Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation.
Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer's disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases.


Expression Analysis of BDNF Gene and BDNF-AS Long Noncoding RNA in Whole Blood Samples of Multiple Sclerosis Patients: Not Always a Negative Correlation between Them.
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS), in which axonal damage is a deteriorative factor. Brain-Derived Neurotrophic Factor (BDNF) is described as a neuronal-survival gene, also capable of exerting pleiotropic effects on the immune cells. Here, we aimed to investigate expression levels of BDNF and its antisense RNA, BDNF-AS, in Iranian MS patients. Our case-control study was based on collecting 50 whole blood samples of relapsing-remitting MS patients and 50 healthy controls. Then, expression analysis of BDNF and BDNF-AS was performed by Real-time quantitative PCR. We found a strong and positive correlation between BDNF and BDNF-AS in MS patients. This is while no significant difference in BDNF and BDNF-AS expression levels was seen between MS patients and controls (p>0.05). A significant and strong positive correlation was found between the expression levels of BDNF-AS and BDNF (r=0.785, p<0.0001). Further, significant positive moderate correlations of BDNF and BDNF-AS with other lncRNAs (GSTT1-AS1 and IFNG-AS1) and genes (TNF and IFNG) were revealed (p<0.0001). Additionally, there was no correlation between the BDNF and BDNF-AS expressions and disease duration, age at onset, and Expanded Disability Status Scale of Kurtzke (EDSS) (p>0.05). BDNF and BDNF-AS expression levels revealed insignificant discrepancies in patients and controls. We found a strong and positive correlation between BDNF and BDNF-AS in MS patients, which is, based on previous studies, a quit novel finding and can be further discussed by future works to unravel its possible application in MS. We suggest evaluation of different leukocytes subsets separately along with large cohort studies comprising a higher number of individuals from different ages to unravel the effects of other possible aspects.


Retinoic acid receptor-alpha messenger RNA expression is increased and retinoic acid receptor-gamma expression is decreased in Barrett's intestinal metaplasia, dysplasia, adenocarcinoma sequence.
Expression levels of the retinoic acid receptors (RAR-alpha, RAR-beta, and RAR-gamma) are significantly different in neoplastic tissues compared with non-neoplastic tissues for some tumors. This study investigated whether retinoic acid receptor messenger RNA (mRNA) expression levels are altered in Barrett's esophagus and Barrett's adenocarcinoma tissues. Relative mRNA expression levels of the RARs were quantified by using the ABI 7700 Sequence Detector (Taqman) system in Barrett's intestinal metaplasia (n = 15), dysplasia (n = 6), adenocarcinoma (n = 17), and matching normal esophagus tissues (n = 36). RAR-alpha expression was significantly increased, and RAR-gamma expression was significantly decreased, at higher stages in the Barrett's sequence. There was almost complete loss of RAR-gamma expression (relative expression level < or = 1) in a majority (70%) of the dysplasia and adenocarcinoma tissues. There were significant differences in RAR-alpha and RAR-gamma expression in histopathologically normal tissues in patients with cancer versus patients without cancer. RAR-beta expression levels were significantly elevated in adenocarcinoma versus normal esophagus tissues. The RAR expression profile was similar for cancers arising within the esophagus and for cancers arising at the gastroesophageal junction. RAR mRNA expression levels are significantly different in Barrett's tissues compared with normal esophagus tissues, and these levels are significantly different in Barrett's dysplasia and adenocarcinoma tissues compared with nondysplastic tissues. These results suggest that RAR mRNA levels may be useful biomarkers for this disease and that gastroesophageal junction adenocarcinomas are genetically similar to esophageal adenocarcinomas. These results also suggest that a cancer field is present in the esophagus in patients with cancer and that genetic alterations can precede histopathologic alterations in this disease.


Evaluation of the approach of primary care physicians to the management of streptococcal pharyngotonsillitis. IPROS Network.
Streptococcal pharyngotonsillitis remains a common illness in children and can lead to serious complications if left untreated. To evaluate the diagnostic and management approach of a sample of primary care physicians in the largest sick fund in Israel to streptococcal pharyngotonsillitis in children. A questionnaire was mailed to all physicians who treat children and are employed by the General Health Services (Kupat Holim Klalit) in the Jerusalem District. The questionnaire included data on demographics, practice type and size, and availability of throat culture and rapid strep test; as well as a description of three hypothetical cases followed by questions relating to their diagnosis and treatment. Of the 188 eligible physicians, 118 (62.5%) responded, including 65 of 89 pediatricians (73%) and 53 of 99 family and general practitioners (53.5%). Fifty-six physicians (47.4%) had more than 18 years experience, and 82 (70%) completed specialization in Israel. Mean practice size was 950 patients. Fifty-three physicians (43%) worked in Kupat Holim community clinics, 25 (21%) worked independently in private clinics, and 40 (34%) did both. A total of 91 (77%) had access to laboratory facilities for daily throat culture. The time it took for the results to arrive was 48 to 72 hours. For the three clinical scenarios, 90% of the physicians accurately evaluated case A, a 1-year-old with viral pharyngotonsillitis, and 100 (85%) correctly diagnosed case C, a 7-year-old with streptococcal infection. As expected, opinions were divided on case B, a 3-year-old child with uncertain diagnosis. Accordingly, 75 (65.3%) physicians did not recommend treatment for case A, compared to 109 (92.5%) for case C. For case B, 22 (19%) said they would always treat, 43 (36%) would sometimes treat, and 35 (30%) would await the result of the throat culture. For 104 (88%) physicians the antibiotic of choice for case C was penicillin, while only 9 (7.5%) chose amoxicillin. However, the recommended dosage regimens varied from 250 to 500 mg per dose, and from two to four doses daily. For case C, 110 physicians (93%) chose a 10 day duration of treatment. The primary care physicians in the sample (pediatricians, general practitioners and family physicians) accurately diagnosed viral and streptococcal pharyngotonsillitis. However, there was a lack of uniformity regarding its management in general, and the dosage regimen for penicillin in particular.


Immunogenicity of cancer cells: An overview.
The immune system assumes a pivotal role in the organism's capacity to discern and obliterate malignant cells. The immunogenicity of a cancer cell pertains to its proficiency in inciting an immunological response. The prowess of immunogenicity stands as a pivotal determinant in the triumph of formulating immunotherapeutic methodologies. Immunotherapeutic strategies include immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and on vaccines. Immunogenic cell death (ICD) epitomizes a form of cellular demise that incites an immune response against dying cells. ICD is characterized by the liberation of distinct specific molecules that activate the immune system, thereby leading to the identification and elimination of dying cells by immunocytes. One of the salient characteristics inherent to the ICD phenomenon resides in the vigorous liberation of adenosine triphosphate (ATP) by cellular entities dedicated to embarking upon the process of programmed cell death, yet refraining from complete apoptotic demise. ICD is initiated by a sequence of molecular events that occur during cell death. These occurrences encompass the unveiling or discharge of molecules such as calreticulin, high-mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) from dying cells. These molecules act as "eat me" signals, which are recognized by immune cells, thereby prompting the engulfment and deterioration of expiring cells by phagocytes including various pathways such as Necroptosis, Apoptosis, and pyroptosis. Here, we review our current understanding of the pathophysiological importance of the immune responses against dying cells and the mechanisms underlying their activation. Overall, the ICD represents an important mechanism by which the immune system recognizes and eliminates dying cells, including cancer cells. Understanding the molecular events that underlie ICD bears the potential to engender innovative cancer therapeutics that harness the power of the immune system to combat cancer.


[Effect of nonachlazine on ino- and chronotropic function].
As a result of the stimulation of beta-adrenostructures of the myocardium nonachlazin intensifies ino- and chronotropic functions of the heart. This effect does not manifest after administration of practolol and is less pronounced in animals anesthesized with urethane and alpha-chloralose since the sensitivity of the beta-adrenostructures of the myocardium decreases under the influence of the anesthetics. Apart from the stimulation of ino- and chronotropic function of the heart nonachlazin reduces concurrently the intensity of positive chronotropic effect of isoproterenol. Such a combination of the efects called a "partial" beta-adrenoblockade seems likely to play an important role in the manifestation of the antianginal action of nonachlazin.


The pattern of DNA cleavage intensity around indels.
Indels (insertions and deletions) are the second most common form of genetic variations in the eukaryotic genomes and are responsible for a multitude of genetic diseases. Despite its significance, detailed molecular mechanisms for indel generation are still unclear. Here we examined 2,656,597 small human and mouse germline indels, 16,742 human somatic indels, 10,599 large human insertions, and 5,822 large chimpanzee insertions and systematically analyzed the patterns of DNA cleavage intensities in the 200 base pair regions surrounding these indels. Our results show that DNA cleavage intensities close to the start and end points of indels are significantly lower than other regions, for both small human germline and somatic indels and also for mouse small indels. Compared to small indels, the patterns of DNA cleavage intensity around large indels are more complex, and there are two low intensity regions near each end of the indels that are approximately 13 bp apart from each other. Detailed analyses of a subset of indels show that there is slight difference in cleavage intensity distribution between insertion indels and deletion indels that could be contributed by their respective enrichment of different repetitive elements. These results will provide new insight into indel generation mechanisms.


