting recommendations for fat or calcium intakes confirms that the assessment of baseline dietary habits and nutrition education and intervention should be an essential component of the management of menopausal women.


Suppression of colonic microflora by cefoperazone and evaluation of the drug as potential prophylaxis in bowel surgery.
We evaluated the activity of cefoperazone (CPZ) on the intestinal flora in terms of its use as a single prophylactic drug in colon surgery. Twenty-four healthy male volunteers between the ages of 20 and 40 were assigned to receive either CPZ, oral neomycin-erythromycin, or no antibiotics. A mechanical bowel preparation, Golytely, was also given to each of the subjects. With intravenous CPZ, antibiotic levels in the stool ranged from less than 2 to 649 micrograms/ml and the total fecal bacterial counts dropped 3 to 4 log10 CFU/g. Higher levels of CPZ were detected in the stools when an oral dose was added, 1,446 to 5,445 micrograms/ml, and the bacterial counts were reduced maximally 4 to 6 log10 CFU/g. The combination of the oral and intravenous doses produced suppression of the microflora and high levels in blood, all with a single antibiotic.


Saving the ends for last: the role of pol mu in DNA end joining.
At least three DNA polymerases participate in nonhomologous end joining in mammalian cells: pol mu, pol kappa, and TdT. A study in this issue of Molecular Cell (Nick McElhinny et al., 2005) clarifies the role of pol mu in end joining at the kappa light chain locus and also provides a biochemical explanation for the unique polymerization functions of pol mu on DNA ends.


Chemerin gene expression is regulated by food restriction and food restriction-refeeding in rat adipose tissue but not in liver.
Chemerin is an adipokine that regulates adipocyte development and metabolism as well as inflammatory and immune function of some cells. Although chemerin may be linked to obesity and related diseases, little is known about the nutritional regulation of chemerin gene expression. We investigated the effect of prolonged food restriction, a common approach in treating obesity and related diseases, and prolonged food restriction-refeeding on chemerin gene expression in rat white adipose tissue and liver. The prolonged food restriction was accompanied by an approximately 2-fold decrease in chemerin mRNA level in rat white adipose tissue. Upon refeeding, an increase (approximately 8-fold as compared to rats maintained on restricted diet and 4-fold as compared to control) in chemerin mRNA level in white adipose tissue was found. Surprisingly, no effect of food restriction and food restriction-refeeding on chemerin mRNA level in the liver was found. Chemerin mRNA level in adipose tissue was positively correlated with serum insulin concentration. Moreover insulin increased significantly chemerin gene expression in primary rat adipocytes. The changes in chemerin mRNA level in adipose tissue and serum chemerin concentrations were associated with changes in serum leptin and free fatty acid concentrations. Collectively, the data presented here indicate that chemerin gene expression is regulated by nutritional status in rat adipose tissue but not in liver. It seems that insulin plays important role in stimulation of chemerin gene expression in adipose tissue. However, changes in serum leptin and free fatty acids concentrations after food restriction-refeeding suggest that the role of these factors in the regulation of chemerin gene expression in adipose tissue cannot be excluded. Lack of the effect of food restriction and food restriction-refeeding on liver chemerin gene expression suggests that adipose tissue is the dietary modifiable source of serum chemerin concentration.


Linguistic aspects of magnitude-estimation scaling of instrumental music, instrumental music with vocal accompaniment, and spoken lyrics.
An analysis of variance of magnitude estimates of loudness of three different types of complex auditory stimuli, instrumental music, instrumental music with vocal accompaniment, and spoken lyrics showed, for 100 young adults, no differences for the types of stimuli. The linguistic aspects of these complex auditory stimuli do not differentially influence loudness judgments.


Balance of pro-apoptotic transforming growth factor-beta and anti-apoptotic insulin effects in the control of cell death in the postnatal mouse retina.
Transforming growth factor (TGF)-beta and insulin display opposite effects in regulating programmed cell death during vertebrate retina development; the former induces apoptosis while the latter prevents it. In the present study we investigated coordinated actions of TGF-beta and insulin in an organotypic culture system of early postnatal mouse retina. Addition of exogenous TGF-beta resulted in a significant increase in cell death whereas exogenous insulin attenuated apoptosis and was capable of blocking TGF-beta-induced apoptosis. This effect appeared to be modulated via insulin-induced transcriptional down-regulation of TGF-beta receptor II levels. The analysis of downstream signalling molecules also revealed opposite effects of both factors; insulin provided survival signalling by increasing the level of anti-apoptotic Bcl-2 protein expression and phosphorylation and down-regulating caspase 3 activity whereas pro-apoptotic TGF-beta signalling reduced Bcl-2 mRNA levels and Bcl-2 phosphorylation and induced the expression of TGF-induced immediate-early gene (TIEG), a Krüppel-like zinc-finger transcription factor, mimicking TGF-beta activity.


Psoriasis.
Psoriasis is an inflammatory disorder of the skin that involves complex interactions between the dermis and epidermis. There are several forms of psoriasis, the most common being plaque type psoriasis. Other forms include guttate, pustular and erythrodermic psoriasis. Both the skin and joints are affected in this disease. Psoriasis ranges in severity from a few small plaques to involvement of the entire cutaneous surface. Therapy of psoriasis depends on the location, type and severity of the disease. Treatments include a wide array of topical medications including tars, anthralin, topical corticosteroids, vitamin D(3) analogs, retinoids and over-the-counter preparations. Phototherapy with ultraviolet B and PUVA are used for more widespread involvement. Common systemic therapies include methotrexate, retinoids and cyclosporin. This article will review the pathogenesis and clinical features of psoriasis, as well as current and future therapies.


