Healthcare of pregnant women with diabetes during the COVID-19 pandemic: a Southern Brazilian cross-sectional panel data.
To evaluate the indirect effects of the COVID-19 pandemic on the care of women with pregnancies complicated by gestational or pre-existing diabetes, and their maternal-fetal outcomes. A cross-sectional panel data conducted in a University Hospital in Southern Brazil. Maternal-fetal outcomes and predictors of care from 235 pregnant women with type 1, type 2, or gestational diabetes were evaluated. Two time periods were compared: six months preceding the pandemic, in 2019, and the COVID-19 period from September 2020 to March 2021. Comparisons were performed using analysis of variance, Mann-Whitney U, Fisher's exact and T-tests. Risks were calculated using the Poisson regression with robust estimates. Maternal age was lower (32.1 ± 6.8 vs. 34.4 ± 6.6, p=0.009) and rates of depression/anxiety were higher (16.5 vs. 7.4%, p=0.046) in the group evaluated during the COVID-19. Neonatal hypoglycemia (RR 4.04; 95% CI 1.37-11.98, p=0.012), and SGA rates (RR 4.29; 95% CI 1.93-9.54, p<0.001) were higher in the group assessed before the pandemic. Despite economic, social and structural impacts of the pandemic, parameters of maternal care were similar; diabetes control improved, and neonatal hypoglycemia and SGA rates were lower among pregnant women with diabetes during the pandemic.


Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation.
Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-γ and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17-promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN--induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models.


In vitro antifungal and antibiofilm activities of halogenated quinoline analogues against Candida albicans and Cryptococcus neoformans.
With the increasing prevalence of fungal infections coupled with emerging drug resistance, there is an urgent need for new and effective antifungal agents. Here we report the antifungal activities of 19 diverse halogenated quinoline (HQ) small molecules against Candida albicans and Cryptococcus neoformans. Four HQ analogues inhibited C. albicans growth with a minimum inhibitory concentration (MIC) of 100 nM, whilst 16 analogues effectively inhibited C. neoformans at MICs of 50-780 nM. Remarkably, two HQ analogues eradicated mature C. albicans and C. neoformans biofilms [minimum biofilm eradication concentration (MBEC) = 6.25-62.5 µM]. Several active HQs were found to penetrate into fungal cells, whilst one inactive analogue was unable to, suggesting that HQs elicit their antifungal activities through an intracellular mode of action. HQs are a promising class of small molecules that may be useful in future antifungal treatments.


Dataset on modeling and optimization analysis of biodegradation of paracetamol.
This article contains the experimental and statistical data related to degradation of acetaminophen (paracetamol, APAP) by bacterial strains. The strains used in this study were isolated from wastewater by enrichment culture method. The optimization was important to identify the physical conditions at which the strain degraded the APAP effectively. Therefore, the Box-Behnken design (BBD) was used to know the influence of physical parameters (viz. pH, temperature, agitation speed, and concentration) on the degradation of APAP. The effects of the physical factor on the degradation process were investigated by a mathematical model, and this had indicated that all physical factors having some effect on the biodegradation of the APAP. Analysis of variance (ANOVA) showed that the strains DPP1, DPP3, DKP1, and DKP2 had the F-value of 12.89, 6.45, 4.58, and 5.31, respectively. This indicated, the model was significant with regression coefficient (R) value of 0.01%, 0.06%, 0.37%, and 0.18%, respectively. The experimental values, predicted data, and ANOVA analysis has suggested that the model was satisfactory.


A comparison of paediatric and adult infectious diseases consultations in Australia and New Zealand.
The objective of this paper is to describe paediatric infectious diseases consultations across Australia and New Zealand. We surveyed infectious diseases physicians at 51 hospitals over a period of 2 weeks in 2012. Compared with adult consults, paediatric consults were more frequently received from general paediatricians/physicians and intensive care, yet less frequently from surgeons and emergency. Respiratory, skin/soft tissue and bone/joint infections were the most frequent consultations in children. These data demonstrate the breadth of formal infectious diseases consults in children. Differences between paediatric and infectious diseases consultations need to be considered when planning both paediatric and adult physician training and future curriculum development.


An in vitro alveolar macrophage assay for predicting the short-term inhalation toxicity of nanomaterials.
Most in vitro studies investigating nanomaterial pulmonary toxicity poorly correlate to in vivo inhalation studies. Alveolar macrophages (AMs) play an outstanding role during inhalation exposure since they effectively clear the alveoli from particles. This study addresses the applicability of an in vitro alveolar macrophage assay to distinguish biologically active from passive nanomaterials. Rat NR8383 alveolar macrophages were exposed to 18 inorganic nanomaterials, covering AlOOH, BaSO4, CeO2, Fe2O3, TiO2, ZrO2, and ZnO NMs, amorphous SiO2 and graphite nanoplatelets, and two nanosized organic pigments. ZrO2 and amorphous SiO2 were tested without and with surface functionalization. Non-nanosized quartz DQ12 and corundum were used as positive and negative controls, respectively. The test materials were incubated with the cells in protein-free culture medium. Lactate dehydrogenase, glucuronidase, and tumour necrosis factor alpha were assessed after 16 h. In parallel, H2O2 was assessed after 1.5 h. Using the no-observed-adverse-effect concentrations (NOAECs) from available rat short-term inhalation studies (STIS), the test materials were categorized as active (NOAEC < 10 mg/m(3)) or passive. In vitro data reflected the STIS categorization if a particle surface area-based threshold of <6000 mm(2)/mL was used to determine the biological relevance of the lowest observed significant in vitro effects. Significant effects that were recorded above this threshold were assessed as resulting from test material-unspecific cellular 'overload'. Test materials were assessed as active if ≥2 of the 4 in vitro parameters undercut this threshold. They were assessed as passive if 0 or 1 parameter was altered. An overall assay accuracy of 95 % was achieved. The in vitro NR8383 alveolar macrophage assay allows distinguishing active from passive nanomaterials. Thereby, it allows determining whether in vivo short-term inhalation testing is necessary for hazard assessment. Results may also be used to group nanomaterials by biological activity. Further work should aim at validating the assay.


Navigating the complexities of medicating paediatric patients: Insights from an enteral feeding tube workshop.
Enteral feeding tubes (EFT) are used to administer nutrition into the gastrointestinal tract of patients who are unable to take nutrition via mouth. A wide range of children may require enteral feeding through EFT which are also used to administer medication. However, many medicines are not licensed for administration via this route. Numerous factors can impact EFT medicine administration, including for example, dosage form properties and composition, EFT size, design and material, and operational aspects such as tube flushing. As a result, the risk of sub-optimal dosing and medication error is much higher in patients with EFT compared to those without. EuPFI organised a preconference workshop to review the current state of knowledge around aspects to be considered in the verification of EFT administration of medications to children, and considerations for EFT use, and to highlight the areas that remain challenging. Healthcare professional, pharmaceutical industry and regulatory agency perspectives were shared, and case studies discussed. It was agreed that simple and clear standardised global procedures are required for the evaluation and administration of medicines via EFT, and collaboration between all key stakeholders is recommended.


Estimating lung mechanics of dogs with unilateral lung injury.
Extended least-squares algorithms using transpulmonary pressure and airway flow data from ventilatory waveforms were studied for their ability to track parameters of one- and two-compartment models of lung mechanics. A recursive extended least-squares algorithm with discounted measures estimated parameters of discrete-time models during synchronized intermittent mandatory ventilation. In tests on seven dogs developing oleic acid-induced unilateral hemorrhagic pulmonary edema, the one-compartment estimator responded rapidly and appropriately to changes in mechanics: compliance fell to 0.55 +/- 0.15 of its initial value and resistance rose by a factor of 1.8 +/- 0.5 in 3 h following injection of oleic acid. One-compartment parameter estimates revealed a difference between the airway resistance of inspiration and expiration. Two-compartment estimates were seldom physiologically plausible. The difference between inspiratory and expiratory resistance may have caused the two-compartment estimator to fail when applied to data from the entire respiratory cycle; when only expiratory data were used for estimation, the two-compartment estimates were meaningful. These estimates demonstrated increasing lung inhomogeneity after oleic acid was injected; at the end of 3 h, the ratio of the time constants of the two compartments ranged from 5 to 20 in six of the seven dogs. We conclude that the one- and two-compartment estimates may be combined to provide a meaningful assessment of lung mechanics.


