Premature Fusion of the Sagittal Suture as an Incidental Radiographic Finding in Young Children.
Craniosynostosis typically develops prenatally and creates characteristic changes in craniofacial form. Nevertheless, postnatal forms of craniosynostosis have been described. The purpose of this study was to determine the prevalence of incidentally identified, but temporally premature, cranial suture fusion in normocephalic children. Computed tomographic scans obtained from children aged 1 to 5 years evaluated in the authors' emergency department between 2005 and 2016 were reviewed for evidence of craniosynostosis. Patients with prior ventriculoperitoneal shunt, brain or cranial abnormality, or known syndromes were excluded. The presence of craniosynostosis and cranial index was assessed by a panel of three craniofacial surgeons and one pediatric neurosurgeon. Demographic information, fusion type, reason for the computed tomographic scan, and medical history were recorded as covariates. Cranial shape and intracranial volume were calculated using a previously validated automated system. Three hundred thirty-one patients met the inclusion criteria. The mean age was 2.4 ± 1.3 years. Eleven patients (3.3 percent) were found to have a complete (n = 9) or partial (n = 2) fusion of the sagittal suture. All patients had a normal cranial index (0.80; range, 0.72 to 0.87) and a grossly normal head shape. Only two fusions (18.2 percent) were documented by the radiologist. Cranial shape analysis performed in five of the 11 patients showed subtle phenotypic changes along the scaphocephaly spectrum in four patients, with a normal shape in the remaining case. Sagittal fusion is present in 3.3 percent of otherwise phenotypically normal children aged 1 to 5 years. The clinical significance of this result is unclear, but routine screening of affected patients is paramount. Risk, IV.


Impact of grass cover on the magnetic susceptibility measurements for assessing metal contamination in urban topsoil.
In recent decades, magnetic susceptibility monitoring has developed as a useful technique in environmental pollution studies, particularly metal contamination of soil. This study provides the first ever examination of the effects of grass cover on magnetic susceptibility (MS) measurements of underlying urban soils. Magnetic measurements were taken in situ to determine the effects on κ (volume magnetic susceptibility) when the grass layer was present (κgrass) and after the grass layer was trimmed down to the root (κno grass). Height of grass was recorded in situ at each grid point. Soil samples (n=185) were collected and measurements of mass specific magnetic susceptibility (χ) were performed in the laboratory and frequency dependence (χfd%) calculated. Metal concentrations (Pb, Cu, Zn and Fe) in the soil samples were determined and a gradiometry survey carried out in situ on a section of the study area. Significant correlations were found between each of the MS measurements and the metal content of the soil at the p<0.01 level. Spatial distribution maps were created using Inverse Distance Weighting (IDW) and Local Indicators of Spatial Association (LISA) to identify common patterns. κgrass (ranged from 1.67 to 301.00×10-5 SI) and κno grass (ranged from 2.08 to 530.67×10-5 SI) measured in situ are highly correlated [r=0.966, n=194, p<0.01]. The volume susceptibility datasets in the presence and absence of grass coverage share a similar spatial distribution pattern. This study re-evaluates in situ κ monitoring techniques and the results suggest that the removal of grass coverage prior to obtaining in situ κ measurements of urban soil is unnecessary. This layer does not impede the MS sensor from accurately measuring elevated κ in soils, and therefore κ measurements recorded with grass coverage present can be reliably used to identify areas of urban soil metal contamination.


Reconciling the positive and negative roles of histone H2A.Z in gene transcription.
The incorporation of variant histone H2A.Z within chromatin is important for proper gene expression and genome stability. H2A.Z is inserted at discrete loci by the Swr1 or Swr1-like remodeling complexes, although very little is known about the nature of the targeting mechanism involved. Replacement of canonical histone H2A for H2A.Z has been shown to modify nucleosome dynamics, although discrepancies still exist in the literature regarding the mechanisms. Recent experiments have shown that H2A.Z can allow nucleosomes to adopt stable translational positions as compared to H2A, which could influence the accessibility to DNA regulatory proteins. This review provides a brief overview of H2A.Z biology and presents hypotheses that could reconcile contradictory reports that are found in the literature regarding the influence of H2A.Z on nucleosome stability.


Intimate partner stalking and femicide: urgent implications for women's safety.
This study describes the type and extent of intimate partner stalking and threatening behaviors that occurred within 12 months prior to a major assault or attempted or actual partner femicide and specifies which behaviors were associated with an increased risk of potential or actual lethality. The design was a ten-city case-control study of 821 women: 384 abuse victims and 437 attempted or actual femicide informants. Data were derived using a 16-item inventory. Logistic regressions, with adjustments for demographic variables, were used to identify the significant perpetrator behaviors associated with attempted/actual femicide. Women who reported the perpetrator followed or spied on them were more than twice as likely t o become attempted/actual femicide victims. Threats by the perpetrator to harm the children if the woman left or did not return to the relationship place the woman at a ninefold increase in the risk of attempted/actual femicide. Conclusions are that certain stalking and threatening behaviors are strong risk factors for lethality, and women must be so advised.


Comparative Environmental Impacts and Development Benefits of Coastal Aquaculture in Three Tropical Countries: Madagascar, Tanzania and Indonesia.
Aquaculture is still in early development in Madagascar and Tanzania, while in Indonesia, aquaculture has a long history. In Madagascar, villagers are farming seaweed and sea cucumbers, as part of small-scale community-based aquaculture (CBA). They followed a contractual model between a private farming company and farmers. Local non-governmental organisations (NGOs) and public institutions in Madagascar jointly strive to reverse the trend of ongoing anthropogenic coastal degradation. In Tanzania, the cultivation of red seaweeds has been established for over 30 years, with declining production attributed to climate change. While shrimp farming still involves, to some extent, clearing of mangroves in Tanzania, seaweed culture has only mild impact on coastal ecosystems. Farming areas provide shelter and habitat for juvenile fish, crabs and other organisms. Therefore, NGOs ask for support to improve culture methods. Various problems and shortcomings in Indonesia have been clearly identified, including issues related to new aquaculture areas, pollutants, emerging diseases, insufficient broodstock and fry supply, as well as a lack of technology and manpower. To address these challenges and ensure the growth of aquaculture production, the government has implemented national policies and established training and broodstock centers throughout the country. In Madagascar, the CBA programme stands out as a success story and can serve as a template for other coastal regions and countries. In Tanzania, the adoption of CBA model for co-culture could be the future. In Indonesia, due to a very long coastlines and complicated legislation, IMTA seems to be particularly suitable, as successfully tested in model regions.


Typical findings for bronchiolitis in high resolution computed tomography.
High resolution computed tomography is a diagnostic modality of choice in imaging of interstitial lung diseases. HRCT enables visualization of the pathological findings invisible on plain radiographs and their evaluation at the level of the pulmonary lobule. The aim of the study was evaluation of typical HRCT findings in patients with bronchiolitis, and assessment of their usefulness in differential diagnosis. Tree in bud is a typical sign seen on HRCT sections in patients with bronchiolitis, resulting from filling the small centrilobular bronchioles with puss, mucus, granulomas or inflammatory cells. Material filling the bronchioles causes their obstruction resulting in the presence of air-trapping, visible on expiratory sections. Thickening of the bronchiolar walls and dilatation of the small bronchioles is also very often seen. Ground glass opacities and small nodules are also seen in some patients with bronchiolitis.


Evaluation of prenatal risk factors for prediction of outcome in right heart lesions: CVP score in fetal right heart defects.
To determine the prenatal variables predicting the risk of perinatal death in congenital right heart defects. Retrospective analysis of 28 fetuses with right heart defects was performed. Logistic regression analyses were performed to obtain odds ratios (OR) for the relationship between the risk of death and echocardiographic parameters. The parameters that correlated with the outcome were incorporated in an attempt to devise a disease-specific cardiovascular profile score. Fetal echocardiograms (143) from 28 patients were analyzed. The cardiovascular profile score predicted the risk of death. A lower right ventricle (RV) pressure was associated with mortality (OR 0.959; 95% confidence intervals (CI) 0.940-0.978). Higher peak aortic velocity through the aortic valve (OR 0.104; 95% CI 0.020-0.529) was associated with a better outcome. These cardiac function parameters were incorporated in a modified disease-specific CVP Score. Patients with a mean modified cardiovascular profile score of ≤ 6 were over 3.7 times more likely to die than those with scores of 7-10. The original Cardiovascular Profile Score predicted the risk of death in right heart defects. The modified score was not validated as a good prediction tool by this study. Fetal RV pressure estimate and peak aortic velocity can be used as independent prognostic predictors.


Understanding College Students' Perceived Help-Seeking Knowledge and Awareness about Sexual Misconduct Policies and Procedures.
Institutions of higher education have attempted to respond to students' experiences of sexual victimization by developing resources and processes for addressing sexual misconduct. However, extant research suggests that students rarely use campus-based resources and many students lack knowledge about campus services and the processes that institutions of higher education take to respond to sexual misconduct. This study uses data from a campus climate survey at one midsized southeast university to examine students' perceived and actual knowledge about help-seeking and policies and procedures (i.e., mandatory reporting, investigation mandates, confidential resources, accommodations for survivors) at their university. Additionally, we explore gaps in their knowledge of these measures (N = 2261). We also consider the factors that predict these outcomes. On average, students report moderate perceived knowledge about help-seeking on campus. However, roughly 67% did not have a fully comprehensive and accurate understanding of policies and procedures to address sexual misconduct at the university. These findings are problematic, as institutions of higher education rely on survivors coming forward to report their experiences and participate in investigative processes when detecting and elevating complaints. We highlight implications for institutions of higher education.