Characterization of subtypes of gamma-aminobutyric acid receptors in an Ascaris muscle preparation by binding assay and binding of PF1022A, a new anthelmintic, on the receptors.
We examined the effect of PF1022A, one of the gabergic anthelmintics newly developed in Japan, on gamma-aminobutyric acid (GABA) receptors using a radioligand binding technique in isolated membrane preparations of the nematode Ascaris suum. Membrane protein was prepared from the homogenate of somatic muscle cells after ultracentrifugation. In addition to the basic binding of [2,3-3H-(N)]-GABA, the radioligand [methyl-3H]-bicuculline is used to identify the GABAA receptor, whereas [butyl-4-3H]-baclofen is employed for GABAB receptor sites. The dissociation constants (Kd values) and the maximal numbers of binding sites (Bmax values) from Scatchard plotting for GABA receptors are close to those obtained in mammalian brain. PF1022A displaced in a concentration-dependent way the binding of [2,3-3H(N)]-GABA and [methyl-3H]-bicuculline as did other specific gabergic agents. In addition, PF1022A decreased the binding of [butyl-4-3H]-baclofen at a higher concentration, although this binding did not represent GABAB sites. In a comparison of the inhibition constants (Ki values) of PF1022A with those of other agents, it is conclusive that PF1022A bound with GABA receptors. A direct effect of PF1022A on GABA receptors can thus be postulated.


Imported Malaria in the Material of the Institute of Maritime and Tropical Medicine: A Review of 82 Patients in the Years 2002-2014.
Malaria is, along with tuberculosis and HIV/AIDS, one of the three most dangerous infectious diseases in the world. In the absence of native cases since 1963, malaria has remained in Poland an exclusively imported disease, mainly occurring in people travelling to tropical and subtropical areas for professional reasons. The aim of this study was the epidemiological and clinical analysis of 82 patients admitted to the University Center for Maritime and Tropical Medicine (UCMTM), Gdynia, Poland, with a diagnosis of malaria between 2002 and 2014. The "typical" patient with malaria was male, middle-aged, returned from Africa within the preceding 4 weeks, had not used appropriate chemoprophylaxis, and had not applied nonpharmacological methods of prophylaxis, except for window insect screens. P. falciparum was the most frequent species. The most common symptoms included fever, shivers and intensive sweating, thrombocytopenia, elevated creatinine, LDH, D-dimers and CRP, hepatomegaly, and splenomegaly. Within the analyzed group, severe malaria according to WHO standards was diagnosed in 20.7% of patients. Our report presents analysis of the largest series of patients treated for imported malaria in Poland.


Metabolic activation of drugs by cytochrome P450 enzymes: Biochemical insights into mechanism-based inactivation by fibroblast growth factor receptor inhibitors and chemical approaches to attenuate reactive metabolite formation.
Metabolic activation of drugs by cytochrome P450 enzymes (P450) to chemically reactive electrophiles is commonly regarded as a key molecular-initiating event underpinning idiosyncratic drug-induced liver injury. However, apart from precipitating toxicities, these labile intermediates can be sequestered within the P450 active site and engender a unique form of irreversible inhibition known as mechanism-based inactivation (MBI) which bears profound clinical implications (i.e., drug-drug interactions, autoinhibition of hepatic elimination, time-dependent and/or nonlinear pharmacokinetics). Consequently, there has been considerable attempts to develop medicinal chemistry strategies to attenuate or abolish metabolic activation and its deleterious downstream effects (i.e., MBI). In this review, we will first summarize the fundamental aspects and consequences of P450 metabolic activation with a focus on MBI. Following which, we will share our recent discoveries on the arcane metabolic activation pathways of an emerging class of tyrosine kinase inhibitors known as the fibroblast growth factor receptor (FGFR) inhibitors which in turn unravelled mechanistic insights into the biochemical basis and pharmacokinetic implications of its MBI. Finally, we will discuss, using relevant examples from the literature as well as from our laboratory, limitations of existing chemical approaches to minimize metabolic activation and highlight a promising new paradigm which involves the rational deuteration of a drug molecule at its known bioactivation 'hot-spot' to shunt metabolism away from these aberrant pathways and reduce reactive metabolite formation.


Pleiotropic mutations within two yeast mitochondrial cytochrome genes block mRNA processing.
The mRNAs from two yeast mitochondrial genes cob-box (cytochrome b) and oxi-3 (cytochrome oxidase 40,000 dalton subunit) are processed from large (7-10 kb) precursors. Certain mutations in each gene block the maturation of the RNAs from both genes at a variety of specific steps. The pleiotropic cytochrome b mutants seem to lack a functional trans-acting RNA required for the processing of both messengers. In contrast, the oxi-3 mutants may act by producing an activity that inhibits specific steps.


Single-cell RNA sequencing of a poorly metastatic melanoma cell line and its subclones with high lung and brain metastasis potential reveals gene expression signature of metastasis with prognostic implication.
The molecular mechanisms underlying melanoma metastasis remain poorly understood. In this study, we aimed to delineate the mechanisms underlying gene expression alterations during metastatic potential acquisition and characterize the metastatic subclones within primary cell lines. We performed single-cell RNA sequencing of a poorly metastatic melanoma cell line (WM239A) and its subclones with high metastatic potential to the lung (113/6-4L) and the brain (131/4-5B1 and 131/4-5B2). Unsupervised clustering of 8173 melanoma cells identified three distinct clusters according to cell type ('Primary', 'Lung' and 'Brain' clusters) with differential expression of MITF and AXL pathways and putative cancer and cell cycle drivers, with the lung cluster expressing intermediate but distinct gene profiles between primary and brain clusters. Principal component (PC) analysis revealed that PC2 (the second PC), which was positively associated with MITF expression and negatively with AXL pathways, primarily segregated cell types, in addition to PC1 of the cell cycle pathway. Pseudotime trajectory and RNA velocity analyses suggested the existence of cellular subsets with metastatic potential in the Primary cluster and an association between PC2 signature alteration and metastasis potential acquisition. Analysis of The Cancer Genome Atlas melanoma samples by clustering into PC2-high and -low clusters by quartiles of PC2 signature expression revealed that the PC2-high cluster was an independent significant factor for poor prognosis (p-value = 0.003) with distinct genomic and transcriptomic characteristics, compared to the PC2-low cluster. In conclusion, we identified signatures of melanoma metastasis with prognostic significance and putative pro-metastatic subclones within a primary cell line.