Identification of ionotrophic purinergic receptors in Huh-7 cells and their response towards structural proteins of HCV genotype 3a.
Hepatitis C virus (HCV) is a major health problem in developing countries including Pakistan. Chronic HCV infection results in progressive liver disease including fibrosis, cirrhosis, insulin resistance and eventually hepatocellular carcinoma (HCC). Ionotrophic purinergic (P2X) receptors are identified to involve in a spectrum of physiological and pathophysiological processes. However, the role of P2X receptors in HCV liver associated diseases still remains to be investigated. The current study was designed to identify the presence of P2X receptors in human liver cells. Furthermore, it investigates the response of P2X receptors towards HCV structural proteins (E1E2). To determine that how many isoforms of P2X receptors are expressed in human liver cells, human hepatoma cell line (Huh-7) was used. Transcripts (mRNA) of five different isoforms of P2X receptors were identified in Huh-7 cells. To examine the gene expression of identified isoforms of P2X receptors in presence of HCV structural proteins E1E2, Huh-7/E1E2 cell line (stably expressing HCV structural proteins E1E2) was used. The results showed significant increase (6.2 fold) in gene expression of P2X4 receptors in Huh-7/E1E2 cells as compared to control Huh-7 cells. The findings of present study confirmed the presence of transcripts of five different isoforms of P2X receptors in human liver cells and suggest that P2X4 receptors could be represented an important component of the purinergic signaling complex in HCV induced liver pathogenesis.


[A case of successful resection of pulmonary arteriovenous fistula with a high shunt ratio].
We report on a 25-year-old cyanotic man who was diagnosed as having a pulmonary arteriovenous fistula. His chief complaint had been shortness of breath since childhood. Polycythemia (Hb 21.4 g/dl) was detected during a health checkup at his company. A chest X-ray showed an abnormal mass in the left lung. Blood gas analysis showed severe hypoxia with PaO2 of 38.6 mmHg at room air. Angio-CT showed a large aneurysmal lesion at S6 of the left lung with a large feeding artery and vein. Oxygen saturation was 75.2% in the radial artery and 62.5% in the right atrium. The right-to-left shunt ratio was therefore calculated as 62%. The aneurysmal lesion was resected by segmentectomy of the left S6 following division of A6 and V6. After a successful operation, the patient no longer had shortness of breath or cyanosis and blood gas analysis showed PaO2 as 84.3 mmHg at room air. Pulmonary angiography showed no residual shunt lesion.


Second- and third-generation ALK inhibitors for non-small cell lung cancer.
Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications for ALK+ NSCLC. In addition, a third-generation ALK inhibitor, lorlatinib (PF-06463922), was reported to resensitize NSCLC to crizotinib. This review provided a summary of clinical development of alectinib, ceritinib, brigatinib (AP26113), and lorlatinib.


Early Vs. Expectant Management of Spina Bifida Patients-Are We All Talking About a Risk Stratified Approach?
Advancements in the care of patients affected by myelomeningocele have flourished in recent years especially with respect to renal preservation and continence. Involvement of urologists both prenatally and early in life has driven many developments in preventative care and early intervention. As of yet, however, the ideal management algorithm that offers these patients the least invasive diagnostic testing and interventions while still preserving renal and bladder function remains ill defined. In a shift from prior years where the use of surgical intervention and intermittent catheterization were more liberally employed, some providers have more recently advocated for monitoring patients in a more conservative manner with a variety of diagnostic tests until radiographic or clinical changes are discovered. The criteria used to define the need for catheterization and the timing to initiate CIC or more invasive interventions is disparate across pediatric urology and there is published data to support several approaches. This review presents some of these criteria for use of CIC and some newer evidence to support different approaches along with supporting the trend toward individualized medicine and use of risk stratification in developing clinical treatment algorithms.


Dynamic integration of splicing within gene regulatory pathways.
Precursor mRNA splicing is one of the most highly regulated processes in metazoan species. In addition to generating vast repertoires of RNAs and proteins, splicing has a profound impact on other gene regulatory layers, including mRNA transcription, turnover, transport, and translation. Conversely, factors regulating chromatin and transcription complexes impact the splicing process. This extensive crosstalk between gene regulatory layers takes advantage of dynamic spatial, physical, and temporal organizational properties of the cell nucleus, and further emphasizes the importance of developing a multidimensional understanding of splicing control.


Photo-driven anti-Markovnikov alkyne hydration in self-assembled hollow complexes.
Under UV-light irradiation, the anti-Markovnikov hydration of internal arylalkynes proceeds in the cavity of an electron-deficient coordination cage to give benzyl ketones; the reaction is triggered by cage-mediated, photo-induced electron transfer from the alkynes to the cage.


Tritium and radiocarbon in the water column of the Red Sea.
Despite being the busiest transient sea in the world due to the Suez Canal, radionuclide distribution studies in seawater and sediment of the Red Sea remain rare. A sampling expedition in the Red Sea was conducted from June 9 to July 6, 2021, visiting a transect of several deep sampling stations located along the central axis of the basin from the Gulf of Aqaba to the southern Red Sea (near Farasan Island, Saudi Arabia). The collected seawater profile samples were analyzed for tritium, radiocarbon and oxygen-18. The observed tritium levels in surface waters of the Red Sea peaked at 0.3-0.4 TU, similar to the values observed in the western Arabian Sea (decay corrected). The values observed at waters below 150 m were around 0.2 TU, however, at depths of 450 and 750 m, tritium minima (<0.2 TU) were observed, which could be associated with a partial return flow of bottom waters from the southern to the northern Red Sea. At two stations at the depth of about 550 m, deep Δ14C minima were observed as well (-4‰ and -10‰), documenting ongoing transport of carbon in the water column, important for sink of anthropogenic carbon.


An ergonomic evaluation of surgeons' axial skeletal and upper extremity movements during laparoscopic and open surgery.
Many surgeons have complained of fatigue and musculoskeletal pain after laparoscopic surgery. We evaluated differences in surgeons' axial skeletal and upper extremity movements during laparoscopic and open operations. Five surgeons were videotaped performing 16 operations (8 laparoscopic and 8 open) to record their neck, trunk, shoulder, elbow, and wrist movements during the first hour of surgery. We also compared postprocedural complaints of pain, stiffness, or numbness between the two groups. Compared with surgeons performing open surgery, surgeons performing laparoscopic surgery exhibited less lateral neck flexion; less trunk flexion; more internal rotation of the shoulders; more elbow flexion; more wrist supination and wrist ulnar and radial deviation. There was a trend of more shoulder stiffness after laparoscopic operations than after open operations. Laparoscopic surgery involves a more static posture of the neck and trunk, but more frequent awkward movements of the upper extremities than open surgery. Ergonomic changes in the operating room environment and instrument design could ease the physical stress imposed on surgeons during laparoscopic operations.