Taming the rugged landscape: production, reordering, and stabilization of selected cluster inherent structures in the X13-nYn system.
We present studies of the potential energy landscape of selected binary Lennard-Jones 13 atom clusters. The effect of adding selected impurity atoms to a homogeneous cluster is explored. We analyze the energy landscapes of the studied systems using disconnectivity graphs. The required inherent structures and transition states for the construction of disconnectivity graphs are found by combination of conjugate gradient and eigenvector-following methods. We show that it is possible to controllably induce new structures as well as reorder and stabilize existing structures that are characteristic of higher-lying minima. Moreover, it is shown that the selected structures can have experimentally relevant lifetimes.


Acupuncture for chemotherapy-induced peripheral neuropathy: a randomised controlled pilot study.
Chemotherapy-induced peripheral neuropathy (CIPN) can cause loss of independence and poor quality of life (QoL) due to severe disabilities, but in spite of its importance there is still a lack of data for the management of CIPN. Acupuncture has showed promising results and may be a cost-effective option for the treatment. To evaluate the effect of acupuncture treatment on neurological symptoms of CIPN and QoL of oncological patients. We performed a clinical, single-centre, randomised and controlled pilot study that involved 33 adult patients with cancer and CIPN randomised into two groups (control and acupuncture treated with 10 sessions, two times per week). Both groups were subjected to a complete physical examination and clinical assessment with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Scale V.2.0, FIM Scale, European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) Scale and Visual Analogue Scale for pain before and 5 weeks after treatment. There were no adverse events, and we found statistical differences in groups in physical (p=0.03) and function (p=0.04) domains of EORTC QLQ-C30 when comparing control and acupuncture groups. About NCI CTCAE Scale and neuropathy sensory symptoms, we found better results in acupuncture group, comparing pretreatment and post-treatment analyses (p=0.01). In control group, we have no differences after 5 weeks (p=0.11). Although these results suggest an interesting effect of acupuncture on this patient population, the clinical significance has remained unclear. Given the tendency towards benefit and the lack of adverse effects, the authors recommend a follow-up acupuncture trial using higher follow-up time and better sample size. NCT02309164.


Effects of common chronic medical conditions on psychometric tests used to diagnose minimal hepatic encephalopathy.
Many chronic medical conditions are accompanied by cognitive disturbances but these have only to a very limited extent been psychometrically quantified. An exception is liver cirrhosis where hepatic encephalopathy is an inherent risk and mild forms are diagnosed by psychometric tests. The preferred diagnostic test battery in cirrhosis is often the Continuous Reaction Time (CRT) and the Portosystemic Encephalopathy (PSE) tests but the effect on these of other medical conditions is not known. We aimed to examine the effects of common chronic (non-cirrhosis) medical conditions on the CRT and PSE tests. We studied 15 patients with heart failure (HF), 15 with end stage renal failure (ESRF), 15 with dysregulated type II diabetes (DMII), 15 with chronic obstructive pulmonary disease (COPD), and 15 healthy persons. We applied the CRT test, which is a 10-min computerized test measuring sustained attention and reaction time stability and the PSE test, which is a paper-pencil test battery consisting of 5 subtests. We found that a high fraction of the patients with HF (8/15, 0.002) or COPD (7/15, p = 0.006) had pathological CRT test results; and COPD patients also frequently had an abnormal PSE test result (6/15, p < 0.0001). Both tests were unaffected by ESRF and DMII. Half of the patients with HF or COPD had psychometrically measurable cognitive deficits, whereas those with ESRF or DMII had not. This adds to the understanding of the clinical consequences of chronic heart- and lung disease, and implies that the psychometric tests should be interpreted with great caution in cirrhosis patients with heart- or lung comorbidity.


Direct relationship of fetal carboxyhemoglobin with hemolysis in alloimmunized pregnancies.
Because carbon monoxide (CO) is a byproduct of heme degradation and because placental diffusing capacity of CO is limited, we hypothesized that the concentration of CO transported in fetal blood as carboxyhemoglobin (HbCO) would correlate with the severity of fetal hemolytic disease. Fetal blood was obtained by cordocentesis and HbCO was measured by gas chromatography. The two primary study groups included control fetuses (n = 26) and fetuses of Coombs-positive mothers before in utero transfusion (n = 15). Compared with controls, fetuses with hemolytic disease had higher HbCO levels (0.0111 +/- 0.0014 versus 0.0159 +/- 0.0072 fraction of total Hb, mean +/- SD, p < 0.002). In contrast, HbCO levels in simultaneously sampled maternal blood samples were not different in the control and alloimmune groups [0.0110 +/- 0.0025 (n = 20) versus 0.0115 +/- 0.0021 (n = 11)]. There was a significant inverse correlation observed between fetal HbCO and Hb concentrations in the group with hemolytic disease (r = -0.73, p < 0.002) but not in controls. In fetuses with hemolytic disease, HbCO and bilirubin were highly correlated (r = 0.88, p < 0.0001). Data from four anemic fetuses who were Coombs negative, three of whom had no evidence of hemolysis, indicated normal HbCO and normal plasma bilirubin levels. A fourth fetus with anemia had viral sepsis and elevated HbCO and plasma bilirubin levels. We conclude that elevated HbCO levels detected in fetuses of nonsmoking mothers with erythrocyte alloimmunization are likely the result of accelerated hemolysis.


Current Technology to Maximize Cardiac Resynchronization Therapy Benefit for Patients With Symptomatic Heart Failure.
The incidence of heart failure (HF) continues to increase, affecting millions of people in the United States each year. Cardiac resynchronization therapy (CRT) has been used and studied for patients with symptomatic HF for more than 20 years. The purpose of this article is to review technologies and developments to help maximize CRT for patients with symptomatic HF. Although most interventions to optimize CRT are physician directed, nurses also have an important role in the care and education of patients with symptomatic HF and can affect clinical outcomes. Therefore, nurses' understanding of CRT and measures to maximize this life-saving therapy is critical in HF management.


Palatal shape covariation in extraction versus nonextraction borderline patients: A geometric morphometric study.
This study aimed to evaluate changes in palatal shape after orthodontic treatment from a borderline sample of extraction and nonextraction patients with a Class I relationship. A borderline sample regarding premolar extractions was obtained through discriminant analysis and comprised 30 nonextraction and 23 extraction patients. The digital dental casts of these patients were digitized with 3 curves and 239 landmarks placed on the hard palate. Procrustes superimposition and principal component analysis were implemented to assess group shape variability patterns. The success of the discriminant analysis in identifying a borderline sample regarding the extraction modality was validated using geometric morphometrics. Concerning palatal shape, no sexual dimorphism was found (P = 0.78). The first 6 principal components that were statistically significant accounted for 79.2% of the total shape variance. Palatal changes were 61% more pronounced in the extraction group, which exhibited a decrease in palatal length (P = 0.02; 10,000 permutations). In contrast, the nonextraction group showed an increase in the palatal width (P <0.001; 10,000 permutations). Intergroup comparisons indicated that the nonextraction group exhibited longer palates, whereas the extraction group exhibited higher palates (P = 0.02; 10,000 permutations). Considerable changes in palatal shape were seen for the nonextraction and extraction treatment group, with the latter exhibiting more pronounced changes, mainly in terms of palatal length. Further investigations are needed to clarify the clinical significance of the palatal shape changes in borderline patients after extraction and nonextraction treatment.


Multiword Constructions in the Grammar.
There is ample evidence that speakers' linguistic knowledge extends well beyond what can be described in terms of rules of compositional interpretation stated over combinations of single words. We explore a range of multiword constructions (MWCs) to get a handle both on the extent of the phenomenon and on the grammatical constraints that may govern it. We consider idioms of various sorts, collocations, compounds, light verbs, syntactic nuts, and assorted other constructions, as well as morphology. Our conclusion is that MWCs highlight the central role that grammar plays in licensing MWCs in the lexicon and the creation of novel MWCs, and they help to clarify how the lexicon articulates with the rest of the grammar.


Ischemic stroke with vertebrobasilar artery dissection extended to posterior cerebral artery.
A 45-year-old woman was admitted with headache following sudden disturbance of consciousness that occurred two hours beforehand. A neurological examination identified disorientation, left homonymous hemianopia, left hemiplegia, and sensory disturbance in the left limbs. Brain MRI DWI showed acute infarcts in the right occipital lobe and bilateral thalami, and MRA poorly depicted right vertebral artery and right posterior cerebral artery. Anticoagulation was started to treat acute ischemic stroke, but her consciousness level deteriorated at 12 hours after onset. MRI revealed a double lumen in the basilar artery, indicating a diagnosis of vertebrobasilar artery dissection. Serial MRA findings showed that images of the basilar artery and posterior cerebral artery changed over time, suggesting vertebral artery dissection extension to the posterior cerebral artery.


Patient characteristics in relation to dental care payment model: capitation vs fee for service.
To analyse patient profiles in two payment models, the capitation (DCH) and the fee-for-service (FFS) systems, in relation to socioeconomic status, self-reported health and health behavior, as well as patient attitudes to and satisfaction with the DCH model in the Public Dental Service (PDS) in Sweden. The present survey included a random national sample of the adult population in Sweden. A telemarketing company, TNS SIFO, was responsible for the sample selection and telephone interviews conducted in May 2013. The 3,500 adults (aged =19 years) included in the sample gave a participation rate of 49.7%. Individuals choosing DCH were younger. FFS patients rated their health as less good, were less physically active, were more often smokers and had a lower household income. The DCH patients were more satisfied with their payment model than the FFS patients (98% vs 85%). A multivariate analysis showed that three of the variables significantly contributed to the model predicting DCH patients: age, with an odds ratio of 0.95, household income (OR=1.85) and importance of oral health for well-being (OR=2.05). There was a pattern of dimensions indicating the choice of payment model among adult patients in the Swedish Public Dental Service. The patients in DCH had higher socioeconomic position, were younger, rated their oral health as better and were more satisfied with the payment model (DCH) than the patients in the FFS system.


