Cytokeratin 13 (CK13) expression in cancer: a tissue microarray study on 10,439 tumors.
Cytokeratin 13 (CK13) is a type I acidic low molecular weight cytokeratin, which is mainly expressed in urothelium and in the squamous epithelium of various sites of origin. Loss of CK13 has been implicated in the development and progression of squamous epithelial neoplasms. To comprehensively determine CK13 expression in normal and neoplastic tissues, a tissue microarray containing 10,439 samples from 131 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. CK13 immunostaining was detectable in 42 (32.1%) of the 131 tumor categories including 24 (18.3%) tumor types with at least one strongly positive case. The highest rate of positive staining was found in various urothelial neoplasms (52.1-92.3%) including Brenner tumor of the ovary (86.8%) and in squamous cell carcinomas from various sites of origin (39.1-77.6%), Warthin tumors of parotid glands (66.7%), adenosquamous carcinomas of the cervix (33.3%), thymomas (16.0%), and endometroid carcinomas of the ovary (15.3%). Twenty other epithelial or germ cell neoplasms showed - a usually weak - CK13 positivity in less than 15% of the cases. In bladder cancer, reduced CK13 expression was linked to high grade and advanced stage (p < 0.0001 each). In squamous cell carcinoma of the cervix, reduced CK13 immunostaining was related to high grade (p = 0.0295) and shortened recurrence-free (p = 0.0094) and overall survival (p = 0.0274). In a combined analysis of 1,151 squamous cell carcinomas from 11 different sites of origin, reduced CK13 staining was linked to high grade (p = 0.0050). Our data provide a comprehensive overview on CK13 expression in normal and neoplastic human tissues. CK13 expression predominates in urothelial neoplasms and in squamous cell carcinomas of different organs, and a loss of CK13 expression is associated with aggressive disease in these tumors.


Self-guided Online Medical Hypnosis Program Improves Dry Nights in Children With Nocturnal Enuresis in a Prospective Single-Center Pilot Study.
Bedwetting is a common condition in children. We evaluated the effectiveness of medical hypnosis as a first-line therapy in children with primary monosymptomatic nocturnal enuresis (PMNE). The study enrolled children in a prospective single-center pilot clinical trial consisting of 1 month diary of dry nights prior to using the commercially available hypnosis intervention (www.keepingthebeddry.com), followed by 3 consecutive months diary following intervention. Seventeen children aged 8 to 15 years old were enrolled and 12 recorded at least 1 month data after the hypnosis intervention. The median dry nights prior to intervention was 8 (0-17) days and improved to 15.5 (7-28) days by the third month post-intervention (P = .0033). All patients who completed the study showed an improvement. Self-guided medical hypnosis therapy showed significant improvement in dry nights without any side effects and any identifiable risk to patients. It should be considered for use in children as first-line therapy for PMNE.


Dead space washout by intentional leakage flow during conventional ventilation of premature infants-an experimental study.
Invasive mechanical ventilation poses a strong risk factor for the development of chronic lung disease in preterm infants. A reduction of the dead space as part of the total breathing volume would reduce the ventilation effort and thereby lower the risk of ventilator-induced lung injuries. In this experimental study, we compared the efficacy of mechanical dead space washout via uncontrolled and controlled leakage flow in their ability to eliminate CO2 during conventional ventilation in preterm infants. Three frequently used neonatal ventilators, operating under standard conventional ventilating parameters, were individually connected to a test lung. To maintain a constant physiological end-expiratory pCO2 level during ventilation, the test lung was continuously flooded with CO2 . A side port in the area of the connector between the endotracheal tube and the flow sensor allowed breathing gas to escape passively or in a second experimental setup, regulated by a pump. Measurements of end-expiratory pCO2 were taken in both experiments and compared to end-expiratory pCO2 levels of ventilation without active dead space leakage. Following dead space washout, a significant reduction of end-expiratory pCO2 was attained. Under conditions of uncontrolled leakage, the mean decrease was 14.1% while controlled leakage saw a mean reduction of 16.1%. Washout of dead space by way of leakage flow is an effective method to reduce end-expiratory pCO2 . Both controlled and uncontrolled leakage provide comparable results, but precise regulation of leakage allows for a more stable ventilation by preventing uncontrolled loss of tidal volume during inspiration.


Anti-VEGF therapy: the search for clinical biomarkers.
Despite the large diffusion and rapid development of anti-VEGF therapy in clinical practice and in contrast to the consolidated evidence with imatinib and trastuzumab that demonstrated a direct correlation between pre-treatment target expression and drug activity, it is very difficult, at present, to identify validated and useful biomarkers to monitor the efficacy of these compounds and to appropriately select patients most likely to benefit from such treatments. However, emerging data suggest that this is not presently feasible for antiangiogenic drugs. Although tumoral and/or circulating VEGF levels have been associated with tumor progression and/or poor prognosis, to date, there is no validated evidence suggesting their role as potential predictive biomarkers of response to anti-VEGF therapy. Recently, many studies have documented promising results with the evaluation of circulating endothelial cells and/or progenitors, and the use of several imaging techniques, such as dynamic contrast-enhanced MRI, PET, dynamic CT scan and functional ultrasound. These preliminary data need a validation in larger prospective trials.


[Tuberculosis treatment for children: An update].
Tuberculosis (TB) is the most important infectious disease all over the world, with a high morbidity and mortality. Pediatric tuberculosis has been a neglected epidemic, due to the difficulties in assessing its global impact, reduced incidence and lower infectivity compared to adults. In 2015, the WHO reported 1 million cases of paediatric TB and 169,000 deaths. In Europe, the emergence of MDR TB is a major concern, representing 16% of the new diagnosis in Eastern Europe. In 2014, it was estimated that about 219,000 children were infected by MDR-TB-strains in Europe, and 2,120 developed the disease. Spain is the Western European country with more paediatric cases, with an incidence 4.3/100,000 inhabitants in 2014. Paediatric tuberculosis mortality in Spain is rare, but extra-pulmonary disease is associated with significant complications. The prevalence of paediatric drug resistant TB in Spain is over 4%, higher than the estimated incidence in adult population, representing mayor difficulties for therapeutic intervention. These data reveal that paediatric TB is still a Public Health priority in our country. The difficulties in diagnosis and the lack of optimal paediatric drug formulations are the major challenges for controlling the childhood's tuberculosis epidemic. A group of national paeditric TB experts has reviewed the international guidelines and the most recent evidences, and has established new recommendations for the management of paediatric TB contacts, latent infection and active TB disease, especially focused in drug resistant cases. This document replaces the former national guidelines from the Spanish Society for Pediatric Infectios Diseases, although the prior recommendations on the diagnosis remain valid.


Chronic Pain Self-Management Program for Low-Income Patients: Themes from a Qualitative Inquiry.
To examine factors influencing initial engagement, ongoing participation, learned behaviors, and subjective functional outcomes after a trial of the Living Better Beyond Pain (LBBP) chronic pain self-management program. Qualitative study using the Grounded Theory approach. Two 60-minute focus groups and phone interviews in May 2017. Focus groups with 18 participants who completed LBBP and six-month measures; telephone interviews with 17 participants who stopped attending. Study coordinators randomly selected program completers for focus groups and conducted phone interviews with noncompleters. Inductive thematic analysis was used to identify patterns in semantic content with a recursive process applied to focus group transcripts and interview transcriptions to codify into themes. Themes were categorized according to the Theory of Planned Behavior. Focus group and telephone interview participants were primarily Hispanic and unemployed. Attitudes fostering participation in LBBP included dissatisfaction with the status quo, need to reduce pain medication, and lack of training and knowledge about chronic pain. Positive social norms from meeting others with chronic pain and support from the LBBP team encouraged attendance and adoption of behaviors. Transportation, pain, and competing activities were barriers, whereas adapting activities for the disabled was a facilitator. Maintaining behaviors and activities at home was challenging but ultimately rewarding due to improvement in daily function with less pain medication. This qualitative study complements quantitative results showing clinically significant improvements in function after the LBBP program by adding practical insights into ways to increase participation and outcomes. Participants strongly endorsed the need for chronic pain self-management training.


Extinction-induced mirror responding as a baseline for studying drug effects on aggression.
Pigeons worked individually in a chamber containing a response key and a mirror. Responding on the key was controlled by a multiple schedule in which a brief period of continuous food reinforcement alternated with a 5 min period of extinction. Under baseline conditions, aggressive behavior (responding on the mirror) occurred at the onset of each extinction period. After 10 saline control sessions, 5 mg/kg of chlordiazepoxide was injected IM 30 min presession for 60 daily sessions. The drug initially produced a marked decrease in aggressive behavior but had little or no effect on key pecking. The aggressive behavior generally remained suppressed during the chronic drug regimen and returned to control levels when the drug was withdrawn. It was concluded that the technique of extinction-induced mirror responding in pigeons provides a stable, sensitive and recoverable baseline for objectively assessing selective drug effects on aggression.


KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment.
Type 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects. Based on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl's VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively. Based on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl's VEP. Our study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy.


Immediate replacement of single upper posterior teeth: a report of cases.
The immediate replacement of upper molar teeth with implants poses a significant challenge to the clinician because of its sinus involvement. The purpose of this article is to report a protocol in which single molar teeth are replaced immediately with implants, minimizing the need for other surgical procedures. This protocol has been employed in eight cases. Briefly, the teeth are extracted atraumatically, the sockets evaluated, an osteotomy performed following the direction of the socket, and a wide diameter implant placed using the socket walls and sinus floor to anchor it. A grafting material is placed when the space between implant and socket wall is considerably large. Three cases are reviewed here, and all eight are summarized. All cases have excellent soft and hard tissue healing after 6 months. Furthermore, the overall time needed to restore the cases has been considerably reduced and the need for sinus management eliminated. The cases presented support the use of the described protocol in the placement of implants in maxillary molar areas without any other sinus procedures.