31P NMR spectroscopy of blood plasma: determination and quantification of phospholipid classes in patients with renal cell carcinoma.
Advanced renal cell carcinoma (RCC) has a poor prognosis and is characterized by an unpredictable clinical course. The aim of this study was to assess the systemic phospholipid distribution as a possible marker of tumor stage and tumor spread beyond the kidney. To this end, the effect of renal cell carcinoma (RCC) on phospholipid concentrations in blood plasma using 31P NMR spectroscopy was studied in: (a) 29 patients with RCC prior to nephrectomy; (b) 19 healthy volunteers; (c) three patients with other renal tumors (renal metastases of bronchial carcinoma and of renal pelvic carcinoma, and a benign renal tumor). Furthermore, the phospholipid concentrations of eight patients of group (a) were determined 6 months after nephrectomy, when they were in remission. We found considerable deviations in the concentrations of the lysophosphatidylcholines (LPC1, LPC2) in both male and female patients with RCC compared to healthy volunteers (male--LPC1 0.217+/-0.062 vs 0.297+/-0.049 mmol/l, LPC2 0.036+/-0.014 vs 0.068+/-0.024 mmol/l; female--LPC1 0.195+/-0.071 vs 0.296+/-0.044 mmol/l, LPC2 0.037+/-0.027 vs 0.044+/-0.014 mmol/l). In addition, female patients with RCC showed lower concentrations of phosphatidylcholines (PC; 1.409+/-0.268 vs 1.947+/-0.259 mmol/l). The low phospholipid concentrations normalized for patients in remission. Phospholipid concentrations were found to depend on tumor stage and metastatic spread. The deviations in phospholipid concentrations (LPC1, LPC2, PC) observed may be attributable to systemic effects caused by the tumor as well as changes in enzyme activities.


The effect of Baduanjin Qigong combined with five-elements music on anxiety and quality of sleep in asymptomatic patients with COVID-19 infection: A randomised controlled trial.
Infections of Coronavirus Disease-2019 (COVID-19) and the subsequent quarantine can culminate in anxious mood and sleep disturbances. The objective of this clinical trial was to investigate the effect of traditional Qigong with music therapy on relieving anxiety and improving the quality of sleep in Chinese adults with COVID-19 infection. A total of 200 asymptomatic COVID-19 infected patients were randomly assigned into two groups during their quarantine period in Chongming Island, Shanghai. The patients in the treatment group daily received Baduanjin Qigong, five-elements music therapy and routine care, while the patients in the control group only took the routine care. The primary outcome was anxiety levels measured by the 7-item Generalized Anxiety Disorder scale (GAD-7). Secondary outcomes included the quality of sleep measured by the Jenkins Sleep Scale (JSS), the degree of depression measured by the Patient Health Questionnaire (PHQ-9), as well as the self-efficacy in the Perceived Health Competence Scale (PHCS). An online questionnaire was given to all participants on the day of arrival to determine the baseline for all outcomes and then given again on the day of discharge. A one-way analysis of covariance was used to analyze the differences between the two groups after intervention. At the end of the intervention, 177 (88.5%) patients finished the questionnaire. Patients in the treatment group had clearly decreased GAD-7 scores (MD = 2.7, 95% CI = 2.3, 3.2) after the daily exercise and music. Patients in the control group had little changes in the GAD-7 (MD = -0.2, 95%CI = -0.7, 0.3, P = 0.07), as well as the PHQ-9 (MD = 0.1, 95%CI = -0.5, 0.6, P = 0.66) after the routine care, when compared to their baseline scores. There were statistical between-group differences in GAD-7 (MD = 2.9, 95% CI = 2.2, 3.6, P < 0.001)and in the PHQ-9 scores (MD = 3.6, 95% CI = 2.9, 4.4, P < 0.001) at the post-treatment. Compared with the control group, patients had significantly lower scores on the JSS (MD = 2.7, 95% CI = 2.0, 3.3, P < 0.001), and higher scores on the PHCS (MD = -5.0, 95% CI = -6.1, -3.9, P < 0.001) after receiving Qigong and the music therapy. Traditional Baduanjin Qigong and five-elements music therapy help to relieve anxiety and depression, and improve the sleep quality in patients with COVID-19 infection. Chinese Clinical Trial Registry ChiCTR2200059800.


Mobilization of colonic kallikrein following pelvic nerve stimulation in the atropinized cat.
1. Pelvic nerve stimulation (p.n.s.) in cats induces atropine-resistant colonic vasodilatation and colonic contraction. The effects of this on cat colon are mimicked by synthetic bradykinin infusions. The present study examines the effect of p.n.s. on the activation of kallikrein, the kinin-forming enzyme present in colonic tissue and its effects on the plasma kinin system in the atropinized cat.2. Mean level (+/- S.D.) of mucosal kallikrein was found to be about 37 times higher in unstimulated colonic mucosa (300 +/- 100 ng bradykinin equivalents min(-1)g(-1)) than in the underlying muscle (8.2 +/- 6.3 ng bradykinin equiv min(-1)g(-1)).3. After a p.n.s. of 5 min, mean kallikrein level in colonic muscle was 7.3 +/- 3.5 ng bradykinin equiv min(-1)g(-1), which was not significantly different from the control muscle kallikrein. However, there was an 86% fall in mucosal kallikrein to 41.3 +/- 34.7 ng bradykinin equiv min(-1)g(-1) after 5 min p.n.s., indicating a rapid activation and secretion of mucosal kallikrein.4. Secretion of mucosal kallikrein was paralleled by specific depletion of plasma kininogen, the precursor of active kinin in blood draining the colon. The mean plasma kininogen level fell to 79 and 68% of the prestimulated value (3.1 +/- 1.1 S.D. mug bradykinin equiv per ml. plasma) after 5 and 10 min p.n.s. respectively. Total plasma protein and haematocrit remained unaltered excluding non-specific changes due to protein extravasation or haemodilution and indicating utilization of the plasma kinin precursor.5. Following 2 hr p.n.s., raised levels of kallikrein were detected in both colonic muscle (28 +/- 2.0 bradykinin equiv min(-1)g(-1)) and mucosa 434 +/- 118 ng bradykinin equiv min(-1)g(-1)). Preliminary studies using a kallikrein inhibitor indicated that the increased kallikrein levels originated from plasma.6. Direct stimulation of the parasympathetic pelvic nerve in the atropinized cat thus produced activation of the plasma kinin system in the colon and formation of free kinins may be responsible for the mucosal vasodilatation and strong motor contraction which is not blocked by large doses of atropine. The observation that prolonged stimulation causes extravasation of plasma kallikrein, a potential inflammatory mediator, into the tissues may be of clinical significance.


Machine learning algorithms to predict risk of postoperative pneumonia in elderly with hip fracture.
Hip fracture (HF) is one of the most common fractures in the elderly and is significantly associated with high mortality and unfavorable prognosis. Postoperative pneumonia (POP), the most common postoperative complication of HF, can seriously affect patient prognosis and increase the burden on the healthcare system. The aim of this study was to develop machine learning models for identifying elderly patients at high risk of pneumonia after hip fracture surgery. From May 2016 to November 2022, patients admitted to a single central hospital for HF served as the study population. We extracted data that could be collected within 24 h of patient admission. The dataset was divided into training and validation sets according to 70:30. Based on the screened risk factors, prediction models were developed using seven machine learning algorithms, namely CART, GBM, KNN, LR, NNet, RF, and XGBoost, and their performance was evaluated. Eight hundred five patients were finally included in the analysis and 75 (9.3%) patients suffered from POP. Age, CI, COPD, WBC, HB, GLU, STB, GLOB, Ka+ which are used as features to build machine learning models. By evaluating the model's AUC value, accuracy, sensitivity, specificity, Kappa value, MCC value, Brier score value, calibration curve, and DCA curve, the model constructed by XGBoost algorithm has the best and near-perfect performance. The machine learning model we created is ideal for detecting elderly patients at high risk of POP after HF at an early stage.


