[Early activation of coagulation and fibrinolysis in traumatic brain injury and spontaneous intracerebral hemorrhage: a comparative study].
Traumatic brain injury (TBI) and spontaneous intracerebral hemorrhage (SIH) are associated with acute brain injury. Both increase intracranial pressure because of hemorrhages which activate the coagulation system. The relationship between acute brain injury and coagulation activation can be explained by the tissue factor release from the damaged brain to the circulation. This problem has been addressed in several studies, though detailed investigations are lacking mainly in SIH. To study the activation of hemostasis in a group of patients with TBI and with SIH. Patients and methods. Prospective observational study. Seventy-five intensive care patients were divided in two groups. The first group (n = 45) included TBI and the second (n = 30) SIH. There were 40 healthy persons as a control group. Thrombin-antithrombin III complex, D-dimer and 1 + 2 thrombin fragment levels were measured. All the studied markers were significantly higher in the two patient groups. Thrombin-antithrombin III complex and D-dimer were significantly higher in TBI. We have confirmed a relationship between higher levels of markers and the injury severity, measured with the Glasgow coma scale. Acute brain injury secondary to TBI and SIH activates coagulation system and fibrinolysis early. This activation attempts to achieve a hemostasia status. The activation is more intense in patients with low Glasgow coma scores on admission.


Ramularia leaf spot: PCR-based methods reveal widespread distribution of Ramulariopsis pseudoglycines and limited presence of R. gossypii in Brazil.
Whilst Brazil is the fourth largest cotton producer globally, incidence of ramularia leaf spot (RLS) has decreased yield. In 2017-18 and 2018-19, ca. 300 fungal samples were collected throughout Brazil. Hyphal tip cultures were obtained for amplification of the RNA polymerase II (RPB2), 28S rRNA, the ribosomal DNA internal transcribed spacers (ITS), actin (ACT), elongation factor (EF1-α) and histone H3 (HIS3) genomic regions. Additionally, sequences of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were obtained by nanopore sequencing and the EF1-α region was selected as a marker for rapid recognition of Ramulariopsis species. Clade assignments based on the concatenated-sequence tree were identical to those in tree generated by RPB2-sequences, as well as in an RPB2 haplotype network and an ISSR (TGTC)4 dendrogram, in identification with species-specific primers and based on morphological comparisons. Out of 267 examined isolates, 252 were identified as Ramulariopsis pseudoglycines, indicating this species as the most widespread causal agent of cotton RLS in the Brazilian growing regions. Species-specific primers developed in the study that target the EF1-α gene provide an opportunity for extensive RLS sampling worldwide to study the distribution of Ramulariopsis species. Such data will aid breeders and plant pathologists in cotton disease resistance development and fungicide resistance avoidance.


Measuring School Climate among Japanese Students-Development of the Japan School Climate Inventory (JaSC).
School climate is a significant determinant of students' behavioral problems and academic achievement. In this study, we developed the Japan School Climate Inventory (JaSC) to see whether it measures school climate properly. To do so, we investigated whether or not the measurement with JaSC varies across sub-groups of varying grade and of gender and examined the relationship between the perception of school climate and the psychological and behavioral traits at individual levels in a sample of Japanese elementary and junior high school students (n = 1399; grade 4-9). The results showed that the measurement was consistent, since single-factor structures, factor loadings and thresholds of the items were found not to vary across sub-groups of the participants. The participants' perception of school climate was associated positively with quality of life, especially in school (β = 0.152, p < 0.001) and associated negatively with involvement in ijime (bullying) as "victim" and "bully/victim" (β = -0.098, p = 0.001; β = -0.188, p = 0.001, respectively) and peer relationship problems (β = -0.107, p = 0.025). JaSC was found to measure school climate consistently among varying populations of Japanese students, with satisfactory validity.


Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss.
Telomere length plays a significant role in various disorders; however, its role in idiopathic recurrent pregnancy loss (iRPL) is not known. The objective of this study was to assess telomere length in peripheral blood leukocytes in couples experiencing unexplained recurrent pregnancy loss (iRPL). The study included 25 couples experiencing iRPL and 20 controls. The mean relative telomere length was measured by quantitative Real Time PCR (Q-PCR) based assay, which measures the average ratio of telomere repeat copy number to a single copy gene (36B4) copy number (T/S ratio) in each sample. The relative leukocyte mean telomere length (T/S) in both men and women from iRPL group was significantly lower (p < 0.05) when compared to controls. A significant (P < 0.05) negative correlation was found between age and leukocyte telomere length (T/S ratio). Among the sperm parameters seminal volume was found to be negatively (r = -0.4679) associated with the telomere T/S ratio. The DNA fragmentation index of sperm showed positive correlation (r = 0.4744) with telomere length. In this preliminary study, we found that shorter telomere length in both men and women may be associated with early pregnancy loss. In conclusion, shorter telomere length in both male and female partners appears to play a role in the idiopathic recurrent pregnancy loss. Loss of telomeric DNA due to oxidative stress needs further analysis. Analysis of telomere length in germ cells are needed to further substantiate the findings of this study.


Histamine Neuroimaging in Stress-Related Disorders.
Although histamine plays a major role in animal models of stress-related disorders, human neuroimaging data are sparse. Histamine H1 receptors in the human brain were first imaged by Professor Kazuhiko Yanai in 1992 by using 11C-doxepin, a potent ligand of H1 receptors, and positron emission tomography (PET). Subsequent work revealed that H1 receptors are reduced in the prefrontal and anterior cingulate cortices in patients with major depressive disorders. A sex difference in H1 receptor binding in the brain has also been found, with women exhibiting more abundant H1 receptor binding than men. Moreover, female patients with anorexia nervosa show higher H1 receptor binding in the amygdala and lentiform nucleus. These studies also found an inverse correlation of depression scores with H1 receptor binding. Histamine is considered to play a major role in the pathophysiology of irritable bowel syndrome (IBS), a representative disorder of brain-gut interactions. Along these lines, hypnotic suggestion dramatically changes the waveforms of viscerosensory cerebral evoked potentials in response to electrical rectal stimulation and these changes are modified by the administration of H1 antagonist. The direction of the H1 antagonist-induced changes in the viscerosensory cerebral evoked potentials differs between IBS patients and healthy controls. Thus, histamine likely plays an important role in stress-related disorders. Further histamine brain imaging studies of humans are warranted.


Molecular profiles of BRCA1-associated ovarian cancer treated by platinum-based therapy: Analysis of primary, residual and relapsed tumors.
Our study aimed to analyze the evolution of molecular portraits of BRCA1-driven ovarian cancer (OC) during treatment. BRCA1 loss-of-heterozygosity status (LOH) and exome profiles were investigated in serial OC samples from 13 patients, which included primary tumors (n = 11) obtained before neoadjuvant therapy (NACT) or at primary debulking surgery, residual post-NACT cancer tissues (n = 13) and tumor relapses (16 samples from 13 patients). Loss of the wild-type BRCA1 allele was detected in 11/11 (100%) primary tumors, 6/13 (46%) residual post-NACT OC samples and 15/16 (94%) OC relapses. Full tumor triplets were available for four patients undergoing NACT; whereas primary carcinomas from these patients demonstrated BRCA1 LOH, the retention of the wild-type allele was detected in all four post-NACT residual tumors. These four women provided to the study 5 recurrent OC samples; 4 out of 5 tumor relapses had BRCA1 LOH thus resembling BRCA1 status observed in primary but not residual OC tissues. TP53 mutation was detected in 12 out of 13 patients and was retained across all serial samples. OC relapses tended to acquire additional intragenic mutations in genes involved in cell migration, adhesion and cell junction assembly. BRCA1-driven OCs demonstrate the plasticity of BRCA1 status during the treatment course. NACT results in rapid selection of pre-existing BRCA1-proficient cells. However, BRCA1 proficiency appears to be disadvantageous in the absence of platinum exposure, as tumor relapses usually re-acquire BRCA1 LOH during therapy holidays.


Analysis of the 4-hydroxytamoxifen (4-OHTAM) bound nuclear estrogen receptor from MCF-7 cells by limited proteolysis.
The assumption that a different conformational form was induced in the nuclear estrogen receptor following binding by antiestrogens compared to estrogens was studied by analysing the proteolytic fragments of the receptor following limited digestion with chymotrypsin and trypsin. Nuclei were isolated from MCF-7 cells previously exposed to [3H] 4-OHTAM. The proteolytic digestion was performed either on the micrococcal nuclease hydrolysate or on intact nuclei. The molecular weights (Mr) were calculated from the sedimentation coefficients (S) determined on a sucrose gradient and from the Stokes radii (Rs) estimated by gel filtration. Digestion of the nuclei with micrococcal nuclease solubilized a receptor form of Mr = 155,000. This receptor form was degraded by chymotrypsin to a receptor of Mr = 63,000 which could not be further dissociated by 0.4 M KCl and 3 M urea. A similar receptor molecule was released by chymotrypsin from intact nuclei. Digestion of the micrococcal nuclease hydrolysate with trypsin degraded the receptor to a form of a Mr = 67,000 which could not be further dissociated by 0.4 M KCl and 3 M urea. Digestion of intact nuclei with trypsin followed by micrococcal nuclease, solubilized a receptor form of Mr = 80,000 which could be further dissociated with 0.4 M KCl and 3 M urea to a receptor form of Mr = 67,000. This trypsin degraded receptor form seems to be similar in Mr to the chymotrypsin degraded form. On the other hand different receptor fragments of Mr = 33,000 and Mr = 60,000 were excised by chymotrypsin and trypsin respectively from the estradiol ligated estrogen receptor. (Geier et al., J. steroid Biochem. 26 [1987] 35-40.) These results support the assumption of a different conformational form for the antiestrogen ligated receptor, compared to the estrogen ligated receptor since they were differentially susceptible to proteolytic degradation by chymotrypsin.


Lymphocyte migration into brain modelled in vitro: control by lymphocyte activation, cytokines, and antigen.
Factors controlling lymphocyte adhesion to brain endothelium were investigated in vitro. Mitogen activation of lymphocytes causes increased adhesion to endothelium, which is maximal at 7-24 hr, declines to normal levels after the cells divide, and requires protein synthesis. Rat brain endothelium can be stimulated with IFN-gamma to increase its adhesion to either normal or activated lymphocytes. The endothelium is sensitive to low levels of cytokine: adhesion develops rapidly after stimulation and requires new protein synthesis. Antigen-specific line cells also adhere more effectively to endothelium than normal lymph node cells. This is enhanced by IFN-gamma treatment of the endothelium and is further increased marginally in the presence of the cognate antigen. The results suggest that either local stimulation of endothelium with cytokines or lymphocyte activation in the periphery will modulate lymphocyte traffic into brain.