Intensive Sleep Re-Training: From Bench to Bedside.
Intensive sleep re-training is a promising new therapy for chronic insomnia. Therapy is completed over a 24-h period during a state of sleep deprivation. Improvements of sleep and daytime impairments are comparable to the use of stimulus control therapy but with the advantage of a rapid reversal of the insomnia. The initial studies have been laboratory based and not readily accessible to the patient population. However, new smart phone technology, using a behavioral response to external stimuli as a measure of sleep/wake state instead of EEG determination of sleep, has made this new therapy readily available. Technological improvements are still being made allowing the therapy to provide further improvements in the effectiveness of Intensive Sleep Re-training.


Influence of on-going treatment with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker on the outcome of patients treated with intravenous rt-PA for ischemic stroke.
Many patients who receive intravenous (i.v.) recombinant tissue-plasminogen activator (rt-PA) for acute cerebral ischemia were under angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) at stroke onset. ACE-Is and ARBs have neuroprotective properties in animal models. To evaluate whether the 3-month outcome of patients treated with i.v. rt-PA for cerebral ischemia was influenced by on-going therapy with ACE-Is or ARBs. This study was observational, conducted in two prospective registries of stroke patients treated with i.v. rt-PA. We evaluated outcomes with the modified Rankin scale and symptomatic intracranial hemorrhages (s-ICH) according to the ECASS2 criteria. We compared outcomes between patients with and without ACE-Is/ARBs according to the modified Rankin scale (mRS) at month 3, using logistic regression analyses adjusted on propensity scores, and propensity-matched analyses. Of 1803 patients, 455 (25.2%) were under ACE-Is (259), ARBs (188) or both (8). At 3 months, patients under ACE-Is or ARBs were more likely to have an mRS 0-1, but did not differ for mRS 0-2, s-ICH and death. After adjustment on propensity scores, the association between ACE-Is/ARBs and mRS 0-1 disappeared. The propensity-matched analysis, performed in 397 pairs of patients, found no difference in outcomes between patients with and without ACE-Is or ARBs. In patients treated by intravenous thrombolytic therapy for ischemic stroke, on-going treatment with ACE-Is or ARBs does not influence on outcomes after adjustment on baseline characteristics and propensity scores.


Analysis of the behaviours mediating barnacle cyprid reversible adhesion.
When exploring immersed surfaces the cypris larvae of barnacles employ a tenacious and rapidly reversible adhesion mechanism to facilitate their characteristic 'walking' behaviour. Although of direct relevance to the fields of marine biofouling and bio-inspired adhesive development, the mechanism of temporary adhesion in cyprids remains poorly understood. Cyprids secrete deposits of a proteinaceous substance during surface attachment and these are often visible as 'footprints' on previously explored surfaces. The attachment structures, the antennular discs, of cyprids also present a complex morphology reminiscent of both the hairy appendages used by some terrestrial invertebrates for temporary adhesion and a classic 'suction cup'. Despite the numerous analytical approaches so-far employed, it has not been possible to resolve conclusively the respective contributions of viscoelastic adhesion via the proteinaceous 'temporary adhesive', 'dry' adhesion via the cuticular villi present on the disc and the behavioural contribution by the organism. In this study, high-speed photography was used for the first time to capture the behaviour of cyprids at the instant of temporary attachment and detachment. Attachment is facilitated by a constantly sticky disc surface - presumably due to the presence of the proteinaceous temporary adhesive. The tenacity of the resulting bond, however, is mediated behaviourally. For weak attachment the disc is constantly moved on the surface, whereas for a strong attachment the disc is spread out on the surface. Voluntary detachment is by force, requiring twisting or peeling of the bond - seemingly without any more subtle detachment behaviours. Micro-bubbles were observed at the adhesive interface as the cyprid detached, possibly an adaptation for energy dissipation. These observations will allow future work to focus more specifically on the cyprid temporary adhesive proteins, which appear to be fundamental to adhesion, inherently sticky and exquisitely adapted for reversible adhesion underwater.


[CPAP in acute pulmonary edema. Our experience of the nurse role in the out of hospital life support].
The evolution of the nurse role in out of hospital life support yielded to the employment of tools typical of in-hospital setting, like helmet delivered CPAP. Some elements in the use of this tool have been analyzed: indications, contraindications, application modality and protocol, patient's record, practical aspects of the treatment and problems related to the material employed. Data concerning the application of this technique in 21 patients confirm the indication for its use in advanced nurse out of hospital life support.


Chromatin Conformation in Development and Disease.
Chromatin domains and loops are important elements of chromatin structure and dynamics, but much remains to be learned about their exact biological role and nature. Topological associated domains and functional loops are key to gene expression and hold the answer to many questions regarding developmental decisions and diseases. Here, we discuss new findings, which have linked chromatin conformation with development, differentiation and diseases and hypothesized on various models while integrating all recent findings on how chromatin architecture affects gene expression during development, evolution and disease.


A comparative analysis of the C1-binding ability of fragments derived from complement-fixing and noncomplement-fixing IgM proteins.
The purpose of this study was to examine the molecular parameters necessary for initiation of complement fixation by IgM proteins. To determine why some IgM molecules are capable of complement fixation while others are not, several different Waldenström IgM proteins were examined for their ability to fix total hemolytic complement in the CH(50) assay. Subsequently, the C1 fixing ability of a 56-residue fragment derived from the Cmu4 domain of each of these IgM molecules was studied with C1 fixation assay. One of the three Waldenström IgM proteins (Gr) used in the present study was found unable to consume complement in a CH(50) assay when tested at the same concentration as the two complement-consuming IgM molecules (Dau and Bus). However, when the 56-residue C(H)4 fragment from the Cmu4 domain of each IgM molecule was tested for C1-fixing ability, all three were found to bind C1. On the basis of these observations, it is proposed that a C1 binding site exists within the Cmu4 domain of both complement-fixing and noncomplement-fixing IgM molecules. Presumably, the latter molecules are unable to interact in their native state with C1 in the manner required for initiation of the classical complement pathway, possibly due to the configurational inaccessibility of the entire C1 binding site.


Green tea and the risk of prostate cancer: A systematic review and meta-analysis.
Prostate cancer (PCa) now remains the 2nd most frequently diagnosed cancer. In recent years, chemoprevention for PCa becomes a possible concept. Especially, many phytochemicals rich foods are suggested to lower the risk of cancer. Among these foods, green tea is considered as effective prevention for various cancers. However, clinical trials and previous meta-analyses on the relationship between green tea consumption and the risk of PCa have produced inconsistent outcomes. This study aims to determine the dose-response association of green tea intake with PCa risk and the preventive effect of green tea catechins on PCa risk. Seven observational studies and 3 randomized controlled trials were retrieved from Cochrane Library, PubMed, Sciencedirect Online, and hand searching. The STATA (version 12.0) was applied to analyze the data. The relative risks (RRs) and 95% confidence intervals were pooled by fixed or random effect modeling. Dose-response relations were evaluated with categories of green tea intake. Although there was no statistical significance in the comparison of the highest versus lowest category, there was a trend of reduced incidence of PCa with each 1 cup/day increase of green tea (P = 0.08). Our dose-response meta-analysis further demonstrated that higher green tea consumption was linearly associated with a reduced risk of PCa with more than 7 cups/day. In addition, green tea catechins were effective for preventing PCa with an RR of 0.38 (P = 0.02). In conclusion, our dose-response meta-analysis evaluated the association of green tea intake with PCa risk systematically and quantitatively. And this is the first meta-analysis of green tea catechins consumption and PCa incidence. Our novel data demonstrated that higher green tea consumption was linearly reduced PCa risk with more than 7 cups/day and green tea catechins were effective for preventing PCa. However, further studies are required to substantiate these conclusions.


Clinical Course and Outcome of ESRD Patients on Maintenance Hemodialysis Infected with COVID-19: A Single-Center Study.
In an ESRD subset of patients, COVID-19 infection is associated with increased disease burden and higher mortality rates. We conducted a retrospective single-center cohort study in which 43 ESRD patients had a diagnosis of COVID-19. Association of risk factors with mortality was assessed by chi-square test and logistic regression analysis. Data were collected on a structured performa which included variables like age, gender, comorbid conditions, drug history, clinical presentation, hemodynamic status and laboratory parameters. Outcome variables were recovery and death. All patients received standard treatment for COVID-19 according to hospital protocols, along with hemodialysis and continuous renal replacement therapy (CRRT) when needed. Those most affected were found to be male, 25 (58.1%), while the number of females affected was 18 (41.9%). The most frequent comorbid condition was hypertension (HTN), seen in 35 (81.4%) patients; however, thromboembolic complications were very few in these patients. The mortality rate in our study was 25.6%, and the population most susceptible to poor outcomes in the ESRD subgroup was elderly people (45.5%), while younger patients recovered the most from COVID-19 (53.1%). Hypoalbuminemia, leukocytosis, lymphopenia and raised LDH were also found to be associated with death in ESRD patients suffering from COVID-19 (81.8, 72.7, 100 and 100%, respectively). In multivariate logistic regression analysis, we found that the odds ratio of dying from COVID-19 was 19.5 times higher in patients aged >65 years as compared to patients aged 18-50 years (p=0.039). Similarly, patients with a high TLC were 24.1 times more likely to die than patients with a normal TLC (p=0.008). In our center, the mortality rate of ESRD patients affected with COVID-19 disease was 25.6%, and older age, leukocytosis, lymphopenia, hypoalbuminemia and high LDH were significantly associated with mortality.