Polymorphisms associated with oral clefts as potential markers for oral pre and malignant disorders.
To investigate whether genes in the Wnt pathway, which have been previously associated with both oral clefts and oral squamous cell carcinoma, are also associated with oral potentially malignant disorders (leukoplakia, erythroplakia and lichen planus). Case-control study: Dataset consisted of clinical information linked to DNA samples from affected subjects diagnosed with oral potential malignant disorders and oral cancer and their matched controls. Individual samples, clinical history, and potential risk factors were obtained through the Dental Registry and DNA Repository project of the School of Dental Medicine, University of Pittsburgh. The rs1533767 (WNT11), rs9879992 (GSK3B), and rs3923087 (AXIN2) were tested. After genomic DNA had been extracted, genotyping was performed blindly to clinical diagnosis status. Representation of genotypes and alleles in affected subjects in comparison to the unaffected individuals was determined using PLINK. Additional analysis was performed to investigate associations between environmental (socioeconomic/lifestyle) risk factors and the oral pathologies studied using STATA. Two of the SNPs tested (rs9879992 in GSK3B and rs3923087 in AXIN2) were statistically, significantly associated with the pathologies studied (p = 0.039 and 0.038, respectively). Single-nucleotide polymorphisms in genes in the Wnt pathway were associated with oral potentially malignant disorders.


Electromyography of selected lower-limb muscles fatigued by exercise at the intensity of soccer match-play.
Surface electromyography has been useful in comparing muscular activity among different sports movements and it is a valuable technique for evaluating muscle activation, co-ordination and fatigue. Since these important variables have not been investigated during the full game in soccer, the present study aimed to investigate the activity of major muscles of the lower extremity during a soccer-simulation fatiguing protocol. Ten amateur soccer players (age 21.40+/-3.13 years; height 1.77+/-0.06 m; mass 74.55+/-8.5 kg) were tested. The exercise protocol, performed on a programmable motorised treadmill, consisted of the different intensities observed during soccer match-play (walking, jogging, running, sprinting). Electromyographic activity was recorded from the rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA) and gastrocnemius (GC) muscles before exercise, at half-time and immediately after the 90-min exercise protocol. The EMG data were analysed using custom-written software to compute the root mean square (RMS) value over ten gait cycles. With regard to RF, BF and TA, a significant main effect (P< 0.05) was found for condition (pre-game, half-time and post-game), speed (6, 12, 15 and 21 km h(-1)) (P<0.05) and interaction between condition and speed (P< 0.05). For GC, a significant effect was not found for condition or interaction between condition and speed, but a significant main effect (P< 0.001) was found for speed, with the RMS value increasing continually with increasing speed from 6 to 2 1km h(-1). The results indicated that after a simulation of the exercise intensity of soccer-play the EMG activity in major lower-limb muscles was less than before. This decrease indicated that prolonged intermittent exercise had an effect on muscle activity even when work-rate was sustained.


Bioequivalence of two oseltamivir formulations in healthy Chinese volunteers .
The aim of this study was to compare the bioavailability of a new generic formulation of oseltamivir 75-mg capsule (test) and a branded formulation Tamiflu® (reference) to meet regulatory criteria for marketing the test product in healthy Chinese male volunteers. This single-dose, randomized-sequence, open-label, two-period crossover study was conducted in fasted healthy Chinese male volunteers, who first received a single oral dose of the test or reference formulation with a 7-day washout period, and then the alternative formulation. The study drug was administered after a 10-hour overnight fast. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, 6, 8, 10, 12, 24, and 36 hours after administration of the study drug. Plasma concentrations of the parent oseltamivir and its metabolite oseltamivir carboxylate were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% confidence intervals (CIs) for the log-transformed values were within the predetermined equivalence range (70 - 143% for Cmax, 80 - 125% for AUC) according to the guidelines of the State Food and Drug Administration of China. Adverse events (AEs) were monitored throughout the study based on clinical parameters and patient reports. Characteristics of the 20 male volunteers included were as follows: mean age 23 (± 0.7, SD) years (range 21 - 24 years); weight 69 (± 7.1) kg (range 60 - 88 kg); height 177 (± 5.9) cm (range 168 - 192 cm). All included subjects completed the study. The mean geometric ratio between the test and reference formulations of oseltamivir was 99.5% (90% CI), 86.3 - 114.8%) for Cmax, 104.4% (95.7 - 113.9%) for AUC0-t, and 104.4% (95.6 - 113.9%) for AUC0-∞. That of oseltamivir carboxylate was 103.7% (90% CI, 95.3 - 112.8%) for Cmax, 101.7% (96.6 - 107.1%) for AUC0-t, and 101.4% (96.5 - 106.5%) for AUC0-∞. There was no significant difference in pharmacokinetic parameters between the two groups. Only 1 AE (nausea) occurred in 1 subject who received the test formulation; the AE resolved without any treatment. The result of this single-dose study indicated that the test formulation of oseltamivir capsule met the Chinese regulatory criteria for bioequivalence vs. the reference formulation in fasted healthy Chinese male volunteers. .


COVID-19: Establishing, implementing and assessment safety strategy, descriptive interventional study.
The increase in severe acute respiratory syndrome SARS-CoV-2 has invariably affected medical professionals in their training, academic and professional development. The present study was an interventional descriptive study aimed at reducing the risk of exposure to COVID-19 and enabling physical attendance to the practical session for applied medical students by establishing and implementing a safety strategy. The adopted safety strategy has eight conditions and 50 requirements. Compliance with the safety strategy along with the serological diagnosis of COVID-19 was used as a key performance indicator for assessing the efficiency of the safety strategy. A total of 197 students were enrolled at the beginning of the study. The overall results showed that 78.1% of the respondents strictly followed the protocol, 14.5% of the individuals partially responded to the protocol and 7.4% of the individuals did not respond to the protocol. Twenty-two (12.6%) out of the 175 participants who completed the study had positive COVID-19 during the study period, whereas the remaining 153 participants (87.4%) appeared to be healthy. The serological results showed that 68 (38.9%) and 66 (37.7%) individuals of the study population had positive IgM+IgA and IgG of COVID-19, respectively; the majority of the participants who developed antibodies did not show symptoms and appeared to be healthy during the study. The physical distancing condition was the only condition that displayed a significant relationship with seropositive IgM+IgA. The compiling of standardized protocols along with serological diagnoses can be an effective tool in measuring the effectiveness of safety protocol and reducing the risk of exposure to COVID-19.


Autoantigen Ku and its role in multiple cellular processes.
Ku is a DNA binding protein composed of 70 and 80 kDa subunits which was discovered as autoantigen in a patient with scleroderma-polymyositis overlap syndrome. Ku can bind to the end of DNA and also to some internal sequences. Ku-autoantigen acts as a potential transcription factor for several RNA polymerase II genes and RNA polymerase I gene. Ku is also associated with DNA-dependent protein kinase and involved in V(D)J recombination and DNA break repair mechanisms. Ku may be involved in replication, helicase activity and cell signaling. Therefore, Ku-autoantigen is a very important cellular factor which plays important role in the multiple cellular processes.


Differential Pharmacophore Definition of the cAMP Binding Sites of Neuritogenic cAMP Sensor-Rapgef2, Protein Kinase A, and Exchange Protein Activated by cAMP in Neuroendocrine Cells Using an Adenine-Based Scaffold.
We recently reported that the adenylate cyclase (AC) inhibitor SQ22,536 (9-tetrahydrofuranyl-adenine) also has inhibitory activity against the neuroendocrine-specific neuritogenic cAMP sensor-Rapgef2 (NCS-Rapgef2), a guanine nucleotide exchanger and activator for the small effector GTPase Rap1. Cell-based assays that distinguish signaling through the three intracellular cAMP sensors NCS-Rapgef2, exchange protein activated by cAMP (Epac), and protein kinase A (PKA), as well as AC, were used. These, collectively, assess the activities of adenine (6-amino-purine) derivatives modified at several positions to enhance selectivity for NCS-Rapgef2 by decreasing affinity for adenylate cyclase (AC), without increasing affinity for PKA or Epac. Testing of each adenine derivative in whole-cell assays incorporates features of cell permeability, target selectivity, and intrinsic potency into a single EC50 or IC50, making robust extrapolation to compound activity in vivo more likely. N6-MBC-cAMP is a selective PKA activator (EC50 = 265 μM) with low efficacy at NCS-Rapgef2. 8-CPT-2'-O-Me-cAMP and ESI-09 are confirmed as Epac-selective, for stimulation and inhibition, respectively, versus both PKA and NCS-Rapgef2. The compound N6-Phe-cAMP is a full agonist of NCS-Rapgef2 (EC50 = 256 μM). It has little or no activity against Epac or PKA. The compound N6-phenyl-9-tetrahydrofuranyladenine is a novel and potent NCS-Rapgef2 inhibitor without activity at PKA, Epac, or ACs, as assayed in the neuroendocrine NS-1 cell line. This line has been engineered to allow high-content screening for activation and inhibition of AC, PKA, Epac, and NCS-Rapgef2 and the cellular activities initiated by these signaling pathway protein components.


Cardiometabolic risk profiles in pre- versus postmenopausal women with spinal cord injury:: preliminary findings.
To compare the cardiometabolic risk (CMR) profile of premenopausal and postmenopausal women with spinal cord injury (SCI). Post hoc analysis of a multicenter cross-sectional study assessing CMR. Seventeen women with ASIA Impairment Scale (AIS) A or B SCI between C5 and T12 were stratified into 2 groups according to menopausal status (11 premenopausal vs 6 postmenopausal women). Data collected included demographic, social, medical, menopausal, hormone use, and menstrual histories. Assessments included physical, anthropometric, and blood pressure measures; fasting serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and hemoglobin A1C (Hb1Ac); calculated low-density lipoprotein (LDL-C); and an oral glucose tolerance test. The premenopausal group had a mean age of 32.4 years compared with 56.0 years in the postmenopausal group. Similar group findings included body mass index (BMI) (22.4 vs 22.2), HDL-C (52.5 vs 53 mg/dL), HbA1c (4.9 vs 5.1%), fasting blood glucose (FBG) (79.3 vs 84.8 mg/dL), and systolic blood pressure (SBP) (104.6 vs 111.8 mm Hg). TG, TC and LDL-C were significantly higher in postmenopausal group (55.7 vs 101.8 mg/dL, P = .01; 158.3 vs 191.6 mg/dL, P = .04; 94.7 vs 118.2 mg/dL, P = .04). The findings from this study suggest that postmenopausal women with SCI have CMR trends similar to those observed in nondisabled women, characterized by increases in TG, TC, and LDL-C despite favorable BMIs and glycemic indices. Even though the present study includes significant limitations, future evidence may also suggest that heightened surveillance and guideline-driven interventions are indicated for perimenopausal and postmenopausal women with SCI.