Evaluation of miniscrew stability using an automatic embedding auxiliary skeletal anchorage device.
To clarify the in vivo effect of an automatic embedding device on miniscrew stability. 42 miniscrews were implanted into rabbit femurs. The miniscrews with the novel auxiliary device formed the auxiliary group (n = 11 at 4 weeks; n = 11 at 8 weeks) and the miniscrews without the auxiliary device formed the nonauxiliary control group (n = 9 at 4 weeks; n = 11 at 8 weeks). Cortical bone thickness, distance from the cortical bone surface to the miniscrew head, and implantation depth of the spike were measured using micro-computed tomography. The mechanical retention force was evaluated by measuring the displacement of the miniscrew head after it was loaded perpendicular to its long axis. In the lateral displacement test, effects of the auxiliary (with vs without auxiliary), and time (4 vs 8 weeks) were assessed using the Brunner-Langer nonparametric analysis of longitudinal data in factorial experiments. The mean implantation depth of the spike in the auxiliary group at 4 and 8 weeks was 0.28 mm (median: 0.33; SD: 0.12) and 0.37 mm (median: 0.33; SD: 0.19), respectively. The retention force was approximately 2.0 to 2.8 and 1.6 to 1.8 times greater in the auxiliary group than in the nonauxiliary group at 4 and 8 weeks, respectively. The auxiliary device improved the mechanical retention force without the need to increase miniscrew length or diameter. This may enable the safe use of miniscrews in difficult areas.


The providing of well-baby care within parent-infant groups. "Pediatricians are encouraged to explore the parent-infant group model in their practices".
A model has been described for the practice of pediatrics using parent-infant groups. In a one year experience, three parent-infant groups met at monthly intervals. A one-hour parent discussion was followed by examination of the infants within the group setting. Among the benefits observed were much more attention of well-baby care and infant development, and the surfacing and alleviation of parental concerns and anxieties.


Functional role of CD95 ligand in concanavalin A-induced intestinal intraepithelial lymphocyte cytotoxicity.
Freshly isolated murine intestinal intraepithelial lymphocytes (IEL) express CD95 ligand (CD95L), as shown by reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence-activated cell sorter (FACS) analysis. Between 15 and 25% of IEL could be stained with an antibody to CD95L. Therefore it was investigated whether the CD95L/CD95 pathway was effective in IEL cytotoxicity. Stimulation of IEL in vitro with concanavalin A (Con A) induced a strong cytotoxic response, which was much higher when using CD95-expressing target cells. This effect was most evident when comparing the specific lysis of CD95-transfected target cells of the leukaemia cell line L1210 with that of the untransfected parental cell line. In addition, an antibody to CD95 was able to dramatically reduce the specific lysis of CD95-expressing target cells. After stimulation with Con A, which is able to bind to CD95L, the effects were more obvious compared with the triggering of the T-cell receptor (TCR)-alphabeta or gamma delta. On the other hand, EGTA reduced the Con A-induced cytotoxicity. Together these findings support a role of the CD95L/CD95 pathway in IEL cytotoxicity, even though the reaction was Ca2+ sensitive. As a function, CD95L-expressing IEL should be able to contribute to the elimination of CD95-expressing target cells in the intestine.


A comparison of chromosomal aberrations induced by in vivo radiotherapy in human sperm and lymphocytes.
Chromosomal aberrations in human sperm and lymphocytes were compared before and after in vivo radiation treatment of 13 cancer patients. The times of analyses after radiotherapy (RT) were 1, 3, 12, 24, 36, 48 and 60 months. The median total radiation dose was 30 Gy and the testicular dose varied from 0.4 to 5.0 Gy. Human sperm chromosome complements were analysed after fusion with golden hamster eggs. There were no abnormalities in sperm or lymphocytes before RT. Following RT there was an increase in the frequency of numerical and structural chromosomal abnormalities in both lymphocytes and sperm. For structural abnormalities there were more rejoined lesions (dicentrics, rings) in lymphocytes and more unrejoined lesions (chromosome breaks, fragments) in sperm. After RT there was a dramatic increase in the frequency of chromosomal abnormalities in lymphocytes: at 1 mo. the frequency was 42%, at 3 mo. 25%, at 12 mo. 14%, at 24 mo. 11%, at 36 mo. 9%, at 48 mo. 7% and at 6 mo. 4%. Since the majority of men were azoospermic after RT, there is little data on sperm chromosome complements before the analyses performed at 24 mo. post-RT. At 24 mo. the frequency of abnormalities was 13%, followed by 21% at 36 mo., 12% at 48 mo. and 22% at 60 mo. Thus it appears that the frequency of lymphocyte chromosomal abnormalities had an initial marked increase after RT followed by a gradual decrease with time whereas the frequency of sperm chromosomal abnormalities was elevated when sperm production recovered and remained elevated from 24 to 60 mo. post-RT. This difference in the effect of time makes it very difficult to compare abnormality rates in lymphocytes and sperm and to use analysis of induced damage in somatic cells as surrogates for germ cells since the ratio between sperm and lymphocytes varied from 1:1 (at 24 mo. post-RT) to 5:1 (at 60 mo. post-RT).


Psychological aspects of hematologic diseases.
This article focused on two hematologic diseases that have received significant attention in the pediatric literature: sickle cell anemia and hemophilia. As the data indicate, these illnesses present lifelong challenges to individuals afflicted. With advances in medical interventions, many children with these hematologic diseases are living longer and with fewer serious complications. Intervention efforts only recently have begun to consider issues related to quality of life and increased psychological adjustment, including active coping strategies by children and their parents and necessary social support for all family members. Theoretical models [54] have highlighted the multiple factors that play a role in illness adjustment and the complex interactions of these factors. Individual, family, and community characteristics are impacted by and, in turn, impact on illness-related characteristics. The notion that illness severity is predictive of psychological adjustment has been discarded in favor of a model that recognizes multiple influences and multiple outcomes. Child coping, parent coping, social support, adaptive functioning, treatment compliance, and illness severity are being considered to better understand and influence overall psychological functioning. The field of pediatric psychology has made tremendous advances in improving knowledge of illness and its impact on development. Even with these advances, however, there remains much to be discovered. To date, pediatric psychology research has focused primarily on individual illness categories, making comparisons across illness types difficult. By considering different illnesses within the same study, characteristics that are crucial to improved adjustment and common across illnesses can be identified. As we continue to work for cures for these debilitating illnesses, our goal remains to improve quality of life for children.


"Good things come in small packages": application of exosome-based therapeutics in neonatal lung injury.
Infants born at very low gestational age contribute disproportionately to neonatal morbidity and mortality. Advancements in antenatal steroid therapies and surfactant replacement have favored the survival of infants with ever-more immature lungs. Despite such advances in medical care, cardiopulmonary and neurological impairment prevail in constituting the major adverse outcomes for neonatal intensive care unit survivors. With no single effective therapy for either the prevention or treatment of such neonatal disorders, the need for new tools to treat and reduce risk of further complications associated with extreme preterm birth is urgent. Mesenchymal stem/stromal cell (MSC)-based approaches have shown promise in numerous experimental models of lung injury relevant to neonatology. Recent studies have highlighted that the therapeutic potential of MSCs is harnessed in their secretome, and that the therapeutic vector therein is represented by the exosomes released by MSCs. In this review, we summarize the development and significance of stem cell-based therapies for neonatal diseases, focusing on preclinical models of neonatal lung injury. We emphasize the development of MSC exosome-based therapeutics and comment on the challenges in bringing these promising interventions to clinic.


Sexual Desire Mediates the Relationship-Promoting Effects of Perceived Partner Mate Value.
Although sexual desire for one's partner is theorized to serve as a gut-level indicator of partner mate value that motivates investment in valued partners, there is scant empirical evidence to support this hypothesis. Five studies addressed this possibility, examining whether experiencing sexual desire encouraged the enactment of relationship-promoting behaviors and whether perceptions of partner mate value motivated this proposed process. In a pilot study and Study 1, participants relived an activity they experienced with their partner, which was either sexual or non-sexual. Then, participants rated their desire to engage in sex and other non-sexual relationship-promoting activities with their partner (pilot study) and their partner's responsiveness to personal disclosures. Participants' enacted responsiveness was also evaluated by judges (Study 1). Results showed that experiences of desire enhanced relationship-promoting tendencies. Using experimental, daily experiences, and longitudinal methods, Studies 2-4 extended these findings, indicating that both manipulated and perceived partner mate value predicted desire, which, in turn, was associated with engagement in relationship-promoting behaviors. These findings demonstrate that sexual desire functions as a mechanism encouraging investment in partners who are perceived to be worth pursuing and retaining.