Soil nematode responses to crop management and conversion to native grasses.
Soil nematode community response to treatments of three, four-year crop rotations (spring wheat-pea-spring wheat-flax, spring wheat-green manure-spring wheat-flax, and spring wheat-alfalfa-alfalfa-flax) under conventional and organic management, and native tall grass restoration (restored prairie) were assessed in June 2003, and July and August 2004. The research site was the Glenlea Long-term Rotation and Crop Management Study, in the Red River Valley, Manitoba, established in 1992. The nematode community varied more with sample occasion than management and rotation. The restored prairie favored high colonizer-persister (c-p) value omnivores and carnivores, and fungivores but less bacterivores. The restored prairie soil food web was highly structured, mature and low-to-moderately enriched as indicated by structure (SI), maturity (MI) and enrichment (EI) index values, respectively. Higher abundance of fungivores and channel index (CI) values suggested fungal-dominated decomposition. Nematode diversity was low even after more than a decade of restoration. A longer time may be required to attain higher diversity for this restored fragmented prairie site distant from native prairies. No consistent differences were found between organic and conventional management for nematode trophic abundance, with the exception of enrichment opportunists of the c-p 1 group which were favored by conventional management. Although EI was lower and SI was higher for organic than conventional their absolute values suggested decomposition channels to be primarily bacterial, and fewer trophic links with both management scenarios. A high abundance of fungivores in the rotation including the green manure indicates greater fungal decomposition.


The diagnostic value of varicella-zoster virus (VZV)-specific antibodies in the early phase of varicella in immunocompromized children.
Varicella-zoster virus (VZV)-specific antibodies were tested by indirect membrane immunofluorescent technique in sera of 32 immunocompromized children during the first week after onset of varicella. VZV-specific IgM antibodies were found in sera of all but four patients. Three of the four IgM negative patients were followed up, and it was demonstrated that all of them gave a retarded antibody response. They had severe leukopenia and had several relapses of their VZV-infection. The results indicate (a) that the demonstration of VZV-specific IgM antibodies is of diagnostic value even in atypical varicella of immunocompromized patients; and (b) that in cases with retarded antibody response relapses can be expected.


Integrated metabolomics and genomics analysis provides new insights into the fiber elongation process in Ligon lintless-2 mutant cotton (Gossypium hirsutum L.).
The length of cotton fiber is an important agronomic trait characteristic that directly affects the quality of yarn and fabric. The cotton (Gossypium hirsutum L.) fiber mutation, Ligon lintless-2, is controlled by a single dominant gene (Li(2)) and results in extremely shortened lint fibers on mature seeds with no visible pleiotropic effects on vegetative growth and development. The Li(2) mutant phenotype provides an ideal model system to study fiber elongation. To understand metabolic processes involved in cotton fiber elongation, changes in metabolites and transcripts in the Li(2) mutant fibers were compared to wild-type fibers during development. Principal component analysis of metabolites from GC-MS data separated Li(2) mutant fiber samples from WT fiber samples at the WT elongation stage, indicating that the Li(2) mutation altered the metabolome of the mutant fibers. The observed alterations in the Li(2) metabolome included significant reductions in the levels of detected free sugars, sugar alcohols, sugar acids, and sugar phosphates. Biological processes associated with carbohydrate biosynthesis, cell wall loosening, and cytoskeleton were also down-regulated in Li(2) fibers. Gamma-aminobutyric acid, known as a signaling factor in many organisms, was significantly elevated in mutant fibers. Higher accumulation of 2-ketoglutarate, succinate, and malate suggested higher nitrate assimilation in the Li(2) line. Transcriptional activation of genes involved in nitrogen compound metabolism along with changes in the levels of nitrogen transport amino acids suggested re-direction of carbon flow into nitrogen metabolism in Li(2) mutant fibers. This report provides the first comprehensive analysis of metabolite and transcript changes in response to the Li(2) mutation in elongating fibers. A number of factors associated with cell elongation found in this study will facilitate further research in understanding metabolic processes of cotton fiber elongation.


Human periosteum is a source of cells for orthopaedic tissue engineering: a pilot study.
Periosteal cells are important in embryogenesis, fracture healing, and cartilage repair and could provide cells for osteochondral tissue engineering. We determined whether a population of cells isolated from human periosteal tissue contains cells with a mesenchymal stem cell (MSC) phenotype and whether these cells can be expanded in culture and used to form tissue in vitro. We obtained periosteal tissue from six patients. Initial expression of cell surface markers was assessed using flow cytometry. Cells were cultured over 10 generations and changes in gene expression evaluated to assess phenotypic stability. Phenotype was confirmed using flow cytometry and colony-forming ability assays. Mineral formation was assessed by culturing Stro-1(-) and unsorted cells with osteogenic supplements. Three cell culture samples were used for a reverse transcription-polymerase chain reaction, four for flow cytometry, three for colony-forming assay, and three for mineralization. Primary cultures, containing large numbers of hematopoietic cells were replaced initially by Stro-1 and ALP-expressing immature osteoblastic cell types and later by ALP-expressing cells, which lacked Stro-1 and which became the predominant cell population during subculture. Approximately 10% of the total cell population continued to express markers for Stro1(+)/ALP(-) cells throughout. These data suggest periosteum contains a large number of undifferentiated cells that can differentiate into neotissue and persist despite culture in noncell-specific media for over 10 passages. Cultured periosteal cells may contribute to tissue formation and may be applicable for tissue engineering applications.


Presence of S100A9-positive inflammatory cells in cancer tissues correlates with an early stage cancer and a better prognosis in patients with gastric cancer.
S100A9 was originally discovered as a factor secreted by inflammatory cells. Recently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in gastric cancer and explore its role in cancer progression. S100A9 expression in gastric tissue samples from 177 gastric cancer patients was assessed by immunohistochemistry. The expression of its dimerization partner S100A8 and the S100A8/A9 heterodimer were also assessed by the same method. The effect of exogenous S100A9 on motility of gastric cancer cells AGS and BGC-823 was then investigated. S100A9 was specifically expressed by inflammatory cells such as macrophages and neutrophils in human gastric cancer and gastritis tissues. Statistical analysis showed that a high S100A9 cell count (> = 200) per 200x magnification microscopic field in cancer tissues was predictive of early stage gastric cancer. High S100A9-positive cell count was negatively correlated with lymph node metastasis (P = 0.009) and tumor invasion (P = 0.011). S100A9 was identified as an independent prognostic predictor of overall survival of patients with gastric cancer (P = 0.04). Patients with high S100A9 cell count were with favorable prognosis (P = 0.021). Further investigation found that S100A8 distribution in human gastric cancer tissues was similar to S100A9. However, the number of S100A8-positive cells did not positively correlate with patient survival. The inflammatory cells infiltrating cancer were S100A8/A9 negative, while those in gastritis were positive. Furthermore, exogenous S100A9 protein inhibited migration and invasion of gastric cancer cells. Our results suggested S100A9-positive inflammatory cells in gastric cancer tissues are associated with early stage of gastric cancer and good prognosis.


A multiresolution image based approach for correction of partial volume effects in emission tomography.
Partial volume effects (PVEs) are consequences of the limited spatial resolution in emission tomography. They lead to a loss of signal in tissues of size similar to the point spread function and induce activity spillover between regions. Although PVE can be corrected for by using algorithms that provide the correct radioactivity concentration in a series of regions of interest (ROIs), so far little attention has been given to the possibility of creating improved images as a result of PVE correction. Potential advantages of PVE-corrected images include the ability to accurately delineate functional volumes as well as improving tumour-to-background ratio, resulting in an associated improvement in the analysis of response to therapy studies and diagnostic examinations, respectively. The objective of our study was therefore to develop a methodology for PVE correction not only to enable the accurate recuperation of activity concentrations, but also to generate PVE-corrected images. In the multiresolution analysis that we define here, details of a high-resolution image H (MRI or CT) are extracted, transformed and integrated in a low-resolution image L (PET or SPECT). A discrete wavelet transform of both H and L images is performed by using the "à trous" algorithm, which allows the spatial frequencies (details, edges, textures) to be obtained easily at a level of resolution common to H and L. A model is then inferred to build the lacking details of L from the high-frequency details in H. The process was successfully tested on synthetic and simulated data, proving the ability to obtain accurately corrected images. Quantitative PVE correction was found to be comparable with a method considered as a reference but limited to ROI analyses. Visual improvement and quantitative correction were also obtained in two examples of clinical images, the first using a combined PET/CT scanner with a lymphoma patient and the second using a FDG brain PET and corresponding T1-weighted MRI in an epileptic patient.


Prevalence of alcohol use and the interventions needed among adults: A community study in a rural area in South India.
The health issues and social problems associated with alcohol use are well known. This study seeks to identify the prevalence of alcohol consumption and dependence among alcohol users in a rural area of Trivandrum district. To assess the prevalence of alcohol use among adults of Nellanad Panchayat, a rural area in Trivandrum, Kerala, to find out the interventions required among the alcohol users, and to identify persons with harmful and hazardous use of alcohol using AUDIT. Cross-sectional study in Nellanad Panchayat, Trivandrum district, Kerala. A cross-sectional study was carried out among 1545 residents in Nellanad Panchayat, a rural area in Kerala, by interviewing adults with the help of a questionnaire. Data were analyzed using SPSS. The overall prevalence of current alcohol use was 146 (9.5%). The prevalence among males was 143 (18.3%) and females was 3 (0.4%). ASSIST scores showed that 99 (50%) of ever users required health education, 74 (37.8%) required counseling, whereas 23 (11.7%) required de-addiction. Among males, the alcohol consumption is still as high as 18.3%. The most important factor affecting alcohol use is peer pressure. Health education is the most required intervention to reduce burden of alcohol use.