Examining the relationship between HbA1c and diabetes risk models in a European population indicates a lower threshold to identify 'high risk' is required.
This study examined whether changes in HbA1c values are reflected in the risk scores and categories of four validated risk-assessment tools (QDiabetes, Leicester Risk Assessment, Finnish Diabetes Risk Score and Cambridge Risk Score). Retrospective analysis was performed on 651 individuals with no prior diagnosis of cardiovascular disease or diabetes who participated in a UK workplace-based risk-assessment initiative. There were significant positive correlations (p < 0.01) revealed between HbA1c values and predicted risk scores: QDiabetes (r = 0.362), Leicester Risk Assessment (r = 0.315), Finnish Diabetes Risk Score (r = 0.202) and Cambridge Risk Score (r = 0.335). HbA1c values increased within risk prediction categories, and at 'high-risk' categories, median HbA1c values were at least 39 mmol mol(-1) (5.7%) irrespective of gender or risk-assessment model. Overall, an association is present between increases in HbA1c scores and predicted risk of type 2 diabetes. Furthermore, the 'high-risk' median HbA1c values in each of the risk assessments are more akin to the lower American recommendations rather than those suggested by the UK expert group.


Preventing obesity in the primary care setting.
This article outlines steps on how to move the treatment of obesity to a new paradigm of prevention in the primary care setting. Almost all Americans visit their primary care physician or health care provider for routine health maintenance or some unexpected illness or sickness at one point or another. The primary care office is the most likely entry point to the health care system for most of the population and should be the preferred venue for addressing chronic disease prevention. Prevention in the primary care setting is the short- and long-term solution to obesity.


Equalization of exercise protocols: not if, but how.
Comparative analysis of high-intensity interval training (HIIT) suffers from a lack of standardized metrics for intervention programming. Given the huge amount of research and general public attention to exercise as medicine, understanding how to compare exercise intervention protocols is both prescient and essential to interpreting the findings of studies of exercise therapy.


Mono-Sized Anion-Exchange Magnetic Microspheres for Protein Adsorption.
In this study, mono-sized anion-exchange microspheres with polyglycidylmethacrylate were engineered and processed to introduce magnetic granules by penetration-deposition approaches. The obtained magnetic microspheres showed a uniform particle diameter of 1.235 μm in average and a good spherical shape with a saturation magnetic intensity of 12.48 emu/g by VSM and 12% magnetite content by TGA. The magnetic microspheres showed no cytotoxicity when the concentration was below 10 μg/mg. The magnetic microspheres possess respective adsorption capacity for three proteins including Bovine albumin, Hemoglobin from bovine blood, and Cytochrome C. These magnetic microspheres are also potential biomaterials as targeting medicine carriers or protein separation carriers at low concentration.


Therapeutic Effect of a Xeno-Free Three-Dimensional Stem Cell Mass in a Hind Limb Ischemia Model.
We describe an innovative method of culturing a three-dimensional cell mass (3DCM) of human adipose-derived stem cells (hASCs) in the xeno-free (XF) condition for the treatment of severe ischemic diseases. The majority of the mice injected with XF-3DCMs exhibited limb salvaging and displayed similar blood perfusion compared to normal limbs. In vivo tumorigenicity and toxicity analysis showed that XF-3DCMs did not transform into tumor cells and induce toxicity, respectively. Our results strongly suggest that XF-3DCMs can be effectively used for therapeutic applications and eliminate immunological reaction of animal-derived material contamination.


Splanchnic sympathetic nerve denervation improves bacterial clearance and clinical recovery in established ovine Gram-negative bacteremia.
The autonomic nervous system can modulate the innate immune responses to bacterial infections via the splanchnic sympathetic nerves. Here, we aimed to determine the effects of bilateral splanchnic sympathetic nerve denervation on blood pressure, plasma cytokines, blood bacterial counts and the clinical state in sheep with established bacteremia. Conscious Merino ewes received an intravenous infusion of Escherichia coli for 30 h (1 × 109 colony forming units/mL/h) to induce bacteremia. At 24 h, sheep were randomized to have bilaterally surgically implanted snares pulled to induce splanchnic denervation (N = 10), or not pulled (sham; N = 9). Splanchnic denervation did not affect mean arterial pressure (84 ± 3 vs. 84 ± 4 mmHg, mean ± SEM; PGroup = 0.7) compared with sham treatment at 30-h of bacteremia. Splanchnic denervation increased the plasma levels of the pro-inflammatory cytokine interleukin-6 (9.2 ± 2.5 vs. 3.8 ± 0.3 ng/mL, PGroup = 0.031) at 25-h and reduced blood bacterial counts (2.31 ± 0.45 vs. 3.45 ± 0.11 log10 [CFU/mL + 1], PGroup = 0.027) at 26-h compared with sham treatment. Plasma interleukin-6 and blood bacterial counts returned to sham levels by 30-h. There were no differences in the number of bacteria present within the liver (PGroup = 0.3). However, there was a sustained improvement in clinical status, characterized by reduced respiratory rate (PGroup = 0.024) and increased cumulative water consumption (PGroup = 0.008) in splanchnic denervation compared with sham treatment. In experimental Gram-negative bacteremia, interrupting splanchnic sympathetic nerve activity increased plasma interleukin-6, accelerated bacterial clearance, and improved clinical state without inducing hypotension. These findings suggest that splanchnic neural manipulation is a potential target for pharmacological or non-pharmacological interventions.


Spontaneous abortions and work in day nurseries.
420 pregnancies were recorded between 1962 and 1987 among 202 women working for at least one month in day nurseries during 1984. During that time 230 pregnant mothers had worked as childminders in day nurseries ('exposed' pregnancies). The remaining 190 pregnancies were classified as 'unexposed'. 27 spontaneous abortions were exposed and 7 unexposed corresponding to abortion rates of 11.7% and 3.9%, respectively, which is a significant difference. Also 'threatened' abortions during the first trimester of pregnancies ending up in live-born children were accumulated in exposed pregnancies, and the miscarriage rate was possibly increased in unexposed pregnancies of women with their own children in day nurseries. Significant differences were not observed with regard to premature birth, congenital malformations, number of live-born children and sex ratio of live-born children. The cause of the increased frequency of spontaneous and 'threatened' abortions in exposed pregnancies could be a contagious agent.


Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, part 1: improving the pharmacokinetic profile using the structure-property relationship.
We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.


Enhanced enzymatic saccharification of rice straw by microwave pretreatment.
In this study, Box-Behnken design and response surface methodology were employed to plan experiments and optimize the microwave pretreatment of rice straw. Experimental results show that microwave intensity (MI), irradiation time (IT) and substrate concentration (SC) were main factors governing the enzymatic saccharification of rice straw. The maximal efficiencies of cellulose, hemicellulose and total saccharification were respectively increased by 30.6%, 43.3% and 30.3% under the optimal conditions of MI 680 W, IT 24 min and SC 75 g/L. The chemical composition analysis of straw further confirmed that microwave pretreatment could disrupt the silicified waxy surface, break down the lignin-hemicellulose complex and partially remove silicon and lignin.


Manipulation of Xist Imprinting in Mouse Preimplantation Embryos.
X-chromosome inactivation (XCI) is established in preimplantation embryos in mice. Prior to the establishment of XCI, expression of the long noncoding RNA (lncRNA) Xist is essential. Xist expression in mouse preimplantation embryos is imprinted, and paternal Xist is predominantly expressed. Due to the manner of imprinting, maternal Xist is always silenced. However, the nature of imprinting to repress maternal Xist is variable. For example, parthenogenetic embryos that are composed of two maternal genomes exhibit maternal Xist derepression during the preimplantation phases. Maintenance of Xist imprinting to repress maternal Xist depends on the chromatin condensation states and the dosage of Rnf12, an essential Xist activator. Therefore, alterations of chromatin states and Rnf12 expression levels lead to maternal Xist derepression. In this chapter, we describe the method for derepressing maternal Xist by various approaches, such as mRNA injection, small molecule treatment, and nuclear transfer.


The decomposition of protoporphyrin IX by ultrasound is dependent on the generation of hydroxyl radicals.
The ultrasound activation of certain drugs, such as porphyrins, could cause synergistic cytotoxic effects on cells. Both sonomechanical and sonochemical effects occur and the latter play a critical role because antioxidant agents could exert significant protective effects against the cytotoxicity. To investigate the reactive oxygen species involved in the sonochemical effects, aqueous protoporphyrin IX (PpIX) solutions were characterized under ultrasound sonication in this study. Inertial cavitation was indirectly evaluated using terephthalic acid dosimetry. The fluorescence intensity of the PpIX was measured using a fluorescence spectrophotometer. The effects of PpIX concentration, ultrasound parameters and free radical scavengers on the PpIX activation by ultrasound were investigated. Our results showed that the increase in PpIX decomposition was significantly correlated with cavitation activities (R=0.9874, p<0.05), and the decomposing effect increases with ultrasound intensity (0.6-1.5 W/cm(2)), initial PpIX concentration (1-5 μM), duty cycle (10-100%) and the sonication duration (2-10 min). The fluorescence and absorption spectra of PpIX showed a decrease in the peak intensity without spectral shifts or new peak build-up after sonication. The PpIX decomposition was significantly inhibited by hydroxyl radical scavengers, histidine, mannitol, acetone, methanol and ethanol, but the decomposition was not inhibited by sodium azide, catalase or superoxide dismutase. These results suggest that the decomposition of protoporphyrin IX by ultrasound is dependent on the generation of hydroxyl radicals, which sheds some light on the sonochemical effects of the interaction between ultrasound and porphyrins.


Arterial blood pressure in the very low birthweight neonate. Evaluation of an automatic oscillometric technique.
The noninvasive oscillometric technique of arterial blood pressure determination was evaluated in fifteen very low birth weight neonates (less than 1,400 g). Measurement of invasive umbilical artery catheter pressure was used as a reference standard. By using a cuff width to arm circumference ratio of 0.33-0.42, mean blood pressure was overestimated by 6.2 (7.2) mmHg (mean and 1 SD), p less than 0.001. More accurate mean blood pressure measurements were recorded with a cuff width to arm circumference ratio of 0.44-0.55. Measurements of systolic and diastolic blood pressure showed similar results.