Prevalence of and risk factors for trachoma in Kwara state, Nigeria: Results of eight population-based surveys from the Global Trachoma Mapping Project.
To determine the prevalence of and risk factors for trachoma in selected local government areas (LGAs) of Kwara State, Nigeria. Population-based cross-sectional surveys were conducted in eight LGAs of Kwara State using Global Trachoma Mapping Project (GTMP) protocols. In each LGA, 25 villages were selected using probability-proportional-to-size sampling; 25 households were selected from each village using compact segment sampling. All residents of selected households aged ≥1 year were examined by GTMP-certified graders for trachomatous inflammation-follicular (TF) and trichiasis using the simplified trachoma grading scheme. Water, sanitation, and hygiene (WASH) data were also collected. A total of 28,506 residents were enumerated in 4769 households across the eight LGAs. TF prevalence in children aged 1-9 years ranged from 0.2% (95% CI 0.0-0.3%) to 1.3% (95% CI 0.7-2.1%), while trichiasis prevalence in persons ≥15 years was <0.2% in each LGA. Access to improved water source was the lowest in Edu (62%), while access to improved sanitation facilities was the lowest in Asa (6%) and the highest in Ilorin East (64%). Children aged 1-4 years had 0.63 (95% CI 0.40-0.99) times lower odds of having TF compared to children aged 5-9 years. Children in households with ≥5 resident 1-9-year-old children had 1.63 (95% CI 1.02-2.60) times greater odds of having TF compared to those in households with <5 resident children. Trachoma is not a public health problem in Kwara State. Provision of adequate water and sanitation services should be a priority here, as a foundation for the health of the population.


Factors that influence treatment decisions: A qualitative study of racially and ethnically diverse patients with low- and very-low risk prostate cancer.
Factors that influence prostate cancer treatment decisions are complex, multifaceted, and personal, and may vary by race/ethnicity. Although research has been published to quantify factors involved in decision-making, these studies have been limited to primarily white, and to a lesser extent, Black patients, and quantitative studies are limited for discerning the cultural and contextual processes that shape decision-making. We conducted 43 semi-structured interviews with a racially and ethnically diverse sample of patients diagnosed with low- and very-low risk prostate cancer who had undergone treatment for their prostate cancer. Interviews were transcribed, independently coded, and analyzed to identify themes salient for decision-making, with attention to sociocultural differences. We found racial and ethnic differences in three areas. First, we found differences in how socialized masculinity influenced patient's feelings about different treatment options. Second, we found that for some men, religion and spirituality alleviated anxiety associated with the active surveillance protocol. Finally, for racially and ethnically minoritized patients, we found descriptions of how historic and social experiences within the healthcare system influenced decision-making. Our study adds to the current literature by expounding on racial and ethnic differences in the multidimensional, nuanced factors related to decision-making. Our findings suggest that factors associated with prostate cancer decision-making can manifest differently across racial and ethnic groups, and provide some guidance for future research.


Distribution of mast cells in human dermis: development of a mapping technique.
A new method was developed to define the distribution of mast cells in normal human skin. The population density was determined in a number of zones of different depth in the dermis. Two regions of the same limb were studied systematically. Both were shown to have mast cell populations of similar size and distribution, with a maximum density immediately below the dermo-epidermal junction, gradually falling to a minimum density in the deeper layers of the dermis. Small secondary peaks were less clearly defined at the base of the dermis. These findings should provide baseline data for comparisons with mast cell population size and distribution in different areas of normal skin, or in similar areas in clinical disorders or experimental conditions.


The influence of embedding media and fixation on the postembedment ultrastructural demonstration of complex carbohydrates. III. High iron diamine staining for sulfated glycoconjugates.
The high iron diamine (HID) method for detection of sulfated complex carbohydrate has been applied directly on thin sections of variably fixed tissues embedded in epoxy and nonepoxy resins. Results with postembedment HID staining in mouse intestinal epithelium are compared to those previously obtained using preembedment methods. Sections from epoxy-embedded tissues have been found to exhibit the weakest staining intensity. Intense, specific staining was obtained in tissues not postfixed with osmium tetroxide and embedded in polystyrene, polyester resins, styrene-methacrylate, and especially the styrene-Vestopal W embedding mixture. Postosmication of tissues abolished HID staining in epoxy resins and the styrene-Spurr's resin embedding mixture, but only reduced the staining intensity in tissues embedded in nonepoxy resins.


Life cycle environmental impacts of a prospective palm-based biorefinery in Pará State-Brazil.
The availability of about 18 million hectares of grassland in Pará State, Brazil, and the possibility of increasing the livestock density display a good perspective for the oil palm expansion in pasture land. A life cycle assessment is performed for a prospective palm-based biorefinery to view two regional and one global environmental impact and the consequences of the land-use change in terms of GHG emissions. Oil palm cultivation in an area of ∼110,000 hectares of land can annually produce ∼39,000 tons of bioethanol, ∼340,000 tons of biodiesel, ∼268 GW h net electricity and other co-products. The life cycle GHG emissions reduction for biodiesel and bioethanol as compared to fossil diesel and gasoline would be 76.9-79.3% and 83.7-88.6%. The advantage of grassland rehabilitation by oil palm plantation is the removal of ∼188 t CO2/ha from the atmosphere during the plant lifetime. The entire inflows and outflows for the conversion processes are schemed.