Introduction history of Drosophila subobscura in the New World: a microsatellite-based survey using ABC methods.
Drosophila subobscura is a Palearctic species that was first observed in South and North America in the early 1980s, and that rapidly invaded broad latitudinal ranges on both continents. To trace the source and history of this invasion, we obtained genotypic data on nine microsatellite loci from two South American, two North American and five European populations of D. subobscura. We analysed these data with traditional statistics as well as with an approximate Bayesian computation (ABC) framework. ABC methods yielded the strongest support for the scenario involving a serial introduction with founder events from Europe into South America, and then from South America into North America. Stable effective population size of the source population was very large (around one million individuals), and the propagule size was notably smaller for the introduction into South America (i.e. high bottleneck severity index with only a few effective founders) but considerably larger for the subsequent introduction into North America (i.e. low bottleneck severity index with around 100-150 effective founders). Finally, the Mediterranean region of Europe (and most likely Barcelona from the localities so far analysed) is proposed as the source of the New World flies, based on mean individual assignment statistics.


Effect of nutrition awareness on utilization of Orange Fleshed Sweetpotato among vulnerable populations in Kenya.
Malnutrition continues to affect many vulnerable populations worldwide, with the majority of these residing in developing and underdeveloped countries. This problem has been exacerbated by the changing climate and more recently by the COVID-19 pandemic. Urgent efforts geared towards enhancing sustainable production and value chains of nutritious foods to ensure access to healthier diets are therefore critical. A recent partnership between the World Food Programme and the International Potato Center to enhance utilization of biofortified crops in fragile environments in Kenya is a step in this direction, aimed at improving the diets of households at risk of hunger and malnutrition. This study sets out to provide early evidence on the potential impacts of the interventions spearheaded in this partnership, together with lessons for further scaling efforts. Using household level data, the study adopts an impact evaluation framework to understand the effect of nutrition awareness through the dissemination of information on Vitamin A deficiency, on the utilization of orange fleshed sweetpotato, a biofortified crop rich in Vitamin A. Results show positive and significant effects of nutrition awareness on utilization of the orange-fleshed sweetpotato. Several factors were also identified as key to determining the exposure to nutrition awareness, including proximity to markets and extension agents, gender, and education levels. For widespread and inclusive adoption and utilization of orange-fleshed sweetpotato, out-scaling efforts need to consider these determinants in designing interventions aimed at raising nutrition awareness, as a key entry point to enhancing utilization of orange-fleshed sweetpotato.


Does Obesity Affect Preoperative Shoulder Balance in Adolescent Idiopathic Scoliosis?
Obese patients with adolescent idiopathic scoliosis (AIS) have been shown to present with larger curve magnitudes preoperatively. However, the effect of obesity on shoulder balance in AIS remains unknown. The purpose of our study was to determine if overweight and obese patients with AIS have worse radiographic shoulder balance on initial presentation when compared with normal weight patients. AIS patients <18 years old, with Lenke 1 or 2 curves, who underwent a posterior spinal fusion between March 2013 and December 2018 were retrospectively evaluated. BMI-for-age percentiles as defined by the Center for Disease Control and Prevention were used: obese (≥95th percentile), overweight (85th to <95th percentile), and normal weight (5th to <85th percentile). Shoulder height was measured via the radiographic shoulder height (RSH) method, with an RSH ≤ 1 cm considered balanced. The primary outcome was preoperative shoulder balance. Secondary outcomes included postoperative shoulder balance, major curve correction, and UIV selection. One hundred eighty-four patients (116 [63%] normal weight and 68 [37%] overweight/obese) were included. The mean age at surgery was 13.1 ± 2 years, and mean follow-up was 17.4 ± 13 months. Preoperative shoulder imbalance was significantly greater in the overweight/obese group compared to the normal weight group (1.9 ± 1 cm vs. 1.5 ± 1 cm, p = 0.04). The odds ratio of presenting with unbalanced shoulders was 2.0 (95% CI: 1.02-3.83, p = 0.04) for the overweight/obese group. No significant differences were found for postoperative shoulder balance, UIV selection, or major curve correction. Overweight and obese patients with AIS are twice as likely to present with unbalanced shoulders preoperatively; however, this difference is not clinically relevant with a mean difference of 0.4 cm between cohorts. Finally, the preoperative BMI percentile did not show a significant effect on the chosen UIV or curve magnitude correction. Level III: this is a retrospective case-control study.


Early inflammatory response of knee ligaments to prolotherapy in a rat model.
Prolotherapy is an alternative injection-based therapy for chronic musculoskeletal pain. Three different proliferants, D-glucose (dextrose), phenol-glucose-glycerine (P2G), and sodium morrhuate, used in prolotherapy are hypothesized to strengthen and reorganize chronically injured soft tissue and decrease pain through modulation of the inflammatory process. Our hypothesis is that commonly used prolotherapy solutions will induce inflammation (leukocyte and macrophage infiltration) in medial collateral ligaments (MCLs) compared to needlestick, saline injection, and no-injection controls. MCLs of 84 Sprague- Dawley rats were injected one time at both the tibial and femoral insertions. Immunohistochemistry (IHC) was used to determine the inflammatory response at three locations (tibial and femoral insertions and midsubstance) 6, 24, and 72 h after dextrose injection compared to saline- and no-injection controls and collagenase (positive control) (n = 4). qPCR was used to analyze gene expression 24 h postinjection (n = 4). Sodium morrhuate, P2G, and needlestick control were also investigated after 24 h (n = 4). In general, inflammation (CD43+, ED1+, and ED2+ cells) increased after prolotherapy injection compared to no-injection control but did not increase consistently compared to saline and needlestick control injections. This response varied by both location and proliferant. Inflammation was observed at 6 and 24 h postinjection but was resolved by 72 h compared to no-injection controls (p < 0.05). CD43+ leukocytes and ED2+ macrophages increased compared to needlestick and saline-injection control, respectively, 24 h postinjection (p < 0.05). Prolotherapy injections created an inflammatory response, but this response was variable and overall, not uniformly different from that caused by saline injections or needlestick procedures.


Impact of the DRY motif and the missing "ionic lock" on constitutive activity and G-protein coupling of the human histamine H4 receptor.
It is assumed that many G protein-coupled receptors (GPCRs) are restrained in an inactive state by the "ionic lock," an interaction between an arginine in transmembrane domain (TM) 3 (R3.50) and a negatively charged residue in TM6 (D/E6.30). In the human histamine H4 receptor (hH4R), alanine is present in position 6.30. To elucidate whether this mutation causes the high constitutive activity of hH4R, we aimed to reconstitute the ionic lock by constructing the A6.30E mutant. The role of R3.50 was investigated by generating hH4R-R3.50A. Both mutants were expressed alone or together with Galpha(i2) and Gbeta1gamma2 in Sf9 cells and characterized in GTPase, 35S-labeled guanosine 5'-[gamma-thio]triphosphate binding, and high-affinity agonist binding assays. Unexpectedly, compared with hH4R, hH4R-A6.30E showed only nonsignificant reduction of constitutive activity and G protein-coupling efficiency. The KD of [3H]histamine was unaltered. By contrast, hH4R-R3.50A did not stimulate G proteins. Thioperamide affinity at hH(4)R-R3.50A was increased by 300 to 400%, whereas histamine affinity was reduced by approximately 50%. A model of the active hH4R state in complex with the Galpha(i2) C terminus was compared with the crystal structures of turkey beta1 and human beta2 adrenoceptors. We conclude that 1) constitutive activity of hH4R is facilitated by the salt bridge D5.69-R6.31 rather than by the missing ionic lock, 2) Y3.60 may form alternative locks in active and inactive GPCR states, 3) R3.50 is crucial for hH4R-G protein coupling, and 4) hH4R-R3.50A represents an inactive state with increased inverse agonist and reduced agonist affinity. Thus, the ionic lock, although stabilizing the inactive rhodopsin state, is not generally important for all class A GPCRs.


Filipino therapists' experiences and attitudes of interprofessional education and collaboration: A cross-sectional survey.
For the past more than 50 years, the World Health Organisation has acknowledged through empirical findings that health workers that learn together work together effectively to provide the best care for their patients. This study aimed to: (1) describe the perceived extent of interprofessional education (IPE) experience among Filipino occupational therapists (OTs), physical therapists (PTs), and speech-language-pathologists (SLPs); (2) identify their attitudes towards interprofessional collaboration (IPC); and (3) compare their attitudes towards IPC according to: prior IPE experience, classification of IPE experience, profession, years of practice, and practice setting. Using a cross-sectional survey design, a two-part questionnaire was sent to Filipino OTs, PTs, and SLPs working in the Philippines via an online survey application. The first part of the survey contained eight items of demographic information and the second part contained the 14-item Attitudes Towards Health Care Teams Scale (ATHCTS). Findings revealed that among the Filipino OT, PT and SLP respondents (n = 189), 70.9% had prior experience on IPE. Moreover, the three most commonly used IPE teaching-learning strategies were case discussion (clinical setting), small group discussion, didactics, and case discussion (community setting), while the use of didactics and case discussion (community setting) yielded more agreeable attitudes towards IPC. Among the 14 items in the ATHCTS, 11 were rated with agreeability and three items with neutrality. For professional variables, only the practice setting variable yielded a statistically significant finding confirming those working in the academia to be more agreeable towards IPC compared to other settings. However, years of practice and professional background variables both yielded no statistically significant difference implying no association between years of practice and attitude towards IPC and a homogenous composition among respondents, respectively. The results of this research are to springboard IPE initiatives within Philippine higher education institutions to enable evidence-based IPC approaches in clinical practice.