A 2cM genome-wide scan of European Holstein cattle affected by classical BSE.
Classical bovine spongiform encephalopathy (BSE) is an acquired prion disease that is invariably fatal in cattle and has been implicated as a significant human health risk. Polymorphisms that alter the prion protein of sheep or humans have been associated with variations in transmissible spongiform encephalopathy susceptibility or resistance. In contrast, there is no strong evidence that non-synonymous mutations in the bovine prion gene (PRNP) are associated with classical BSE disease susceptibility. However, two bovine PRNP insertion/deletion polymorphisms, one within the promoter region and the other in intron 1, have been associated with susceptibility to classical BSE. These associations do not explain the full extent of BSE susceptibility, and loci outside of PRNP appear to be associated with disease incidence in some cattle populations. To test for associations with BSE susceptibility, we conducted a genome wide scan using a panel of 3,072 single nucleotide polymorphism (SNP) markers on 814 animals representing cases and control Holstein cattle from the United Kingdom BSE epidemic. Two sets of BSE affected Holstein cattle were analyzed in this study, one set with known family relationships and the second set of paired cases with controls. The family set comprises half-sibling progeny from six sires. The progeny from four of these sires had previously been scanned with microsatellite markers. The results obtained from the current analysis of the family set yielded both some supporting and new results compared with those obtained in the earlier study. The results revealed 27 SNPs representing 18 chromosomes associated with incidence of BSE disease. These results confirm a region previously reported on chromosome 20, and identify additional regions on chromosomes 2, 14, 16, 21 and 28. This study did not identify a significant association near the PRNP in the family sample set. The only association found in the PRNP region was in the case-control sample set and this was not significant after multiple test correction. The genome scan of the case-control animals did not identify any associations that passed a stringent genome-wide significance threshold. Several regions of the genome are statistically associated with the incidence of classical BSE in European Holstein cattle. Further investigation of loci on chromosomes 2, 14, 16, 20, 21 and 28 will be required to uncover any biological significance underlying these marker associations.


Nivolumab treatment beyond RECIST-defined progression in recurrent or metastatic squamous cell carcinoma of the head and neck in CheckMate 141: A subgroup analysis of a randomized phase 3 clinical trial.
Response patterns with immune checkpoint inhibitors may be different from those with chemotherapy. Therefore, assessment of response to immunotherapy with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, could result in premature treatment termination. The randomized, open-label, phase 3 CheckMate 141 trial (NCT02105636), which evaluated nivolumab in recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, allowed treatment beyond first RECIST-defined progression (TBP) according to protocol-specified criteria. In CheckMate 141, patients with RECIST-defined progression who had a stable performance status and demonstrated clinical benefit without rapid disease progression were permitted to receive TBP with nivolumab at 3 mg/kg every 2 weeks until further progression, which was defined as an additional ≥10% increase in tumor volume. This post hoc analysis evaluated outcomes for patients who received TBP with nivolumab. Of 240 patients randomized to nivolumab, 146 experienced RECIST-defined progression. Sixty-two of these patients received TBP, and 84 discontinued treatment (no TBP). Among the 60 TBP patients evaluable for response, 15 (25%) had no change in their tumor burden, and 15 (25%) had reductions in target lesion size; 3 patients (5%) had reductions >30%. The median overall survival among TBP patients was 12.7 months (95% confidence interval, 9.7-14.6 months). No new safety signals were observed with TBP. Exploratory analyses of immune cell biomarkers suggested a potential relationship with initial and TBP responses. Tumor burden reduction was noted in a proportion of patients who received TBP with nivolumab in CheckMate 141. Additional research is warranted to identify factors predictive of a TBP benefit in this population.


Bilateral comparison of conventional versus topographic-guided customized ablation for myopic LASIK with the NIDEK EC-5000.
To compare visual acuity and higher order aberrations before and after myopic LASIK using conventional versus customized ablation. This prospective, randomized study included 54 myopic eyes in 27 patients who underwent bilateral LASIK using the NIDEK EC-5000 excimer laser system (NIDEK Technologies, Gamagori, Japan). Customized aspheric treatment zone (CATz) treatment was used in one eye (CATz group) and conventional ablation (conventional group) was used in the fellow eye. Uncorrected visual acuity (UCVA) and higher order aberrations (root-mean-square [RMS] in 4-mm and 6-mm zones) of both groups were observed with the NIDEK OPD-Scan aberrometer before and 3 months after LASIK. Preoperative mean refractive error was similar for both eyes of each patient (P>.05). No statistically significant differences were noted in preoperative higher order aberrations (RMS in 4-mm and 6-mm zones) between groups (P>.05). No statistically significant difference was noted between pre- and postoperative higher order aberrations in the CATz group (P>.05). However, a highly statistically significant increase in higher order aberrations was observed after conventional ablation (P<.001). There was a statistically significant higher increase of higher order aberrations after LASIK in the conventional group than the CATz group (P<.05). Postoperative UCVA with both conventional and customized ablation was not significantly different (P>.05). LASIK with conventional ablation and CATz ablation resulted in the same UCVA. The increase in higher order aberrations after CATz ablation was less than after conventional ablation.


Microwave-Assisted Protocol for Green Functionalization of Thiophenes With a Pd/β-Cyclodextrin Cross-Linked Nanocatalyst.
Microwaves (MW) are often the most efficient, in terms of heat exchange and conversion rate, of all the energy sources used to promote chemical reactions thanks to fast volumetric dielectric heating, and metal-catalyzed synthetic reactions under heterogeneous conditions are an eloquent example. We herein report a MW-assisted green protocol for the C-H arylation of thiophenes with substituted aryl halides. This sustainable protocol carried out in γ-valerolactone (GVL) is catalyzed by Pd nanoparticles embedded in cross-linked β-cyclodextrin. In view of the excellent results achieved with activated substrates, the one-pot synthesis of a 4(3H)-quinazolinone derivative has been accomplished. A pressure-resistant MW reactor, equipped with multiple gas inlets, was used for sequential (i) C-H arylation, (ii) reduction, and (iii) carbonylation in the presence of the same catalyst, but under different gas atmospheres. The robust heterogeneous Pd catalyst showed limited metal leaching in GVL, making this an efficient MW-assisted process with high atom economy.


Genetic aspects of human prion diseases.
Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoform of the native prion protein. The prion protein gene (PRNP) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired. PRNP polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomatic mutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches.


Mechanisms of neuronal cell death in Huntington's disease.
Huntington's disease (HD) is a genetically dominant neurodegenerative condition caused by an unique mutation in the disease gene huntingtin. Although the Huntington protein (Htt) is ubiquitously expressed, expansion of the polyglutamine tract in Htt leads to the progressive loss of specific neuronal subpopulations in HD brains. In this article, we will summarize the current understanding on mechanisms of how mutant Htt can elicit cytotoxicity, as well as how the selective sets of neuronal cell death occur in HD brains.


Explaining the MoVO4- photoelectron spectrum: Rationalization of geometric and electronic structure.
Attempts to reconcile simulated photoelectron spectra of MoVO4- clusters are complicated by the presence of very low energy barriers in the potential energy surfaces (PESs) of the lowest energy spin states and isomers. Transition state structures associated with the inversion of terminal oxygen ligands are found to lie below, or close to, the zero point energy of associated modes, which themselves are found to be of low frequency and thus likely to be significantly populated in the experimental characterization. Our simulations make use of Boltzmann averaging over low-energy coordinates and full mapping of the PES to obtain simulations in good agreement with experimental spectra. Furthermore, molecular orbital analysis of accessible final spin states reveals the existence of low energy two-electron transitions in which the final state is obtained from a finite excitation of an electron along with the main photodetachment event. Two-electron transitions are then used to justify the large difference in intensity between different bands present in the photoelectron spectrum. Owing to the general presence of terminal ligands in metal oxide clusters, this study identifies and proposes a solution to issues that are generally encountered when attempting to simulate transition metal cluster photoelectron spectroscopy.


Dynamic sampling iterative phase retrieval for holographic data storage.
A dynamic sampling iterative phase retrieval method, which dynamically samples the Fourier intensity distribution of the reconstruction beam captured by the detector, is proposed to shorten the iterative number and decrease the phase error rate of phase retrieval in the phase-modulated holographic data storage. By the dynamic sampling method, that keeping relatively low frequency component of Fourier intensity spectrum at the beginning of iteration and gradually releasing more high frequency component at the subsequent iterations, we shortened the iterative number by 2 times and decreased the phase error rate to some extent because our method provided a better convergent path to the phase retrieval. We also believe the thought of our method can be used in more image retrieval fields.


Identification of subgroups of childhood asthmatics: a review.
Given the literature suggesting etiological variability among asthmatics, the research pertaining to the identification of etiological subgroups was reviewed. The most promising prospects are: 1) the presence or absence of emotional precipitants of asthmatic symptoms and 2) the emotional reaction of the patient to his symptoms (e.g., "panic-fear"). These two dimensions have been found to be uncorrelated. The two studies that explored the treatment implications of these factors produced mixed results. Nonetheless, it may be promising to pursue the notion of identifiable subgroups that respond differently to psychological intervention.


Guidelines for computer security in general practice.
As general practice becomes increasingly computerised, data security becomes increasingly important for both patient health and the efficient operation of the practice. To develop guidelines for computer security in general practice based on a literature review, an analysis of available information on current practice and a series of key stakeholder interviews. While the guideline was produced in the context of Australian general practice, we have developed a template that is also relevant for other countries. Current data on computer security measures was sought from Australian divisions of general practice. Semi-structured interviews were conducted with general practitioners (GPs), the medical software industry, senior managers within government responsible for health IT (information technology) initiatives, technical IT experts, divisions of general practice and a member of a health information consumer group. The respondents were asked to assess both the likelihood and the consequences of potential risks in computer security being breached. The study suggested that the most important computer security issues in general practice were: the need for a nominated IT security coordinator; having written IT policies, including a practice disaster recovery plan; controlling access to different levels of electronic data; doing and testing backups; protecting against viruses and other malicious codes; installing firewalls; undertaking routine maintenance of hardware and software; and securing electronic communication, for example via encryption. This information led to the production of computer security guidelines, including a one-page summary checklist, which were subsequently distributed to all GPs in Australia. This paper maps out a process for developing computer security guidelines for general practice. The specific content will vary in different countries according to their levels of adoption of IT, and cultural, technical and other health service factors. Making these guidelines relevant to local contexts should help maximise their uptake.