Acute myocardial infarction and fascicular block.
Left anterior fascicular block may mask an IWMI. On the other hand, a narrow QS deflection in a VF is often misinterpreted as evidence of extensive inferior wall infarction. Vectorcardiographic analysis usually establishes the coexistence of LAFB and IWMI. Standard Lead II of the ECG is the most valuable in differentiating the etiology of ALAD: (1) rS pattern in LAFB, (2) Qr or QR in IWMI, or (3) a QS pattern or a smaller or slurred r wave with a deep S wave in combined IWMI and LAFB.


Jejunal and bladder perforation: complication of intravesical Nd-YAG laser irradiation of bladder tumour.
Nd-YAG laser coagulation is a therapeutic method for the treatment of refractory superficial bladder cancer. Complications resulting from its use are uncommon. We report a case of jejunal and bladder perforation 24 h after Nd-YAG bladder irradiation of a recurrent bladder tumour.


Bonding systems for restorative materials--a comprehensive review.
The acid-etch technique for bonding composite resins to enamel has revolutionized the practice of pediatric restorative dentistry. Although bonding resins to dentin has proved to be a difficult challenge, ongoing advances have improved the reliability and predictability of dentinal adhesion. The purpose of this paper is to review the subject of dentin bonding; its development, current status, and clinical methods to improve performance.


Adipocytokines in renal transplant recipients.
In the last two decades, perceptions about the role of body fat have changed. Adipocytes modulate endocrine and immune homeostasis by synthesizing hundreds of hormones, known as adipocytokines. Many studies have been investigating the influences and effects of these adipocytokines and suggest that they are modulated by the nutritional and immunologic milieu. Kidney transplant recipients (KTRs) are a unique and relevant population in which the function of adipocytokines can be examined, given their altered nutritional and immune status and subsequent dysregulation of adipocytokine metabolism. In this review, we summarize the recent findings about four specific adipocytokines and their respective roles in KTRs. We decided to evaluate the most widely described adipocytokines, including leptin, adiponectin, visfatin and resistin. Increasing evidence suggests that these adipocytokines may lead to cardiovascular events and metabolic changes in the general population and may also increase mortality and graft loss rate in KTRs. In addition, we present findings on the interrelationship between serum adipocytokine levels and nutritional and immunologic status, and mechanisms by which adipocytokines modulate morbidity and outcomes in KTRs.


Platelet-rich plasma for jumper's knee: a comprehensive review of efficacy, protocols, and future directions.
This comprehensive review evaluates the current state of platelet-rich plasma (PRP) treatment for jumper's knee, also known as patellar tendinopathy. The aim is to assess the efficacy of PRP as a therapeutic option compared to other available procedures, investigate the benefits and potential drawbacks of PRP infiltration, and provide insights into the optimal protocols for PRP preparation and administration. A comprehensive literature search of English articles published up to June 2023 was conducted using PubMed and Scopus databases. Studies evaluating PRP for treating jumper's knee or patellar tendinopathy were analyzed to assess the current state of research in this field. PRP has demonstrated promising results in promoting cellular remodeling and accelerating the healing process in the jumper's knee. It shows potential benefits in pain reduction, improved function, and accelerated recovery. However, the efficacy of PRP varies depending on patient characteristics, disease severity, and the specific administration methodology. Establishing standardized PRP preparation and administration protocols are necessary to optimize its effectiveness. Further research is needed to define appropriate patient selection criteria and refine the application of PRP therapy in patellar tendinopathy management. Jumper's knee is commonly managed conservatively, but there is a lack of consensus on further treatment options. PRP treatment holds promise in promoting tissue healing and repair. However, standardized protocols for PRP preparation and administration, as well as optimal dosage and number of injections, require further investigation to enhance its efficacy. Continued research efforts are necessary to ascertain the precise role of PRP and its refinement in the management of patellar tendinopathy.


Return to Golf Following Reverse Total Shoulder Arthroplasty.
The object of this study was to examine return to golf and changes in golf performance after shoulder arthroplasty. Additionally, we set out to determine if there were differences in return to play and performance between total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RTSA). We also examined pain during the golf swing to determine if there is a change in pain level after surgery. Patients were identified using a Current Procedural Terminology code 23472 search for TSA. A 19-question online survey was sent out to each patient with questions detailing golfing performance and pain during the swing before and after surgery. Comparisons were made to determine differences in pain, performance and enjoyment between TSA and RTSA groups before and after surgery. A total of 586 patients who underwent shoulder arthroplasty were sent the online survey via email. Of those patients, 33 identified themselves as golfers and who responded to the survey, resulting in an overall response rate of 5.6%. Twenty-three of 31 (74%) patients were able to return to golf following their procedure. Overall, the respondents who reported pain associated with golfing activity had significantly decreased pain after undergoing either TSA or RTSA. The RTSA group had a significant drop in driving distance following the procedure and this was significantly lower than the postoperative driving distance in the TSA group, despite an insignificant preoperative difference. Overall, TSA offers a safe and effective means for reducing pain during the golf swing in patients suffering from advanced shoulder osteoarthritis. While there were no significant changes in performance following TSA, individuals undergoing RTSA can be counseled that they are at risk for lower driving distances due to altered mechanics. Overall, patients were satisfied with their procedure and their ability to return to the golf course.


Percutaneous techniques for the management of caliceal diverticula containing calculi.
Most frequently caliceal diverticula are found incidentally on routine excretory urograms. Smaller diverticula are associated with a low incidence of complications but larger diverticula with a narrow communication to the main collecting system will predispose to calculous formation as a result of stasis of urine within the diverticulum. The techniques used and results achieved in 10 patients with such calculi who have been successfully managed percutaneously are discussed. Particular reference is made to techniques used specifically to obliterate the diverticula.


Cryopreservation of Ovarian and Testicular Tissue and the Influence on Epigenetic Pattern.
Ovarian tissue cryopreservation (OTC) or testicular tissue cryopreservation (TTC) are effective and often the only options for fertility preservation in female or male patients due to oncological, medical, or social aspects. While TTC and resumption of spermatogenesis, either in vivo or in vitro, has still be considered an experimental approach in humans, OTC and autotransplantation has been applied increasingly to preserve fertility, with more than 200 live births worldwide. However, the cryopreservation of reproductive cells followed by the resumption of gametogenesis, either in vivo or in vitro, may interfere with sensitive and highly regulated cellular processes. In particular, the epigenetic profile, which includes not just reversible modifications of the DNA itself but also post-translational histone modifications, small non-coding RNAs, gene expression and availability, and storage of related proteins or transcripts, have to be considered in this context. Due to complex reprogramming and maintenance mechanisms of the epigenome in germ cells, growing embryos, and offspring, OTC and TTC are carried out at very critical moments early in the life cycle. Given this background, the safety of OTC and TTC, taking into account the epigenetic profile, has to be clarified. Cryopreservation of mature germ cells (including metaphase II oocytes and mature spermatozoa collected via ejaculation or more invasively after testicular biopsy) or embryos has been used successfully for many years in medically assisted reproduction (MAR). However, tissue freezing followed by in vitro or in vivo gametogenesis has become more attractive in the past, while few human studies have analysed the epigenetic effects, with most data deriving from animal studies. In this review, we highlight the potential influence of the cryopreservation of immature germ cells and subsequent in vivo or in vitro growth and differentiation on the epigenetic profile (including DNA methylation, post-translational histone modifications, and the abundance and availability of relevant transcripts and proteins) in humans and animals.


Effect of starvation period on microbial community producing hydrogen from paperboard mill wastewater using anaerobic baffled reactor.
The aim of this study is to highlight the robustness and potentials of the anaerobic baffled reactor (ABR) configuration on keeping the microbial richness and diversity after starvation period of 7 days. The module at steady state operating conditions provided an average volumetric hydrogen production (VHP) of 0.2 ± 0.08 and 0.423 ± 0.5 l/d in the 1st and last compartment (C4). The VHP was gradually decreased from 0.2 to 0.003 l/d and from 0.423 to 0.1 l/d in compartments (C1 and C4) respectively during feed less period. However, the VHP was substantially increased up to 0.035 and 0.152 l/d in 1st (C1) and fourth compartment (C4) within 24 h, after reoperation of the ABR. Moreover, the H2 producers of Clostridiaceae, Ruminococcaceae, and Enterobacteriaceae families were dominant in the reactor after reoperation process. Quantitative polymerase chain reaction and next-generation sequencing methods results revealed that the microbial community structure was mainly composed of Proteobacteria, Firmicutes, Chloroflexi, Bacteroidetes, Planctomycetes, and Actinobacteria. The results showed the unique properties of the ABR configuration for keeping the microbial richness and diversity during feed less period.