Correction to: Genomic diversity and population structure of the Leonberger dog breed.
An amendment to this paper has been published and can be accessed via the original article.


Triple play: promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus.
Oxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, not promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.


Deep hypothermic circulatory arrest during the arterial switch operation is associated with reduction in cerebral oxygen extraction but no increase in white matter injury.
Deep hypothermic circulatory arrest may be associated with increased neural injury. We investigated whether short periods of deep hypothermic circulatory arrest are associated with altered neurophysiologic recovery or greater risk of injury. Eighteen term infants with transposition of the great arteries undergoing the arterial switch operation were enrolled. Deep hypothermic circulatory arrest was used in 11, and bypass alone in 7. Near-infrared spectroscopy and amplitude-integrated electroencephalography were recorded with standard monitoring during and from 4 to 16 h after surgery. Fractional tissue oxygen extraction was determined from arterial oxygen saturation and venous weighted intracerebral oxygenation. Magnetic resonance imaging was performed before and 5 to 7 days after surgery. There were no significant differences between patients requiring deep hypothermic circulatory arrest (median, 5 min; range, 3-6 min) or cardiopulmonary bypass only at the beginning of surgery. At the end of surgery, amplitude-integrated electroencephalography minimum amplitude was significantly lower in the deep hypothermic circulatory arrest group (P < .05), and fractional tissue oxygen extraction tended to be lower (P = .068). After surgery, deep hypothermic circulatory arrest was associated with significantly higher tissue oxygenation index, lower fractional tissue oxygen extraction, and lower core temperature (P < .05). Magnetic resonance imaging-defined white matter injuries before and after surgery were similar between groups. In this prospective, observational study, brief deep hypothermic circulatory arrest during arterial switch was associated with reduced cerebral oxygen uptake during recovery, with transient electroencephalographic suppression but no increase in risk of white matter injury.


Cortical activation during fast repetitive finger movements in humans: steady-state movement-related magnetic fields and their cortical generators.
To study the cortical physiology of fast repetitive finger movements. We recorded steady-state movement-related magnetic fields (ssMRMFs) associated with self-paced, repetitive, 2-Hz finger movements in a 122-channel whole-head magnetometer. The ssMRMF generators were determined by equivalent current dipole (ECD) modeling and co-registered with anatomical magnetic resonance images (MRIs). Two major ssMRMF components occurred in proximity to EMG onset: a motor field (MF) peaking at 37+/-11 ms after EMG onset, and a postmovement field (post-MF), with inverse polarity, peaking at 102+/-13 ms after EMG onset. The ECD for the MF was located in the primary motor cortex (M1), and the ECD for the post-MF in the primary somatosensory cortex (S1). The MF was probably closely related to the generation of corticospinal volleys, whereas the post-MF most likely represented reafferent feedback processing. The present data offer further evidence that the main phasic changes of cortical activity occur in direct proximity to repetitive EMG bursts in the contralateral M1 and S1. They complement previous electroencephalography (EEG) findings on steady-state movement-related cortical potentials (ssMRCPs) by providing more precise anatomical information, and thereby enhance the potential value of ssMRCPs and ssMRMFs for studying human sensorimotor cortex activation non-invasively and with high temporal resolution.


Rehabilitation education program for stroke (REPS): learning and practice outcomes.
New research knowledge acquired from Web-based sources may have a better chance of being translated into practice when accompanied by additional educational strategies. This study was undertaken to investigate that hypothesis. The Rehabilitation Education Program for Stroke (REPS) combines a self-directed online learning module with support from peer mentors, technical skills workshops, and organizational supports. Participants completed learning tests and practice surveys before and after the program and at a 6-month follow-up. Learning and self-reported practice outcomes improved in the areas of assessment, client-centered practice, support for family and caregivers, and detecting depression. Participants also identified and reported specific strategies for individual and programmatic practice change. A multifaceted, interdisciplinary online education intervention can positively influence stroke rehabilitation practices.


Exposure of aircraft maintenance technicians to organophosphates from hydraulic fluids and turbine oils: a pilot study.
Hydraulic fluids and turbine oils contain organophosphates like tricresyl phosphate isomers, triphenyl phosphate and tributyl phosphate from very small up to high percentages. The aim of this pilot study was to determine if aircraft maintenance technicians are exposed to relevant amounts of organophosphates. Dialkyl and diaryl phosphate metabolites of seven organophosphates were quantified in pre- and post-shift spot urine samples of technicians (N=5) by GC-MS/MS after solid phase extraction and derivatization. Pre- and post shift values of tributyl phosphate metabolites (dibutyl phosphate (DBP): median pre-shift: 12.5 μg/L, post-shift: 23.5 μg/L) and triphenyl phosphate metabolites (diphenyl phosphate (DPP): median pre-shift: 2.9 μg/L, post-shift: 3.5 μg/L) were statistically higher than in a control group from the general population (median DBP: <0.25 μg/L, median DPP: 0.5 μg/L). No tricresyl phosphate metabolites were detected. The aircraft maintenance technicians were occupationally exposed to tributyl and triphenyl phosphate but not to tricresyl phosphate, tri-(2-chloroethyl)- and tri-(2-chloropropyl)-phosphate. Further studies are necessary to collect information on sources, routes of uptake and varying exposures during different work tasks, evaluate possible health effects and to set up appropriate protective measures.


Intense 99mTc-MDP Uptake in the Abdominal Soft Tissue Secondary to Subcutaneous Insulin Injection.
A 65-year-old woman with known breast cancer presented with lower back pain over 1 month. Multiple sclerotic foci of increased tracer uptake in the bones were noted on the Tc-MDP bone scintigraphy and SPECT/CT images, suggesting osteoblastic metastasis. Unexpectedly, symmetric Tc-MDP activity was visualized in the soft tissue near the umbilical area, corresponding to the sites of insulin injection.


The innervation of the monkey accessory lateral rectus muscle.
The source and pattern of innervation of the accessory lateral rectus muscle has been re-investigated in 3 Macaca fascicularis monkeys by means of a tracing method employing [125I] wheat germ agglutinin and a morphological analysis of the myo-neuronal junctions. The present findings suggest that this muscle is composed of exclusively singly innervated fibers and that its motoneurons are situated in the accessory abducens nucleus. This is in contrast to a previous study, where the monkey accessory lateral rectus was found to be composed of singly and multiply innervated fibers and to be innervated by a group of motoneurons lying within principle and accessory abducens nucleus. It is concluded that the monkey accessory lateral rectus reflects in principle the organization of the retractor bulbi of other vertebrates, although this muscle is gradually vanishing in primate evolution and remains vestigial in the macaque monkey. The absence of comparable motor units in man is more likely to mean an actual loss of structure and function than their integration into the lateral rectus system.