Thermal desorption as a high removal remediation technique for soils contaminated with per- and polyfluoroalkyl substances (PFASs).
Soils contaminated with per- and polyfluoroalkyl substances (PFASs) are an important source for impacting drinking water delivery systems and surface water bodies world-wide, posing an urgent risk to human health and environmental quality. However, few treatment techniques have been tested for PFAS-contaminated soil hotspots. This study investigated the possibility of thermal desorption as a possible technique to remediate soils contaminated with multiple PFASs. Two fortified soils (∑9PFAS ≈ 4 mg kg-1) and one field-contaminated soil (∑9PFAS ≈ 0.025 mg kg-1) were subjected to a 75-min thermal treatment at temperatures ranging from 150 to 550°C. Soil concentrations of PFASs showed a significant decrease at 350°C, with the ∑9PFAS concentration decreasing by, on average, 43% and 79% in the fortified and field contaminated soils, respectively. At 450°C, >99% of PFASs were removed from the fortified soils, while at 550°C the fraction removed ranged between 71 and 99% for the field contaminated soil. In the field contaminated soil, PFAS classes with functional groups of sulfonates (PFSAs) and sulfonamides (FOSAs) showed higher removal than the perfluoroalkyl carboxylates (PFCAs). Thus thermal desorption has the potential to remove a wide variety of PFASs from soil, although more studies are needed to investigate the cost-effectiveness, creation of transformation products, and air-phase vacuum filtration techniques.


Combined effect of cigarette smoking and allergic rhinitis on airway responsiveness to inhaled methacholine.
A group of healthy nonatopic subjects was compared with a group of atopic subjects with allergic rhinitis who were otherwise healthy. They were matched for sex, age, and smoking habits; 15 pairs were nonsmokers and 11 pairs were smokers. Threshold of airway response to inhaled methacholine based on partial flow-volume curves was not significantly different between nonatopic nonsmokers and nonsmokers with allergic rhinitis. However, smokers with allergic rhinitis had a threshold on the average of 3 doubling doses lower than smokers without allergic rhinitis. We concluded that there is a combined effect of chronic cigarette smoking and allergic rhinitis affecting nonspecific airway responsiveness.


Exploring the double burden of malnutrition at the household level in the Philippines: Analysis of National Nutrition Survey data.
In the Philippines, the rising prevalence of obesity and related chronic diseases alongside persistent undernutrition presents a complex public health challenge. Understanding the patterns and dynamics of this 'double burden of malnutrition' (DBM) is crucial for developing effective intervention strategies. However, evidence of the occurrence of undernutrition and overnutrition within the same household is currently lacking. Using cross-sectional data from the 2013 Philippines National Nutrition Survey this study examined the prevalence of different typologies of household-level DBM from an analytical sample of 5,837 households and 25,417 individuals. Multivariable logistic regression was performed to identify factors associated with overall occurrence of intrahousehold DBM. The overall prevalence of double burden households was 56% based on a comprehensive definition. The most common typology of intrahousehold DBM characterized in this study (% of all households) comprised households with at least one adult with overnutrition and at least one separate adult with undernutrition. Household size, wealth quintile, food insecurity, and household dietary diversity were all associated with household-level DBM. Double burden households were also influenced by head of household characteristics, including sex, level of education, employment status, and age. The findings from this study reveal that the coexistence of overnutrition and undernutrition at the household level is a major public health concern in the Philippines. Further comprehensive assessments of household-level manifestations of the DBM are needed to improve our understanding of the trends and drivers of this phenomenon in order to develop better targeted interventions.


Torin 1 alleviates impairment of TFEB-mediated lysosomal biogenesis and autophagy in TGFBI (p.G623_H626del)-linked Thiel-Behnke corneal dystrophy.
Thiel-Behnke corneal dystrophy (TBCD) is an epithelial-stromal TGFBI dystrophy caused by mutations in the TGFBI (transforming growth factor beta induced) gene, though the underlying mechanisms and pathogenesis of TBCD are still obscure. The study identifies a novel mutation in the TGFBI gene (p.Gly623_His626del) in a TBCD pedigree. Characteristics of the typical vacuole formation, irregular corneal epithelial thickening and thinning, deposition of eosinophilic substances beneath the epithelium, and involvement of the anterior stroma were observed in this pedigree via transmission electron microscopy (TEM) and histological staining. Tgfbi-p.Gly623_Tyr626del mouse models of TBCD were subsequently generated via CRISPR/Cas9 technology, and the above characteristics were further verified via TEM and histological staining. Lysosomal dysfunction and downregulation of differential expression protein CTSD (cathepsin D) were observed using LysoTracker Green DND-26 and proteomic analysis, respectively. Hence, lysosomal dysfunction probably leads to autophagic flux obstruction in TBCD; this was supported by enhanced LC3-II and SQSTM1 levels and decreased CTSD. TFEB (transcription factor EB) was prominently decreased in TBCD corneal fibroblasts and administration of ATP-competitive MTOR inhibitor torin 1 reversed this decline, resulting in the degradation of accumulated mut-TGFBI (mutant TGFBI protein) via the ameliorative lysosomal function and autophagic flux owing to elevated TFEB activity as measured by western blot, confocal microscopy, and flow cytometry. Transfected HEK 293 cells overexpressing human full-length WT-TGFBI and mut-TGFBI were generated to further verify the results obtained in human corneal fibroblasts. Amelioration of lysosome dysfunction may therefore have therapeutic efficacy in the treatment of TBCD.Abbreviations AS-OCT: anterior segment optical coherence tomography; ATP: adenosine triphosphate; Cas9: CRISPR-associated protein 9; CLEAR: coordinated lysosomal expression and regulation; CRISPR: clustered regularly interspaced short palindromic repeats; CTSB: cathepsin B; CTSD: cathepsin D; CTSF: cathepsin F; CTSL: cathepsin L; DNA: deoxyribonucleic acid; ECM: extracellular matrix; Fas1: fasciclin 1; FC: flow cytometry; GAPDH: glyceraldeyde-3-phosphate dehydrogenase; GCD2: granular corneal dystrophy type 2; HE: hematoxylin and eosin; LAMP2: lysosomal-associated membrane protein; MT: mutation type; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; mut-TGFBI: mutant TGFBI protein; SD: standard deviation; TBCD: Thiel-Behnke corneal dystrophy; TEM: transmission electron microscopy; TFEB: transcription factor EB; TGFBI: transforming growth factor beta induced; WT: wild type.


Neurocysticercosis: surgical treatment of an autochthonous case in a non-endemic region.
This study describes a case of autochthonous neurocysticercosis in a non endemic region where a differential diagnosis with more frequent single parenchymal lesions must be carried out. The patient presenting generalized seizures and coma status under the suspicion of cerebral neoplasia was admitted to the neurosurgery division. MRI showed the presence of an ovoidal cystic lesion in right-frontotemporal region. After right fronto-temporal osteoplastic bone flap elevation and usual dural tacking and opening, trans-scissural subaracnoid access was made possible by microsurgical strumentation in right Sylvian fissure. A cystic, translucid lesion was identified in the deep Sylvian fissure, involving the distal segment of the fissure and the frontal lobe, the cystic lesion was removed surgically. Pathological examination showed a typical picture of neurocysticercosis. After both surgical and chemotherapeutic treatment with albendazole the outcome was successful. The diagnosis of neurocysticercosis should be taken into account in the presence of generalized seizures possibly due to single parenchymal lesions, even in non-endemic regions for this parasitic infection.


Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights.
The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at "high-risk". Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.


3D quantitative evaluation of spine proprioceptive perception/motor control through instinctive self-correction maneuver in healthy young subjects' posture: an observational study.
Conservative treatment in spine deformities and spine related disorders is mainly based on proper individual proprioceptive and motor control training. For these reasons, conservative treatment involves the stimulation of individual capability of perceiving/reducing deformities, blocks and/or improper spine posture by voluntary control. The literature describes that habitually adopted relaxed postures often exacerbate low back pain. Typically, youths can be referred to therapeutic programs aimed at improving the quality of body posture along with fostering the awareness of the importance of correct posture. Few studies in literature outline the subject's individual instinctive ability to perceive properly and control his/her posture and produce an improvement through a self-correction maneuver. How do healthy young adult subjects perceive and control their posture and spine shape? Are they able to modify them in a correct way through an instinctive self-correction maneuver? Cross-sectional observational study. A cohort of asymptomatic young adult university students and workers were recruited at Clinic of Rehabilitation, University of Medical Sciences, Poznan, Poland. One hundred and twenty-one healthy subjects (57 females, 64 males), aged 19-34 years (mean age: 23.5±3.2 years). Subject's full body posture including 3D spine shape reconstruction, identified using 27 retro-reflective markers suitably located on anatomical landmarks has been measured by using a non-ionizing 3D optoelectronic stereo-photogrammetric approach and a 3D full skeleton biomechanical model. From the 3D full skeleton and spine reconstruction, eleven quantitative biomechanical parameters describing the nature of body posture have been computed to compare natural erect versus self-corrected standing attitudes. A great number of healthy participants (105, 87%) was unable to modify its spinal shape in the frontal plane. Conversely, the sagittal plane presented significant clinical changes in the thoracic spine, as males reached a greater thoracic spine extension (36.4±8.3) than females (40.8±8.7). When changes occurred, subjects were not able to focus and control their posture globally, but only on few aspects at a time. Instinctive posture proprioception and motor control do not produce an effective self-correction maneuver yielding a global improvement of body posture and spine shape. Self-correction maneuver producing an improvement of body posture and spine shape has to be learned with specific postural training. The 3D stereo-photogrammetric approach is effective in quantitatively describe subject's posture, motor control and proprioceptive capability.