Prediction of corneal back surface power - Deep learning algorithm versus multivariate regression.
The corneal back surface is known to add some against the rule astigmatism, with implications in cataract surgery with toric lens implantation. This study aimed to set up and validate a deep learning algorithm to predict corneal back surface power from the corneal front surface power and biometric measures. This study was based on a large dataset of IOLMaster 700 measurements from two clinical centres. N = 19,553 measurements of 19,553 eyes with valid corneal front (CFSPM) and back surface power (CBSPM) data and other biometric measures. After a vector decomposition of CFSPM and CBSPM into equivalent power and projections of astigmatism to the 0°/90° and 45°/135° axes, a multi-output feedforward neural network was derived to predict vector components of CBSPM from CFSPM and other measurements. The predictions were compared with a multivariate linear regression model based on CFSPM components only. After pre-conditioning, a network with two hidden layers each having 12 neurons was derived. The dataset was split into training (70%), validation (15%) and test (15%) subsets. The prediction error (predicted corneal back surface power CBSPP - CBSPM) of the network after training and crossvalidation showed no systematic offset, narrower distributions for CBSPP - CBSPM and no trend error of CBSPP - CBSPM vs. CBSPM for any of the vector components. The multivariate linear model also showed no systematic offset, but broader distributions of the prediction error components and a systematic trend of all vector components vs. CFSPM components. The neural network approach based on CFSPM vector components and other biometric measures outperforms the multivariate linear model in predicting corneal back surface power vector components. Modern biometers can supply all parameters required for this algorithm, enabling reliable predictions for corneal back surface data where direct corneal back surface data are unavailable.


Examining "success" in post-hip fracture care transitions: a strengths-based approach.
Transitions between health care settings are a high-risk period for care quality and patient safety (Coleman, 2003; Picker Institute, 1999), particularly for older patients - such as those with hip fracture - who have complex needs and may undergo multiple care transitions. We sought to understand the key elements of "success" in care transition. Using a strengths-based perspective (Rapp, 1998; Saleebey, 2006), we focused on interprofessional health care providers' perspectives of what constitutes a "good" care transition for elderly hip fracture patients. As part of a larger ethnographic field study, semi-structured interviews were conducted with 17 health providers across a number of disciplines employed across the continuum of post-hip fracture management in British Columbia, Canada. We found two hallmarks of "success" in care transitions: a focus on process - information gathering and communication, and a focus on outcomes - autonomy and care pathways. Strategies for promoting and improving success, such as using practitioner-driven ground-up solutions to address challenges in care transitions, are highlighted.


LncRNA profiles of Cyanidin-3-O-glucoside ameliorated Zearalenone-induced damage in porcine granulosa cells.
Long non-coding RNA (lncRNA), a class of RNA molecules with transcripts longer than 200 nt, is crucial for maintaining animal reproductive function. Zearalenone (ZEN) damaged animal reproduction by targeting ovarian granulosa cells (GCs), especially in pigs. Nonetheless, it is not quite clear that whether Cyanidin-3-O-glucoside (C3G) exert effects on porcine GCs (pGCs) after ZEN exposure by altering lncRNA expression. Here, we sought to gain novel information regarding C3G protect against damages induced by ZEN in pGCs. The pGCs were divided into control (Ctrl), ZEN, ZEN + C3G (Z + C), and C3G groups. Results revealed that C3G effectively increased cell viability and suppressed ZEN-induced apoptosis in pGCs. 87 and 82 differentially expressed lncRNAs (DELs) were identified in ZEN vs. Ctrl and Z + C vs. ZEN group, respectively. Gene Ontology (GO) analysis observed that the DELs were related to cell metabolism and cell-matrix adhesion biological processes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the DELs were associated with the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) signaling pathway. In brief, we demonstrated that C3G could shield apoptosis induced by ZEN, which may be connected with the changes of lncRNA expression profiles in pGCs. This study complemented our understanding of the genetic basis and molecular mechanisms by which C3G mitigated the toxicity of ZEN in pGCs.


[Genetics of contact allergy].
The genetics of contact allergy (CA) is still only partly understood, despite decades of research. This might be due to inadequately defined phenotypes used in the past. Therefore we suggested studying an extreme phenotype, namely, polysensitization (sensitization to 3 or more unrelated allergens). Another approach to unravel the genetics of CA has been the study of candidate genes. In this review, we summarize studies on the associations between genetic variation (e.g. SNPs) in certain candidate genes and CA. The following polymorphisms and mutations were studied: (1) filaggrin, (2) N-acetyltransferase (NAT1 and 2), (3) glutathione-S-transferase (GST M and T), (4) manganese superoxide dismutase, (5) angiotensin-converting enzyme (ACE), (6) tumor necrosis factor (TNF), and (7) interleukin-16 (IL16). The polymorphisms of NAT1/2, GST M/T, ACE, TNF, and IL16 were shown to be associated with an increased risk of CA. In one of our studies, the increased risk conferred by the TNF and IL16 polymorphisms was confined to polysensitized individuals. Other relevant candidate genes may be identified by studying diseases related to CA in terms of clinical symptoms, a more general pathology (inflammation) and possibly an overlapping genetic background, such as irritant contact dermatitis.


Interleaved 31P NMR with transcutaneous nerve stimulation (TNS): a method of monitoring compliance-independent skeletal muscle metabolic response to exercise.
31P NMR spectroscopy was used to monitor the metabolic response of the tibialis anterior muscle group to transcutaneous nerve stimulation of the peroneal nerve at a rate of 4 Hz for 5 min in human volunteers (n = 8). It is demonstrated that this technique can be used as a method of investigating effort-free and compensation-independent skeletal muscle exercise.


The prevalence and genotypic analysis of Toxoplasma gondii from individuals in Scotland, 2006-2012.
Contemporary information relating to the prevalence of Toxoplasma gondii in humans is lacking for the UK population, with even less information available about the human prevalence of the parasite in Scotland. To address this, two different study groups were used to determine the prevalence and genotypes of Toxoplasma gondii in the Scottish population. The first study group included serum samples from blood donors (n = 3273) over a four-year period (2006-2009) and the second study group comprised of DNA samples extracted from human brains (n = 151) over a five-year period (2008-2012). A T. gondii IgG ELISA was performed to determine seroprevalence and available sera from individuals who had seroconverted were tested by TgERP ELISA (sporozoite specific antigen). Human brain DNA was tested for T. gondii by ITS1 PCR and positives genotyped at the SAG3 and GRA6 loci by PCR-RFLP analysis. Seroprevalence to T. gondii from blood donors was found to be 13.2 % (95 % CI: 11.5-15.1 %). Evidence of seroconversion (n = 2) as well as reversion to sero-negative status (n = 6) was evident from blood donors who had donated within all four collection periods (n = 184). The TgERP ELISA (indicating oocyst infection) was positive for one individual. The molecular detection of T. gondii DNA from human brains indicated a prevalence of 17.9 % (95 % CI: 12.1-24.9 %), with genotyping identifying alleles for types I and III. An increase in age was associated with an increase in detection of the parasite within both study groups. Our research provides current figures for the prevalence of T. gondii in Scotland and also shows evidence of seroreversion within the cohort of blood donors. In both study groups there was a correlation between increasing age and an increase in T. gondii prevalence, indicating that acquired infection plays an important role within the Scottish population.


Perceptions of barriers and facilitators to implement programs for prevention of mother-to-child transmission of HIV-Mozambique.
To understand the perspectives of pregnant and postpartum women living with HIV in Sofala, Mozambique, regarding barriers and facilitators to following Prevention of Mother-to-Child Transmission (PMTCT) recommendations. Qualitative study conducted in three health centers and with a peer support group of women living with HIV, between October 2020 and March 2021. We applied purposeful sampling, semi-structured interviews, and content analysis. Among the barriers that emerged were the social stigma associated with HIV-positive status and fear of discrimination, side effects of medications, economic barriers, and denial of diagnosis/treatment. As facilitating factors: peer support networks and inspiration, innate concern for health and family. Finally, they recommend that the community should become more educated about HIV. The results of this study give a broad understanding of the experience of women living with HIV in this province, making it possible to focus strategies in improving the care of women in PMTCT programs in Mozambique.


Assembly of Tetraspanin-enriched macrodomains contains membrane damage to facilitate repair.
Various mechanisms contribute to membrane repair1-8 but the machinery that mediates the repair of large wounds on the plasma membrane is less clear. We found that shortly after membrane damage, Tetraspanin-enriched macrodomains are assembled around the damage site. Tetraspanin-enriched macrodomains are in the liquid-ordered phase and form a rigid ring around the damaged site. This restricts the spread of the damage and prevents membrane disintegration, thus facilitating membrane repair by other mechanisms. Functionally, Tetraspanin 4 helps cells mitigate damage caused by laser, detergent, pyroptosis and natural killer cells. We propose that assembly of Tetraspanin-enriched macrodomains creates a physical barrier to contain membrane damage.


Evaluation of steelmaking slag as basal media for coastal primary producers.
The use of granular steelmaking slag as a substitute for natural sand in the construction of tidal flats was investigated. Using an intertidal flat simulator, we evaluated dephosphorization slag mixed with 8% by dry weight of dredged sediment (DPS+DS) as a basal medium for the growth of benthic macro- and microalgae in comparison with silica sand mixed with 8% dredged sediment (SS+DS). Species compositions of macro- and microalgae were distinctly different between DPS+DS and SS+DS. The mean dry weight of macroalgae on DPS+DS was three orders of magnitude higher than that on SS+DS. Sediment shear strength and pH were higher in DPS+DS than in SS+DS or in the sediment of natural tidal flats. These results suggest that DPS contributes to changing the sediment environment, thereby changing the algal composition compared to the composition on natural tidal flats.


Role of nurse clinician in urologic oncology.
The incorporation of single and combination chemotherapy into the therapeutic regimen for some advanced genitourinary tumors has greatly added to the myriad of medical and psychologic problems already present in these patients. Working closely with a urologist, a nurse clinician can be of significant help in the total care of this group of patients. Due to the seriousness and chronicity of the neoplastic process, the emotional and social impact as well as physical factors affect all phases of the patient's life, as well as the lives of family members. The incorporation of traditional nursing values into the medical education of nurse clinicians helps to prepare them to deal with these problems, and their participation serves to make the medical team more complete.