Ten tips to help learning.
Facilitating learning for nurses in the healthcare environment is challenging. These 10 tips are designed to help staff development educators explore ways to enhance learning. The emphasis is on active involvement of the learner, with the educator as facilitator rather than "teacher." Tips are evidence-based, specific, and to the point, with suggestions for implementation.


Rat gastric mucin is synthesized and secreted exclusively as filamentous oligomers.
Oligomeric gastric mucin was isolated from the fundic part of the rat stomach. Previously we have shown by biochemical analysis that this oligomeric mucin consists of disulphide-linked homo-oligomers, which contain no other covalently attached proteins [Dekker, Aelmans & Strous (1991) Biochem. J. 277, 423-427]. Electron-microscopic images of the oligomeric mucin revealed a heterogenous population of long filamentous molecules of 300-3000 nm length. After reduction and carboxymethylation the monomeric mucins displayed a length distribution with a single peak at about 279 nm. Length-distribution analysis of oligomeric molecules with length up to 1000 nm revealed three subpopulations with one, two or three times the length of the monomeric mucin. The oligomers displayed small globular domains of about 15 nm, which were equally spaced along the molecule's length. As the distance between these globular domains was similar to the monomer length, these domains most likely indicate attachment sites of the monomers. These results show that the mucin monomers attached end-to-end in the oligomer. Biosynthesis of the mucin oligomers was studied by labelling of stomach explants in vitro with [35S]methionine, [3H]galactose or [35S]sulphate and subsequent immunoprecipitation of the mucin with a specific antiserum. Analysis by electrophoresis and gel filtration revealed that the oligomerization takes place by formation of disulphide bonds between the 300 kDa mucin precursors. The mucin was exclusively synthesized and secreted as fully glycosylated oligomers, as neither precursor proteins nor monomeric mucin were detected in the culture medium. A model for the biosynthesis of rat gastric mucin is proposed in which the filamentous mucin monomers are linked end-to-end by disulphide bonds.


Inhibitory effects of leptin-related synthetic peptide 116-130 on food intake and body weight gain in female C57BL/6J ob/ob mice may not be mediated by peptide activation of the long isoform of the leptin receptor.
We recently reported that intraperitoneal administration of leptin-related synthetic peptide 116-130 [LEP-(116-130)] resulted in reduced food intake and significant weight loss in homozygous female C57BL/6J ob/ob mice. In this study, we used two in vitro bioassays to show that the interaction of LEP-(116-130) with the long form of the leptin receptor (OB-Rb), the receptor isoform that is predominantly expressed in the hypothalamus, is not required for the observed in vivo effects of the peptide on energy balance. LEP-(116-130) was unable to compete the binding of alkaline phosphatase-leptin fusion protein to OB-R. Moreover, LEP-(116-130) was unable to activate signal transduction by OB-Rb in vitro. In homozygous female C57BLKS/J-m db/db mice that do not express OB-Rb, intraperitoneal administration of LEP-(116-130) reduced body weight gain and blood glucose levels but not food intake, which further supports a mechanism of action that does not require peptide interaction with OB-Rb.


Clinicopathologic findings in failed descemet stripping automated endothelial keratoplasty.
To evaluate the clinical features of and histologic findings from failed Descemet stripping automated endothelial keratoplasty (DSAEK). This retrospective observational case series evaluated 47 consecutive corneal specimens from 42 patients who underwent either penetrating keratoplasty or repeated DSAEK for failed DSAEK. Clinical information was obtained for the cases. Sections of the specimens were examined using light microscopy. Immunohistochemical staining was performed for cytokeratins AE1/AE3 and for the myogenic marker smooth-muscle actin when indicated. Transmission electron microscopic examination was performed in some cases. Graft survival ranged from 0.5 to 34 months. Histologic examination showed that 94% of the specimens (44 of 47) had endothelial cell loss. Residual host Descemet membrane (19%; 9 of 47), fibrocellular tissue (19%; 9 of 47), epithelial implantation (15%; 7 of 47), and fungal infection (4%; 2 of 47) were also identified. Immunohistochemical stains were positive for AE1/AE3 in the epithelial implantations and for smooth-muscle actin in cells in the fibrocellular proliferations. The principal cause of failed DSAEK is endothelial cell loss. Residual host Descemet membrane, fibrocellular tissue at the edge of the lenticule, and epithelial implantation are common histologic findings. Fungal infection may occur in the setting of DSAEK.


VAP-33 localizes to both an intracellular vesicle population and with occludin at the tight junction.
Tight junctions create a regulated intercellular seal between epithelial and endothelial cells and also establish polarity between plasma membrane domains within the cell. Tight junctions have also been implicated in many other cellular functions, including cell signaling and growth regulation, but they have yet to be directly implicated in vesicle movement. Occludin is a transmembrane protein located at tight junctions and is known to interact with other tight junction proteins, including ZO-1. To investigate occludin's role in other cellular functions we performed a yeast two-hybrid screen using the cytoplasmic C terminus of occludin and a human liver cDNA library. From this screen we identified VAP-33 which was initially cloned from Aplysia by its ability to interact with VAMP/synaptobrevin and thus was implicated in vesicle docking/fusion. Extraction characteristics indicated that VAP-33 was an integral membrane protein. Antibodies to the human VAP-33 co-localized with occludin at the tight junction in many tissues and tissue culture cell lines. Subcellular fractionation of liver demonstrated that 83% of VAP-33 co-isolated with occludin and DPPIV in a plasma membrane fraction and 14% fractionated in a vesicular pool. Thus, both immunofluorescence and fractionation data suggest that VAP-33 is present in two distinct pools in the cells. In further support of this conclusion, a GFP-VAP-33 chimera also distributed to two sites within MDCK cells and interestingly shifted occludin's localization basally. Since VAP-33 has previously been implicated in vesicle docking/fusion, our results suggest that tight junctions may participate in vesicle targeting at the plasma membrane or alternatively VAP-33 may regulate the localization of occludin.


Healthcare resource utilization in patients on lipid-lowering therapies outside Western Europe and North America: findings of the cross-sectional observational International ChoLesterol management Practice Study (ICLPS).
Few recent large-scale studies have examined healthcare consumption associated with dyslipidemia in countries outside Western Europe and North America. This analysis, from a cross-sectional observational study conducted in 18 countries in Eastern Europe, Asia, Africa, the Middle East and Latin America, evaluated avoidable healthcare consumption (defined as ≥1 hospitalization for cardiovascular reasons or ≥1 visit to the emergency room for any reason in the previous 12 months) in patients receiving stable lipid-lowering therapy (LLT). A total of 9049 patients (aged ≥18 years) receiving LLT for ≥3 months and who had had their low-density lipoprotein cholesterol (LDL-C) value measured on stable LLT in the previous 12 months were enrolled between August 2015 and August 2016. Patients who had received a proprotein convertase subtilisin/kexin type 9 inhibitor in the previous 6 months were excluded. Patients were stratified by cardiovascular risk level using the Systematic Coronary Risk Estimation chart for high-risk countries. The proportion of patients at their LDL-C goal was 32.1% for very-high risk patients compared with 55.7 and 51.9% for patients at moderate and high cardiovascular risk, respectively. Overall, 20.1% of patients had ≥1 reported hospitalization in the previous 12 months (7.9% for cardiovascular reasons), 35.2% had ≥1 intensive care unit stay and 13.8% visited the emergency room. Avoidable healthcare resource consumption was reported for 18.7% patients overall, and in 27.8, 7.7, 7.7 and 13.2% of patients at very-high, high, moderate and low risk, respectively. Across all risk groups 22.4% of patients not at LDL-C goal and 16.6% of patients at LDL-C goal had avoidable healthcare resource consumption. Being at very-high cardiovascular risk, having cardiovascular risk factors (including hypertension and smoking), and having factors indicating that the patient may be difficult to treat (including statin intolerance, comorbidities and chronic medication), were independent risk factors for avoidable healthcare resource consumption (all p <0.05). Healthcare resource consumption associated with adverse clinical outcomes was observed in patients on stable LLT in countries outside Western Europe and North America, particularly those at very-high cardiovascular risk and those who were difficult to treat.