MALDI-FT-ICR-MS for archaeological lipid residue analysis.
Soft-ionization methods are currently at the forefront of developing novel methods for analysing degraded archaeological organic residues. Here, we present little-used soft ionization method of matrix assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance-mass spectrometry (MALDI-FT-ICR-MS) for the identification of archaeological lipid residues. It is a high-resolution and sensitive method with low limits of detection capable of identifying lipid compounds in small concentrations, thus providing a highly potential new technique for the analysis of degraded lipid components. A thorough methodology development for analysing cooked and degraded food remains from ceramic vessels was carried out, and the most efficient sample preparation protocol is described. The identified components, also controlled by independent parallel analysis by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS), demonstrate its capability of identifying very different food residues including dairy, adipose fats as well as lipids of aquatic origin. The results obtained from experimentally cooked and original archaeological samples prove the suitability of MALDI-FT-ICR-MS for analysing archaeological organic residues. Sample preparation protocol and identification of compounds provide future reference for analysing various aged and degraded lipid residues in different organic and mineral matrices.


CHLAMYDIA PSITTACI IN FERAL ROSY-FACED LOVEBIRDS ( AGAPORNIS ROSEICOLLIS) AND OTHER BACKYARD BIRDS IN MARICOPA COUNTY, ARIZONA, USA.
In 2013, a mortality event of nonnative, feral Rosy-faced Lovebirds ( Agapornis roseicollis) in residential backyards in Maricopa County, Arizona, US was attributed to infection with Chlamydia psittaci. In June 2014, additional mortality occurred in the same region. Accordingly, in August 2014 we sampled live lovebirds and sympatric bird species visiting backyard bird feeders to determine the prevalence of DNA and the seroprevalence of antibodies to C. psittaci using real-time PCR-based testing and elementary body agglutination, respectively. Chlamydia psittaci DNA was present in conjunctival-choanal or cloacal swabs in 93% (43/46) of lovebirds and 10% (14/142) of sympatric birds. Antibodies to C. psittaci were detected in 76% (31/41) of lovebirds and 7% (7/102) of sympatric birds. Among the sympatric birds, Rock Doves ( Columba livia) had the highest prevalence of C. psittaci DNA (75%; 6/8) and seroprevalence (25%; 2/8). Psittacine circovirus 1 DNA was also identified, using real-time PCR-based testing, from the same swab samples in 69% (11/16) of species sampled, with a prevalence of 80% (37/46) in lovebirds and 27% (38/142) in sympatric species. The presence of either Rosy-faced Lovebirds or Rock Doves at residential bird feeders may be cause for concern for epizootic and zoonotic transmission of C. psittaci in this region.


Rhizobium strains differ considerably in outer membrane permeability and polymyxin B resistance.
Six rhizobium (Rhizobium leguminosarum bv. Trifolii TA1, Sinorhizobium meliloti 1021, Mesorhizobium huakuii IFO 15243(T), Ochrobactrum lupini LUP 21(T), Bradyrhizobium japonicum USDA110 and B. elkanii USDA 76) and two Escherichia coli strains (E. coli ATCC 25922 and E. coli HB 101) were compared in respect to polymyxin B and EDTA resistance, as well as bacterial outer membrane (OM) permeability to a fluorescent hydrophobic agent (N-phenyl-1-naphthylamine - NPN). TEM (Transmission Electron Microscopy) and a microbial test demonstrated that all the rhizobia were much more resistant to polymyxin B in comparison with E. coli strains. EDTA and polymyxin B enhance permeability of B. japonicum and O. lupini OM. Other rhizobia incorporated NPN independently of the presence of membrane-deteriorating agents; however, the level of fluorescence (measured as NPN absorption) was strain dependent.


Thermodynamics of blue phases in electric fields.
We present extensive numerical studies to determine the phase diagrams of cubic and hexagonal blue phases in an electric field. We confirm the earlier prediction that hexagonal phases, both two and three dimensional, are stabilized by a field, but we significantly refine the phase boundaries, which were previously estimated by means of a semianalytical approximation. In particular, our simulations show that the blue phase I-blue phase II transition at fixed chirality is largely unaffected by electric field, as observed experimentally.


Differentiation between Shallow and Deep Charge Trap States on Single Poly(3-hexylthiophene) Chains through Fluorescence Photon Statistics.
Blinking of the photoluminescence (PL) emitted from individual conjugated polymer chains is one of the central observations made by single-molecule spectroscopy (SMS). Important information, for example regarding excitation energy transfer, can be extracted by evaluating dynamic quenching. However, the nature of trap states, which are responsible for PL quenching, often remains obscured. We present a detailed investigation of the photon statistics of single poly(3-hexylthiophene) (P3HT) chains obtained by SMS. The photon statistics provide a measure of the number and brightness of independently emitting areas on a single chain. These observables can be followed during blinking. A decrease in PL intensity is shown to be correlated with either 1) a decrease in the average brightness of the emitting sites; or 2) a decrease in the number of emitting regions. We attribute these phenomena to the formation of 1) shallow charge traps, which can weakly affect all emitting areas of a single chain at once; and 2) deep traps, which have a strong effect on small regions within the single chains.


Coenzyme Q10 serum concentration and redox status in European adults: influence of age, sex, and lipoprotein concentration.
Coenzyme Q10 (CoQ10) is synthesized in almost all human tissues and presumably involved in age-related alterations and diseases. Here, we examined the impact of aging and sex on the serum CoQ10 status in 860 European adults ranging in age from 18 to 82 years. We identified an inverse U-shaped relationship between CoQ10 concentration and age. Women showed lower cholesterol-adjusted CoQ10 levels than men, irrespective of age. As observed in both sexes, the decrease in CoQ10 concentration in older subjects was accompanied by a shift in the redox status in favour of the oxidized form. A strong positive correlation was found for total CoQ10 and cholesterol concentrations (Spearman's, p≤1E-74). We found strong negative correlations between total (Spearman's, p≤1E-07) and between cholesterol-adjusted CoQ10 concentration (Spearman's, p≤1E-14) and the proportion of the oxidized form of CoQ10. These correlations were not dependent on age and sex and were attenuated by supplementation with 150 mg/day reduced CoQ10 for 14 days. Overall, our results are useful to define risk groups with critical CoQ10 status in humans. In particular, older subjects were characterized by impaired CoQ10 status due to their lowered serum CoQ10 concentration and concomitant decrease of CoQ10 redox capacity.


Performance of the general-model-space state-universal coupled-cluster method.
The capabilities of the recently developed multireference, general-model-space (GMS), state-universal (SU) coupled-cluster (CC) method have been extended in order to enable the handling of any excited state that represents a single (S) or a double (D) excitation relative to the ground state. A series of calculations concerning the ground and excited states of the CH(+), HF, F(2), H(2)O, NH(2), and CH(2) molecules were carried out so as to assess the performance of the GMS SU CCSD method. For diatomics we have computed the entire potential energy curves, while for triatomics we have focused on vertical excitation energies. We demonstrate how a systematic enlargement of the model space enables a consideration of a larger and larger number of excited states. A comparison of the CC and full configuration interaction or large-scale CI results enables an assessment of the accuracy and reliability of the GMS SU CCSD method within a given basis set. In all cases very good results have been obtained, including highly excited states and those having a doubly-excited character.


queryMed: Semantic Web functions for linking pharmacological and medical knowledge to data.
In public health research and more precisely in the reuse of electronic health data, selecting patients, identifying specific events and interpreting results typically requires biomedical knowledge. The queryMed R package aims to facilitate the integration of medical and pharmacological knowledge stored in formats compliant with the Linked Data paradigm (e.g. OWL ontologies and RDF datasets) into the R statistical programming environment. We show how it allowed us to identify all the drugs prescribed for critical limb ischemia (CLI) and also to detect one contraindicated prescription for one patient by linking a medical database of 1003 CLI patients to ontologies. queryMed is readily usable for medical data mappings and enrichment. Sources, R vignettes and test data are available on GitHub (https://github.com/yannrivault/queryMed) and are archived on Zenodo (https://doi.org/10.5281/zenodo.1323481).


Mechanisms through which ammonia regulates cortical collecting duct net proton secretion.
Ammonia stimulates cortical collecting duct (CCD) net bicarbonate reabsorption by activating an apical H(+)-K(+)-ATPase through mechanisms that are independent of ammonia's known effects on intracellular pH and active sodium transport. The present studies examined whether this stimulation occurs through soluble N-ethylmaleimide-sensitive fusion attachment receptor (SNARE) protein-mediated vesicle fusion. Rabbit CCD segments were studied using in vitro microperfusion, and transepithelial bicarbonate transport was measured using microcalorimetry. Ammonia's stimulation of bicarbonate reabsorption was blocked by either chelating intracellular calcium with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester or by inhibiting microtubule polymerization with colchicine compared with parallel studies performed in the absence of these inhibitors. An inactive structural analog of colchicine, lumicolchicine, did not alter ammonia's stimulation of bicarbonate reabsorption. Tetanus toxin, a zinc endopeptidase specific for vesicle-associated SNARE (v-SNARE) proteins, prevented ammonia from stimulating net bicarbonate reabsorption. Consistent with the functional evidence for v-SNARE involvement, antibodies directed against a conserved region of isoforms 1-3 of the tetanus toxin-sensitive, vesicle-associated membrane protein (VAMP) members of v-SNARE proteins labeled the apical and subapical region of collecting duct intercalated cells. Similarly, antibodies to NSF protein, a protein involved in activation of SNARE proteins for subsequent vesicle fusion, localized to the apical and subapical region of collecting duct intercalated cells. These results indicate that ammonia stimulates CCD bicarbonate reabsorption through an intracellular calcium-dependent, microtubule-dependent, and v-SNARE-dependent mechanism that appears to involve insertion of cytoplasmic vesicles into the apical plasma membrane of CCD intercalated cells.