A Mixed-Methods Evaluation of Clinician Education Modules on Reducing Surgical Opioid Prescribing.
In this study, we developed online interactive clinician education modules highlighting best practices to minimize opioid prescribing at discharge after surgery. The modules were implemented as part of a multicomponent quality improvement initiative across a six-hospital health system. This article describes the development and evaluation of this educational intervention. Clinician education modules targeting surgical prescribers, nurses, and pharmacists were developed and implemented by an interdisciplinary team. Clinicians were invited to participate in an evaluation survey after completing the modules. Survey items assessed clinicians' rating of the module and intention to change clinical practice because of the module. Quantitative and qualitative survey responses were analyzed by the study team. A total of 2119 clinicians completed the module and 1831 of these clinicians (86.4%) completed the survey. Of clinicians completing the survey, 65.6% reported that they intend to change clinical practice after completing the module. Intended changes were related to increased knowledge and awareness, provider empowerment, opioid prescribing practices, nonopioid prescribing practices, and patient education. Many clinicians who indicated they do not intend to change practice reported that their clinical practices were already in line with module recommendations. Some clinicians did not perceive the module to be relevant to their role. Module completion was associated with the intention to improve clinical practice in areas related to provider empowerment, opioid prescribing, nonopioid prescribing, and patient education. Evaluation data will inform future module improvements. There is an opportunity to ensure that all clinicians, including those who are not prescribers, recognize their role in opioid stewardship.


A 1978 perspective of hemoperfusion.
The present status of adsorbent hemoperfusion is introduced with emphasis on available systems and their roles in uremia, acute intoxication, fulminant hepatic failure and chronic schizophrenia.


Association Between Area-Level Socioeconomic Deprivation and Diabetes Care Quality in US Primary Care Practices.
Diabetes management operates under a complex interrelationship between behavioral, social, and economic factors that affect a patient's ability to self-manage and access care. To examine the association between 2 complementary area-based metrics, area deprivation index (ADI) score and rurality, and optimal diabetes care. This cross-sectional study analyzed the electronic health records of patients who were receiving care at any of the 75 Mayo Clinic or Mayo Clinic Health System primary care practices in Minnesota, Iowa, and Wisconsin in 2019. Participants were adults with diabetes aged 18 to 75 years. All data were abstracted and analyzed between June 1 and November 30, 2020. The primary outcome was the attainment of all 5 components of the D5 metric of optimal diabetes care: glycemic control (hemoglobin A1c <8.0%), blood pressure (BP) control (systolic BP <140 mm Hg and diastolic BP <90 mm Hg), lipid control (use of statin therapy according to recommended guidelines), aspirin use (for patients with ischemic vascular disease), and no tobacco use. The proportion of patients receiving optimal diabetes care was calculated as a function of block group-level ADI score (a composite measure of 17 US Census indicators) and zip code-level rurality (calculated using Rural-Urban Commuting Area codes). Odds of achieving the D5 metric and its components were assessed using logistic regression that was adjusted for demographic characteristics, coronary artery disease history, and primary care team specialty. Among the 31 934 patients included in the study (mean [SD] age, 59 [11.7] years; 17 645 men [55.3%]), 13 138 (41.1%) achieved the D5 metric of optimal diabetes care. Overall, 4090 patients (12.8%) resided in the least deprived quintile (quintile 1) of block groups and 1614 (5.1%) lived in the most deprived quintile (quintile 5), while 9193 patients (28.8%) lived in rural areas and 2299 (7.2%) in highly rural areas. The odds of meeting the D5 metric were lower for individuals residing in quintile 5 vs quintile 1 block groups (odds ratio [OR], 0.72; 95% CI, 0.67-0.78). Patients residing in rural (OR, 0.84; 95% CI, 0.73-0.97) and highly rural (OR, 0.81; 95% CI, 0.72-0.91) zip codes were also less likely to attain the D5 metric compared with those in urban areas. This cross-sectional study found that patients living in more deprived and rural areas were significantly less likely to attain high-quality diabetes care compared with those living in less deprived and urban areas. The results call for geographically targeted population health management efforts by health systems, public health agencies, and payers.


1,3-Dinitrobenzene-induced encephalopathy in rats.
Exposure to 1,3-dinitrobenzene (1,3-DNB) in humans induces methaemoglobinaemia, nausea and nervous symptoms. When given to conventional rats, twice-daily oral doses of 10 mg kg-1 1,3-DNB produce methaemoglobinaemia and frequently ataxia after four or five doses. In germ free rats given only a single oral dose of 20 mg kg-1, similar symptoms occur but are of more rapid onset. Light and electron microscope examinations reveal an acute thiamine deficiency-like lesion in the brain stems of both ataxic and apparently normal rats. Bilaterally symmetrical vacuolated lesions involve cerebellar roof, vestibular and superior olivary nuclei and the inferior colliculi. Frequent petechial haemorrhages are associated with these lesions, the erythrocytes usually being limited to enlarged Virchow-Robin spaces but sometimes spreading more widely. The primary cellular targets appear to be astrocytes, oligodendrocytes and vascular elements with secondary neuronal involvement. It is suggested that 1,3-DNB interferes with intracellular redox mechanisms resulting in impaired glucose oxidation.