Anti-H1N1 influenza effects and its possible mechanism of Huanglian Xiangru Decoction.
Huangliang Xiangru Decoction (HXD), which is described in a famous TCM monograph "Book of Nanyang for Life Savin", is frequently used for treating cold in summer and summer heat-dampness. To date, no pharmacological study on the anti-H1N1 influenza properties of HXD has been reported. The aim of the present study was to evaluate the therapeutic action of HXD on HIN1-induced acute pulmonary inflammation and its anti-influenza mechanism focus to TLRs signal pathway in a mouse model. the mice were intranasally infected with influenza virus to induce viral pneumonia, and then treated with different doses of HXD. The Lung index and pathological changes in the lung tissue of mice were investigated to value the anti-influenza virus effect of HXD. The concentrations of cytokines (IL-2, IL-6, TNF-α and IFN-γ) and anti-oxidant factor (NO, SOD and GSH) in serum of mice were determined with ELISA. RT-PCR and Western blot were used to determine the mRNA and protein expression of TLR3, TLR7, MyD88,TRAF3 and NF-κB p65 in the lung tissues, which are the key targets of TLRs pathway. Compared with the infection group, the lung index of mice in ribavirin group, HXD high dose group and HXD middle dose group were significantly decreased, the lung indexes of these groups were 10.36±1.14mg/g, 9.89±0.79mg/g, and 10.97±0.67mg/g. Moreover, pathological changes were remarkable alleviated. HXD can reduce the contents of IL-6, TNF-α and IFN-γ, NO, and increase the contents of IL-2, SOD, GSH in serum of infected-mice significantly. At the same time, HXD can reduce the mRNA and protein expression of TLR3, TLR7, MyD88,TRAF3 and NF-κB p65 in the lung tissues of infected-mice significantly. HXD has significant effects on H1N1 influenza by a quantity-effect relationship, and plays its anti-influenza effect by enhancing the body's antioxidant capacity, regulating the body's immune function and the host's TLRs pathway.


Efficient total synthesis of (+)-negamycin, a potential chemotherapeutic agent for genetic diseases.
Herein, we describe an efficient strategy for the total synthesis of (+)-negamycin using commercially available achiral N-Boc-2-aminoacetaldehyde as starting material with 42% overall yield for a limited number of steps.


TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.
To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.


Hippo Pathway Activation in Aged Mesenchymal Stem Cells Contributes to the Dysregulation of Hepatic Inflammation in Aged Mice.
Aging is always accompanied by chronic diseases which probably attribute to long-term chronic inflammation in the aging body. Whereas, the mechanism of chronic inflammation in aging body is still obscure. Mesenchymal stem cells (MSCs) are capable of local chemotaxis to sites of inflammation and play a powerful role in immune regulation. Whether degeneration of MSCs in the aging body is associated with unbalanced inflammation is still not clear. In this study, immunosuppressive properties of aged MSCs are found to be repressed. The impaired immunosuppressive function of aged MSCs is associated with lower expression of the Hippo effector Yes-associated protein 1 (YAP1) and its target gene signal transducer and activator of transcription 1 (STAT1). YAP1 regulates the transcription of STAT1 through binding with its promoter. In conclusion, a novel YAP1/STAT1 axis maintaining immunosuppressive function of MSCs is revealed and impairment of this signal pathway in aged MSCs probably resulted in higher inflammation in aged mice liver.


Resistance of vegetative cells and endospores of Sporolactobacillus to gamma-irradiation.
Vegetative cells of Sporolactobacillus showed average resistance to gamma-irradiation compared to other vegetative bacteria with D10 values ranging from 0.350 to 0.525 kGy. Endospores of Sporolactobacillus showed higher resistance to gamma-irradiation than most Bacillus species but were close to that of Clostridium species. The average D10 value for Sporolactobacillus endospores was 2.5 kGy.


Hypoperfusion Distal to Anterior Circulation Intracranial Atherosclerosis is Associated with Recurrent Stroke.
In patients with symptomatic vertebrobasilar intracranial atherosclerotic disease (ICAD), impaired distal flow predicts recurrent stroke, but limited data exist on the association between perfusion status and recurrent stroke in anterior circulation ICAD. This is a retrospective study of patients hospitalized for symptomatic ICAD with 50-99% stenosis of the intracranial carotid or middle cerebral artery. The primary outcome is recurrent symptomatic ischemic stroke in the territory of the artery with ≥50% stenosis within 90 days. The primary predictor is distal hypoperfusion on magnetic resonance (MR) or computed tomography (CT) perfusion, defined as a ≥15 mL volume of territory of the symptomatic artery with Tmax >6 seconds. Fifty patients met inclusion criteria, including 15 (30%) with recurrent stroke and 15 (30%) with distal hypoperfusion. Distal hypoperfusion was present in 10 of 15 (66.7%) with recurrent stroke versus 5 of 35 (14.3%) without recurrent stroke (P < .001). The hazard ratio for recurrent stroke in patients with distal hypoperfusion was 6.80 (95% confidence interval [CI] 2.31-20.0). Distal hypoperfusion in acutely symptomatic ICAD with 50-99% stenosis is associated with stroke recurrence. Distal hypoperfusion could be used to enrich future trials of secondary stroke prevention in ICAD patients.


Subarachnoid hemorrhage, cerebral hemorrhage, and serum cholesterol concentration in men and women.
The role of serum cholesterol in predicting the risk of stroke is unclear and may depend on the subtype of the disease. In 1964 to 1965, 54,385 Swedish men and women participated in a health survey with serum cholesterol and diastolic blood pressure determinations. The Swedish mortality register was used to identify causes of death in this cohort during 20.5 years of follow-up (1964 to 1985). A person-year-based Poisson model was used for multivariate analysis. Relative risk increased with decreasing serum cholesterol level for subarachnoid hemorrhage in men and for cerebral hemorrhage in women but not for subarachnoid hemorrhage in women. For cerebral hemorrhage in men, the risk function was U-shaped. Adjustment for diastolic blood pressure did not significantly change the relation between the risk for any of the different stroke types and the cholesterol level. A low cholesterol level predicts death from intracranial bleeding, but the data suggest that there is differing risk pattern for men and women.


Anti-tubercular agents. Part 3. Benzothiadiazine as a novel scaffold for anti-Mycobacterium activity.
In an effort to develop new and more effective therapies to treat tuberculosis, a series of benzothiadiazine 1,1-dioxide derivatives were synthesized and their in vitro activity against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare was evaluated. One of the compounds, 8c, exhibited potent anti-tubercular activity, particularly for the resistant strains and thus prompted us to investigate its in vivo profile. However, the in vivo testing in a mouse model of tuberculosis infection did not show significant anti-tubercular activity, probably because of its poor bioavailability.


Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels.
We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.


Clinical features and natural history of spinocerebellar ataxia type 1.
SCA1 is a dominant spinocerebellar ataxia (SCA) and a multi-systemic syndrome caused by abnormal expansion of unstable CAG repeat in a novel gene located on chromosome 6p22-p23. We clinically studied 35 Japanese SCA1 patients who were assumed to have come from a common origin. The age at onset ranged from 15-63 years, and significantly correlated with CAG repeat units of mutant alleles. Ataxia was the initial symptom, and the majority of patients had a similar history of signs and symptoms. Nystagmus was at first minimal, later attenuated, and a slow saccade followed. Limb tendon reflexes were mostly hyperactive and depressed with the development of diffuse amyotrophy. The cardinal feature was ataxia-hyperreflexia-late slow saccade syndrome with terminal amyotrophy. Although the phenotype of SCA1 overlaps with those of other dominant SCAs, some facets of the neurological events differ from either SCA2 with ataxia-hyporeflexia-slow saccade syndrome, or early-onset Machado-Joseph disease with dystonia-bradykinesia-spasticity syndrome.


Selective carbohydrate or protein restriction: effects on subsequent food intake and cravings.
In order to determine the effects of selective food restriction on subsequent food intake and cravings, participants were randomly assigned to one of three conditions: carbohydrate-restriction, protein-restriction, or control (no restriction). Participants in the restriction conditions were asked to restrict their intake of either complex carbohydrates or animal proteins for 3 days, before coming to the laboratory for an experimental session. During the experimental session, participants' food intake, cravings, and affect were measured. The results indicated that selective food restriction resulted in selective behavioural consequences. Specifically, carbohydrate-restricted participants consumed more of a high-carbohydrate food than did controls or protein-restrictors, in addition to reporting more cravings for high-carbohydrate foods over the restriction period. Protein-restricted participants reported more cravings for high-protein foods over the restriction period, in comparison to controls and carbohydrate-restrictors; however, protein-restricted participants did not consume more of the particular high-protein food presented to them in the laboratory. The roles of dietary restraint and negative affect in influencing cravings and food intake are discussed. Overall, selective food restriction is demonstrated to have negative psychological and behavioural consequences.