Detection of high frequencies of HIV-1 cross-subtype reactive CD8 T lymphocytes in the peripheral blood of HIV-1-infected Kenyans.
To quantitate rapidly the frequency of HIV-1 subtype-specific and broadly HIV-1 cross-subtype-reactive CD8 T cells in the peripheral blood of HIV-1-infected individuals from a geographical region of multiple subtype endemicity. Autologous B-lymphoblastoid cell lines infected with recombinant vaccinia-viruses expressing gag, env and nef gene products from HIV-1 subtypes A-H were used as antigen-presenting cells to stimulate CD8 T cells from cryopreserved peripheral blood mononuclear cells. Cross-subtype and subtype-specific CD8 cell responses were assessed by flow cytometry for the upregulation of IFN-gamma gene expression in specifically activated CD8 T cells. Strikingly high frequencies of circulating CD8 T cells (up to 11.3% of peripheral CD8 T cells) with specificity for HIV-1 were detectable using this methodology. Both subtype-specific and broadly cross-subtype-reactive CD8 T cells were detected as assessed by IFN-gamma production after stimulation. The pattern of cross-subtype reactivity appeared to be random when the results were assessed as a population, but analysis of the full-length sequence of the infecting virus for each individual showed some skewing of the CD8 cell response towards the infecting subtype. High frequencies of HIV-1 cross-subtype-reactive peripheral CD8 T cells can be detected in individuals from a multiple subtype endemic region, providing an incentive for vaccine advancement in such locations. The future assessment of the subtype specificity of cellular immune responses requires full-length sequencing of the infecting virus in conjunction with a comprehensive analysis of phenotypic and functional parameters.


Neurochemical and microstructural alterations in bipolar and depressive disorders: A multimodal magnetic resonance imaging study.
Depression in bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatments and poor clinical outcomes in many bipolar patients. Herein, we report direct comparisons between medication-free patients with BD and those with UD in terms of the microstructure and neurometabolites in eight brain regions. A total of 20 patients with BD, 30 with UD patients, and 20 matched healthy controls (HCs) underwent 3.0T magnetic resonance imaging with chemical exchange saturation transfer (CEST) for glutamate (Glu; GluCEST) imaging, multivoxel magnetic resonance spectroscopy, and diffusion kurtosis imaging. Compared with HCs, patients with UD showed significantly lower levels of multiple metabolites, GluCEST% values, and diffusional kurtosis [mean kurtosis (MK)] values in most brain regions. In contrast, patients with BD presented significantly higher levels of Glu in their bilateral ventral prefrontal white matter (VPFWM), higher choline (Cho)-containing compounds in their left VPFWM and anterior cingulate cortex (ACC), and higher GluCEST% values in their bilateral VPFWM and ACC; moreover, reduced MK in these patients was more prominent in the left VPFWM and left thalamus. The findings demonstrated that both patients with UD and BD have abnormal microstructure and metabolic alterations, and the changes are not completely consistent in the prefrontal lobe region. Elevated Glu, Cho, and GluCEST% in the ACC and VPFWM of patients with UD and BD may help in differentiating between these two disorders. Our findings support the significance for the microstructural integrity and brain metabolic changes of the prefrontal lobe region in BD and UD.


Effects of heparin on the inhibitory activities of human urinary trypsin inhibitor (ulinastatin) on trypsin, chymotrypsin and leukocyte elastase.
Effects of heparin on the inhibitory activities of human urinary trypsin inhibitor (ulinastatin) on trypsin, chymotrypsin and leukocyte elastase were studied. Heparin per se neither influenced the enzymatic activities nor changed the mode of inhibition of ulinastatin on the enzymes. In the presence of heparin, inhibitory effects of ulinastatin on trypsin were enhanced, whereas its effects on chymotrypsin and elastase were attenuated. These results suggest that the two functional domains in ulinastatin are differently affected by heparin.


Targeting virulence for antimicrobial chemotherapy.
Untreatable bacterial infections constitute a dark but valid threat, with numbers of antibiotic resistant pathogens, as well as newly emerging ones, rising quickly. To combat this dangerous prospect, growing research into antimicrobials could be aimed at targeting the virulence of pathogens. Virulence refers to an organism's ability to establish an infection and cause disease. Many steps involved in the infection process can be targeted, including adherence, invasion and host defense evasion. Identification and characterization of virulence factors that aid in bacterial pathogenicity will lead to new drugs that can be applied to a variety of pathogens.


Homeostatic T cell proliferation as a barrier to T cell tolerance.
The maintenance of T cell numbers in the periphery is mediated by distinct homeostatic mechanisms that ensure the proper representation of naïve and memory T cells. Homeostatic proliferation refers to the process by which T cells in lymphopenic hosts divide in the absence of cognate antigen to reconstitute the peripheral lymphoid compartment. During this process T cells acquire effector-memory like properties, including the ability to respond to low doses of antigen in the absence of CD28 costimulation. Furthermore, this capacity is retained long after proliferation has ceased. Accumulating data implicates homeostatic proliferation in autoimmune diseases and transplant rejection, and suggests that it may represent a barrier to tolerance in protocols that use T cell depletion. Implementing combination therapies that aim to promote the development and expansion of regulatory T cell populations while specifically targeting alloresponsive T cells may be the soundest approach to attaining allograft tolerance in the aftermath of T cell depletion and homeostatic proliferation.


Morphological differences in the response of mouse small intestine to radiobiologically equivalent doses of X and neutron irradiation.
A scale has been developed to describe the effects of radiation on small intestinal villi. The scale has been used to compare the damage done to the villi in the period 0-5 days after irradiation by X-irradiation or neutron irradiation, using 10 Gy X-rays and 5 Gy neutrons, doses which are radiobiologically equivalent when assessed by the microcolony assay method. Use of the scale indicates that the damage done to the villi by neutrons is greater than that produced by X-rays. This has implications for the interpretation of radiobiological equivalent doses (R.B.E.). Resin light microscopy and transmission electron microscopy (T.E.M.) have also been used to examine small intestinal damage after 10 Gy X-irradiation and 5 Gy neutron irradiation. Differences include variations in crypt shape, mitotic activity and the proportion of crypts which are heavily parasitised. As well as the differences in villous shape which have been reflected in the different values on the scoring system, there are also variations in the response of the constituent cells of the epithelial compartment of the villi. In general, the effect of the neutron irradiation is more severe than that of the X-rays, particularly as would be suggested by a simple quantitation of crypt regeneration.


Electrically Controlled Scattering in a Hybrid Dielectric-Plasmonic Nanoantenna.
Electrically tunable devices in nanophotonics offer an exciting opportunity to combine electrical and optical functions, opening up their applications in active photonic devices. Silicon as a kind of high refractive index dielectric material has shown comparable performances with plasmonic nanostructures in tailoring and modulating the electromagnetic waves. However, there are few studies on electrically tunable silicon nanoantennas. Here, for the first time we realize the spectral tailoring of an individual silicon nanoparticle in the visible range through changing the applied voltage. We observe that the plasmon-dielectric hybrid resonant peaks experience blue shift and obvious intensity attenuation with increasing the bias voltages from 0 to 1.5 V. A physical model has been established to explain how the applied voltage influences the carrier concentration and how carrier concentration modifies the permittivity of silicon and then the final scattering spectra. Our findings pave a new approach to build excellent tunable nanoantennas or other nanophotonics devices where the optical responses can be purposely controlled by electrical signals.


Sex differences in the influence of body mass index on anatomical architecture of brain networks.
The brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters. Structural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age. In both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions. In individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology.


Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies.
Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAF(V600E) inhibitor, Vemurafenib, in adult zebrafish harboring BRAF(V600E) melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases.


Cytokines affect procathepsin D-stimulated proliferation of breast cancer cells.
Procathepsin D is over secreted by certain human cancer cells. This enzymatically inactive precursor has been established as playing an important role in the development of several types of cancer. Due to their pleiotropical effects, numerous cytokines have also been recognized as important immunotherapeutic agents. In this study, we focused on the role of IL-4, IL-10 and IL-13 on procathepsin D-stimulated proliferation of breast cancer cells. Our results clearly showed that only ER+ breast cancer cells responded to the presence of cytokines by proliferation; ER- cells were resistant to the addition of cytokines. Since addition of anti-procathepsin D antibodies blocked the growth potentiation, we concluded that addition of these cytokines resulted in stimulation of synthesis and/or release of procathepsin D. This conclusion was further supported by findings of procathepsin D in culture supematants of cells incubated with cytokines.


Organic osmolytes and embryos: substrates of the Gly and beta transport systems protect mouse zygotes against the effects of raised osmolarity.
Mouse embryo development is identically inhibited by raised osmolarity, whether produced by added NaCl or raffinose, demonstrating that high osmolarity is itself detrimental to embryos. In the face of increased osmolarity, cells in the brain and kidney, and likely many other cells, accumulate nonperturbing organic osmolytes in their cytoplasm. In the presence of any of a number of organic compounds that were proven or probable substrates of either the Gly or the beta transport systems, mouse embryo development in vitro was protected from raised osmolarity. Zygotes developed past the "2-cell block," and with most Gly or beta substrates, to the blastocyst stage. The most effective osmoprotectants were glycine, glutamine, betaine, proline, beta-alanine, and hypotaurine; several others were partially effective. A model Gly substrate, glycine, was effective at a much lower concentration (EC50 = 50 microM) than was a model beta substrate, beta-alanine (EC50 = 1.3 mM). The protective effect of these two compounds was additive, indicating a common mode of action. The various effective compounds tested do not all share metabolic pathways or other such properties in common. Thus, it is likely that cleavage-stage mouse embryos utilize them, in large part, as organic osmolytes.