Density-dependent germination response by seeds of desert annuals.
Field observations and experiments indicate that the presence of seedlings at high densities inhibits subsequent germination of desert annuals. Since plants growing at high densities face severe competition for limited resources, this response by seeds is interpreted as an adaptation to avoid an unfavorable competitive climate where growth and survivorship are likely to be low.


Phlebotomine sand flies and Leishmania parasites: friends or foes?
Leishmania parasites need phlebotomine sand flies to complete their life cycle and to propagate. This review looks at Leishmania-sand fly interactions as the parasites develop from amastigotes to infectious metacyclics, highlighting recent findings concerning the evolutionary adaptations that ensure survival of the parasites. Such adaptations include secretion of phosphoglycans, which protect the parasite from digestive enzymes; production of chitinases that degrade the stomodeal valve of the sand fly; secretion of a neuropeptide that arrests midgut and hindgut peristalsis; and attaching to the midgut to avoid expulsion.


Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events.
Cognitive dysfunction has been one of the most reported and studied adverse effects of cancer treatment, but, for many years, it was overlooked by the medical community. Nevertheless, the medical and scientific communities have now recognized that the cognitive deficits caused by chemotherapy have a strong impact on the morbidity of cancer treated patients. In fact, chemotherapy-induced cognitive dysfunction or 'chemobrain' (also named also chemofog) is at present a well-recognized effect of chemotherapy that could affect up to 78% of treated patients. Nonetheless, its underlying neurotoxic mechanism is still not fully elucidated. Therefore, this work aimed to provide a comprehensive review using PubMed as a database to assess the studies published on the field and, therefore, highlight the clinical manifestations of chemobrain and the putative neurotoxicity mechanisms.In the last two decades, a great number of papers was published on the topic, mainly with clinical observations. Chemotherapy-treated patients showed that the cognitive domains most often impaired were verbal memory, psychomotor function, visual memory, visuospatial and verbal learning, memory function and attention. Chemotherapy alters the brain's metabolism, white and grey matter and functional connectivity of brain areas. Several mechanisms have been proposed to cause chemobrain but increase of proinflammatory cytokines with oxidative stress seem more relevant, not excluding the action on neurotransmission and cellular death or impaired hippocampal neurogenesis. The interplay between these mechanisms and susceptible factors makes the clinical management of chemobrain even more difficult. New studies, mainly referring to the underlying mechanisms of chemobrain and protective measures, are important in the future, as it is expected that chemobrain will have more clinical impact in the coming years, since the number of cancer survivors is steadily increasing.


t t ¯ H production at NNLO: the flavour off-diagonal channels.
We consider QCD radiative corrections to the associated production of a heavy-quark pair ( Q Q ¯ ) with a generic colourless system F at hadron colliders. We discuss the resummation formalism for the production of the Q Q ¯ F system at small values of its total transverse momentum q T . We present the results of the corresponding resummation coefficients at next-to-leading and, partly, next-to-next-to-leading order. The perturbative expansion of the resummation formula leads to the explicit ingredients that can be used to apply the q T subtraction formalism to fixed-order calculations for this class of processes. We use the q T subtraction formalism to perform a fully differential perturbative computation for the production of a top-antitop quark pair and a Higgs boson. At next-to-leading order we compare our results with those obtained with established subtraction methods and we find complete agreement. We present, for the first time, the results for the flavour off-diagonal partonic channels at the next-to-next-to-leading order.


Genetic factors modulating the response to stimulant drugs in humans.
Individuals vary in their responses to stimulant drugs, and several lines of evidence suggest that the basis for this variation is at least partially genetic in origin. Association studies have examined the effects of polymorphisms in specific genes on acute and chronic responses to stimulant drugs. Several of these genetic polymorphisms are also associated with other psychiatric dimensions and disorders.This chapter examines the evidence for genetic associations between the genes that have been most carefully examined for their influence on the response to stimulant drugs.


Physician-assisted weight loss and maintenance in the elderly.
Although commonly addressed in magazines, across airwaves, and within gyms nationwide, health care providers must now face the growing epidemic of obesity in their daily practice. With the graying of America, it is all the more important to realize that weight increases the risk for disease and mortality in the elderly. Despite overwhelming evidence that weight loss can reduce health risks, many patients who are overweight never receive needed advice from their primary care physicians. This article addresses the barriers to physician intervention, methods to assess obesity risk, and readiness to change. Effective approaches for assisting in successful weight loss and maintenance are discussed.


Occurrence of oxalyl-CoA synthetase in Indian pulses.
The presence of oxalyl-CoA synthetase was observed in common edible pulses. Excepting in chick pea, the changes in oxalyl-CoA synthetase activity of winter pulses proceeded in stages. The enzyme remained more active in late strains than in early strains of winter pulses. Unlike the activity of the enzyme in winter pulses, that in summer pulses behaved differently.


Alterations in differentially expressed genes by exposure to a mixture of carcinogenic polycyclic aromatic hydrocarbons in the liver of Oryzias latipes.
The effects of a mixture of carcinogenic polycyclic aromatic hydrocarbons (cPAHs) on transcriptional responses in the liver of medaka, Oryzias latipes, were investigated by identifying differentially expressed genes (DEGs). Five DEGs were identified as cytochrome P450 2P1 (CYP450 2P1), malate dehydrogenase, anti-thrombin III, NADH dehydrogenase subunit 4, and transferrin. These DEGs were quantified by real-time polymerase chain reaction. Only CYP450 2P1 mRNA was found to be upregulated by exposure to cPAHs mixture, suggesting that CYP450 2P1 mRNA can be a potential marker for prediction of the biological effects of a mixture of cPAHs on fish.


Aspiration of dead space in the management of chronic obstructive pulmonary disease patients with respiratory failure.
Carbon dioxide clearance can be improved by reducing respiratory dead space or by increasing the clearance of carbon-dioxide-laden expiratory gas from the dead space. Aspiration of dead space (ASPIDS) improves carbon dioxide clearance by suctioning out (during expiration) the carbon-dioxide-rich expiratory gas while replacing the suctioned-out gas with oxygenated gas. We hypothesized that ASPIDS would allow lower tidal volume and thus reduce exposure to potentially injurious airway pressures. With 8 hemodynamically stable, normothermic, ventilated patients suffering severe chronic obstructive pulmonary disease we tested the dead-space-clearance effects of ASPIDS. We compared ASPIDS to phasic tracheal gas insufflation (PTGI) during conventional mechanical ventilation and during permissive hypercapnia, which was induced by decreasing tidal volume by 30%. The mean P(aCO(2)) reductions with PTGI flows of 4.0 and 6.0 L/min and during ASPIDS (at 4.0 L/min) were 32.7%, 51.8%, and 53.5%, respectively. Peak, plateau, and mean airway pressure during permissive hypercapnia were significantly lower than during conventional mechanical ventilation but PTGI increased peak, plateau, and mean airway pressure. However, pressures were decreased during permissive hypercapnia while applying ASPIDS. Intrinsic positive end-expiratory pressure also increased with PTGI, but ASPIDS had no obvious influence on intrinsic positive end-expiratory pressure. ASPIDS had no effect on cardiovascular status. ASPIDS is a simple adjunct to mechanical ventilation that can decrease P(aCO(2)) during conventional mechanical ventilation and permissive hypercapnia.


A monoclonal antibody which detects a cell surface antigen on murine embryonal carcinoma and early mouse embryo stages may recognize a carbohydrate determinant involving alpha-linked galactose.
A rat monoclonal antibody (5D4) apparently specific for murine embryonal carcinoma cells and cells of the pre-implantation embryo is described. It does not react with differentiated cells from a variety of different tumours and tissues of the mouse. Biochemical studies show that the molecules that carry 5D4 antigen are resistant to protease digestion on the cell surface but susceptible to procedures which affect carbohydrate structure. It is likely that this antibody detects a carbohydrate bearing determinant which may include an alpha-linked galactose residue.


Spray dried powders for nasal delivery: Process and formulation considerations.
Powders for nasal delivery have been recognized as advantageous dosage forms over liquids due to increased stability and residence time on nasal mucosa, with improved bioavailability. They can be manufactured by spray-drying, allowing the optimization of the particle properties that are critical to guarantee nasal deposition, as size and shape. It is also a scalable and flexible method already explored extensively in the pharmaceutical industry. However, it is important to understand how process parameters, particle physical properties and formulation considerations affect the product performance. Hence, this review aims to provide an overview of nasal powder formulation and processing through spray drying, with an emphasis on the variables that impact on performance. To this purpose, we describe the physical, biological and pharmacological phenomena prior to drug absorption as well as the most relevant powder properties. Formulation considerations including qualitative and quantitative composition are then reviewed, as well as manufacturing considerations including spray drying relevant parameters.


Sexual function in obese women: impact of lower urinary tract dysfunction.
To assess the impact on sexual function attributed to lower urinary tract dysfunction in a female obese population. We performed a case-control study based on the registry of a university hospital obesity unit. A consecutive sample of women with body mass index(BMI) >or=30 (obese) was randomly matched by age, gender and residential county to control subjects using the computerized Register of the Total Population. Data were collected by a self-reported postal survey including the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). The questionnaire was completed and returned by 279/446 patients (62%) and 430/892 control subjects (48%). Obese women reported significantly lesser satisfaction with their sexual life, more frequent symptoms of urinary incontinence at intercourse, more often fear of urine leakage at intercourse, a higher tendency toward avoiding intercourse and more frequent feelings of guilt and disgust during intercourse (P<0.001). While considering sexual function in a subset of women with urge or stress urinary incontinence, the overall PISQ-12 scores were significantly lower in obese women compared to their age-matched nonobese controls for both the conditions (P<0.001). In an adjusted multivariate analysis, a BMI >30 was independently associated with a significantly increased risk for sexual dysfunction (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.1-2.9), as were symptoms of urge or stress urinary incontinence (OR, 2.0; 95% CI, 1.3-3.1 and OR, 2.6; 95% CI, 1.7-4.0), respectively. Urge and stress urinary incontinences are more common and have greater impact on sexual function in obese women.