The regulatory effect of memantine on expression and synthesis of heat shock protein 70 gene in neonatal rat models with cerebral hypoxic ischemia.
To evaluate the neuroprotective effect of memantine, a non-competitive antagonist at the N-methyl-D-aspartate receptor, against hypoxic ischemia (HI) by exploring its regulation on the expression and synthesis of heat shock protein 70 (HSP70) gene in neonatal rat models with cerebral HI. Memantine was intraperitoneally injected at a dose of 20 mg/kg in neonatal rat models either before (PRE group) or after (POST group) induction of HI. The expression and synthesis of the HSP70 gene and its corresponding product were determined by rapid competitive PCR and immunohistochemistry, respectively. There was an increase in the expression of HSP70 mRNA two hours after induction of HI, which reached its peak at 48 hours, then decreased gradually. The same expression occurred at relatively low levels in the control group. Also, HSP70 synthesis was detected as early as 2h after HI, reached its peak between 48 and 72 hours, then declined over time. After memantine administration, the expression of the gene and its synthesis of the corresponding product decreased significantly during the time intervals 24 - 72 h for the gene and 48 - 72 h for the product compared to the HI group. It was shown that HI is very sensitive to the expression of the HSP70 gene and synthesis of its corresponding product, which could be regulated by memantine. The latter may have the ability to reduce brain damage; thus decreased HSP70 mRNA expression could be a marker for HI. It is suggested that memantine can be a promising agent for neuroprotection against HI, although an overall and objective assessment of memantine is required to see if it can be used on neonates clinically later on.


Chronic prenatal ethanol exposure alters expression of central and peripheral insulin signaling molecules in adult guinea pig offspring.
Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150-200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 ± 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling molecules at the mRNA level, which may be related to metabolic dysregulation in adult offspring. Furthermore, altered insulin and IGF signaling may be a mechanism of ethanol neurobehavioral teratogenicity.


Family planning operations research in Africa: reviewing a decade of experience.
Between 1979 and 1990, Columbia University conducted 26 family planning operations research (OR) projects in 13 sub-Saharan African countries. Most of these projects were implemented in settings where family planning service delivery had not yet been initiated or was new and poorly developed. In keeping with program needs in the early stages of development, the majority of the OR projects were based on demonstration or diagnostic designs. Only four of the 23 projects were comparative or quasi-experimental in design. Projects demonstrated the growing demand for family planning, and the feasibility and acceptability of a range of service delivery models. Sixteen of the projects have been sustained or replicated by national or local governments and institutions following the initial OR phase, replication of two others is planned, and another four resulted in policy formulation or improvements in existing national programs. OR in Africa played an important role in generating political and medical support for contraceptive services, and served to improve project management. OR proved more useful in the implementation and strengthening of individual programs than in generating universal lessons regarding service delivery. In order to maximize OR's utility in Africa, simple research designs and methods should be adopted.


Morphological and functional polymorphism within clonal thyroid nodules.
Thirty-nine thyroid nodules, removed because of recent growth, were analyzed morphologically by serial histological sections for the classical histomorphological hallmarks of follicular cell replication and for immunohistochemically demonstrable overexpression of the growth-associated ras-gene product p21ras. Clonal analysis was performed using the highly informative probe M27 beta that detects polymorphisms on the locus DXS255 of the X-chromosome. Twenty-four nodules were of clonal and 15 nodules were of poly-clonal origin. Only 3 out of the 24 clonal nodules were histomorphologically uniform. In all others, the structural hallmarks of active growth and the P21ras growth-marker expression were remarkably heterogeneous throughout the tumors. There were no histomorphological characteristics distinguishing these clonal tumors from polyclonal nodules. Even if a clonal thyroid tumor may be originally homogeneous in respect to the parameters studied here, mechanisms must exist that create wide heterogeneity of growth and of morphogenetic potential among the individual follicular cells during further expansion of the nodule. Thus, clonal nodules are much more common in nodular goiters than hitherto assumed on grounds of the classical morphological criteria. The diagnosis of a true monoclonal nodule can no longer rely on morphological and functional criteria alone but requires molecular or cytogenetic analysis of clonality.


Influence of sodium content on the thermal behavior of low vacancy Prussian white cathode material.
Rechargeable sodium-ion batteries are the most attractive substitutes for lithium-ion batteries in large-scale energy storage devices due to wide spread reserves and low-cost of sodium resources and the similarities between sodium and lithium chemistry. However, finding a suitable cathode material is still a hurdle to be overcome. To date, Prussian white (PW), NaxFe[Fe(CN)6]y·nH2O has stood out as one of the most promising Na-host materials due to its low cost, facile synthesis and competitive electrochemical capacity. Despite this, there are concerns that this material will thermally decompose at relatively low temperatures to form cyanogen gas, which is a safety hazard. Thus, low vacancy NaxFe[Fe(CN)6]y·nH2O (x = 1.5, 1, 0.5 and 0) has been synthesized, and the influence of x on its thermal behavior systematically investigated. It is demonstrated that the thermal decomposition temperature, water content and moisture sensitivity of the samples strongly depend on the sodium content. The sample with x = 1.5 is found to be the most thermally stable and has the highest water content under the same experimental conditions. In addition, the sodium-rich samples (x = 1.5, 1 and 0.5) have higher surface water than the sodium-deficient one (x = 0). The local structure for this sample is also very different to the sodium-rich ones. Our findings offer new insights into the profound implications of proper material handling and safer operating conditions for practical Na-ion batteries and may be extended to analogous systems.


Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.
The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Boehringer Ingelheim.


Discordance Between Clinical and Pathological Staging and Grading in Upper Tract Urothelial Carcinoma.
This study aimed to evaluate the concordance in tumor stage and grade between ureteroscopic (URS) biopsy and radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC). Records of 1,214 UTUC patients who had undergone URS biopsy followed by RNU were included. Univariable and multivariable logistic regression analyses were performed to identify factors contributing to the pathological upstaging. The concordance between URS biopsy-based clinical and RNU pathological staging was 34.5%. Clinical understaging occurred in 59.5% patients. Upstaging to muscle-invasive disease occurred in 240 (41.7%) of 575 patients diagnosed with ≤cT1 disease. Of those diagnosed with muscle-invasive disease on final pathology, 89.6% had been clinically diagnosed with ≤cT1 disease. In the univariable analyses, computed tomography urography (CTU)-based invasion, ureter location, hydronephrosis, high-grade cytology, high-grade biopsy, sessile architecture, age, and women sex were significantly associated with pathological upstaging (P < .05). In the multivariable analyses, CTU-based invasion and hydronephrosis remained associated with pathological upstaging (P < .05). URS biopsy-based clinical and pathological gradings were concordant in 634 (54.2%) patients. Clinical undergrading occurred in 496 (42.4%) patients. Clinical understaging/undergrading and upstaging to muscle-invasive disease occurred in a high proportion of UTUC patients undergoing RNU. Despite the inherent selection bias, these data underline the challenges of accurate UTUC staging and grading. In daily clinical practice, URS biopsy and CTU offer the most accurate preoperative information albeit with limited predictive value when used alone. These findings should be considered when utilizing preoperative, risk-adapted strategies.


Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications.
Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.


Conformational flexibility models for the receptor in structure based drug design.
The problem of incorporating receptor flexibility in routine in silico screening of databases of small chemical compounds for the purposes of structure based drug design is still an unsolved problem. The main reason behind this difficulty is the large number of degrees of freedom that have to be considered to represent receptor flexibility. In this paper we review protein flexibility models that have been developed to limit the number of additional search parameters. These models can be roughly divided into five different categories. These are a) use of soft receptors which relax energetic penalties due to steric clashes, b) selection of a few critical degrees of freedom in the receptor binding site, c) use of multiple receptor structures either individually or by combining them using an averaging scheme, d) use of modified molecular simulation methods, and e) use of collective degrees of freedom as a new basis of representation for protein flexibility. All these flexible receptor models strive to balance an improvement in the accuracy of the binding predictions with an increase in computational cost. In addition, other challenges such as the development of accurate solvation models and scoring functions make the receptor flexibility problem even harder.


The association between body mass index and mortality in septic older adults.
There is limited evidence on the association between body mass index (BMI) and outcomes in older adults with sepsis. The purpose of this study was to explore the relationship between BMI and the clinical outcome in the older adults with sepsis. All older adults (age 65 or older) with sepsis were analyzed retrospectively in the Intensive Care Medical Information Mart (MIMIC)- IV database. The primary outcome was 30-day mortality. The relationship between BMI and 30-day mortality was estimated by multivariate logistic regression model. The interaction and stratified analysis were performed by sex, race, renal disease, congestive heart failure (CHF), diabetes, and chronic pulmonary disease. The total number of participants was 6604. After adjustment for potential covariates, there was a significant correlation between BMI and 30-day mortality. A 1 kg/m2 increase in BMI was associated with a 3 % decrease in 30-day mortality (adjusted HR = 0.97, 95 % CI: 0.96-0.98, P < 0.001). The correlation between BMI and 30-day mortality showed a statistically significant nonlinear association with an l-shaped curve (p = 0.001). Significant interactions were observed only for sex in the stratified analyses (P = 0.001). In this study, it was observed that a higher BMI is linked with better survival rates among older adults suffering from sepsis, while being underweight raises the risk of mortality. Notably, male patients with a higher BMI had a lower mortality risk compared to female patients.


[Influences of open thoracoscopy on human body: experience in 65 cases].
The influence of open thoracoscopy with fiber-bronchoscope on human body was studied in 65 patients with pleural disease. The items observed included blood pressure, Pulse rate, respiration rate, blood gas analysis and clinical manifestations. It was found that open thoracoscopy has little influence on human body and the patients tolerated it well. No severe complication was found and operative procedures might be avoided popularization of this technique is therefore suggested.