VAB-5 combination chemotherapy in prognostically poor risk patients with germ cell tumors.
Forty-four patients with nonseminomatous germ cell tumors with "poor prognostic features" were entered on the VAB-5 regimen and 38 are evaluable. VAB-5 represents an intensified version of the VAB-4 protocol. Poor prognostic features were considered to be bulky metastases ( greater than 5 cm in diameter), palpable retroperitoneal disease, liver metastases, brain metastases, involvement of two or more parenchymal organs, pure choriocarcinoma, alpha fetoprotein or human chorionic gonadotropin serum levels over 1000 ng/ml, lactic acid dehydrogenase serum levels over 400 mg/dl, and failure to prior chemotherapy. Eighteen of 38 evaluable patients became free of neoplasm, 11 with chemotherapy alone, and seven with combined chemotherapy and surgery. Fourteen of 18 complete responders remain alive and free of disease with a median follow-up of 50 months. Complete remission with testis tumor occurred in 13/15 without and 5/15 with prior chemotherapy and in none of eight patients with primary extragonadal germ cell tumors. Thirty-one patients received antibiotics when they developed fever during myelosuppression. Ten patients developed transient serum creatinine levels over 2 mg/dl after cis-platinum and one required hemodialysis with subsequent recovery. All patients had severe mucositis after induction. An apparent improvement of results over prior VAB protocols in patients with poor prognostic features was compromised by significant increases in toxicity and such patients require special study to improve cure rates.


Voltage-sensor conformation shapes the intra-membrane drug binding site that determines gambierol affinity in Kv channels.
Marine ladder-shaped polyether toxins are implicated in neurological symptoms of fish-borne food poisonings. The toxin gambierol, produced by the marine dinoflagellate Gambierdiscus toxicus, belongs to the group of ladder-shaped polyether toxins and inhibits Kv3.1 channels with nanomolar affinity through a mechanism of gating modification. Binding determinants for gambierol localize at the lipid-exposed interface of the pore forming S5 and S6 segments, suggesting that gambierol binds outside of the permeation pathway. To explore a possible involvement of the voltage-sensing domain (VSD), we made different chimeric channels between Kv3.1 and Kv2.1, exchanging distinct parts of the gating machinery. Our results showed that neither the electro-mechanical coupling nor the S1-S3a region of the VSD affect gambierol sensitivity. In contrast, the S3b-S4 part of the VSD (paddle motif) decreased gambierol sensitivity in Kv3.1 more than 100-fold. Structure determination by homology modeling indicated that the position of the S3b-S4 paddle and its primary structure defines the shape and∖or the accessibility of the binding site for gambierol, explaining the observed differences in gambierol affinity between the channel chimeras. Furthermore, these findings explain the observed difference in gambierol affinity for the closed and open channel configurations of Kv3.1, opening new possibilities for exploring the VSDs as selectivity determinants in drug design.


Brain cytochrome oxidase in Alzheimer's disease.
A recent demonstration of markedly reduced (-50%) activity of cytochrome oxidase (CO; complex 4), the terminal enzyme of the mitochondrial enzyme transport chain, in platelets of patients with Alzheimer's disease (AD) suggested the possibility of a systemic and etiologically fundamental CO defect in AD. To determine whether a CO deficiency occurs in AD brain, we measured the activity of CO in homogenates of autopsied brain regions of 19 patients with AD and 30 controls matched with respect to age, postmortem time, sex, and, as indices of agonal status, brain pH and lactic acid concentration. Mean CO activity in AD brain was reduced in frontal (-26%: p less than 0.01), temporal (-17%; p less than 0.05), and parietal (-16%; not significant, p = 0.055) cortices. In occipital cortex and putamen, mean CO levels were normal, whereas in hippocampus, CO activity, on average, was nonsignificantly elevated (20%). The reduction of CO activity, which is tightly coupled to neuronal metabolic activity, could be explained by hypofunction of neurons, neuronal or mitochondrial loss, or possibly by a more primary, but region-specific, defect in the enzyme itself. The absence of a CO activity reduction in all of the examined brain areas does not support the notion of a generalized brain CO abnormality. Although the functional significance of a 16-26% cerebral cortical CO deficit in human brain is not known, a deficiency of this key energy-metabolizing enzyme could reduce energy stores and thereby contribute to the brain dysfunction and neurodegenerative processes in AD.


Circadian growth hormone secretion in short multitransfused prepubertal children with thalassaemia major.
Growth hormone (GH) secretion was determined by evaluating circadian GH profiles for 24 h and GH responses to clonidine stimulation test and insulin-stimulated hypoglycaemia (ITT), in nine prepubertal children with beta-thalassaemia major (TM) and 17 with non-GH deficient short stature (NGHDSS). The TM children were multitransfused and had early and intensive chelation therapy. All patients had normal hypoglycaemia to ITT, with peak GH levels of 15.71 +/- 5.86 ng/ml for children with NGHDSS and 13.91 +/- 7.20 ng/ml for children with TM. Peak GH levels during a clonidine test were 17.54 +/- 5.30 and 17.15 +/- 1.38 ng/ml, respectively. The GH peak parameters such as the number of peaks, the integrated GH concentration and the area under the curve (AUC) were similar in both groups of children and reflected the total 24-h secretion and the daily and nocturnal secretion separately. An abnormal 24-h GH profile compatible with the diagnosis of endogenous neurosecretory GH dysfunction was found in only two out of nine children with TM and in four out of seven children with NGHDSS. Our data suggest that growth hormone neurosecretory dysfunction is not a universal finding in children with thalassaemia major but might depend on the degree of iron deposit in the pituitary.


Surgical management and outcomes of accessory parotid gland neoplasms: A systematic review.
To evaluate surgical approaches and outcomes associated with accessory parotid gland neoplasms. MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. A systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was performed. Studies were included if they reported surgical management and outcomes of patients with accessory parotid gland neoplasms. After screening 3532 records, 15 studies were included with a total of 187 patients. Benign tumors consisted of 61.5% of cases. External open, transoral, and preauricular endoscopic approaches were used for 82.3%, 11.3%, and 6.5% of cases, respectively. Accessory lobe resection alone, concurrent with partial parotidectomy, and concurrent with total parotidectomy were used in 54.8%, 43.0%, and 2.2% of cases, respectively. Complication rates were similar between histology groups (7.8% benign vs. 8.3% malignant, p = 0.82). Accessory lobe resection with concurrent partial parotidectomy had the lowest overall complication rate (6.3%). Resections limited to the accessory lobe were found to have an overall complication rate of 8.7%. The results offer an overview of the surgical management and complications for accessory parotid gland tumors. Overall surgical complication rates found in these case series may be lower for management of accessory gland tumors than rates available in the literature for tumors within the main parotid gland.