Minimal energy foldings of eukaryotic mRNAs form a separate leader domain.
We have investigated the minimal energy foldings of 38 mature mRNAs, including the globin family, the insulins, the growth hormones and interleukin-2, and have compared these foldings with those of fully and partly randomised sequences. The mRNAs differ from the random sequences in that they form a separate leader hairpin of 40-60 nucleotides, with the initiation codon typically located downstream of this hairpin, followed by a main fold in which a region flanking the initiation codon is basepaired with the trailer: resulting in a close proximity of the 5' and 3' end of the mRNA. The formation of this conformation depends not only--or primarily--on the structure of the leader, but on both the leader and trailer sequence and their interaction with the coding sequence. Thus if, as the frequent occurrence of this pattern suggests, the secondary structure of the leader regions plays a role in the initiation of translation, possibly accounting for the specificity of initiation and the different translational efficiencies of various mRNAs, we expect that these features may be influenced both by leader and trailer mutants.


Role of cytoplasmic membrane in the screening of potential tumour promoters.
The functional changes of cytoplasmic membrane of mammalian cells as an alternative approach for evaluating the tumor promoter activity were investigated. The V79 metabolic cooperation assay, as the standard method for detection of tumor promoters in vitro was used. From three known tumor promoters only phenobarbital increased the efflux of [3H]2-deoxy-D-glucose-6-phosphate from the cells in the same concentration range where the inhibition of metabolic cooperation was estimated. Neither TPA, saccharin nor theophylline caused any functional changes of cytoplasmic membrane of V79 cells. On the basis of the results with known tumor promoters we suggest that following the functional changes of cytoplasmic membrane is not a convenient approach for screening potential tumor promoters.


[Antithrombotic treatment and cancer].
Five to 10 % of cancers are complicated by venous thromboembolism. A score is available to classify patients according to their risk of venous thromboembolism. The long-term prophylaxis is not recommended in patients with cancer, even if it reduces the incidence of thromboembolic events, due to the high number of patients to treat to prevent one event. The treatment of venous thromboembolism in cancer is based on the use of low-molecular weight heparin for at least 3 months. The potential role of antithrombotic drugs in the prevention and adjuvant treatment of some cancers is being evaluated.


Fatty acid sensing GPCR (GPR84) signaling safeguards cartilage homeostasis and protects against osteoarthritis.
It is well known that free fatty acids (FFAs) have beneficial effects on the skeletal system, however, which fatty acid sensing GPCR(s) and how the GPCR(s) regulating cartilage development and osteoarthritis (OA) pathogenesis is largely unknown. In this study, we found Gpr84, a receptor for medium-chain FFAs (MCFA), was the only FFA-sensing GPCR in human and mouse chondrocytes that exhibited elevated expression when stimulated by interleukin (IL)-1β. Gpr84-deficiency upregulated cartilage catabolic regulator expression and downregulated anabolic factor expression in the IL-1β-induced cell model and the destabilization of the medial meniscus (DMM)-induced OA mouse model. Gpr84-/- mice exhibited an aggravated OA phenotype characterized by severe cartilage degradation, osteophyte formation and subchondral bone sclerosis. Moreover, activating Gpr84 directly enhanced cartilage extracellular matrix (ECM) generation while knockout of Gpr84 suppressed ECM-related gene expression. Especially, the agonists of GPR84 protected human OA cartilage explants against degeneration by inducing cartilage anabolic factor expression. At the molecular level, GPR84 activation inhibited IL-1β-induced NF-κB signaling pathway. Furthermore, deletion of Gpr84 had little effect on articular and spine cartilaginous tissues during skeletal growth. Together, all of our results demonstrated that fatty acid sensing GPCR (Gpr84) signaling played a critical role in OA pathogenesis, and activation of GPR84 or MCFA supplementation has potential in preventing the pathogenesis and progression of OA without severe cartilaginous side effect.


Substructure of cisternal organelles of neuronal perikarya in immature rat brains revealed by quick-freeze and deep-etch techniques.
Membrane-bounded organelles possessing cisternae, i.e., rough endoplasmic reticulum and Golgi apparatus, in immature rat central neurons were examined by quick-freeze and deep-etch techniques to see how their intracisternal structures are organized and how ribosomes are associated with the membrane of the endoplasmic reticulum. Cisternae of endoplasmic reticulum, 60-100 nm wide, were bridged with randomly-distributed strands (trabecular strands, 12.5 nm in mean diameter). Luminal surfaces of cisternae of the endoplasmic reticulum were decorated with various-sized globular particles, some as small as intramembrane particles, and others as large as granules formed by soluble proteins seen in the cytoplasm. A closer examination revealed much thinner strands (3.3 nm in mean diameter). Such thin strands were short, usually winding toward the luminal surface, and sometimes touching the luminal surface with one end. Ribosomes appeared to be embedded into the entire thickness of cross-fractured membranes of endoplasmic reticulum, that is, their internal portions appeared to be situated at almost the same level as the cisternal luminal surface. From the internal portion of ribosomes, single thin strands occasionally protruded into the lumen, suggesting that these thin strands were newly synthesized polypeptides. A horizontal separation within ribosomes appeared to occur at the same level as the hydrophobic middle of the membrane of the endoplasmic reticulum. Interiors of the Golgi apparatus cisternae, which were much narrower than cisternae of endoplasmic reticulum, were similarly bridged with trabecular strands, but the Golgi trabecular strands were thinner and more frequent. Their cisternal lumina were also dotted with globular particles. No identifiable profiles corresponding to the thin strands in the endoplasmic reticulum were observed. Golgi cisternae showed a heterogeneous distribution of membrane granularity; the membrane in narrow cisternal space was granule-rich, while that in expanded space was granule-poor, suggesting a functional compartmentalization of the Golgi cisternae.


The neuropathological findings of developmental and epileptic encephalopathy-43 (DEE43) and delineation of a the molecular spectrum of novel case.
Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course. The neuropathological analysis revealed co-existing developmental anomalies and retardation of myelination resulting from disturbed early brain growth as well as lesions caused by epileptic hypoxic-ischemic episodes. Developmental anomalies included misplaced neurons in the cerebellar white matter, heterotopic neurons in the cortical molecular layer and in the molecular layer of the hippocampal dentate gyrus, dysmorphic cerebellar dentate nuclei and inferior olivary nuclei in the medulla oblongata. The migrational and maturational disorders leading to the neuronal network dysfunction could be the cause of both the lack of development and the ineffectiveness of antiepileptic treatment in children affected by DEE. Giving the presented neuropathological description and based on the literature, we discuss the pathomechanism of the disease, to improve current understanding of both the lack of development and the ineffectiveness of treatment of affected children.


Congenital chylothorax: report of unique case associated with 'H' -type tracheo-oesophageal fistula.
A case of congenital chylothorax associated with a congenital 'H'-type tracheo-oesophageal fistula is reported. The development of the thoracic duct is described and the possible embryological association with tracheo-oesophageal fistula is discussed. The management of the case is reviewed.


Distinct physiological role of amidino-TAPA-sensitive and DAMGO-insensitive μ-opioid receptor splice variants in the mouse spinal cord.
The physiological role of the distinct splice variants for cloned mouse μ-opioid receptor (mMOR-1), mMOR-1J, mMOR-1K and mMOR-1L, which are sensitive to N(α)-amidino-Tyr-D-Arg-Phe-β-Ala (amidino-TAPA) and insensitive to [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO), was described in the mouse spinal cord. The antinociception induced by intrathecally (i.t.) injected amidino-TAPA was attenuated by i.t. pretreatment with antisera against the endogenous opioid peptides dynorphin A, dynorphin B, α-neo-endorphin, or [Leu(5)]enkephalin in naïve mice. However, in mice whose spinal mMOR-1J had been knocked-down using the antisense oligodeoxynucleotide (ODN) for exon-12 of mMOR-1 gene, the inhibiting effect of antiserum against dynorphin A on amidino-TAPA-induced antinociception was eliminated. In contrast, the inhibiting effect of antisera against dynorphin B or α-neo-endorphin on amidino-TAPA-induced antinociception was eliminated in mice whose spinal mMOR-1K had been knocked-down using the antisense ODN for exon-13 of mMOR-1 gene. Moreover, the inhibiting effect of antisera against dynorphin A or [Leu(5)]enkephalin on amidino-TAPA-induced antinociception was eliminated in mice whose spinal mMOR-1L had been knocked-down using the antisense ODN for exon-14 of mMOR-1 gene. The present results suggest that the distinct antinociceptive profile of amidino-TAPA, that is the release of endogenous κ- and δ-opioid peptides in spinal cord, is mediated through the activation of mMOR-1J, mMOR-1K or mMOR-1L, which contain the sequence encoded by exon-12, exon-13 or exon-14 of mMOR-1 gene, respectively.


Ecotoxicology and geostatistical techniques employed in subtropical reservoirs sediments after decades of copper sulfate application.
Spatial distribution linked to geostatistical techniques contributes to sum up information into an easier-to-comprehend knowledge. This study compares copper spatial distribution in surface sediments and subsequent categorization according to its toxicological potential in two reservoirs, Rio Grande (RG) and Itupararanga (ITU) (São Paulo-Brazil), where copper sulfate is applied and not applied, respectively. Sediments from 47 sites in RG and 52 sites in ITU were collected, and then, copper concentrations were interpolated using geostatistical techniques (kriging). The resulting sediment distributions were classified in categories based on sediment quality guides: threshold effect level and probable effect level; regional reference values (RRVs) and enrichment factor (EF). Copper presented a heterogenic distribution and higher concentrations in RG (2283.00 ± 1308.75 mg/kg) especially on the upstream downstream, associated with algicide application as well as the sediment grain size, contrary to ITU (21.81 ± 8.28 mg/kg) where a no-clear pattern of distribution was observed. Sediments in RG are predominantly categorized as "Very Bad", whereas sediments in ITU are mainly categorized as "Good", showing values higher than RRV. The classification is supported by the EF categorization, which in RG is primarily categorized as "Very High" contrasting to ITU classified as "Absent/Very Low". Copper total stock in superficial sediment estimated for RG is 4515.35 Ton of Cu and for ITU is 27.45 Ton of Cu.