Epigenetic signatures in cardiac fibrosis: Focusing on noncoding RNA regulators as the gatekeepers of cardiac fibroblast identity.
Cardiac fibroblasts play a pivotal role in cardiac fibrosis by transformation of fibroblasts into myofibroblasts, which synthesis and secrete a large number of extracellular matrix proteins. Ultimately, this will lead to cardiac wall stiffness and impaired cardiac performance. The epigenetic regulation and fate reprogramming of cardiac fibroblasts has been advanced considerably in recent decades. Non coding RNAs (microRNAs, lncRNAs, circRNAs) regulate the functions and behaviors of cardiac fibroblasts, including proliferation, migration, phenotypic transformation, inflammation, pyroptosis, apoptosis, autophagy, which can provide the basis for novel targeted therapeutic treatments that abrogate activation and inflammation of cardiac fibroblasts, induce different death pathways in cardiac fibroblasts, or make it sensitive to established pathogenic cells targeted cytotoxic agents and biotherapy. This review summarizes our current knowledge in this field of ncRNAs function in epigenetic regulation and fate determination of cardiac fibroblasts as well as the details of signaling pathways contribute to cardiac fibrosis. Moreover, we will comment on the emerging landscape of lncRNAs and circRNAs function in regulating signal transduction pathways, gene translation processes and post-translational regulation of gene expression in cardiac fibroblast. In the end, the prospect of cardiac fibroblasts targeted therapy for cardiac fibrosis based on ncRNAs is discussed.


Abnormal umbilical artery Doppler findings in the recipient twin before laser surgery for twin-twin transfusion syndrome.
In twin-twin transfusion syndrome (TTTS), persistent absent or reversed end-diastolic flow in the umbilical artery is a rare finding in the recipient twin, and the clinical implications of this finding are not well characterized. We sought to study the clinical importance of abnormal umbilical artery Doppler waveforms in recipient twins and determine the perinatal survival of these twins after laser surgery. A retrospective study of patients with TTTS treated with laser surgery between 2006 and 2012 was conducted. Recipient twins with absent or reversed umbilical artery end-diastolic flow on preoperative sonography were identified, and clinical and perinatal outcomes were compared to the remaining cohort. Statistical analyses were performed with Fisher exact and χ(2) tests. Of 369 consecutive TTTS cases, 14 (3.8%) had absent or reversed umbilical artery end-diastolic flow in the recipient twin. The rate of hydrops was higher in this group compared to those without absent or reversed flow (35.7% [5 of 14] versus 10.1% [36 of 355]; P = .0125). The rate of recipient twin growth restriction was also higher in the absent or reversed flow group (28.6% [4 of 14] versus 3.9% [14 of 355]; P = .0029). There was an increased rate of recipient fetal demise within 24 hours after surgery in those with absent or reversed flow (21.4% [3 of 14] versus 2.5% [9 of 355]; P = .0078), although there was no statistical difference in 30-day survival between the groups (78.6% [11 of 14] versus 89.9% [319 of 355]; P = .1751). Doppler findings of absent or reversed umbilical artery end-diastolic flow are rare in recipient twins. Although immediate post-laser surgery survival is relatively decreased in this group, overall perinatal survival rates appear to be favorable.


Accuracy of intraoperative determination of central node metastasis by the surgeon in papillary thyroid carcinoma.
Prophylactic central neck dissection (CND) in papillary thyroid carcinoma (PTC) remains controversial. If the presence of central lymph node metastasis could be assessed preoperatively or intraoperatively, unnecessary CND could be avoided. The aim of this study was to evaluate the accuracy of intraoperative determination of central lymph node metastasis by the surgeon using palpation and inspection in clinically node-negative PTC. Prospective study. University tertiary care facility. A total of 122 consecutive patients with clinically node-negative PTC were enrolled. Any suspicious lymph nodes on intraoperative palpation or inspection were sent for frozen biopsy, and then bilateral CND with total thyroidectomy was carried out in all patients. The criteria for a suspicious lymph node included palpable hardness, dark discoloration, or size exceeding 5 mm in diameter. We compared the surgeon's judgments with the final pathologic results. Suspicious lymph nodes were found in 37 (30.3%) patients, and 15 of them had metastasis on permanent biopsy. Of 85 patients with no suspicious lymph nodes, 27 (31.8%) had metastasis on permanent biopsy. The sensitivity and specificity as well as positive and negative predictive values of intraoperative determination of central lymph node metastasis were 35.7%, 72.5%, 40.5%, and 68.2%, respectively. The positive predictive values of enlarged lymph nodes, dark discoloration, and hardness were 30.4%, 50.0%, and 78.6%, respectively. Intraoperative determination of central lymph node metastasis by the surgeon is a limited guide for CND in clinically node-negative PTC because of its low sensitivity and specificity.


Dental anomaly patterns associated with tooth agenesis.
The objective of this study is to evaluate the relationship between tooth agenesis and the occurrence of other dental anomalies in children and adolescents. Panoramic radiographs of 195 subjects with tooth agenesis, except for the third molar, were retrospectively examined and compared with a non-agenesis control group of 600 subjects. Their ages ranged from 7 to 15 years. Panoramic and periapical radiographs were used to analyze the presence of other associated dental anomalies. The occurrences of these anomalies were compared with those in the non-agenesis group. Subjects with tooth agenesis showed a significantly higher prevalence of a small maxillary lateral incisor (17.7%), distoangulation of the mandibular second premolar (6.5%), delayed development of a permanent tooth (10.8%), and hypo-occlusion of a primary molar (11.8%). In contrast, the prevalence of a supernumerary tooth was higher in the control group, and no difference was observed in the prevalence of ectopic eruption of a first molar. According to the agenesis area, microdontia of the maxillary lateral incisors occurred more often in patients with anterior or premolar agenesis than in the molar agenesis groups. Distoangulation of the mandibular second premolars, delayed tooth development, and hypo-occlusion of the primary molars were associated with premolar tooth agenesis. A small maxillary lateral incisor, distoangulation of the mandibular second premolar, delayed development of a permanent tooth, and hypo-occlusion of a primary molar were frequently associated with tooth agenesis, providing additional evidence of a genetic interrelationship in the causes of these dental anomalies.


Effects of habitat modifications on the movement behavior of animals: the case study of Fish Aggregating Devices (FADs) and tropical tunas.
Aggregation sites represent important sources of environmental heterogeneity and can modify the movement behavior of animals. When these sites are artificially established through anthropogenic actions, the consequent alterations to animal movements may impact their ecology with potential implications for their fitness. Floating objects represent important sources of habitat heterogeneity for tropical tunas, beneath which these species naturally aggregate in large numbers. Man-made floating objects, called Fish Aggregating Devices (FAD), are used by fishers on a massive scale to facilitate fishing operations. In addition to the direct impacts that fishing with FADs has on tuna populations, assessing the effects of increasing the numbers of FADs on the ecology of tuna is key for generating sound management and conservation measures. This study investigates the effects of increasing numbers of FADs (aggregation sites) on the movements of tunas, through the comparison of electronic tagging data recorded from 146 individuals tunas (yellowfin tuna, Thunnus albacares, and skipjack tuna, Katsuwonus pelamis) tagged in three instrumented anchored FAD arrays (Mauritius, Oahu-Hawaii and Maldives), that differed according to their distances among neighboring FADs. The effect of increasing inter-FAD distances is studied considering a set of indices (residence times at FADs and absence (travel) times between two visits at FADs) and their trends. When inter-FAD distances decrease, tuna visit more FADs (higher connectivity between FADs), spend less time travelling between FADs and more time associated with them. The trends observed for the absence (travel) times appear to be compatible with a random-search component in the movement behaviour of tunas. Conversely, FAD residence times showed opposite trends, which could be a result of social behavior and/or prey availability. Our results provide the first evidence of changes in tuna associative behavior for increasing FAD densities. More generally, they highlight the need for comparing animal movements in heterogeneous habitats in order to improve understanding of the impacts of anthropogenic habitat modifications on the ecology of wild animals.


Parental schooling & children's health.
Nearly one in every four children in the United States is born to a mother who has not finished high school, and more than one in eight is reared by such a mother during the critical preschool period. Large-scale studies show that the health and welfare of children are linked to the education level of their parents, with parent education often being a stronger predictor of child well-being than family income, single parenthood, or family size. Higher parent education levels make it more likely that children will receive adequate medical care and that their daily environments will be protected and responsive to their needs. Average parent education levels have risen over the last 30 years, but progress has slowed because of high rates of immigration from countries with lower education standards and the tendency of more advantaged women to have children later than less advantaged women. The education system and community organizations must provide young people who are not doing well in school with positive alternatives to low- education, high-risk parenthood. Health care providers should be proactive, teaching parents with few resources how best to promote their children's growth and development. The changing global economy makes it more important than ever that current and future generations of children are reared by parents who have adequate skills and training to be competent members of society and effective and responsible parents.


Frataxin point mutations in two patients with Friedreich's ataxia and unusual clinical features.
Two patients with a progressive ataxia are presented with clinical features consistent with classic Friedreich's ataxia (FRDA), but also with features unusual for FRDA. Analysis of DNA showed that each patient is heterozygous for the expanded GAA repeat of FRDA, but carries a base change on his other frataxin allele. For one patient a non-conservative arginine to cysteine amino acid change is predicted at amino acid 165 whereas the other mutation is found at the junction of exon one and intron one. Muscle biopsy showed an absence of frataxin immunoreactivity in the patient harbouring the intronic mutation, confirming the pathological nature of the base change. These mutations extend the range of point mutations seen in FRDA, and agree with recent reports suggesting phenotypic variation in patients with FRDA harbouring point mutations in conjunction with an expanded GAA repeat.