The outcome of intra-aortic balloon pump support in acute myocardial infarction complicated by cardiogenic shock according to the type of revascularization: a comprehensive meta-analysis.
Despite the recommendations of the current guidelines, scientific evidence continue to challenge the effectiveness of intra-aortic balloon pump (IABP) in acute myocardial infarction (AMI) complicated by cardiogenic shock. Moreover, 2 recent meta-analyses showed contrasting results. The aim of this study is to test the effect of IABP according to the type of therapeutic treatment of AMI: percutaneous coronary intervention (PCI), thrombolytic therapy (TT), or medical therapy without reperfusion. Articles published from January 1, 1986, to December 31, 2012, were collected and analyzed by meta-analysis. We evaluated the IABP impact on inhospital mortality, on safety end points (stroke, severe bleeding) and long-term survival, using risk ratio (RR) and risk difference (RD) estimates. We found that the risk of death was (i) not significantly different between the IABP and control groups (RR 0.95, P = .52; RD -0.04, P = .28), (ii) significantly reduced in the TT subgroup (RR 0.77, P < .0001; RD -0.16, P < .0001), and (iii) significantly increased in the PCI subgroup (RR 1.18, P = .01; RD 0.07, P = .01). There were no significant differences in secondary end points (P, not significant). In addition, we compared the meta-analyses collected over the same search period. The results show that IABP support is significantly effective in TT reperfusion but is associated with a significant increase of the inhospital mortality with primary PCI. The comparison of the meta-analyses demonstrates the key role of analysing primary clinical treatments to avoid systematic errors.


Nutritional causes of anemia in Mexican children under 5 years. Results from the 2006 National Health and Nutrition Survey.
To describe the frequency and severity of anemia and the nutritional variables associated to hemoglobin levels (Hb) in children <5 years of age. We studied 981 children measuring hemoglobin and serum concentrations of ferritin, soluble transferrin receptors (sTfR), C-reactive protein (CRP), zinc, iron, copper, magnesium, folate and vitamin B12. Ordinal logit or multiple regression models were constructed to assess the risk for anemia and the associations among nutritional variables. The overall prevalence of anemia was 20.6%, of which 14% were mild cases and 6.38% moderate. Anemia was associated with iron deficiency (ID) in 42.17% of the cases, whereas ID coexisted with either folate or vitamin B12 deficiency in 9%. Only 2% of cases of anemia were associated with either folate or vitamin B12 deficiencies. CRP (coef: 0.17 g/dl) and third tertile of s-copper (coef: -0.85 g/dl) were associated to unexplained anemia (p<0.05). ID is the main cause of anemia in children <5 y. Folate and vitamin B12 concentrations were associated with anemia. CRP was associated to unexplained anemia. However, vitamin A deficiency, which is associated with anemia, was not studied.


Grk5l controls heart development by limiting mTOR signaling during symmetry breaking.
The correct asymmetric placement of inner organs is termed situs solitus and is determined early during development. Failure in symmetry breaking results in conditions ranging from randomized organ arrangement to a complete mirror image, often accompanied by severe congenital heart defects (CHDs). We found that the zebrafish homolog of mammalian G protein-coupled receptor kinase 5 (GRK5) employs noncanonical, receptor-independent functions to secure symmetry breaking. Knockdown of GRK5's closest homolog in zebrafish embryos, Grk5l, is sufficient to randomize cardiac looping and left-right asymmetry. Mechanistically, we found that loss of GRK5 increases mammalian target of rapamycin complex 1 (mTORC1) activity. This causes elongation of motile cilia in the organ of laterality, a consequence that is known to be sufficient to trigger aberrant organ arrangement. By fine-tuning mTORC1, GRK5 thus serves an unanticipated function during early development, besides its well-characterized role in the adult heart. These findings could implicate GRK5 as a susceptibility allele for certain cases of CHD.


Regular Sport Activity Is Able to Reduce the Level of Genomic Damage.
Regular physical activity is considered one of the most valid tools capable of reducing the risk of onset of many diseases in humans. However, it is known that intense physical activity can induce high levels of genomic damage, while moderate exercise can elicit a favorable adaptive response by the organism. We evaluated, by the buccal micronuclei assay, the frequencies of micronuclei, nuclear buds and binucleated cells in a sample of amateur athletes practicing different disciplines, comparing the obtained data with those of subjects who practiced sports just occasionally and subjects that did not practice sport at all. The aim was to evaluate whether physical activity affects background levels of genomic damage and whether the different sports disciplines, as well as some gene polymorphisms, differentially affect these levels. A total of 206 subjects, 125 athletes and 81 controls, were recruited. Athletes showed significantly lower values of micronuclei, nuclear buds and binucleated cells with respect to controls. Sprinters and Martial Artists displayed significantly higher frequencies of micronuclei than other categories of athletes. Finally, neither sex nor gene polymorphisms seemed to influence the levels of genomic damage, confirming that the observed genomic damage is probably due to the nature of the sport activity.


Synthesis of furo-salicylanilides and their heterocyclic derivatives with anticipated molluscicidal activity.
The synthesis of new furo-salicylanilides and their heterocyclic derivatives is described. Twenty-three compounds were screened for their molluscicidal activity against Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni. Five of the tested compounds showed no activity, while eighteen compounds showed strong to moderate activity using bayluscide as a reference.