Miniaturized fluorescence detection chip for capillary electrophoresis immunoassay of agricultural herbicide atrazine.
This paper reports a miniaturized fluorescence detection chip for capillary electrophoresis immunoassay of atrazine, which effectively reduces the size of fluorescence detection system. The photodiode with fluorescence filter was embedded in PDMS (polydimethylsiloxane) microfluidic chip and was placed just below the microfluidic channel. This detection chip is only few mm thick without loss of fluorescence due to the proximity of photodiode and channel. To investigate the feasibility of in situ detection of agricultural herbicide, atrazine was detected using capillary electrophoresis immunoassay in microfluidic chip. Mixture of 570 nM fluorescence-labeled atrazine (Ag*) and 700 nM anti-atrazine antibody (Ab) was injected and separated in 25 mm long microfluidic channel. The separated peaks of Ab-Ag* immunocomplex and Ag* were detected by the miniaturized detector and the change of peak magnitude was also observed with the variation of Ab concentration. The result was verified with those of external PMT (photomultiplier tube) and commercial capillary electrophoresis system. Hence, we have demonstrated the feasibility of portable CE immunoassay of atrazine with on-chip fluorescence detector.


No change in NMDA receptor-mediated response rise-time during development: evidence against transmitter spillover.
Glutamatergic transmission was examined in tadpole optic tectum to test the possibility that transmitter concentration reaching N-methyl-D-aspartate (NMDA) receptors increases over development. Pharmacologically isolated NMDA receptor-mediated transmission was monitored with whole-cell recordings. Synaptic responses were recorded from cells at different locations in the optic tectum, corresponding to different stages of development. Rise-times and decay-times of NMDA currents were analyzed. We found no significant correlation between rise-time and developmental stage. As NMDA rise-times can correlate with concentration for glutamate concentrations below 200 microM, these results argue that, if there is developmental variation in transmitter concentration, this occurs for values greater than 200 microM. Furthermore, we found a correlation between rise-times and decay-times, consistent with a model in which transmitter concentration is high and rise-time is controlled by channel closings. These results argue against synaptic models in which low concentrations of transmitter (as by spillover from nearby release sites) selectively activates NMDA receptors.


Moyamoya Disease in an 18-Month-Old Female Caucasian Complicated by Cerebral Hyperperfusion Syndrome Following Indirect Revascularization.
BACKGROUND Cerebral hyperperfusion syndrome is a rare complication of indirect revascularization due to moyamoya disease, but has not been reported previously in the pediatric population. We present a case of an 18-month-old girl with moyamoya disease that was treated with bilateral pial synangiosis and had complications consistent with cerebral hyperperfusion syndrome. This case report discusses the pathophysiological mechanisms involved in cerebral hyperperfusion in moyamoya syndrome. CASE REPORT An 18-month-old female Caucasian presented with seizures and weakness of the left side. Angiography confirmed bilateral cerebral moyamoya disease that was worse on the right side. Indirect revascularization with pial synangiosis was first performed on the right side to allow for healing. Five months later, pial synangiosis was then performed on the left side. Postoperatively, the patient experienced increased intracranial pressure (ICP), suggesting cerebral hyperperfusion syndrome. She was treated with a repeat lumbar puncture, a lumbar drain, and a lumbar shunt. CONCLUSIONS This report demonstrates a case of cerebral hyperperfusion syndrome as a complication of moyamoya disease in a pediatric patient. Although the patient progressed well after placement of a lumbar shunt, this case demonstrates the occurrence of cerebral hyperperfusion syndrome as a complication of revascularization in pediatric patients and highlights the need for further research in this area.


User introduced uncertainties in the measurement of field misalignment by a computer aided technique.
While images acquired using an electronic portal imager may be visually compared to other portal or simulator images to assess patient alignment, a more quantitative comparison is desirable. Computer aided alignment tools are available which are based on user placed landmarks. The purpose of this study was to estimate uncertainties introduced by the user to the final measurement of field misalignment using such a tool. Both intra- and inter-user reproducibility were assessed. To complete this task, a number of image pairs including both phantom and patient images were compared by multiple observers. Results of the comparisons (x- and y- translation and rotation) were tabulated for each image pair and their reproducibility assessed by calculating a mean and standard deviation. User introduced uncertainty was found to be independent of the magnitude of rotation or x- or y- translation. In all cases, there was no difference between intra-observer and inter-observer uncertainty. For clinical cases, there is a significant difference between uncertainty in x- and y-translation due to both image quality and patient anatomy. In addition, the magnitude of uncertainty tracks qualitatively with image quality and number of available anatomical landmarks. The decision to make a correction in field alignment must be made considering these uncertainty estimates. Image comparison must be fully automated to eliminate uncertainties introduced by the user.


Epidemiology of poly-parasitism. I. Occurrence, frequency and distribution of multiple infections in rural communities in Chad, Peru, Afghanistan, and Zaire.
Parasitic diseases are predominantly rural diseases. They are often associated with poverty, illiteracy, poor sanitation and high risks of exposure to environmental and biological hazards. Because these factors are also essential determinants in the epidemiology of a variety of other infections with quite different etiologies, occurrence of multiple infections in the same people is common. In the tropics, polyparasitism may involve diseases of major public health inportance such as malaria, schistosomiasis, filarial infections, trypanosomiasis, and others. The paper presents data on the frequency and types of multiple infections with different parasitic and other infectious agents for thirteen villages of Chad, Peru and Afghanistan. The age and sex patterns of a number of observed combinations of parasitic and other diseases are shown for different ecological zones. Concomitant infections with up to five species of filarial worms are found in residents of villages in the Congo River Basin of Zaire. The specific types of combinations of these infections vary from place to place and appear to be closely linked to ecological factors.


Forgetting the best when predicting the worst: Preliminary observations on neural circuit function in adolescent social anxiety.
Social anxiety disorder typically begins in adolescence, a sensitive period for brain development, when increased complexity and salience of peer relationships requires novel forms of social learning. Disordered social learning in adolescence may explain how brain dysfunction promotes social anxiety. Socially anxious adolescents (n = 15) and adults (n = 19) and non-anxious adolescents (n = 24) and adults (n = 32) predicted, then received, social feedback from high and low-value peers while undergoing functional magnetic resonance imaging (fMRI). A surprise recall task assessed memory biases for feedback. Neural correlates of social evaluation prediction errors (PEs) were assessed by comparing engagement to expected and unexpected positive and negative feedback. For socially anxious adolescents, but not adults or healthy participants of either age group, PEs elicited heightened striatal activity and negative fronto-striatal functional connectivity. This occurred selectively to unexpected positive feedback from high-value peers and corresponded with impaired memory for social feedback. While impaired memory also occurred in socially-anxious adults, this impairment was unrelated to brain-based PE activity. Thus, social anxiety in adolescence may relate to altered neural correlates of PEs that contribute to impaired learning about social feedback. Small samples necessitate replication. Nevertheless, results suggest that the relationship between learning and fronto-striatal function may attenuate as development progresses.


Author Correction: Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Working together: neonatal nurse practitioners in practice.
The aim of this study was to examine the relatively new role of neonatal nurse practitioners (NNPs) in the United Kingdom, comparing practice in different types of neonatal units and work undertaken by junior medical staff (JMS). Diary checklists sent to the total population of qualified NNPs in neonatal units (NNUs) and JMS in six regional centres with qualified NNPs were returned from 68 out of 109 qualified NNPs (62%), working in 50 different NNUs and from 25 out of 48 JMS (52%). Direct observations (totalling 263.5 h) were made by an experienced neonatal nurse researcher on 30 different NNPs. Frequencies of activities and specific procedures were compared between groups. Observational measures included type and duration of activity and interactions with other members of staff. NNPs were found to be undertaking a range of activities: in the NNU, which usually involved blood sampling, siting of intravenous cannulae, presenting at ward rounds and teaching. Outside the unit, NNPs attended the delivery suite and the postnatal ward. Significant differences were found in the nature and organization of their work in different types of NNUs. A comparison between NNPs and JMS showed similar activities, with greater direct involvement by NNPs in the NNU and in teaching. The diary data were supported by observations and together these are evidence of current NNP practice. To a large extent there is an overlap in the work of JMS and NNPs in neonatal units, but although the clinical work and areas of activity are similar, there are differences in emphasis and in work organization.


Isolation and identification of S(+)-3-hydroxyisobutyric acid in the urine of rats loaded with isobutyric acid.
3-Hydroxyisobutyric acid has been isolated from the urine of rats loaded with sodium isobutyrate. An optical rotation measurement of the methyl ester derivative shows this compound to be the S(+) stereoisomer. This is the same stereoisomer that has been previously identified in cultures of bacteria incubated with ammonium isobutyrate (Aberhart, D.J. (1977) Bioorg. Chem. 6, 191--201).


Durable HIV Suppression Among People Who Inject Drugs From a Community-Based Cohort Study in Baltimore, Maryland, 1997-2017.
People who inject drugs (PWID) face disparities in human immunodeficiency virus (HIV) treatment outcomes and may be less likely to achieve durable viral suppression. We characterized transitions into and out of viral suppression from 1997 to 2017 in a long-standing community-based cohort study of PWID, the AIDS Link to Intravenous Experience (ALIVE) Study, analyzing HIV-positive participants who had made a study visit in or after 1997. We defined the probabilities of transitioning between 4 states: 1) suppressed, 2) detectable, 3) lost to follow-up, and 4) deceased. We used multinomial logistic regression analysis to examine factors associated with transition probabilities, with a focus on transitions from suppression to other states. Among 1,061 participants, the median age was 44 years, 32% were female, 93% were African-American, 59% had recently injected drugs, and 28% were virologically suppressed at baseline. Significant improvements in durable viral suppression were observed over time; however, death rates remained relatively stable. In adjusted analysis, injection drug use and homelessness were associated with increased virological rebound in earlier time periods, while only age and race were associated with virological rebound in 2012-2017. Opioid use was associated with an increased risk of death following suppression in 2012-2017. Despite significant improvements in durable viral suppression, subgroups of PWID may need additional efforts to maintain viral suppression and prevent premature mortality.


A semiparametric efficient estimator in case-control studies for gene-environment independent models.
Case-controls studies are popular epidemiological designs for detecting gene-environment interactions in the etiology of complex diseases, where the genetic susceptibility and environmental exposures may often be reasonably assumed independent in the source population. Various papers have presented analytical methods exploiting gene-environment independence to achieve better efficiency, all of which require either a rare disease assumption or a distributional assumption on the genetic variables. We relax both assumptions. We construct a semiparametric estimator in case-control studies exploiting gene-environment independence, while the distributions of genetic susceptibility and environmental exposures are both unspecified and the disease rate is assumed unknown and is not required to be close to zero. The resulting estimator is semiparametric efficient and its superiority over prospective logistic regression, the usual analysis in case-control studies, is demonstrated in various numerical illustrations.