Excessive rest time during active phase is reliably detected in a mouse model of myotonic dystrophy type 1 using home cage monitoring.
Myotonic dystrophy type 1 (DM1) is a dominantly inherited neuromuscular disease caused by the abnormal expansion of CTG-repeats in the 3'-untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene, characterized by multisystemic symptoms including muscle weakness, myotonia, cardio-respiratory problems, hypersomnia, cognitive dysfunction and behavioral abnormalities. Sleep-related disturbances are among the most reported symptoms that negatively affect the quality of life of patients and that are present in early and adult-onset forms of the disease. DMSXL mice carry a mutated human DMPK transgene containing >1,000 CTGrepeats, modeling an early onset, severe form of DM1. They exhibit a pathologic neuromuscular phenotype and also synaptic dysfunction resulting in neurological and behavioral deficits similar to those observed in patients. Additionally, they are underweight with a very high mortality within the first month after birth presenting several welfare issues. To specifically explore sleep/rest-related behaviors of this frail DM1 mouse model we used an automated home cage-based system that allows 24/7 monitoring of their activity non-invasively. We tested male and female DMSXL mice and their wild-type (WT) littermates in Digital Ventilated Cages (DVCR) assessing activity and rest parameters on day and night for 5 weeks. We demonstrated that DMSXL mice show reduced activity and regularity disruption index (RDI), higher percentage of zero activity per each hour and longer periods of rest during the active phase compared to WT. This novel rest-related phenotype in DMSXL mice, assessed unobtrusively, could be valuable to further explore mechanisms and potential therapeutic interventions to alleviate the very common symptom of excessive daytime sleepiness in DM1 patients.


Introduction, transmission and aggravation of malaria in desert ecosystem of Rajasthan, India.
Malaria is an important public health problem in northwestern desert part of Rajasthan. Since desert malaria is seasonal or unstable, there is a need to study its epidemiology in the totality to address factors like how malaria is introduced into desert every year and what are desert-specific transmission risk factors leading to epidemics? Twenty-six villages in irrigated, semi-irrigated and non-irrigated settings of the desert have been selected. Periodic investigations were undertaken in all the seasons from 2001 through 2002 to determine causes of introduction of disease, the factors involved in its transmission and the epidemic risk factors. Standard methods/procedures for mosquito collection, preservation and identification and for parasitological studies were employed. Rainfall data were analysed and correlated. Importation of malaria infection through individuals was the major cause of introduction of disease in all the 12 villages showing some initial load of infection. Areas having higher population of cattle in relation to humans (human to cattle ratio of 1:25) had less transmission of disease (ratio of primary to secondary cases 1:3) as compared to relatively less cattle (human to cattle ratio 1:3) resulting into high transmission of disease with 1:47 ratio of primary to secondary cases. Introduced through migration, prospective transmission of malaria was observed as a resultant interaction of density of three components namely malaria cases, vector density and cattle to human ratio. Rainfall more than average when coupled with more cases of imported malaria leads to the eruption of malaria epidemics. Importation of malaria cases was the major cause of seasonal introduction of malaria in the desert. This initial or primary parasitic load available in a village leads to a particular transmission quantum depending upon the density of vectors, human and cattle population at a particular time. Areas with more imported cases when coupled with profuse vector population lead to epidemic malaria situations in the desert.


Numerical simulation of bypass evaporation system treating FGD wastewater using high temperature flue gas.
A novel zero-liquid discharge (ZLD) technology for desulfurization wastewater treatment is put forward in this paper. A ZLD reconstruction project performed on 2 × 320 MW desulfurization system was taken as the research object, to study the evaporator structure and the key factors affecting spray evaporation through CFD numerical simulation. The result shows that when the evaporator diameter is 2.4 m, the central density difference and the temperature difference of evaporator outlets are 0 kg/L and 0°C, under this condition, the wall sticking can be avoided effectively, and the uniformity of evaporator's outlet flow field is improved. As for the same amount of wastewater, small atomized particle size, high flue gas flow rate and high flue gas temperature are conducive to complete evaporation, and the optimum atomized particle size is 100-150 μm, flue gas velocity is 3-4 m/s and flue gas temperature is 250-260°C. In order to reduce adverse impact on the main flue duct, the optimized design scheme that extracting flue gas before and after the air preheater is put forward in the purpose of energy saving.


Strategies Employed by Community-Based Service Providers to Address HIV-Associated Neurocognitive Challenges: A Qualitative Study.
HIV-associated neurocognitive disorders and other causes of neurocognitive challenges experienced by people living with HIV (PLWH) persist as public health concerns in developed countries. Consequently, PLWH who experience neurocognitive challenges increasingly require social support and mental health services from community-based providers in the HIV sector. Thirty-three providers from 22 AIDS service organizations across Ontario, Canada, were interviewed to determine the strategies they used to support PLWH experiencing neurocognitive difficulties. Thematic analysis was conducted to determine key themes from the interview data. Three types of strategies were identified: (a) intrapersonal, (b) interpersonal, and (c) organizational. Intrapersonal strategies involved learning and staying informed about causes of neurocognitive challenges. Interpersonal strategies included providing practical assistance, information, counseling, and/or referrals to PLWH. Organizational strategies included creating dedicated support groups for PLWH experiencing neurocognitive challenges, partnering with other organizations with services not available within their own organization, and advocating for greater access to services with expertise and experience working with PLWH. Through concerted efforts in the future, it is likely that empirically investigating, developing, and customizing these strategies specifically to address HIV-associated neurocognitive challenges will yield improved social support and mental health outcomes for PLWH.


How Team-Level and Individual-Level Conflict Influences Team Commitment: A Multilevel Investigation.
We investigate how two different types of conflict (task conflict and relationship conflict) at two different levels (individual-level and team-level) influence individual team commitment. The analysis was conducted using data we collected from 193 employees in 31 branch offices of a Korean commercial bank. The relationships at multiple levels were tested using hierarchical linear modeling (HLM). The results showed that individual-level relationship conflict was negatively related to team commitment while individual-level task conflict was not. In addition, both team-level task and relationship conflict were negatively associated with team commitment. Finally, only team-level relationship conflict significantly moderated the relationship between individual-level relationship conflict and team commitment. We further derive theoretical implications of these findings.


Quantum Hair from Gravity.
We explore the relationship between the quantum state of a compact matter source and of its asymptotic graviton field. For a matter source in an energy eigenstate, the graviton state is determined at leading order by the energy eigenvalue. Insofar as there are no accidental energy degeneracies there is a one to one map between graviton states on the boundary of spacetime and the matter source states. Effective field theory allows us to compute a purely quantum gravitational effect which causes the subleading asymptotic behavior of the graviton state to depend on the internal structure of the source. This establishes the existence of ubiquitous quantum hair due to gravitational effects.


The best peak expiratory flow is flow-limited and effort-independent in normal subjects.
Recently, it has been suggested that peak expiratory flow (PEF) may be determined by the wave speed flow-limiting mechanism. In six normal male subjects (age = 33 +/- 8 years) performing expiratory forced vital capacity (FVC) maneuvers, a negative expiratory pressure (NEP) of -10 cm H2O was randomly applied at the beginning of maximal expiration to assess changes in PEF as compared with baseline. During FVC maneuvers, the expiratory effort was measured by changes in esophageal pressure (Pes), as either peak expiratory Pes-Pes at end expiratory lung volume (DeltaPes(peak)) or maximal rate of rise of Pes (dPes/dt(max)). In each experimental condition, at least three FVC maneuvers with comparable expiratory effort were selected for analysis for each subject. With similar DeltaPes(peak) (107.2 +/- 34.9 versus 111.7 +/- 40.5 cm H2O) and dPes/dt(max) (1181 +/- 518 versus 1177 +/- 546 cm H2O/second) PEF amounted to 10.84 +/- 1.08 L/second and to 10.82 +/- 1.03 L/second with and without NEP, respectively. These data show that PEF obtained by normal subjects to the best of their abilities (best PEF) does not increase with NEP and indicate that the best PEF is a flow-limited and effort-independent parameter, reflecting only lung and airways mechanics as the other subsequent maximal expiratory flows achieved during the FVC maneuver.


The role of organisational justice, burnout and commitment in the understanding of absenteeism in the Canadian healthcare sector.
The purpose of this paper is to integrate Greenberg's perspective on the connection between injustice and stress in order to clarify the role of organisational justice, burnout and organisational commitment in the understanding of absenteeism. The study was carried out among 457 workers of a large healthcare establishment in the Canadian public healthcare sector. The model was tested using structural equation methods. The results reveal that procedural and interactional justices have an indirect effect on exhaustion through distributive injustice. Moreover, it was found that distributive injustice is indirectly linked to short-term absences through exhaustion. By contrast, the relationship between distributive injustice and long-term absence can be explained by two mediating variables, namely, exhaustion and psychosomatic complaints. In spite of the non-longitudinal nature of this study, the results suggest that the stress model and the medical model best explain the relationship between organisational injustice and absenteeism, while the withdrawal model via organisational commitment is not associated in this study with absenteeism. Healthcare managers should consider the possibility of better involving employees in the decision-making process in order to increase their perception of procedural and interactional justice, and indirectly reduce exhaustion and absenteeism through a greater perception of distributive justice. For the healthcare sector, the need to reduce absenteeism is particularly urgent because of budget restrictions and the shortage of labour around the world. This is one of the first studies to provide a complete model that analyses the stress process in terms of how organisational justice affects short- and long-term absences, in a bid to understand the specific process and factors that lead to shorter and longer episodes of absence.


[Hand, foot, and mouth disease in a hospital in Callao in 2016].
Hand, foot, and mouth disease (HFMD) is an exanthematous viral disease caused mainly by Coxsackie A16 with a typical symptomatology of fever, papulovesicular rash on the hands, feet, and genitals, and an ulcerous enanthem in the mouth. In the summer of 2016, a variety of cases presented at a hospital in Callao in children and adults with a symptomatology consistent with HFMD. A clinical diagnosis was made, and support therapy was applied, resulting in the resolution of symptoms. In the last decade, reports have emerged in some countries of an atypical involvement caused by Coxsackie A6, producing lesions that are more widely distributed in adults. However, the diagnosis remains clinical, only requiring virological confirmation in atypical cases or when the diagnosis is unclear. The importance of this report stems from its description of the cases in Callao that occurred in the summer of 2016 and serve as an example for health professionals in the diagnosis and management of patients with similar symptomatology.