The ameliorating effects of selenium and vitamin C against fenitrothion-induced blood toxicity in Wistar rats.
Fenitrothion is widely used organophosphate pesticide in agriculture and health programs, but besides, it causes several toxic effects. The present study was designed to evaluate the possible protective effects of selenium (0.5mg/kg b.w.) and vitamin C (100mg/kg b.w) on altered haematological, biochemical and oxidative stress parameters in the blood of rats orally treated with fenitrothion (20mg/kg b.w) for 30days. Fenitrothion caused changes in body weight, food and water intake, and some haematological and biochemical parameters. Fenitrothion altered the glutathione redox status (GSH and GSSG) and decreased activity of antioxidant enzymes (GSH-Px, GST, SOD and CAT), leading to a lipid peroxidation. Selenium and vitamin C, by improving the activity of antioxidants, reduced oxidative stress and a lipid peroxidation, maintaining the values of examined parameters to optimal levels. Therefore, selenium and vitamin C could be useful in providing protection of exposed non-target organisms including people from fenitrothion.


Leukodystrophies with astrocytic dysfunction.
Astrocytic dysfunctions have been recently identified in four leukosdystrophies without peripheral nervous system myelin involvement. Alexander disease, the first primary genetic astrocytic disorder identified, is due to dominant GFAP mutations. The presence of Rosenthal fibers throughout the CNS is the pathological hallmark of this disease. Neurological degradation, megalencephaly, and typical MRI pattern are characteristic of infantile sporadic patients. Nevertheless, clinical and MRI expression is large, including late onset forms which can be familial. Spongiform or cystic white matter CNS degeneration is present in the other three recessive disorders. The visualization of a white matter cystic breakdown on MRI has led to the identification of CACH/VWM and MLC diseases. CACH/VWM is due to mutations in one of the five subunits of EIF2B which compromise the astrocytic lineage. The clinical spectrum is large, from antenatal to adult forms, and several extraneurological organs can be affected. Mutations in MLC1, which is mainly expressed in astrocyte endfeet, produce megalencephaly, whereas the mild clinical course contrasts with severe MRI features. An increased concentration of NAA in the urine is sufficient to diagnose Canavan disease, which is due to mutations of the ASPA gene. These disorders highlight the role of astrocytes in myelination or myelin maintenance.


Responses of soil extracellular enzyme activities and microbial community properties to interaction between nitrogen addition and increased precipitation in a semi-arid grassland ecosystem.
Both atmospheric nitrogen (N) deposition and precipitation can strongly impact below-ground biogeochemical processes. Soil extracellular enzymes activities (EEAs) and microorganisms are considered as the key agents in ecosystem nutrient cycling. However, how the interaction between increasing N deposition and precipitation may affect soil EEAs and microbes remain poorly understood. In a 5-year field experiment in a meadow steppe in northern China, we tested the effects of N addition (N0, 0; N1, 5; N2, 10 g N m-2 yr-1) and increased precipitation (W0, ambient precipitation; W1, increase of 15% ambient precipitation; W2, increase of 30% ambient precipitation) on soil EEAs, microbial and chemical properties. Results showed that their interaction significantly affected all hydrolase activities, except for β-1,4-xylosidase (βX). Furthermore, increased precipitation and N addition interactively affected bacterial gene copies (P ≤ 0.05), and increased precipitation comparatively had a stronger effects. The results on the combination of N addition and increased precipitation showed that increased precipitation alleviated the positive effects of N addition on soil EEAs. This implies that the effects of either treatment alone on grassland biogeochemical processes may be alleviated by their simultaneous occurrence. Our results suggested that soil EEAs were mainly controlled by the content of N and phosphorus (P), and the ratio of C: N and C: P. Therefore, soil element content and stoichiometry could better explain the responses of EEAs to global changes. Moreover, soil microbial communities were mainly controlled by soil P content. Overall, our study highlights that the interaction between N deposition and precipitation may play a vital role in predicting the responses of soil enzyme activities to global changes in grassland ecosystems.


Methylation of yeast tRNAPhe by enzymes from cytoplasm, chloroplasts and mitochondria of Phaseolus vulgaris.
Pure yeast tRNAPhe was used as a substrate to compare the tRNA methylating activities in Phaseolus vulgaris cytoplasm, chloroplasts and mitochondria, in the presence of S-adenosyl[Me-3H]methionine. The resulting [Me-3H]-tRNAPhe was then analyzed, using the techniques of nucleotide sequence determination. Cytoplasmic and mitochondrial enzymes catalyze the methylation (into m5C) of C48 present in the extra-loop, while chloroplast enzyme preparations catalyze the modification (into m1A) of A14 present in the dihydrouridine loop of tRNAPhe.


Patients' perspective on the impact of sentinel node biopsy in oral cancer treatment.
Assessment of the impact of a sentinel node biopsy (SNB)-based strategy in cT1/T2 N0 oral cancer on the course of health related quality of life, psychological distress, and shoulder disability, and evaluation of the patients' perspective on neck management strategies. Fifty-two patients (39 SNB negative; 13 SNB positive) completed the European Organization for Research and Treatment of Cancer (EORTC) questionnaires-QLQ-C30 and QLQ-H&N35, and the HADS, IES, and SDQ questionnaires at baseline, after SNB diagnosis and at 6 months of follow-up. Objective shoulder measurements were performed after 2 years and interviews were conducted after 4.5 months of follow-up. All the scores of the questionnaires were not significantly different between SNB negative and SNB positive patients. Objective shoulder functioning was similar. Most patients preferred a SNB-based strategy to an elective neck dissection strategy. The impact of a SNB-based strategy in patients with cT1/T2 N0 oral cancer is comparable for SNB-negative and SNB-positive patients in terms of health-related quality of life, psychological distress and shoulder functioning. Most patients preferred the SNB-based strategy over the elective neck dissection strategy.