Lack of evidence that avian oncogenic viruses are infectious for humans: a review.
Chickens may be infected with three different oncogenic viruses: avian leukosis virus (ALV), reticuloendotheliosis virus (REV), and Marek's disease herpesvirus (MDV). Several epidemiological studies have suggested a link between these viruses and different types of cancer in people working in poultry processing plants and with multiple sclerosis. In this article, we analyze the epidemiological evidence that these viruses are causative agents for human cancer, followed by description of the relevant key characteristics of ALV, REV, and MDV. Finally, we discuss the biological evidence or lack thereof that avian tumor viruses are involved in the etiology of human cancer and multiple sclerosis (MS). The recent primary epidemiologic articles that we reviewed as examples were only hypothesis-generating studies examining massive numbers of risk factors for associations with various imprecise, non-viral-specific outcomes. The studies lacked precise evidence of exposure to the relevant viruses and the statistical methods failed to adjust for the large risks of false-positive claims. ALV subgroups A-D and J have been eradicated in the United States from the pure lines down to the parent stocks by the breeder companies, which have greatly reduced the incidence of infection in layer flocks and broilers. As a consequence, potential exposure of humans to these viruses has greatly diminished. Infection of humans working in processing plants with ALV-A and ALV-B is unlikely, because broilers are generally resistant to infection with these two subgroups. Moreover, these viruses enter cells by specific receptors present on chicken, but not on mammalian, cells. Infection of mammalian cell cultures or animals with ALV-A, ALV-B, and ALV-J has not been reported. Moreover, humans vaccinated with exogenous or endogenous ALV-contaminated vaccines against yellow fever, measles, and mumps did not become antibody- or virus-positive for ALV. The risks for human infection with REV are similarly limited. First of all, REV also has been eradicated from pure lines down to parent stock by breeder companies in the United States. Broilers can still become infected with REV through infection with fowl pox virus containing REV. However, there is no indication that REV can infect human cells. Low levels of antibodies to ALV and REV in human sera have been reported by a few groups. Absorption of sera with chicken antigens reduced the antibody titers, and there was no clear association with contacts with poultry. Possible cross-reactions with human endogenous or exogenous retroviruses were not considered in these publications. MDV is typically associated with infection of chickens, and almost all experimental data show that MDV cannot infect mammalian cells or animals, including nonhuman primates. One study reports the presence of MDV gD DNA in human sera, but this finding could not be confirmed by another group. A Medline search of the term "gene expression in human cancers" was negative for publications with avian retroviruses or MDV. In conclusion, there is no indication that avian oncogenic viruses are involved in human cancer or MS or even able to infect and replicate in humans.


Interdisiplinary and intraobserver reliability of the Greulich-Pyle method among Turkish children.
Greulich-Pyle (GP) is one of the most used method for bone age determination (BAD) in various orthopedic, pediatric, radiological, and forensic situations. We aimed to investigate the inter- and intra-observer reliability of the GP method between the most relevant disciplines and its applicability to the Turkish population. One-hundred and eighty (90 boys, 90 girls) patients with a chronological age younger than 18 (mean 9.33) were included. X-rays mixed by the blinded investigator were evaluated by two orthopedists, two radiologists, and two pediatric endocrinologists to determine skeletal age according to the GP atlas. A month later the process was repeated. As a statistical method, Paired t-test was used for comparison, an Intraclass Correlation Coefficients test was used for reliability and a 95 % confidence interval was determined. Results were classified according to Landis-Koch. All results were consistent with chronological age (p<0.001), according to the investigators' evaluations compared with chronological age. At the initial evaluation, the interobserver reliability of the method was 0.999 (excellent); at the second evaluation, the interobserver reliability was 0.997 (excellent). The intra-observer reliability of the method was 'excellent' in all observers. When results were separately evaluated by gender, excellent intraobserver correlation and excellent correlation with chronological age were found among all researchers (>0.9). When X-rays were divided into three groups based on age ranges and evaluated, 'moderate' and 'good' correlations with chronological age were obtained during the peripubertal period. The GP method used in skeletal age determination has excellent inter- and intra-observer reliability. During the peripubertal period, potential discrepancies in bone age assessments should be kept in mind. This method can be used safely and reproducibly by the relevant specialists.


Type I Interferon Responses by HIV-1 Infection: Association with Disease Progression and Control.
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome and its infection leads to the onset of several disorders such as the depletion of peripheral CD4+ T cells and immune activation. HIV-1 is recognized by innate immune sensors that then trigger the production of type I interferons (IFN-Is). IFN-Is are well-known cytokines eliciting broad anti-viral effects by inducing the expression of anti-viral genes called interferon-stimulated genes (ISGs). Extensive in vitro studies using cell culture systems have elucidated that certain ISGs such as APOBEC3G, tetherin, SAM domain and HD domain-containing protein 1, MX dynamin-like GTPase 2, guanylate-binding protein 5, and schlafen 11 exert robust anti-HIV-1 activity, suggesting that IFN-I responses triggered by HIV-1 infection are detrimental for viral replication and spread. However, recent studies using animal models have demonstrated that at both the acute and chronic phase of infection, the role of IFN-Is produced by HIV or SIV infection in viral replication, spread, and pathogenesis, may not be that straightforward. In this review, we describe the pluses and minuses of HIV-1 infection stimulated IFN-I responses on viral replication and pathogenesis, and further discuss the possibility for therapeutic approaches.


Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4.
Mouse olfactory epithelium (OE) originates from ectodermally derived placode, the olfactory placode that arises at the anterior end of the neural plate. Tissue grafting and recombination experiments suggest that the placode is derived from a common preplacodal domain around the neural plate and its development is directed by signals arising from the underlying mesoderm and adjacent neuroectoderm. In mice, loss of Six1 affects OE morphogenesis but not placode formation. We show here that embryos lacking both Six1 and Six4 failed to form the olfactory placode but the preplacodal region appeared to be specified as judged by the expression of Eya2, which marks the common preplacodal domain, suggesting a synergistic requirement of Six1 and Six4 in patterning the preplacodal ectoderm to a morphologic placode. Our results show that Six1 and Six4 are coexpressed in the preplacodal ectoderm from E8.0. In the olfactory pit, Six4 expression was observed in the peripheral precursors that overlap with Mash1-expressing cells, the early committed neuronal lineage. In contrast, Six1 is highly distributed in the peripheral regions where stem cells reside at E10.5 and it overlaps with Sox2 expression. Both genes are expressed in the basal and apical neuronal progenitors in the OE. Analyses of Six1;Six4 double mutant embryos demonstrated that the slightly thickened epithelium observed in the mutant was not induced for neuronal development. In contrast, in Six1(-/-) embryos, all neuronal lineage markers were initially expressed but the pattern of their expression was altered. Although very few, the pioneer neurons were initially present in the Six1 mutant OE. However, neurogenesis ceased by E12.5 due to markedly increased cell apoptosis and reduced proliferation, thus defining the cellular defects occurring in Six1(-/-) OE that have not been previously observed. Our findings demonstrate that Six1/4 function at the top of early events controlling olfactory placode formation and neuronal development. Our analyses show that the threshold of Six1/4 may be crucial for the expression of olfactory specific genes and that Six1 and Six4 may act synergistically to mediate olfactory placode specification and patterning through Fgf and Bmp signaling pathways.


The first stage of the history of orthopaedics in Norway: the therapy of "self-correction".
In this contribution, an account is intended for the earliest stage of the Norwegian history of orthopaedics, which runs from 1838 up to about 1880 and is characterized by a peculiar method for the straightening out of spine curvatures, the so-called therapy of "self-correction". In particular some possible causes of the high degree of recognition this orthopaedic therapy received in Norway are indicated.


Effect of malnutrition during pregnancy on the development of the mammary glands of rats.
Sprague-Dawley rats fed 50% of normal food intake from day 5 of gestation had a marked reduction in the weight of their left mammary glands compared with control nonrestricted animals. The affected glands had a significant reduction in DNA, RNA and protein content. Protein/DNA ratio was also reduced while RNA/DNA ratio was unchanged. Histological studies of the glands revealed a reduced number of parenchymal cells, reduced cell size and larger lumen within the alveoli.


Induction of axonal differentiation by silencing plasma membrane-associated sialidase Neu3 in neuroblastoma cells.
A reduction of 70% of the plasma membrane-associated sialidase Neu3 activity, due to a corresponding reduction of the enzyme expression by transducing cells with a short hairpin RNA encoding a sequence target (complementary messenger of mouse Neu3), caused neurite elongation in Neuro2a murine neuroblastoma cells. The differentiation process was accompanied in parallel by an increase of the acetylcholinesterase activity, a moderate increase of the c-Src expression and by the presence of the axonal marker tau protein on the neurites. The sphingolipid pattern and turnover in transduced and control cells were characterized by thin layer chromatography, mass spectrometry and metabolic radiolabeling after feeding cells with tritiated sphingosine. Control cells contained about 2 nmol of gangliosides/mg cell protein. GM2 was the main compound, followed by GD1a, GM3 and GM1. In Neu3 silenced cells, the total ganglioside content remained quite similar, but GM2 increased by 54%, GM3 remain constant, and GM1 and GD1a decreased by 66% and 50%, respectively. Within the organic phase sphingolipids, ceramide decreased by 50%, whereas the sphingomyelin content did not change in Neu3 silenced cells.