Behavioral Determinants of Routine Health Information System Data Use in Senegal: A Qualitative Inquiry Based on the Integrated Behavioral Model.
Routine health information system (RHIS) data are essential in driving decision making and planning in health systems as well as health programs. However, despite their importance, these data are underutilized, and the underlying individual-level facilitators and barriers to use remain understudied. In this research, we applied the Integrated Behavior Model (IBM) to examine how attitudes toward RHIS data, perceived norms concerning RHIS data use, and the ability to use RHIS data influence the demand and use of RHIS data among stakeholders in Senegal. Using data from interviews with respondents working at national levels of malaria, HIV, and TB control programs in Senegal, we used a framework analysis approach to apply the IBM behavioral constructs and identify their linkages to RHIS data use. We found that attitudes about the quality, availability, and relevance of RHIS data for decision making were important in driving data use among respondents. Institutional expectations, organizational protocols, policies, and practices around RHIS data ultimately shape social norms around the use of the data. Although we found that perceived ability and self-efficacy to use RHIS data were not barriers to RHIS data use among stakeholders at the strategic levels of their respective organizations, these were reported to be barriers at lower levels of the health system. Low perceived control of the RHIS data production process ultimately reduced RHIS data use for decision making among the strategic-level respondents. We recommend context-specific reexamination of existing RHIS interventions with a renewed emphasis on behavioral aspects of data use. The IBM can help guide practitioners, policy makers, and academics to address multiple socioecological factors that influence data use behavior when recommending RHIS and data use solutions.


Plasma protein extravasation and vascular endothelial growth factor expression with endothelial nitric oxide synthase induction in gentamicin-induced acute renal failure in rats.
Microvascular hyperpermeability to plasma proteins via vascular endothelial growth factor (VEGF) with endothelial nitric oxide synthase (eNOS) induction may contribute to wound healing through matrix remodeling. However, vascular hyperpermeability is not examined in acute renal failure (ARF), a unique form of wound healing. Subcutaneous injection of gentamicin (400 mg/kg per day for 2 days in divided doses every 8 h) in rats increased serum creatinine levels and induced tubular damage, which peaked at day 6, after the last gentamicin injection. Ki67-positive regenerating proximal tubules (PTs) peaked in number at day 6 and almost covered the bare tubular basement membrane (TBM) by day 10. Staining of fibrinogen and plasma fibronectin began to increase in the peritubular regions as early as day 0, steadily increased in TBM and tubular lumen until day 6 and then decreased. Hyperpermeable peritubular capillaries were identified by extravasation of perfused-fluoresceinated dextran (both 70 kDa and 250 kDa) into peritubular regions as early as day 0 and prominently into TBM and tubular lumen at day 6. Electron microscopy further suggested the intraendothelial pathway of dextran. Immunoreactive VEGF increased in the damaged and regenerating PTs. Immunoreactive VEGF receptors-1 and -2 did not change, but immunoreactive eNOS increased in the peritubular capillaries after induction of ARF. Western blotting for VEGF and eNOS supported the immunostaining findings. In addition, we assessed the effects of NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) on vascular hyperpermeability during the recovery phase of this model. Treatment with L-NAME (s.c. at a dose of 100 mg/kg/day from day 3 to day 6) decreased extravasation of perfused-250-kDa dextran and significantly inhibited the regenerative repair of PTs at day 6 when compared with vehicle-treated rats. In conclusion, plasma protein extravasation occurred, leading to matrix remodeling, such as the process of wound healing during the tubular repair in gentamicin-induced ARF. Since VEGF-induced vascular hyperpermeability may depend on NO production, VEGF/VEGF receptor system with eNOS induction might be responsible for this process.


Standardised step by step approach to adnexectomy by Vaginal Natural Orifice Transluminal Endoscopic Surgery.
Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) combines the advantages of vaginal surgery with those of laparoscopic surgery. Feasibility of vNOTES for other indications such as hysterectomy, ovarian cystectomy and myomectomy has been established. In this article, we describe a standardised step by step process to perform adnexal surgery by vNOTES.


Synthesis, characterization and vibrational spectroscopic study of Co, Mg co-doped LiMnPO₄.
The isostructural olivine-like LiM(II)PO4 compounds [M(II)=Mn, Mn0.9Co0.1, Mn0.8Co0.1Mg0.1] were successfully generated through the solid state reaction from the synthesized NH4M(II)PO4∙H2O precursors. The TG/DTG/DTA, AAS/AES, FTIR and XRD methods were employed to confirm both NH4M(II)PO4∙H2O and LiM(II)PO4 compounds. Their morphologies were studied by SEM method. The shift of two theta angle of XRD to higher values was observed in metal doping compounds, which indicate the formation of the single phase of isodivalent doping of Co(2+) and Mg(2+) ions according to the change in the lattice parameters and cell volumes. Their infrared spectra are reported and discussed with respect to the normal vibrations of NH4(+), PO4(3-), P2O7(4-) and H2O molecules using factor group analysis. The correlation field splitting analysis of PO4(3-) in NH4M(II)PO4∙H2O (orthorhombic system, Pmn2(1), C(2v)(7) and Z=2, [(3×5)-6]×2=18 internal modes) symbolized as T(d)-C(s)-C(2v)(7) suggested the number of vibrational modes to be: Γ(Vib)=A1(6)+A2(3)+B1(6)+B2(3) and A1(6)+A2(3)+B1(3)+B2(6) for zx and yz plane respectively. While, LiM(II)PO4 crystallizes in the orthorhombic system the space group Pnma (D(2h)(16)), Z=4 and the site symmetry of PO4(3-) is C(s). The correlation field splitting of type T(d)-C(s)-D(2h)(16) were reported in relation to [(3×5)-6]×4=36 internal modes for PO4(3-) unit in the structure.


Comparison of the efficacy of gossypol acetate enantiomers in rats with uterine leiomyoma.
Gossypol acetate (GA), as the product of racemic gossypol and acetic acid conjugated by hydrogen bond, is hydrolyzed into gossypol to exert its effect on treating uterine leiomyoma (UL), which has been listed in China. But hypokalemia and mild changes of liver function limit its clinical application. It had been reported that the biological activities of gossypol optical isomers were different. In this study, we aimed to clarify whether there were differences in the efficacy of gossypol enantiomers and whether a single gossypol optical isomer could alleviate adverse reactions in the treatment of UL. The results indicated that (-)-GA and (+)-GA had significant therapeutic effect on rats with UL. Interestingly, (-)-GA could better significantly ameliorate the pathological structure, inhibit the secretion of estrogen, and downregulate the expression of estrogen receptor-alpha (ER-α) and progesterone receptor (PR) than (+)-GA. Additionally, (-)-GA could better evidently decrease the symptoms of abnormally elevated inflammatory factors caused by UL. In contrast, (-)-GA and (+)-GA had certain effects on potassium ion concentration in serum, liver and kidney function, and the effects of (+)-GA on liver function were more obvious than (-)-GA. These findings will be of great significance to the drug development of gossypol optical isomers.


Intrinsic BMP Antagonist Gremlin-1 as a Novel Circulating Marker in Pulmonary Arterial Hypertension.
Gremlin-1, an intrinsic antagonist of bone morphogenetic protein (BMP) signaling, has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, it is unknown whether gremlin-1 can be detected in the circulation of PAH patients and whether it is associated with patients' functional status and outcome. With a mean level of 242 ± 24 ng/ml, gremlin-1 levels of 31 PAH patients were significantly elevated compared to 151 ± 18 ng/ml in 15 age- and gender-matched healthy subject (p = 0.016). In PAH patients, increasing gremlin-1 levels correlated with N-terminal prohormone of brain natriuretic peptide levels (r = 0.608, p < 0.001) and inversely with the 6-minute walking distance (r = -0.412, p = 0.029). Furthermore, gremlin-1 significantly stratified survival in PAH patients (p = 0.015). Gremlin-1 may represent a new biomarker for PAH which can be linked directly to the underlying pathomechanism. Elevated levels of gremlin-1 are associated with patients' functional status and survival, thus gremlin-1 neutralization could represent a potential therapeutic strategy to increase BMPR2 signaling.


Arteriographic demonstration of the release of coronary artery spasm by isosorbide dinitrate: a twenty-five-year retrospective.
It has been 25 years since my colleagues and I were first approached to apply the then newly emerging technique of coronary arteriography to the study of the effects of the new vasodilator isosorbide dinitrate (ISDN) on coronary arteries in vivo. Through a combination of careful patient assessment and serendipity, we were able to visualize the prompt release of coronary artery spasm by ISDN. Ensuing years have seen dramatic advances both in angiographic techniques and in the knowledge of ISDN efficacy. This review will briefly summarize the early work with ISDN and detail how the improvements in cineangiography have fostered better understanding of the actions of ISDN.


Neuroimaging features and predictors of outcome in eclamptic encephalopathy: a prospective observational study.
Posterior reversible encephalopathy syndrome is associated with eclampsia. We assessed the distribution and nature of typical and atypical cranial MR imaging findings in these patients and their correlation with clinical and laboratory data and predictors of outcome. Forty-five clinically confirmed cases of eclampsia were included in this prospective observational study. Subjects with hemolysis, elevated liver enzymes, and low platelets syndrome (n = 9) and pre-existing neurologic conditions (1 with cerebral solitary cysticercus granuloma) were excluded. Patients underwent blood investigations and cranial MR imaging. Twenty-seven patients had abnormal while 8 had normal MR imaging findings. Involvement of brain regions was as follows: frontal, 88.89%; temporal, 44.44%; parietal, 100%; occipital, 100%; deep gray matter, 29.63%; cerebellum, 22.22%; brain stem, 14.81%. Cytotoxic edema was present in 33.33% of cases; 66.67% of patients had mild posterior reversible encephalopathy syndrome; 25.92% had moderate posterior reversible encephalopathy syndrome; and 7.41% had severe posterior reversible encephalopathy syndrome. Abnormal neuroimaging findings were significantly associated with altered sensorium; visual disturbances; status epilepticus; and elevated serum creatinine, uric acid, and lactate dehydrogenase (P=.006, P=.018, P=.015, P=.019, P=.003, and P=.001, respectively). Serum creatinine, uric acid, and lactate dehydrogenase values and the presence of moderate or severe posterior reversible encephalopathy syndrome were significantly associated with mortality (P<.001, P<.001, P=.009, and P=.027, respectively). Neuroimaging in eclampsia demonstrates a higher incidence of atypical distributions and cytotoxic edema than previously thought. Altered sensorium; visual disturbances; status epilepticus; and elevated serum uric acid, lactate dehydrogenase, and creatinine are associated with abnormal neuroimaging findings. Higher serum creatinine, uric acid, and lactate dehydrogenase levels and moderate and severe forms of posterior reversible encephalopathy syndrome are possible predictors of poor outcome.