Prolongation of injection interval after switching therapy from ranibizumab to aflibercept in Japanese patients with macular edema secondary to branch retinal vein occlusion.
This study was conducted to investigate the outcome of switching therapy from ranibizumab to aflibercept in Japanese patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO) in daily practice. This retrospective study enrolled 15 eyes in 15 Japanese patients with ME secondary to BRVO who had been receiving a pro re nata regimen of ranibizumab and had provided written informed consent to switch to aflibercept therapy. The intravitreal injection interval, central retinal thickness, and visual acuity were evaluated before and after switching. The mean period of ranibizumab treatment was 11.8±4.2 months. The mean observation period after switching to aflibercept was 10.6±3.4 months, and seven patients were observed for more than 12 months after switching. The mean intravitreal injection interval was prolonged by 23.6 days with aflibercept (68.2±26.4 days with ranibizumab vs 91.8±33.2 days with aflibercept; P=0.0011). The mean intravitreal injection interval just before the switch was 81.3±35.6 days and was significantly prolonged to 100.8±34.2 days just after the switch to aflibercept (P=0.0309). The mean central retinal thickness did not change before or after the switch to aflibercept (295±55 μm with ranibizumab vs 276±25 μm with aflibercept; P=0.12). The mean visual acuity also remained at an improved level after the switch. No systemic or ocular side effects were evident during the study period. Switching therapy from ranibizumab to aflibercept in Japanese patients with ME secondary to BRVO prolonged the intravitreal injection interval without anatomical or functional degradation.


Guidelines for vaginal birth after previous Caesarean birth.
To provide evidence-based guidelines for the provision of a trial of labour (TOL) after Caesarean section. Fetal and maternal morbidity and mortality associated with vaginal birth after Caesarean (VBAC) and repeat Caesarean section. MEDLINE database was searched for articles published from January 1995 to February 2004, using the key words "vaginal birth after Caesarean (Cesarean) section." The quality of evidence is described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. 1. Provided there are no contraindications, a woman with 1 previous transverse low-segment Caesarean section should be offered a trial of labour after Caesarean with appropriate discussion of maternal and perinatal risks and benefits. The process of informed consent with appropriate documentation should be an important part of the birth plan in a woman with a previous Caesarean section. (II-2B) 2. The intention of a woman undergoing a TOL after Caesarean should be clearly stated and documentation of the previous uterine scar should be clearly marked on the prenatal record. (II-2B) 3. For a safe labour after Caesarean section, the woman should deliver in a hospital where an immediate Caesarean section is available. The woman and her health-care provider must be aware of the hospital resources and the availability of obstetric, anaesthesia, pediatric, and operating-room staff. (II-2A) 4. Each hospital should have a written policy in place regarding the notification and/or consultation for the physicians responsible for a possible immediate Caesarean. (III B) 5. Continuous electronic fetal monitoring of women attempting a TOL after Caesarean is recommended. (II-2A) 6. Suspected uterine rupture requires urgent attention and expedited laparotomy in order to attempt to decrease maternal and perinatal morbidity and mortality. (II-2A) 7. Oxytocin augmentation is not contraindicated in women undergoing a TOL after Caesarean. (II-2A) 8. Medical induction of labour with oxytocin may be associated with an increased risk of uterine rupture and should be used carefully after appropriate counselling. (II-2B)9. Medical induction of labour with prostaglandin E2 (dinoprostone) is associated with an increased risk of uterine rupture and should not be used except in rare circumstances after appropriate counselling. (II-2B) 10. Prostaglandin E1 (misoprostol) is associated with a high risk of uterine rupture and should not be used as part of a TOL after Caesarean. (II-2A) 11. A foley catheter may be used safely to ripen the cervix in a woman planning a TOL after Caesarean. (II-2A) 12. The available data suggest that a trial of labour in women with more than one previous Caesarean section is likely to be successful but is associated with a higher risk of uterine rupture. (II-2B) 13. Multiple gestation is not a contraindication to a TOL after Caesarean. (II-2B) 14. Diabetes mellitus is not a contraindication to TOL after Caesarean. (II-2B) 15. Suspected fetal macrosomia is not a contraindication to a TOL after Caesarean. (II-2B) 16. Women delivering within 18 to 24 months of a Caesarean section should be counselled about an increased risk of uterine rupture in labour. (II-2B) 17. Postdatism is not a contraindication to a TOL after Caesarean. (II-2B) 18. Every effort should be made to obtain the previous Caesarean section operative report to determine the type of uterine incision used. In situations where the scar is unknown, information concerning the circumstances of the previous delivery is helpful in determining the likelihood of a low transverse incision. If the likelihood of a lower transverse incision is high, TOL after Caesarean can be offered. (II-2B) VALIDATION: These guidelines were approved by the Clinical Practice Obstetrics and Executive Committees of the Society of Obstetricians and Gynaecologists of Canada.


Glycemic Excursions in Type 1 Diabetes in Pregnancy: A Semiparametric Statistical Approach to Identify Sensitive Time Points during Gestation.
Aim. To examine the gestational glycemic profile and identify specific times during pregnancy that variability in glucose levels, measured by change in velocity and acceleration/deceleration of blood glucose fluctuations, is associated with delivery of a large-for-gestational-age (LGA) baby, in women with type 1 diabetes. Methods. Retrospective analysis of capillary blood glucose levels measured multiple times daily throughout gestation in women with type 1 diabetes was performed using semiparametric mixed models. Results. Velocity and acceleration/deceleration in glucose levels varied across gestation regardless of delivery outcome. Compared to women delivering LGA babies, those delivering babies appropriate for gestational age exhibited significantly smaller rates of change and less variation in glucose levels between 180 days of gestation and birth. Conclusions. Use of innovative statistical methods enabled detection of gestational intervals in which blood glucose fluctuation parameters might influence the likelihood of delivering LGA baby in mothers with type 1 diabetes. Understanding dynamics and being able to visualize gestational changes in blood glucose are a potentially useful tool to assist care providers in determining the optimal timing to initiate continuous glucose monitoring.


Impact of Hyperbaric Oxygen on More Advanced Wagner Grades 3 and 4 Diabetic Foot Ulcers: Matching Therapy to Specific Wound Conditions.
Objective: The goal of this research was to identify a population of diabetic foot ulcer patients who demonstrate a significant response to hyperbaric oxygen therapy (HBOT) using a large sample size to provide guidance for clinicians when treating these complicated patients. Approach: The effect of HBOT on diabetic foot ulcers, Wagner grades 3 and 4, was evaluated using a retrospective observational real-world data set. The study reported on the overall healing rate, (74.2%) at the population level, for >2 million wounds. Results: When a subgroup of patients of only foot ulcers with a Wagner grade 3 or 4 were considered, the healing rate was only 56.04%. The use of HBOT, without filtering for the number of treatments received, improved the healing rate to 60.01% overall. Healing rates for this same subgroup, however, were improved to 75.24% for patients who completed the prescribed number of hyperbaric treatments. Innovation: This observational study discusses the importance of reporting at the population level, specific wound etiology level, a risk-stratified level, and to then overlay the effect of treatment adherence on those outcomes to provide clinicians with a comprehensive understanding of when to prescribe an advanced modality such as hyperbaric oxygen. Conclusion: The authors provide healing outcomes data from several prior HBOT studies as well as other advanced modalities that have been used in diabetic foot ulcer care for comparison and context.


The political structure of the brain: cerebral localization in Bismarckian Germany.
Eduard Hitzig and Gustav Fritsch's experimental "demonstration" of cerebral localization in 1870 was a major event in the history of attempts to relate behavior to the central nervous system. Their work transformed the vague speculations that began with Franz Josef Gall into professionally responsible activity. In Germany the work of Hitzig and his followers led to violent controversies concerning both the observations and interpretations of cerebral localization. This paper considers why German scientists, who had universally opposed the work of British and French localizers up to 1870, suddenly became interested in the subject at this time, and also why the issue of cerebral localization evoked such passion within the German scientific community. Adequate answers to these questions must involve consideration of the professional relations between physiologists and the developing field of psychiatry. They must also include discussion of the reactions of scientific intellectuals to the most important political development of the time, namely, the unification of Germany.


Raman, WAXS, and Solid-State NMR Characterizations of Regenerated Silk Fibroin Using Lanthanide Ions as Chaotropic Agents.
Bombyx mori silk fibroin (SF) has been reported as a convenient natural material for regenerative medicine, optoelectronics, and many other technological applications. SF owes its unique features to the hierarchical organization of the fibers. Many efforts have been made to set up protocols for dissolution since many applications of SF are based on regenerated solutions and fibers, but chaotropic conditions required to disassemble the packing of the polymer afford solutions with poor crystalline behavior. Our previous research has disclosed a dissolution and regeneration process of highly crystalline fibers involving lanthanide ions as chaotropic agents, demonstrating that each lanthanide has its own unique interaction with SF. Herein, we report elucidation of the structure of Ln-SF fibers by the combined use of Raman spectroscopy, wide-angle X-ray scattering (WAXS), and solid-state NMR techniques. Raman spectra confirmed the coordination of metal ions to SF, WAXS results highlighted the crystalline content of fibers, and solid-state NMR enabled the assessment of different ratios of secondary structures in the protein.