CaBP1 regulates Cav1 L-type Ca2+ channels and their coupling to neurite growth and gene transcription in mouse spiral ganglion neurons.
CaBP1 is a Ca2+ binding protein that is widely expressed in neurons in the brain, retina, and cochlea. In heterologous expression systems, CaBP1 interacts with and regulates voltage-gated Cav Ca2+ channels but whether this is the case in neurons is unknown. Here, we investigated the cellular functions of CaBP1 in cochlear spiral ganglion neurons (SGNs), which express high levels of CaBP1. Consistent with the role of CaBP1 as a suppressor of Ca2+-dependent inactivation (CDI) of Cav1 (L-type) channels, Cav1 currents underwent greater CDI in SGNs from mice lacking CaBP1 (C-KO) than in wild-type (WT) SGNs. The coupling of Cav1 channels to downstream signaling pathways was also disrupted in C-KO SGNs. Activity-dependent repression of neurite growth was significantly blunted and unresponsive to Cav1 antagonists in C-KO SGNs in contrast to WT SGNs. Moreover, Cav1-mediated Ca2+ signals and phosphorylation of cAMP-response element binding protein were reduced in C-KO SGNs compared to WT SGNs. Our findings establish a role for CaBP1 as an essential regulator of Cav1 channels in SGNs and their coupling to downstream pathways controlling activity-dependent transcription and neurite growth.


Risk factors for the development of autism spectrum disorder in children with tuberous sclerosis complex: protocol for a systematic review.
Tuberous sclerosis complex (TSC) is an autosomal dominant condition, caused by mutations in either the TSC1 or TSC2 gene. It has widespread systemic manifestations and is associated with significant neurological morbidity. In addition to seizures and cerebral pathology including cortical tubers, subependymal nodules, subependymal giant cell astrocytoma and abnormal white matter, there are recognised neuropsychiatric difficulties including intellectual disability, autism spectrum disorder (ASD) and a range of learning and behaviour problems, recently conceptualised as "tuberous sclerosis-associated neuropsychiatric disorders", or "TAND". ASD in TSC is of particular importance because (1) it affects up to 50% of people with TSC and is a source of considerable difficulty for them and their families and (2) it provides a model for considering neurobiological pathways involved in ASD. Multiple factors are implicated in the development of ASD in TSC, including (1) seizures and related electrophysiological factors, (2) cerebral pathology, (3) genotype and (4) child characteristics. However, the neurobiological pathway remains unclear. We will conduct a systematic review to investigate and synthesise existing evidence about the role of these risk factors, individually and in combination, in leading to the development of ASD. Our review will report on all studies that include one or more of four predefined risk factors in the development of ASD in children with TSC. We will search five databases: MEDLINE, EMBASE, PubMed, The Cochrane Library and Web of Science (Conference Proceedings Citation Index). Studies will be selected for reporting after two authors independently (1) review all titles and abstracts, (2) read full text of all appropriate papers and (3) assess for bias using the Newcastle-Ottawa Scale recommended by the Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies (MOOSE guidelines) and the ROBINS-I. To our knowledge, this is the first systematic review investigating multiple risk factors in the development of ASD in children with TSC. Clarifying the evidence in this area will be important to researchers in the field and to clinicians providing prognostic information to families. PROSPERO CRD42016042841.


Chiari I malformation in a child with PTEN hamartoma tumor syndrome: Association or coincidence?
PTEN hamartoma tumor syndrome (PHTS) refers to a group of clinical conditions caused by germline mutations in the PTEN tumor suppressor gene. Increasing evidence has documented that PHTS may be associated with a broader spectrum of structural brain abnormalities, including dysplastic gangliocytoma of the cerebellum, brain tumors, vascular malformations, white matter abnormalities, dilated perivascular spaces and cortical dysplasia. We report a PTEN-mutated child showing macrocephaly, mild intellectual disability and epilepsy symptomatic of right occipital polymicrogyria, who also developed Chiari I Malformation (CIM) that repeatedly required surgical correction. We suppose that the association between PHTS and CIM could be not coincidental, thus extending the spectrum of neurological manifestations of PHTS and highlighting the role of brain MRI in the management of PHTS patients. We suggest that genes within the RAS-MAPK and PI3-AKT pathways might have a significant role in the pathogenesis of CIM in such patients.


Changes in glucose, insulin, and growth hormone levels associated with bedrest.
Changes in plasma glucose, insulin, and growth hormone (HGH) resulting from exposure to 56 d of bedrest were determined in five healthy young male subjects. Blood samples were collected by repeated venous puncture at 4-h intervals for 48-h periods before bedrest, at 10, 20, 30, 42 and 54 d after confinement to bed and at 10 and 20 d after bedrest. Changes in the daily levels of these factors for each subject were expressed as the mean of the six samples per 24-h period. The level of HGH dropped after 10 d of bedrest, then showed a 1.5-fold increase at 20 d (p less than 0.05) and subsequently decreased gradually reaching levels of 2.5 mg/ml/24 h, well below pre-bedrest controls of 4.2 mg/ml/24 h, by the 54th d. In spite of a marked increase in the daily plasma insulin levels during the first 30 d of bedrest, glucose levels remained unchanged. Beyond 30 d of bedrest, insulin began decreasing toward pre-bedrest levels and glucose followed with a similar reduction to below the control levels of 75 mg/100 ml/24 h on day 54. The daily mean changes reflect a change in the amplitude of the diurnal variation. The daily peak in plasma insulin shifted progressively to the late evening during the bedrest period.


Effects of a Program to Improve Mental Health Literacy for Married Immigrant Women in Korea.
This study aimed to develop and evaluate a mental health improvement program for the acculturative stress and mental health literacy of married immigrant women using bilingual gatekeepers. Bilingual gatekeepers were recruited from multicultural centers and trained to provide 8-week structured mental health improvement services to the women in the experimental group using a mental health improvement guidebook developed by the authors in 8 different languages. The program was effective in improving mental health and mental health literacy scores as well as reducing the degree of acculturative stress. This study offers a model of effective mental healthcare for multicultural communities.


[Loss of CD20 expression following rituximab-combined chemotherapy in CD20-positive and CyclinD1-positive multiple myeloma].
Several studies have confirmed that CD20 is expressed in about 20% of multiple myeloma (MM) cases. This is closely related to a chromosomal translocation between chromosome 11 and chromosome 14, which results in the expression of CyclinD1. The use of rituximab (RIT) in the treatment of CD20-positive MM has been reported, however its effectiveness is still not well established. We encountered a case of CD20-positive/CyclinD1-positive MM; interestingly, CD20 expression could not be detected in MM cells following RIT-combined chemotherapy, while it gradually recovered when RIT therapy was discontinued. This is the first report in which the transition of CD20 expression was accurately analyzed by flow cytometry and immunohistochemical staining before, during and after RIT treatment. Consequently, this case provides insight regarding the mechanism through which CD20 expression is lost following RIT therapy for CD20-positive lymphoid neoplasm, as well as the efficacy of RIT in CD20-positive MM.


Plasticity after brain lesions: contemporary concepts.
Medical management of the patient with central nervous tissue injuries has many frontiers. We now realize that the concept of the adult mammalian brain as largely static is no longer tenable. Numerous studies show that experimental manipulations can lead to growth and plasticity in the adult brain. We have confirmed that growth and plasticity, including neurogenesis and synaptogenesis, can also occur throughout the animal's natural life. New approaches may soon be designed to repopulate injured nervous tissue with appropriate cells. Surgical neural tissue transplantation research is one direction. Another approach involves the inherent plasticity of the nervous system, including neurogenesis, which may be modulated by the rehabilitation plan (the environment) with a variety of possible pharmacological approaches.


Contemporary outcomes with percutaneous vascular interventions for peripheral critical limb ischemia in those with and without poly-vascular disease.
Given the very ill nature of patients with critical limb ischemia (CLI), the use of percutaneous vascular interventions (PVIs) for limb salvage may or may not be efficacious; in particular, for those with polyvascular arterial disease. Herein, we reviewed large, multi-institutional outcomes of PVI in polyvascular and peripheral arterial disease (PAD) patients with CLI. An 18-hospital consortium collected prospective data on patients undergoing endovascular interventions for PAD with 6-month follow-up from January 2008 to December 2011. The patient cohort included 4459 patients with CLI; of those, 3141 patients had polyvascular (coronary artery disease, cerebrovascular disease and PAD) disease, whereas 1318 patients suffered from only PAD. All patients were elderly and with significant comorbidities. The mean ankle-brachial index (ABI) was 0.44 and was not different between those with and without polyvascular disease. Polyvascular patients had more femoropopliteal and infra-inguinal interventions and less aortoiliac interventions than PAD patients. Pre- and post-procedural cardioprotective medication use was less in the PAD patients as compared with polyvascular patients. Vascular complications requiring surgery were higher in PAD patients whereas other access complications were similar between groups. At 6-month follow-up, death was more common in the polyvascular group (6.7% vs 4.1%, p<0.001) as was repeat PVI, but no difference was found in the amputation rate. Considering the group as a whole at the 6-month follow-up, predictors of amputation/death included age (HR=1.01; 95% CI=1.002-1.02), anemia (HR=2.6; 95% CI=2.1-3.2), diabetes mellitus (HR=1.6; 95% CI=1.3-1.9), congestive heart failure (HR=1.6; 95% CI=1.4-1.9), and end-stage renal failure (HR=1.9; 95% CI=1.5-2.3), while female sex was protective (HR=0.7; 95% CI=0.6-0.8). In conclusion, from examination of this large, multicenter, multi-specialist practice registry, patients with polyvascular disease had higher 6-month mortality than PAD patients, but this was not a factor in 6-month limb amputation outcomes. This study also underscores that PAD patients still lag in cardioprotective medication use as compared with polyvascular patients.