Sex-Based Differences in the Utilization of Shoulder, Hip, and Knee Arthroplasty.
Studies show that females have a higher prevalence of osteoarthritis, worse symptoms, but lower rates of joint replacement surgery (JRS). The reason for this remains unknown. A database of JRS candidates was created for patients seen in 2019 at an academic center. Demographics, Kellgren-Lawrence grades, symptom duration, visual analogue pain score, Charlson Comorbidity Index, and nonsurgical treatments were collected. Patients who were offered but declined surgery were invited to focus groups. Two independent sample t-tests, Mann-Whitney U tests, and chi-square tests were used for continuous, scored, and categorical variables, respectively, with two-tailed significance <0.05. Qualitative, code-based analysis was performed for the focus groups. The cohort included 321 patients (81 shoulder, 59 hip, and 181 knee) including 199 females (62.0%). There were no differences in proportions of females versus males who underwent JRS or in nonsurgical treatments. Female shoulder arthritis patients were older, had a higher visual analogue pain score, and had a higher Charlson Comorbidity Index. In focus groups, males prioritized waiting for technology advancements to return to an active lifestyle, whereas females experienced negative provider interactions, self-advocated for treatment, concerned about pain, and believed that their sex affected their treatment. We found equal utilization of JRS at our institution. However, female patients experienced unique barriers to surgery.


Treatment of adult, child and newborn cardiac arrest victims with COVID-19. Recommendations from the Interamerican Society of Cardiology / Sociedad Interamericana de Cardiología (SIAC), Mexican National Cardiologists Association / Asociación Nacional de Cardiólogos de México (ANCAM) and Mexican Society of Cardiology / Sociedad Mexicana de Cardiología (SMC).
La pandemia de COVID-19 ha infligido grandes estragos a la población y en especial al personal de salud. Los esfuerzos de reanimación exigen modificaciones potenciales de las guías internacionales existentes de reanimación cardiopulmonar (RCP) debido al elevado índice de contagiosidad del virus SARS-CoV-2. Se considera que hasta 15% de los casos de COVID-19 tiene una enfermedad grave y 5% padece un trastorno crítico con una mortalidad promedio del 3%, la cual varía según sean el país y las características de los pacientes. La edad y las comorbilidades como la hipertensión arterial, enfermedad cardiovascular, obesidad y diabetes incrementan la mortalidad hasta 24%. También se ha informado un aumento reciente del número de casos de paro cardíaco extrahospitalario (PCEH). Aunque el paro cardíaco (PC) puede ser efecto de factores diversos en estos pacientes, en la mayoría de los casos se ha demostrado que el origen es respiratorio, con muy pocos casos de causa cardíaca. Se debe considerar la indicación de iniciar o continuar las maniobras de RCP por dos razones fundamentales: la posibilidad de sobrevida de las víctimas, que hasta la fecha se ha registrado muy baja, y el riesgo de contagiar al personal de salud, que es muy alto. The COVID-19 pandemic is having a large impact on the general population, but it has taken a specially high toll on healthcare personnel. Resuscitation efforts require potential modifications of the present Cardiopulmonary Resuscitation (CPR) international guidelines because of the transmissibility rate of the new SARS-CoV 2 virus. It has been seen that up to 15% of COVID-19 patients have a severe disease, 5% have a critical form of infection and the mean death rate is 3%, although there are significant differences according to the country that reports it and patients' baseline conditions that include age, presence of arterial hypertension, cardiovascular disease, diabetes or obesity. In these high risk subjects, mortality might go up to 24%. There are also reports of a recent increase in out-of-hospital cardiopulmonary arrest (OHCA) victims. Cardiac arrest (CA) in these subjects might be related to many causes, but apparently, that phenomenon is related to respiratory diseases rather than cardiac issues. In this context, the decision to start or continue CPR maneuvers has to be carefully assessed, because of the low survival rate reported so far and the high contagion risk among healthcare personnel.


An age-period-cohort analysis for prevalence of common psychiatric disorders in Japan, 1999-2017.
This study aimed to analyze the prevalence of common psychiatric disorders in Japan via an age-period-cohort (APC) analysis. Data were used on the prevalence of schizophrenia, schizotypal, and delusional disorders; mood [affective] disorders (mood disorders, hereafter); and neurotic, stress-related, and somatoform disorders from the 1999-2017 Patient Survey in Japan. The age group was defined as 20-89 years with 5-year increments; the cohort was assigned for each age group of each year with a 1-year shift. A Bayesian APC analysis was used to decompose changes in prevalence into three effects: age, period, and cohort. The APC analysis revealed that the peaks of age effect varied among sexes and diseases. The period effects for all the diseases showed increasing trends over the analyzed years. Although the cohort effect for the prevalence of schizophrenia, schizotypal, and delusional disorders increased until the 1960s, it decreased afterwards. On the other hand, the cohort effects for the prevalence of mood disorders and neurotic, stress-related, and somatoform disorders increased from around the 1950s, and it indicates the prevalence increased particularly in young ages over the years. Also, the trends of each effect were relatively similar between mood disorders and neurotic, stress-related, and somatoform disorders. Increase in public awareness and psychological stress associated with a change in a social environment is thought to affect the period and cohort effects on the prevalence of mood disorders and neurotic, stress-related, and somatoform disorders.


Direct and Indirect Effects of Filamin A on Tau Pathology in Neuronal Cells.
In Alzheimer disease (AD), Tau, an axonal microtubule-associated protein, becomes hyperphosphorylated, detaches from microtubules, accumulates, and self-aggregates in the somatodendritic (SD) compartment. The accumulation of hyperphosphorylated and aggregated Tau is also seen in other neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD-Tau). Previous studies reported a link between filamin A (FLNA), an actin-binding protein found in the SD compartment, and Tau pathology. In the present study, we further explored this link. We confirmed the interaction of Tau with FLNA in neuroblastoma 2a (N2a) cells. This interaction was mediated by a domain located between the 157 and 383 amino acids (a.a.) of Tau. Our results also revealed that the overexpression of FLNA resulted in an intracellular accumulation of wild-type Tau and Tau mutants (P301L, V337M, and R406W) in N2a cells. Tau phosphorylation and cleavage by caspase-3 but not its aggregation were increased upon FLNA overexpression in N2a cells. In the parietal cortex of AD brain, insoluble FLNA was increased compared to control brain, but it did not correlate with Tau pathology. Interestingly, Tau binding to microtubules and F-actin was preserved upon FLNA overexpression in N2a cells. Lastly, our results revealed that FLNA also induced the accumulation of annexin A2, a Tau interacting partner involved in its axonal localization. Collectively, our data indicated that in Tauopathies, FLNA could contribute to Tau pathology by acting on Tau and annexin A2.


The nucleolus: a model for the organization of nuclear functions.
Nucleoli are the prominent contrasted structures of the cell nucleus. In the nucleolus, ribosomal RNAs (rRNAs) are synthesized, processed and assembled with ribosomal proteins. The size and organization of the nucleolus are directly related to ribosome production. The organization of the nucleolus reveals the functional compartmentation of the nucleolar machineries that depends on nucleolar activity. When this activity is blocked, disrupted or impossible, the nucleolar proteins have the capacity to interact independently of the processing activity. In addition, nucleoli are dynamic structures in which nucleolar proteins rapidly associate and dissociate with nucleolar components in continuous exchanges with the nucleoplasm. At the time of nucleolar assembly, the processing machineries are recruited in a regulated manner in time and space, controlled by different kinases and form intermediate structures, the prenucleolar bodies. The participation of stable pre-rRNAs in nucleolar assembly was demonstrated after mitosis and during development but this is an intriguing observation since the role of these pre-rRNAs is presently unknown. A brief report on the nucleolus and diseases is proposed as well as of nucleolar functions different from ribosome biogenesis.


Fragile 19p13 in a family with mental illness.
We describe a family where four brothers show the rare heritable folate sensitive autosomal fragile site (FSAFS) at 19p13 when cells were grown in TC199. Two of the brothers are schizophrenic while one brother is mentally retarded with autistic-like features. The clinical significance of this fragile site however is still unknown.


Altered local gyrification index and corresponding resting-state functional connectivity in individuals with high test anxiety.
Previous studies have reported that test anxiety is closely related to unreasonable cognitive patterns and maladaptive emotional responses. However, its underlying brain structural and functional basis has not been thoroughly studied. This study aimed to evaluate the potential difference in local gyration index (LGI) and corresponding resting-state functional connectivity (RSFC) in individuals with high test anxiety (HTA) compared with low test anxiety (LTA). Twenty-six individuals with HTA and 28 individuals with LTA underwent T1-weighted structural and resting-state functional magnetic resonance imaging scans. Using FreeSurfer software, we contrasted the LGI between the HTA and LTA groups using a surface-based general linear model to map group contrasts on a vertex-by-vertex basis. By selecting the cortical regions with significant differences in the LGI analysis as the regions of interest, the seed-based RSFC analysis was further carried out using the Resting-State fMRI Data Analysis Toolkit to examine the differences in the functional connectivity of these cortical regions with the whole brain between the two groups. The results showed that the LGI in several cortical regions of the executive control network (ECN) and the right lateral occipital gyrus was lower in the HTA group than in the LTA group. Furthermore, compared with the LTA group, the HTA group exhibited abnormal RSFC within the ECN, between the ECN and the visual network, and between the ECN and the sensorimotor network. Our findings might provide preliminary evidence for brain morphology and functional alterations in individuals with HTA and contribute to a better understanding of the pathophysiology of TA.