Percutaneous Impella RP use for refractory right heart failure in adolescents and young adults-A multicenter U.S. experience.
To assess the outcomes of the use of the percutaneous Impella RP device (Abiomed, Danvers, MA) in adolescents and young adults. Results of the Impella RP device have been reported in adults, but a multicenter experience in adolescents and young adults has yet to be reported. Patients ≤21 years of age who underwent implantation of an Impella RP device for refractory right heart failure from June, 2016 to April, 2018 at nine U.S. Centers were included. A total of 12 adolescents, median age of 18 (14-21) years and median weight 74.4 (49-112.4) kg underwent Impella RP implantation (INTERMACS Profile 1 in nine and Profile 2 in three patients. The central venous pressure decreased from 20 (16-35) to 12 (7-17) mmHg, (p = .001). One patient was concomitantly supported with an intra-aortic balloon pump (IABP) and the rest with a percutaneous/surgically placed left ventricular assist device. There was one adverse event related to the Impella RP device (thrombosis requiring explant). The support duration was 6.5 days (4.8 hr-18.4 days) and survival to hospital discharge was 83%. At a median follow-up of 11 months (5 days-2.5 years), 8 of 12 (67%) patients are alive. In this multicenter experience, the Impella RP device was found to be efficacious and safe when used in adolescents and young adults. Further studies are warranted to identify suitable young/pediatric candidates for Impella RP therapy for right heart failure.


Thymoquinone reverses nonalcoholic fatty liver disease (NAFLD) associated with experimental hypothyroidism.
To assess the efficacy of thymoquinone (TQ), the most active constituent in Nigella sativa, which is a medicinal plant from the Ranunculaceae family, in restoring the normal liver structure after 6-propyl-2-thiouracil (PTU)-induced hypothyroidism and explore the mechanism behind this. Hypothyroidism was induced in rats by injection of PTU [6 mg∕kg body weight (b.w.)] for six weeks. Twenty-four adult male Wistar rats were divided into four groups; the control, TQ-treated at the dose 400 mg∕kg b.w., untreated hypothyroidism and TQ-treated hypothyroid groups. Serum levels of thyroid hormones and antioxidant profile were measured. Real-time polymerase chain reaction was used to assess gene expression of catalase (CAT). Liver was histopathologically examined using routine and immunohistochemical techniques. Livers of rats with hypothyroidism displayed nonalcoholic fatty liver disease (NAFLD) in the form of steatosis as well as nonalcoholic steatohepatitis (NASH). Moreover, there was an intralobular inflammatory reaction associated with significant (p<0.05) increases in the density of resident hepatic macrophages [cluster of differentiation 68 (CD68)+ cells], as well as in activated hepatic stellate cells, alpha-smooth muscle actin (α-SMA) index in livers with hypothyroidism. Resolution of hypothyroid NAFLD was observed in livers after treatment with TQ. The significantly increased (p<0.05) steatosis, lobular inflammation, NAFLD activity scores, α-SMA index as well as CD68+ cells induced by hypothyroidism were corrected after TQ administration. Up-regulation of the CAT gene in livers with hypothyroidism after treatment with TQ supported our hypothesis of its antioxidant mechanistic hepatoprotective action. TQ efficiently restores the normal liver histology in hypothyroid rats with up-regulation of the antioxidant CAT gene.


[Forecast of physician workforce in the 22 French regions (1998-2013)].
The first chapter provides detailed information on the methodology and data used. As were the other projections carried out in the past by the Centre de sociologie et de démographie médicales, the present work is basically a demographic projection. Whereas a projection of national workforce uses the total number of annual new graduates as inflow, a regional projection has to collect other types of data, as new graduates move freely from one region to another. This fundamental difference implies the use of more complex models for predicting the flows of newcomers at regional level. As concerns the outflow, a single table covering retirement and death is used for all regions. The medical profession is a homogeneous group and such a decision is not irrelevant. The second chapter presents briefly the results of the work as concerns one region. In the high variant, the regional number of physicians will continue to increase from 1998 to 2007 or 2008, then it will decrease. In the low variant, the growth will end in 2004 or 2005, followed by a stronger decreasing process. The decrease is caused by the "graduate boom" cohorts (doctors graduated during the 70's and 80's) reaching retirement age. Given the duration of medical training, the decrease will take place even if the numerous clausus (at the start of medical training) rises steadily right now. The decrease in the number of physicians will be accompanied by an aging process: the proportion of senior active doctors will raise and that of junior doctors will diminish. The third chapter evidences the diversity of the various regional trends.


The Impact of COVID-19 on Supplies of Routine Childhood Immunization in Oromia Regional State, Ethiopia: A Mixed Method Study.
Globally, national immunization programs are at risk of disruption due to severe health system constraints caused by the ongoing Corona Virus Disease 2019 (COVID-19) pandemic. To assess the impact of COVID-19 on the availability of supplies of routine childhood immunization in the Oromia Regional State in Ethiopia. A health facility-based mixed-methods of study design was conducted. Both quantitative and qualitative data were collected using pre-tested questionnaires and key informant interview question guides, respectively. Descriptive statistics such as frequencies, means, and standard deviations were performed. Binary logistic regression analysis was employed to assess the associations between the COVID-19 pandemic and the availability of vaccine-related supplies at health facilities in study area. The qualitative data were analyzed using a thematic content analysis approach. Of the total 448 study participants, 214 (47.8%) reported that COVID-19 has disrupted childhood vaccines availability. A significant proportion of participants agreed with the disruption of BCG (62.1%), OPV (48%), IPV (40.4%), and PENTA (36.9%) vaccine availabilities. These findings were also supported with key informant interviews. Fear of not maintaining physical distance (71.4%) followed by government lockdown (68.1%) and inadequate supply by local providers/suppliers (62.4%) were the most frequently reported likely causes for the observed disruptions. A large proportion of participants (87.7% and 81.7%) reported disruptions in the supply of face masks and hand gloves, respectively. As to the binary logistic regression analysis, the study participants from hospitals were 1.72 (1.01, 2.68; 95% CI) times more likely to report the impacts of COVID-19. Corona Virus Disease -19 significantly disrupted the availability of supplies of childhood immunization in the Oromia region. The most disrupted vaccines and related supplies were BCG, OPV, IPV, PENTA, facemasks, and hand gloves. An effective vaccine supply management is crucial to prevent disruptions during pandemics such as COVID-19.


Schistosoma mansoni venom allergen-like protein 6 (SmVAL6) maintains tegumental barrier function.
The Schistosoma mansoni venom allergen-like protein (SmVAL) superfamily is a collection of at least 29 molecules that have been classified into two distinctive groups (Group 1 and Group 2 SmVALs). The fundamental basis for SmVAL segregation relates to signal peptide and conserved cysteine retention (present in all Group 1 SmVALs, but absent in all Group 2 SmVALs). These structural differences have led to the hypothesis that most Group 1 SmVALs, found as components of schistosome excretory/secretory (E/S) products, predominantly interact with their environment (intermediate or definitive hosts) whereas the Group 2 SmVALs are retained within the schistosome to fulfil parasite-related functions. While experimental evidence to support Group 1 SmVAL/host interactions is growing, similar support for identification of parasite-related Group 2 SmVAL functions is currently lacking. By applying a combination of approaches to the study of SmVAL6, we provide the first known evidence for an essential function of a Group 2 SmVAL in schistosome biology. After whole mount in situ hybridisation (WISH) localised Smval6 to the anterior region of the oesophageal gland (AOG) and cells scattered through the mesenchyme in adult schistosomes, short interfering RNA (siRNA)-mediated silencing of Smval6 was employed to assess loss of function phenotypes. Here, siSmval6-mediated knockdown of transcript and protein levels led to an increase in tegumental permeability as assessed by the quantification of TAMRA-labelled dextran throughout sub-tegumental cells/tissues. Yeast two hybrid screening using SmVAL6 as a bait revealed Sm14 (a fatty acid binding protein) and a dynein light chain (DLC) as directly interacting partners. Interrogation of single-cell RNA-seq (scRNA-seq) data supported these protein interactions by demonstrating the spatial co-expression of Smval6/dlc/Sm14 in a small proportion of adult cell types (e.g. neurons, tegumental cells and neoblasts). In silico modelling of SmVAL6 with Sm14 and DLC provided evidence that opposing faces of SmVAL6 were likely responsible for these protein/protein interactions. Our results suggest that SmVAL6 participates in oesophageal biology, formation of higher order protein complexes and maintenance of tegumental barrier function. Further studies of other Group 2 SmVALs may reveal additional functions of this enigmatic superfamily.