Spectrin as a stabilizer of the phospholipid asymmetry in the human erythrocyte membrane.
After treatment of intact human erythrocytes with SH-oxidizing agents (e.g. tetrathionate and diamide) phospholipase A2 cleaves approx. 30% of the phosphatidylserine and 50% of the phosphatidylethanolamine without causing hemolysis (Haest, C.W.M. and Deuticke, B (1976) Biochim. Biophys. Acta 436, 353--365). These phospholipids are scarcely hydrolysed in fresh erythrocytes and are assumed to be located in the inner lipid layer of the membrane (Verkleij, A.J., Zwaal, R.F.A., Roelofsen, B., Comfurius, P., Kastelijn, D. and van Deenen, L.L.M. (1973) Biochim. Biophys Acta 323, 178--193). The enhancement of the phospholipid cleavage is now shown to be accompanied by a 50% decrease of the membrane SH-groups and a cross-linking of spectrin, located at the inner surface of the membrane, to oligomers of less than 10(6) dalton. Blocking approx. 10% of the membrane SH groups with N-ethylmaleimide suppresses both the polymerization of spectrin and the enhancement of the phospholipid cleavage. N-Ethylmaleimide, under these conditions, reacts with three SH groups per molecule of spectrin, 0.7 SH groups per major intrinsic 100 000 dalton protein (band 3) and 1.1 SH groups per molecule of an extrinsic protein of 72 000 daltons (band 4.2). Blocking studies with iodoacetamide demonstrate that the SH groups of the 100 000-dalton protein are not involved in the effects of the SH-oxidizing agents. It is suggested that a release of constraints imposed by spectrin enables phosphatidylserine and phosphatidylethanolamine to move from the inner to the outer lipid layer of the erythrocyte membrane and that spectrin, in the native erythrocyte, stabilizes the orientation of these phospholipids to the inner surface of the membrane.


Regenerative Endodontic Procedures: Management of Immature Necrotic Permanent Teeth.
Immature permanent teeth are prone to pulpal necrosis due to dental caries, traumatic injury, or developmental malformation. These cases can lead to arrested root development, accompanied by thin root dentinal walls and open apices. Therefore, the efficient disinfection and adequate filling of root canals can often be challenging for clinicians.


Differential expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in chronic murine retroviral encephalitis.
The cell adhesion molecules, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, are important mediators of immune interactions within the central nervous system (CNS). A wide variety of pro-inflammatory insults to the brain, including viral infection, result in upregulation of these molecules on brain endothelial cells, astrocytes, and microglia. This study investigated the expression of ICAM-1 and VCAM-1 in chronic encephalitis induced by infection with a temperature sensitive (ts-1) strain of Moloney murine leukaemia virus (MoMuLV), an ecotropic murine retrovirus. During the late stages of disease, viral antigen was present in both endothelial cells and microglia, but not astrocytes, in regions of spongiform change and gliosis. In these areas, ICAM-1 staining was detected on activated microglia, but not on endothelial cells or astrocytes. In contrast, no cells showed increased VCAM-1 expression in the CNS. These findings demonstrate that there is cell-specific, differential expression of these adhesion molecules in ts-1 retroviral encephalitis. The lack of endothelial cell expression correlates with the characteristic lack of lymphocytic infiltrate in this chronic retroviral encephalitis and suggests that increased microglial ICAM-1 expression may play a role in the pathogenesis of MoMuLV (ts-1)-mediated neurodegeneration.


Correction to: Low-chloride- versus high-chloride-containing hypertonic solution for the treatment of subarachnoid hemorrhage-related complications: The ACETatE (A low ChloriE hyperTonic solution for brain Edema) randomized trial.
[This corrects the article DOI: 10.1186/s40560-020-00449-0.].


A redox system for brain targeted estrogen delivery causes chronic body weight decrease in rats.
The effects of 2 redox based carriers for brain directed delivery of estradiol (CDS-E2) and ethinyl estradiol (CDS-EE) on body weight were examined in rats. A single dose of CDS-E2 (3 mg/kg) decreased weight gain in castrate rats for at least 24 days. The dose response of weight gain and LH suppression were compared 12 days and 12 to 25 after CDS-E2 and CDS-EE, respectively, in ovariectomized (OVX) rats. Weight decrease was detected at a lower dose and was significant for longer after drug treatment than LH decrease. Both compounds were more potent than equimolar estradiol or estradiol valerate in reducing weight gain. Intact rats also showed decreased weight gain but were less sensitive to CDS-E2 compared to OVX rats. The effects appeared to be estrogen specific as carrier-linked testosterone had no effect on weight. The mechanisms of sustained and potent drug effects on weight are being explored.


Polymorphisms of the beta2 -adrenoceptor (ADRB2) gene and essential hypertension: the ECTIM and PEGASE studies.
The beta2-adrenoceptor (ADRB2) plays a pivotal role in signalling in relation to hypertension and obesity. Polymorphisms of the ADRB2 gene have been shown to be potentially related to essential hypertension and other non-cardiovascular disease phenotypes. We investigated whether genetic variation of the ADRB2 gene might be related to essential hypertension or myocardial infarction (MI). Four ADRB2 gene polymorphisms C19R (T-47C), T-20C, G16R (G+46A), Q27E (C+79G) were investigated in two studies: PEGASE, a study of moderate to severe hypertension (707 cases) conducted in France, and ECTIM, a case-control study of MI (1178 cases, 1187 controls) conducted in France, Northern Ireland and Scotland. Genotyping was performed using allele-specific oligonucleotides. The ADRB2 polymorphisms T-20C and Q27E were found to be completely concordant, generating the haplotypes [T-20-Q27] and [C-20-E27]. Three main haplotypes accounted for 94% of all haplotypes: [R19-G16-E27] (39%), [C19-R16-Q27] (35%) and [C19-G16-Q27] (20%). Haplotype frequencies were not significantly different between countries. Allele and genotype frequencies did not differ significantly between cases with essential hypertension or MI and control subjects. There was no association of the polymorphisms with early onset hypertension, blood pressure level, coronary artery stenosis or any other phenotype measured in these study populations. In the ECTIM Study, our calculation revealed that we could have detected an odds ratio (OR) for MI of 1.3 with 80% power at a 5% type I error probability, the corresponding value for the PEGASE Study being an OR of 1.6 for hypertension. From our present analysis we conclude that the ADRB2 gene polymorphisms studied do not contribute in any important way to the risk of essential hypertension or MI in subjects of European ancestry.


Novel monomolecular derivatives of the anti-HIV-1 G-quadruplex-forming Hotoda's aptamer containing inversion of polarity sites.
Here we report on the design, preparation and investigation of four analogues of the anti-HIV G-quadruplex-forming Hotoda's aptamer, based on an unprecedented linear topology. In these derivatives, four TGGGAGT tracts have been joined together by exploiting 3'-3' and 5'-5' inversion of polarity sites formed by canonical phosphodiester bonds or a glycerol-based linker. Circular dichroism data suggest that all oligodeoxynucleotides fold in monomolecular G-quadruplex structures characterized by a parallel strand orientation and three side loops connecting 3'- or 5'-ends. The derivative bearing two lipophilic groups, namely HT353LGly, inhibited virus entry into the host cell, with anti-HIV-1 activity in the low nanomolar range; the other derivatives, albeit sharing the same base sequence and similar topology, were inactive. These results highlight that monomolecular Hotoda's aptamers with inversion of polarity sites represent a successful alternative strategy that merges the easiness of synthesis with the maintenance of remarkable activity. They also indicate that two lipophilic groups are necessary and sufficient for biological activity. Our data will inspire the design of further simplified derivatives with improved biophysical and antiviral properties.