Prognostic factors in ossiculoplasty.
To analyze predictive factors of outcome after ossiculoplasty using a standard ossicular prosthesis system. Retrospective review of 140 ossiculoplasties, performed by the same senior surgeon, with titanium prostheses. Academic hospital and tertiary referral center. All patients undergoing ossiculoplasty with Spiggle and Theis or Kurz titanium total and partial prostheses. Documented, postoperative follow-up had to be provided. A total of 129 patients (140 ears; 53 men and 76 women) were evaluated. These included ossiculoplasties using 75 Spiggle and Theis prostheses (30 partial and 45 total) and 65 Kurz prostheses (35 partial and 30 total). Mean preoperative and postoperative air-bone gaps and the changes in mean hearing loss were analyzed using a four-frequency (500, 1,000, 2,000, and 3,000 Hz) pure tone average. Success rate was defined as postoperative air-bone gap within 20 dB. A one-way analysis of variance was used to analyze group differences. A multivariate statistical analysis was then undertaken to define the significant factors. There were no statistical difference between the Spiggle and Theis and the Kurz prostheses. Multivariate statistical analysis has identified the predictive value of the presence or absence of the malleus handle and the mucosal status of the middle ear in the prognosis of ossiculoplasties. Anatomical and technical factors diversely affect the functional outcome of tympano-ossiculoplasties. A better knowledge of their predictive value will enable accurate, preoperative, individual assessment when counseling patients with regard to the success of any proposed intervention. The use of these factors will also permit precise matching of future series to allow accurate comparisons.


Ventriculoperitoneal shunt malfunction diagnosis based on substance dilution.
Current methods for the diagnosis of ventriculoperitoneal (VP) shunt malfunction lack specific standards; therefore, it may be missed or misdiagnosed. Hence, providing a reliable diagnostic method will help improve the accuracy of preoperative decision-making. Therefore, the aim of the study was to provide a new method for the diagnosis of VP shunt malfunction. After in vitro testing, we enrolled a total of 12 patients with VP shunt malfunction. Before revision surgery, 0.1 mL of a 5% sodium valproate (SV) solution was injected into the reservoir; 0.1 mL of the cerebrospinal fluid (CSF) was withdrawn 20 minutes later from the reservoir to measure the SV concentration. The process was repeated on the seventh day after surgery and compared with the preoperative results. The mean ± standard deviation preoperative SV concentration in the cerebrospinal fluid was greater than the postoperative concentration (5967.8 ± 1281.3 vs 391.1 ± 184.6 μg/mL, P = .001). The proposed method is a reliable, safe, and relatively simple alternative for the diagnosis of VP shunt malfunction and further provides a reference for treatment.


Surgery in pediatric solid tumors with special reference to advanced neuroblastoma.
The role of surgery in Wilms' tumor and hepatoblastoma is well established, but that in advanced neuroblastoma is controversial. We analyzed factors contributing to the long-term survival of patients with MYCN-amplified neuroblastoma. Patients with stage 3, 4, and 4S neuroblastoma with more than 10 copies of MYCN received induction regimen A1 from January 1985 to February 1991, and with regimen A3 which contains twice the dose of cyclophosphamide from March 1991 to September 1993. Most of these patients underwent radical removal of the original tumor and metastatic lymph nodes plus supralethal preconditioning regimens followed by autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT). In assessing the radicality of surgery, three categories of "total", "subtotal", and 'partial" were used. During the study period, 66 patients with more than 10 copies of MYCN were treated, and 19 (29%) of the 66 patients survived disease-free for at least 69 months. All but one who survived, for more than 69 months disease-free underwent ABMT or PBSCT The radicality of surgery was total in 18 (95%), and subtotal in 1 (5%) of the 19 long-term survivors, while it was total in 38 (84%), and subtotal in 7 (16%) of the 45 patients who died (p > 0.05). Nineteen (29%) of the 66 patients with MYCN amplification were long-term disease-free survivors for more than 69 months. The prerequisites for survival in such patients appear to be intensive chemotherapy, total resection of the tumor plus metastases, and the use of ABMT/PBSCT, without any major delay in the time sequence.


Genetic isolation of stem cell-derived pacemaker-nodal cardiac myocytes.
Dysfunction of the cardiac pacemaker tissues due to genetic defects, acquired diseases, or aging results in arrhythmias. When arrhythmias occur, artificial pacemaker implants are used for treatment. However, the numerous limitations of electronic implants have prompted studies of biological pacemakers that can integrate into the myocardium providing a permanent cure. Embryonic stem (ES) cells cultured as three-dimensional (3D) spheroid aggregates termed embryoid bodies possess the ability to generate all cardiac myocyte subtypes. Here, we report the use of a SHOX2 promoter and a Cx30.2 enhancer to genetically identify and isolate ES cell-derived sinoatrial node (SAN) and atrioventricular node (AVN) cells, respectively. The ES cell-derived Shox2 and Cx30.2 cardiac myocytes exhibit a spider cell morphology and high intracellular calcium loading characteristic of pacemaker-nodal myocytes. These cells express abundant levels of pacemaker genes such as endogenous HCN4, Cx45, Cx30.2, Tbx2, and Tbx3. These cells were passaged, frozen, and thawed multiple times while maintaining their pacemaker-nodal phenotype. When cultured as 3D aggregates in an attempt to create a critical mass that simulates in vivo architecture, these cell lines exhibited an increase in the expression level of key regulators of cardiovascular development, such as GATA4 and GATA6 transcription factors. In addition, the aggregate culture system resulted in an increase in the expression level of several ion channels that play a major role in the spontaneous diastolic depolarization characteristic of pacemaker cells. We have isolated pure populations of SAN and AVN cells that will be useful tools for generating biological pacemakers.


A preliminary In Vitro viability study of an electrically active hernia mesh on mouse fibroblasts.
Hernias occur when part of an organ, typically the intestines, protrudes through a disruption of the fascia in the abdominal wall, leading to patient pain, discomfort, and surgical intervention. Over one million hernia repair surgeries occur annually in the USA, but globally, hernia surgeries can exceed 20 million. Standard practice includes hernia repair mesh to help hold the compromised tissue together, depending on where the fascial disruption is located and the patient's condition. However, the recurrence rate for hernias after using the most common type of hernia mesh, synthetic, is currently high. Physiological-level electrical stimulation (ES) has shown beneficial effects in improving healing in soft tissue regeneration. Piezoelectric materials can produce low-level electrical signals from mechanical loading to help speed healing. Combining the novelty of piezo elements to create an electrically active hernia repair mesh for faster healing prospects is explored in this study through simulated transcutaneous mechanical loading of the piezo element with therapeutic ultrasound. A tissue phantom was developed using Gelatin #0 and Metamucil® to better simulate a clinical application of the therapeutic ultrasound loading modality. The cellular viability of varying ultrasound intensities and temporal effects was analyzed. Overall, minimal cytotoxicity was observed across all experimental groups during the ultrasound intensity and temporal viability studies.


The anxiety disorders.
Anxiety commonly accompanies serious illness. However, in some patients anxiety is the primary manifestation of illness. Diagnostic criteria for these "primary" anxiety disorders have been redefined in the most recent revision of the American Psychiatric Association's Diagnostic and Statistical Manual. We discuss these new diagnostic categories; review the theoretical basis for the psychodynamic, behavioral, and physiologic manifestations of each of these disorders; and critically examine the treatments offered for each.


Vascular endothelial growth factor and blood-brain barrier disruption in tuberculous meningitis.
Tuberculous meningitis (TBM) is characterized by disruption of the blood-brain barrier (BBB), cerebral edema and increased intracranial pressure (ICP). Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema. To investigate whether in children with TBM disruption of the BBB relates to VEGF production and to assess the effect of corticosteroids on Mycobacterium tuberculosis-induced VEGF production by mononuclear leukocytes. Blood and CSF samples were collected from 26 children with stage 2-3 TBM and 20 controls. All patients received antituberculous and adjuvant corticosteroid therapy. Children were evaluated by ICP recording, computerized tomography scanning and outcome assessment at 6 months follow-up. BBB disruption was quantified by cerebrospinal fluid (CSF)-serum albumin ratios. VEGF concentrations were measured by enzyme-linked immunosorbent assay. In vitro human monocytic THP-1 cells were stimulated with M. tuberculosis sonicate or culture supernatant, and VEGF production was measured in the presence or absence of corticosteroids. CSF VEGF concentrations were significantly higher in TBM patients than in the controls and correlated with mononuclear cell counts (r = 0.64; P = 0.001) and CSF-serum albumin ratio (r = 0.49; P = 0.015). CSF VEGF did not significantly correlate with elevated ICP. In vitro induction of VEGF production by M. tuberculosis sonicate or culture supernatant could be completely abrogated by corticosteroid treatment. Inflammatory cells secrete VEGF during TBM. CSF VEGF correlates with BBB disruption. Inhibition of VEGF may explain part of the clinical effect of adjuvant corticosteroid therapy in TBM.


Processing and presentation of murine cytomegalovirus pORFm164-derived peptide in fibroblasts in the face of all viral immunosubversive early gene functions.
CD8 T cells are the principal effector cells in the resolution of acute murine cytomegalovirus (mCMV) infection in host organs. This undoubted antiviral and protective in vivo function of CD8 T cells appeared to be inconsistent with immunosubversive strategies of the virus effected by early (E)-phase genes m04, m06, and m152. The so-called immune evasion proteins gp34, gp48, and gp37/40, respectively, were found to interfere with peptide presentation at different steps in the major histocompatibility complex (MHC) class I pathway of antigen processing and presentation in fibroblasts. Accordingly, they were proposed to prevent recognition and lysis of infected fibroblasts by cytolytic T lymphocytes (CTL) during the E phase of viral gene expression. We document here that the previously identified MHC class I D(d)-restricted antigenic peptide (257)AGPPRYSRI(265) encoded by gene m164 is processed as well as presented for recognition by m164-specific CTL during the E and late phases of viral replication in the very same cells in which the immunosubversive viral proteins are effectual in preventing the presentation of processed immediate-early 1 (m123-exon 4) peptide (168)YPHFMPTNL(176). Thus, while immunosubversion is a reality, these mechanisms are apparently not as efficient as the term immune evasion implies. The pORFm164-derived peptide is the first noted peptide that constitutively escapes the immunosubversive viral functions. The most important consequence is that even the concerted action of all immunosubversive E-phase proteins eventually fails to prevent immune recognition in the E phase. The bottom-line message is that there exists no immune evasion of mCMV in fibroblasts.