Changing mortality patterns of motor neuron disease in Japan.
The age-adjusted female death rate from motor neuron disease in Japan was noted to rise after 1952 and to fall rapidly since about 1960. A similar trend was also noticed in the males. Further study will show whether this was a part of a cyclical change or whether the mortality of the disease has entered a period of prolonged decline in that country. Death rates for neurological diseases in various countries were reported previously for 1953-58. Updating this study for 1966-71, a rising trend of deaths from motor neuron disease was identified in European countries, but the rate has been stationary in the United States. The rapidly changing patterns of the mortality seemed incompatible with a purely genetic causation of the disease. This indicates the need for extensive epidemiological studies to identify the extrinsic factors which induced such a trend, and were thus possibly the cause of the disease. In view of the results of the re-evaluation of the diagnosis in death certificates, mortality figures of motor neuron disease in females appeared reasonably reliable for an epidemiological study.


Cembranoids from the Dongsha Atoll soft coral Lobophytum crassum.
Chemical investigation of the Dongsha Atoll soft coral Lobophytum crassum has afforded four new cembranoids, crassumols A-C (1-3) and 13-acetoxysarcophytoxide (4). The structures of these isolated compounds were elucidated by extensive NMR and HRESIMS experiments. The cytotoxicity and anti-HCMV (Human cytomegalovirus) activities of 1-4 were evaluated in vitro. Compound 4 exhibited cytotoxicity against A-549 (human lung carcinoma) cell line with an ED(50) of 3.6 μg/mL.


Inhibition of eosinophil density change and leukotriene C4 generation by nedocromil sodium.
Nedocromil sodium (NS) has been shown to inhibit the late asthma response to inhaled antigen and to control symptoms in chronic asthma; in both processes the eosinophil is thought to be an important contributor. To understand the antiinflammatory actions of NS in asthma, its effects on three eosinophil functions were evaluated: (1) change in cell density during in vitro culture, (2) synthesis of leukotriene C4 (LTC4), and (3) generation of superoxide anion. In these studies normal density (greater than 1.095 gm/ml) purified human peripheral blood eosinophils were cultured for 24 hours in 50% conditioned medium from cow pulmonary arterial endothelial cells. After incubation, 45.2% +/- 8.0% of the eosinophils had a density less than 1.085 gm/ml. In the presence of NS (10 mumol/L), only 32.0% +/- 7.3% became less dense (p = 0.0393). In contrast, NS had no effect on changes in cell density after a 20-minute exposure of eosinophils to functional activators N-formyl-methionyl-leucyl-phenylalanine (0.1 mumol/L) or platelet activating factor (0.1 mumol/L). Furthermore, calcium ionophore-activated LTC4 secretion was found to be significantly inhibited by NS (3.8 +/- 0.6 ng/ml vs. 2.4 +/- 0.3 ng/ml with 1 mumol/L NS or 1.7 +/- 0.6 ng/ml with 10 mumol/L NS, p less than 0.025). However, NS did not significantly alter eosinophil superoxide anion generation. The effects of NS on eosinophil function suggest a mechanism by which this medication may be effective in asthma, particularly in the regulation of the late asthmatic response. Furthermore, the selective regulatory effects of NS may also provide insight into the biologic activities of eosinophils.


The value of PET/CT to assess clinically negative necks.
The aim was to evaluate the efficacy of [(18)F]-2-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in evaluating metastasis of head and neck squamous cell carcinoma (HNSCC) to the cervical lymph nodes, with specific attention to the efficacy in regard to clinically negative necks. This was a retrospective review of 243 patients with HNSCC between years 2005 and 2007 treated at a comprehensive cancer care institution who underwent pre-operative PET/CT and neck dissection with either an N0 (112 patients) or N+ (131 patients) clinical nodal status. PET/CT findings were correlated with histopathological results of surgical specimens. A majority of the primary sites were oral cavity and oropharynx (70%), followed by larynx, unknown primary and hypopharynx. In the group of 112 patients who underwent 144 neck dissections with N0 nodal status, sensitivity, specificity, positive predictive value (PPV) and negative predictive (NPV) and accuracy were 57, 82, 59, 80 and 74%, respectively. In the group of 131 patients who underwent 169 neck dissections with N+ nodal status, sensitivity, specificity, PPV, NPV and accuracy were 93, 70, 96, 58 and 91%, respectively. PET/CT has a much reduced rate of efficacy for the clinically negative neck compared to the clinically positive neck. PET/CT in its current stage does not appear to offer an advantage in staging the clinically N0 neck due to high rates of false positives and negatives.


Distribution of calcitonin gene-related peptide (CGRP), substance P (SP) and galanin (GAL) immunoreactive nerve fibers in the seminal vesicle and prostate of the male sheep.
Double immunohistochemistry was used to determine the occurrence and distribution pattern of nerve fibres immunoreactive to calcitonin gene-related peptide (CGRP), substance P (SP) and galanin (GAL) in seminal vesicles and prostate of the male sheep. Numerous CGRP- and SP-immunoreactive (IR) nerve fibres were found in the mucosal layer and smooth musculature of the seminal vesicles and prostate. In both glands nerve terminals immunoreactive to CGRP were more numerous than SP-IR ones. The majority of CGRP-IR nerve fibers showed colocalization of this peptide and SP. In both layers of the seminal vesicle and prostate, rare nerve terminals immunoreactive to GAL were also found. Immunoreactivity to SP was also found in all GAL-IR nerve fibers. The presence of numerous CGRP- and SP-IR nerve fibers in the seminal vesicle and prostate of the male sheep suggests that these neuropeptides may be involved in the sensory transmission and/or control of smooth muscle contractility. On the other hand, a relatively low number of GAL-IR nerve fibers of the seminal vesicle and prostate suggest that this peptide may act as an anti-nociceptive agent. It cannot be excluded that, in the seminal vesicle, GAL may also be involved in the control of the smooth muscle fiber activity. The possible role of CGRP, SP and GAL in the regulation of functions of the accessory sexual glands needs to be determined in further physiological studies.