Acute toxicosis in swine associated with excessive dietary intake of vitamin D.
Acute toxicosis developed in a group (n = 35) of fattening hogs and replacement gilts that had excessive vitamin D3 inadvertently added to their feed. All of the pigs were lethargic, and emesis was evident in about half of the pigs 1 to 2 days after they consumed the feed. On the 2nd day, 3 of the pigs died. The remaining pigs were given a different ration. Five additional pigs died during the next 2 weeks. Clinical toxicosis also was observed in 1 of 2 feeder pigs fed the suspect feed in the laboratory and in 2 of 2 pigs fed the suspect feed by the company that had mixed the feed. Gross necropsy findings consistently observed were hemorrhagic gastritis and diffuse interstitial pneumonia. Myocardial degeneration and nephrosis were seen in, respectively, 1 of 6 and 4 of 6 pigs necropsied. Histologically, necrosis and mineralization of variable severity were observed in the fundic gastric mucosa, lungs, kidneys, bone, heart, and small blood vessels of the lungs and heart. Less necrosis and more mineralization were observed in pigs that survived longer than 6 days. The 2 pigs fed the suspect feed in the laboratory had increased concentrations of serum calcium from the 3rd to the 9th days or the 1st to the 3rd days, after feeding the suspect feed. Serum phosphorus concentrations were increased from the 1st until the 2nd or 3rd day, and serum magnesium concentrations were increased from the 1st or 2nd to the 3rd day after feeding the suspect feed.(ABSTRACT TRUNCATED AT 250 WORDS)


[Molecular pathogenesis of carcinoma of the esophagus].
Carcinoma of the esophagus is present in two distinct morphological cell types: squamous or pavimentous cell carcinoma and adenocarcinoma. In this article, the main genetic alterations found in both types of carcinomas and their implications are described. The sequence of these alterations is related to histogenesis, making it possible to understand tumor progression from normal epithelium to invasive carcinoma. A comparison is attempted between the molecular development of esophagus carcinomas and that of colorectal carcinoma.


[Effect of eosin Y on ATPase activity of actomyosine complex of the uterus smooth muscle].
The effect of eosin Y (2,4,5,7 - tetrabromofluorescein; 0.1-100 microM) on ATPase activity smooth muscle actomyosine was studied. The inhibition coefficient i50 of ATPase activity with eosin Y was 0.74 +/- 0.07 microM. The inhibitor decreased V(max) of actomyosine ATPase for ATP, but no influence on affinity of actomyosine for ATP was observed. It is suggested that eosin Y inhibits actomyosine ATPase activity noncompetitively in respect of ATP.


YAP and TAZ Promote Periosteal Osteoblast Precursor Expansion and Differentiation for Fracture Repair.
In response to bone fracture, periosteal progenitor cells proliferate, expand, and differentiate to form cartilage and bone in the fracture callus. These cellular functions require the coordinated activation of multiple transcriptional programs, and the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) regulate osteochondroprogenitor activation during endochondral bone development. However, recent observations raise important distinctions between the signaling mechanisms used to control bone morphogenesis and repair. Here, we tested the hypothesis that YAP and TAZ regulate osteochondroprogenitor activation during endochondral bone fracture healing in mice. Constitutive YAP and/or TAZ deletion from Osterix-expressing cells impaired both cartilage callus formation and subsequent mineralization. However, this could be explained either by direct defects in osteochondroprogenitor differentiation after fracture or by developmental deficiencies in the progenitor cell pool before fracture. Consistent with the second possibility, we found that developmental YAP/TAZ deletion produced long bones with impaired periosteal thickness and cellularity. Therefore, to remove the contributions of developmental history, we next generated adult onset-inducible knockout mice (using Osx-CretetOff ) in which YAP and TAZ were deleted before fracture but after normal development. Adult onset-induced YAP/TAZ deletion had no effect on cartilaginous callus formation but impaired bone formation at 14 days post-fracture (dpf). Earlier, at 4 dpf, adult onset-induced YAP/TAZ deletion impaired the proliferation and expansion of osteoblast precursor cells located in the shoulder of the callus. Further, activated periosteal cells isolated from this region at 4 dpf exhibited impaired osteogenic differentiation in vitro upon YAP/TAZ deletion. Finally, confirming the effects on osteoblast function in vivo, adult onset-induced YAP/TAZ deletion impaired bone formation in the callus shoulder at 7 dpf before the initiation of endochondral ossification. Together, these data show that YAP and TAZ promote the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing. © 2020 American Society for Bone and Mineral Research (ASBMR).


[Mortality risk in intravenous drug users in Bologna and its determining factors. Results of a longitudinal study].
this study shows the mortality rates in a retrospective cohort of intravenous drug users attending the public treatment centres (SERT), in the metropolitan area of Bologna, from 1978 to 2004 (3753 subjects, 2926 men and 827 women). The overall mortality rate decreases after 1996 because of the substantial drop of mortality rate owing to AIDS. The overdose mortality increases until 1998 and then decreases; as from 1997 it becomes the first cause of death. The risk of death due to overdose is higher in men than in women, it is higher in subjects treated at SERT during the period 1996-2000 and decreases in subjects treated for more than two years. the study confirms an over mortality, due to all causes, of the cohort compared with the general population, in accordance with the results of other studies, and a remarkably high mortality for women (SMR in men: 1464; 95% CI 13.45-15.93; SMR in women: 25.61; 95% CI21.53-30.45) as well. Major causes of death among men are, besides overdose and AIDS, cirrhosis, cardiovascular disorders, suicide, lung tumour, and road accidents; among women are suicide, cirrhosis and cardiovascular disorders. The risk of death is higher before 1996 with regard to subjects attending SERT before 1990, and to those who are in treatment for less than two years. Also at higher risk are those subjects with a low schooling level and unemployed.


Oral health therapists: what is their role in Australian health care?
The aim of this report was to examine the role of the oral health therapist (OHT) in the contemporary Australian context. The original intent of the OHT role was to address unmet community oral health need in a cost-effective manner. Although it was recognized that OHTs would need to deliver clinical treatment, particularly restorative services for children, the core of their education and their knowledge and proficiency is in oral health and public health promotion. Unmet oral health need persists, and this is especially urgent for the most disadvantaged. Some may argue that this provides evidence that OHTs should provide an expanded range of clinical services, including adult restorative treatment, and that additional training should be provided to enable this to occur. This report counters that view by showing that the current health system does not avail itself of the health promotion services that OHTs are already educated to deliver. Improved health outcomes within the Australian health system are achievable by bringing oral health into the general health system, by introducing models of care aimed at the early detection of risk and disease and by recognizing the importance of public health measures designed to prevent disease.


In vivo assessment of human brain oscillations during application of transcranial electric currents.
Brain oscillations reflect pattern formation of cell assemblies' activity, which is often disturbed in neurological and psychiatric diseases like depression, schizophrenia and stroke. In the neurobiological analysis and treatment of these conditions, transcranial electric currents applied to the brain proved beneficial. However, the direct effects of these currents on brain oscillations have remained an enigma because of the inability to record them simultaneously. Here we report a novel strategy that resolves this problem. We describe accurate reconstructed localization of dipolar sources and changes of brain oscillatory activity associated with motor actions in primary cortical brain regions undergoing transcranial electric stimulation. This new method allows for the first time direct measurement of the effects of non-invasive electrical brain stimulation on brain oscillatory activity and behavior.


CyberKnife for Treatment of Vestibular Schwannoma: A Meta-analysis.
Objectives (1) Perform a meta-analysis of the available data on the outcomes of CyberKnife radiosurgery for treatment of vestibular schwannomas (VSs) in the published English-language literature and (2) evaluate the collective outcomes of CyberKnife treatment with respect to tumor control and hearing preservation. Data Sources A thorough literature search of published English-language articles was performed in the PubMed, Ovid, and Cochrane databases. Review Methods A database search was conducted with the keywords "CyberKnife" and "vestibular schwannoma" or "acoustic neuroma." A total of 25 papers were found and reviewed. Data were extracted for patient demographics, number of patients with neurofibromatosis type 2, pretreatment hearing status, tumor size, margin dose, and follow-up duration. The primary outcome variables evaluated were tumor control and hearing preservation. Results After careful review of the published articles, 11 papers reported data on outcomes of CyberKnife treatment for VS and were included in the analysis, comprising 800 patients studied during 1998 to 2012. The reported mean tumor volume ranged from 0.02 to 19.8 cm3, and the follow-up duration ranged from 6 to 120 months. Margin dose varied from 14 to 25 Gy. The collective mean tumor control rate was 96.3% (95% CI: 94.0%-98.5%). The collective hearing preservation rate was 79.1% (95% CI: 71.0%-87.3%) in 427 patients with measurable hearing. Conclusion Clinical data on outcomes of CyberKnife radiosurgery for treatment of VSs are sparse and primarily limited to single-institution analyses, with considerable variation in tumor volume and follow-up time. This meta-analysis not only provides an in-depth analysis of available data in the literature but also reviews reported outcomes and complications.


New inbred strain of Long-Evans Tokushima lean rats with IDDM without lymphopenia.
Spontaneously diabetic rats with remarkable polyuria, polyphagia, and polydipsia were discovered in 1983 in an outbred colony of Long-Evans rats purchased from Charles River Canada in 1982. They have since been maintained at the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan). A strain of rats (Long-Evans Tokushima Lean [LETL]) with diabetes was bred from these rats. The characteristic features of the disease in LETL rats are 1) sudden onset of polyuria, polyphagia, hyperglycemia, and weight loss; 2) no sex differences in the rate of onset or severity; 3) lymphocyte infiltration into islets followed by destruction of beta-cells and disappearance of lymphocytes at the onset of diabetes; 4) no significant T lymphopenia; 5) lymphocyte infiltration into the salivary glands and lacrimal glands; and 6) at least two recessive genes involved in the pathogenesis of insulitis, one of which is closely linked with RT1u. These characteristics closely resemble those of human insulin-dependent diabetes mellitus (IDDM). Results suggest that the LETL rat is a useful animal model for analysis of genetic and immunologic factors relating to the pathogenesis of human IDDM.