Melanopsin-dependent nonvisual responses: evidence for photopigment bistability in vivo.
In mammals, nonvisual responses to light have been shown to involve intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin and that are modulated by input from both rods and cones. Recent in vitro evidence suggests that melanopsin possesses dual photosensory and photoisomerase functions, previously thought to be a unique feature of invertebrate rhabdomeric photopigments. In cultured cells that normally do not respond to light, heterologous expression of mammalian melanopsin confers light sensitivity that can be restored by prior stimulation with appropriate wavelengths. Using three different physiological and behavioral assays, we show that this in vitro property translates to in vivo, melanopsin-dependent nonvisual responses. We find that prestimulation with long-wavelength light not only restores but enhances single-unit responses of SCN neurons to 480-nm light, whereas the long-wavelength stimulus alone fails to elicit any response. Recordings in Opn4-/- mice confirm that melanopsin provides the main photosensory input to the SCN, and furthermore, demonstrate that melanopsin is required for response enhancement, because this capacity is abolished in the knockout mouse. The efficiency of the light-enhancement effect depends on wavelength, irradiance, and duration. Prior long-wavelength light exposure also enhances short-wavelength-induced phase shifts of locomotor activity and pupillary constriction, consistent with the expression of a photoisomerase-like function in nonvisual responses to light.


Neuroprotective effects of methyl 3,4 dihydroxybenzoate in a mouse model of retinitis pigmentosa.
Retinitis pigmentosa is a photoreceptor-degenerative disease that is currently untreatable and eventually causes blindness. Methyl 3,4 dihydroxybenzoate (MDHB) is a small molecule that exerts neuroprotective effects in vitro. The present study tests whether MDHB protects the retina of rd10 mice, a model of retinitis pigmentosa. MDHB or an equal volume of vehicle was intraperitoneally injected in rd10 mice daily from postnatal day 12 (P12) to P26. Retinal morphology was evaluated by immunostaining, and retinal function by electroretinogram (ERG) and by visual behavior. TUNEL, Iba1, GFAP staining and western blotting were applied to explore the neuroprotective mechanism of MDHB in retina. MDHB treatment significantly promoted photoreceptor survival and preserved cone morphology compared to the untreated animals. The visual behavior and ERG responses were also greatly enhanced in MDHB-treated rd10 mice. Mechanistically, following MDHB treatment, the number of TUNEL-positive cells was decreased in rd10 retina, and the expression of brain-derived neurotrophic factor (BDNF) protein and phosphorylated tropomyosin-related kinase B (TrkB) receptor were increased. Furthermore, blocking TrkB using the antagonist ANA-12 prevented the protective effect of MDHB on photoreceptor survival and structure. MDHB treatment also inhibited microglial activation and Muller cell gliosis in rd10 retina. In conclusion, MDHB treatment delays retinal degeneration in rd10 mice and preserves retinal structure and functions. These effects are likely mediated by the BDNF-TrkB pathway. Due to its neurotrophic effects and ability to reduce reactive gliosis, MDHB may be useful to treat degenerative diseases in retina and brain.


Detailed analysis of the male reproductive system in a potential bio-indicator species - The marine invertebrate Galeolaria caespitosa (Polychaeta: Serpulidae).
For the first time, this study has systemically investigated the male reproductive system in a sessile broadcast-spawning marine invertebrate, Galeolaria caespitosa (Polychaeta: Serpulidae), which has significant potential as a bio-indicator species of coastal marine pollution. The abdomen of G. caespitosa was divided by intersegmental septa into over 80 trunk segments. Each segment served as a germinal chamber with a C-shaped gonadal arrangement consisting of several distinct compartments: a seminiferous epithelium (SE) compartment located in the centre of the chamber, with each of its two ends connecting to a nurse cell (NC) compartment and then an efferent duct (ED) compartment. The SE compartment contained a multilayered seminiferous epithelium where spermatogenesis was initiated. Spermatids were released in pairs into the lumen of the SE compartment and then transported to the NC compartment where they underwent spermiogenesis with the support of secretory vesicles released by the nurse cells. Spermatozoa were stored in the ED compartment and subsequently released into the seawater through the vas deferens. Unlike vertebrates where germ cells differentiated in close proximity to the nurse cell population (i.e. Sertoli cells), the spermatogenic cells of G. caespitosa exhibited no direct contact with supporting cells at any spermatogenic stage. This finding suggested that the spermatogenesis in G. caespitosa was more dependent on intrinsic developmental programming than most species. Notwithstanding such differences, there were clear parallels between the male reproductive system of G. caespitosa and mammals, in terms of the structure and function. The independence of spermatogenic cells from supporting cells in G. caespitosa raised the possibility of inducing spermiogenesis in vitro, which would provide a useful tool to dissect the mechanisms underlying this complex cell differentiation process in invertebrates and other higher order animals.


FXYD6 is a new biomarker of cholangiocarcinoma.
Members of the FXYD domain-containing ion transport regulator protein family, including FXYD3 and FXYD5, play an important role in the pathogenesis of numerous tumors. However, the correlation between the expression of FXYD6 and tumors remains poorly understood. In the current study, the expression of FXYD6 was examined immunohistochemically in 72 cholangiocarcinoma tissues and 30 distal normal bile duct tissues matched with the tumors. The results show that the positive expression rate of FXYD6 was significantly higher in cholangiocarcinoma than that in normal bile duct tissue (69 vs. 33.3%; P=0.002). Furthermore, the positive expression rate of FXYD6 in well- and moderately-differentiated cholangiocarcinoma was clearly higher than that in poorly-differentiated and mucinous cholangiocarcinoma (85.7 vs. 40%; P=0.000). However, there was no significant correlation between the expression of FXYD6 and gender (P=0.393), age (P=0.174), histological type (P=0.123), T stage (P=0.164), lymph node metastasis (P=0.343), perineural invasion (P=0.088) and tumor location (P=0.238). The results of this study indicate that FXYD6 may be a new biomarker for cholangiocarcinoma and may be associated with a favorable prognosis in this malignant disease.


Liquid Crystal Elastomer-Liquid Metal Composite: Ultrafast, Untethered, and Programmable Actuation by Induction Heating.
Liquid crystal elastomers (LCEs) are a class of stimuli-responsive materials that have been intensively studied for applications including artificial muscles, shape morphing structures, and soft robotics due to their capability of large, programmable, and fully reversible actuation strains. To fully take advantage of LCEs, rapid, untethered, and programmable actuation methods are highly desirable. Here, a liquid crystal elastomer-liquid metal (LCE-LM) composite is reported, which enables ultrafast and programmable actuations by eddy current induction heating. The composite consists of LM sandwiched between two LCE layers printed via direct ink writing (DIW). When subjected to a high-frequency alternating magnetic field, the composite is actuated in milliseconds. By moving the magnetic field, the eddy current is spatially controlled for selective actuation. Additionally, sequential actuation is achievable by programming the LM thickness distribution in a sample. With these capabilities, the LCE-LM composite is further exploited for multimodal deformation of a pop-up structure, on-ground omnidirectional robotic motion, and in-water targeted object manipulation and crawling.


Sea monsters & whirlpools: Navigating between examination and reflection in medical education.
The 16th International Ottawa Conference/Canadian Conference on Medical Education (2014) featured a keynote deconstructing the rising discourse of competence-as-reflection in medical education. This paper, an elaborated version of the presentation, is an investigation into the theoretical roots of the diverse forms of reflective practice that are being employed by medical educators. It also raises questions about the degree to which any of these practices is compatible with assessment.


[Endoscopic nasobiliary and nasopancreatic drainage contributing to healing of duodenal ulcer perforation: a case report].
A 75-year-old man with vomiting and right abdominal pain was admitted to the Department of Surgery in our hospital. With a diagnosis of perforated duodenal ulcer, he was treated conservatively. On the day 8 of hospitalization, his general condition worsened and he underwent surgery. During operation, the perforated duodenal ulcer and paraduodenal fluid collection was observed, and percutaneous drainage was accordingly established. After this procedure, renal dysfunction was exacerbated and he was transferred to our department for endoscopic treatment. On day 28 of hospitalization, nasobiliary and nasopancreatic drainage was administered. Renal dysfunction gradually improved, and healing of the perforated duodenal ulcer was recognized on day 93. On day 112, the patient was discharged.


Effect of exercise on catecholamines and plasma renin activity in pregnant women.
Strenuous muscular exercise is known to induce increases in plasma values of adrenalin (A) and noradrenaline (NA) and a twofold increase in plasma renin activity (PRA) in healthy men and women. The effect in pregnant women is not known. In 36 pregnant women, systolic blood pressure and plasma levels of PRA, A and NA were determined at rest, during an orthostatic test and during submaximal leg exercise on a bicycle ergometer. Eight of these women were re-examined after delivery and served as a non-pregnant control group. The pregnant women had a significantly greater increase in systolic blood pressure than the non-pregnant subjects. PRA showed a sevenfold increase during pregnancy, but exercise caused no further change in plasma values. As expected, the non-pregnant PRA values doubled during exercise. Resting values of A and NA were not altered by pregnancy. Near-maximal exercise caused a significant rise in A and NA, both in pregnant and in non-pregnant women. The results indicate that there is no activation of the sympathetic nervous system either at rest or during strenuous exercise in pregnancy and that the sensitivity of the circulatory system seems to be well adjusted to the increased activity of the renin angiotensin system during pregnancy.