Tetrahydroxy stilbene glycoside (TSG) antagonizes Aβ-induced hippocampal neuron injury by suppressing mitochondrial dysfunction via Nrf2-dependent HO-1 pathway.
Amyloid-beta peptide (Aβ) ranks as a pivotal cause of Alzheimer's disease (AD), a common devastating dementia form in elderly. Recent research corroborated the beneficial roles of tetrahydroxystilbene glucoside (TSG) in alleviating the learning and memory of AD model and aged mice. Unfortunately, the underlying mechanism remains poorly elucidated. Here, treatment with non-toxic TSG dose-dependently antagonized Aβ-induced cytotoxic death in hippocampal neuronal cells by increasing cell viability and decreasing cell apoptosis. Furthermore, TSG also alleviated cell oxidative stress injury in response to Aβ by attenuating lactate dehydrogenase (LDH) release, ROS levels and MDA leakage. Importantly, TSG administration abrogated Aβ-triggered loss of mitochondrial membrane potential (Δym), release of cytochrome c from mitochondrial to cytosol, increase in caspase-3 activity and pro-apoptotic protein Bax, and decrease in Bcl-2 protein, indicating that TSG could rescue mitochondrial dysfunctions of neuron cells under adverse Aβ condition. Subsequently, TSG induced the activation of Nrf2-HO-1 pathway. Importantly, blocking this pathway by si-Nrf2 transfection or HO-1 antagonist ZnPP notably muted the cytoprotective effects of TSG on neuronal cell cytotoxic injury upon Aβ stimulation. Together, this research substantiated a new mechanism that TSG protectively antagonized Aβ-induced hippocampal neuronal cell damage by restoring mitochondrial function via Nrf2-HO-1 pathway, implying a promising candidate against neurodegenerative diseases including AD.


The value of electrocardiography in patients with right ventricular endocardial pacemakers in the diagnosis of left ventricular hypertrophy: a correlative study of pace electrocardiography and left ventricular mass derived from M-mode echocardiography.
This study evaluated 51 patients with permanent apical right ventricular endocardial pacemakers. The assessment of the diagnostic value of pace electrocardiograms for the determination of left ventricular hypertrophy revealed specificity of 94% and sensitivity of 66%, applying a new parameter: RL1 + SV3 greater than or equal to 30 mm. The application of this criterion in the interpretation of pace electrocardiograms correlated well with values for the left ventricular mass derived from M-mode echocardiograms (r = 0.644, P less than 0.0001).


Hospital variation in responses to safety warnings about power morcellation in hysterectomy.
Safety warnings about power morcellation in 2014 considerably changed hysterectomy practice, especially for laparoscopic supracervical hysterectomy that typically requires morcellation to remove the corpus uteri while preserving the cervix. Hospitals might vary in how they respond to safety warnings and altered hysterectomy procedures to avoid use of power morcellation. However, there has been little data on how hospitals differ in their practice changes. This study aimed to examine whether hospitals varied in their use of laparoscopic supracervical hysterectomy after safety warnings about power morcellation and compare the risk of surgical complications at hospitals that had different response trajectories in use of laparoscopic supracervical hysterectomy. This was a retrospective analysis of data from the New York Statewide Planning and Research Cooperative System and the State Inpatient Databases and State Ambulatory Surgery and Services Databases from 14 other states. We identified women aged ≥18 years undergoing hysterectomy for benign indications in the hospital inpatient and outpatient settings from October 1, 2013 to September 30, 2015. We calculated a risk-adjusted utilization rate of laparoscopic supracervical hysterectomy for each hospital in each calendar quarter after accounting for patient clinical risk factors. Applying a growth mixture modeling approach, we identified distinct groups of hospitals that exhibited different trajectories of using laparoscopic supracervical hysterectomy over time. Within each trajectory group, we compared patients' risk of surgical complications in the prewarning (2013Q4-2014Q1), transition (2014Q2-2014Q4), and postwarning (2015Q1-2015Q3) period using multivariable regressions. Among 212,146 women undergoing benign hysterectomy at 511 hospitals, the use of laparoscopic supracervical hysterectomy decreased from 15.1% in 2013Q4 to 6.2% in 2015Q3. The use of laparoscopic supracervical hysterectomy at these 511 hospitals exhibited 4 distinct trajectory patterns: persistent low use (mean risk-adjusted utilization rate of laparoscopic supracervical hysterectomy changed from 2.8% in 2013Q4 to 0.6% in 2015Q3), decreased medium use (17.0% to 6.9%), decreased high use (51.4% to 24.2%), and rapid abandonment (30.5% to 0.8%). In the meantime, use of open abdominal hysterectomy increased by 2.1, 4.1, 7.8, and 11.8 percentage points between the prewarning and postwarning periods in these 4 trajectory groups, respectively. Compared with the prewarning period, the risk of major complications in the postwarning period decreased among patients at "persistent low use" hospitals (adjusted odds ratio, 0.88; 95% confidence interval, 0.81-0.94). In contrast, the risk of major complications increased among patients at "rapid abandonment" hospitals (adjusted odds ratio, 1.48; 95% confidence interval, 1.11-1.98), and the risk of minor complications increased among patients at "decreased high use" hospitals (adjusted odds ratio, 1.31; 95% confidence interval, 1.01-1.72). Hospitals varied in their use of laparoscopic supracervical hysterectomy after safety warnings about power morcellation. Complication risk increased at hospitals that shifted considerably toward open abdominal hysterectomy.


Biofuels from inulin-rich feedstocks: A comprehensive review.
Biofuels are considered as a pre-eminent alternate to fossil fuels to meet the demand of future energy supply in a sustainable manner. Conventionally, they are produced from lignocellulosic raw materials. Saccharification of lignocellulosic raw materials for bioethanol production is a cumbersome process as compared to inulin-rich feedstocks. Various inulin-rich feedstocks, viz. jerusalem artichoke, chicory, dahlia, asparagus sp., etc. has also been exploited for the production of biofuels, viz. bioethanol, acetone, butanol, etc. The ubiquitous availability of inulin-rich feedstocks and presence of large amount of inulin makes them a robust substrate for biofuels production. Different strategies, viz. separate hydrolysis and fermentation, simultaneous saccharification and fermentation and consolidated bioprocessing have been explored for the conversion of inulin-rich feedstocks into biofuels. These bioprocess strategies are simple and efficient. The present review elaborates the prospective of inulin-rich feedstocks for biofuels production. Bioprocess strategies exploited for the conversion of inulin-rich feedstocks have also been highlighted.


[The reliability of stereotaxy in diagnosis of intracranial space occupying lesions].
A total of 79 patients with a suspect space occupying intracranial lesion was operated stereotactically. After CT and MR image acquisition, entry and target coordinates were defined and biopsy trajectories were simulated preoperatively using a special planning software. Biopsy specimens allowed a satisfactory neuropathological examination and diagnostic result in 74 of 79 (93.7%) cases. In the remaining 5 of 79 (6.3%) patients, a glioses was diagnosed in three cases; in only two patients could no pathological process be proved. 10 of 79 (12.7%) patients showed an intraoperative bleeding out of the biopsy-cannula during serial stereotaxy, which was associated with a CT-detectable hematoma up to 7 mm in diameter in only three cases (3.8%). In no patient was the detection of intracerebral bleeding the reason for any neurological deficit. In summary, the high percentage of satisfactory neuropathological diagnoses, the low rate of stereotaxy-associated morbidity and the comfortable and safe use of computer and stereotactic devices justify this kind of minimally invasive diagnostic measure as a routine method.


The impact of COVID-19 on clinical outcomes in people undergoing neurosurgery: a systematic review and meta-analysis.
The coronavirus disease-2019 (COVID-19) pandemic has created a global crisis unique to the healthcare system around the world. It also had a profound impact on the management of neurosurgical patients. In our research, we investigated the effect of the COVID-19 pandemic on clinical outcomes in people undergoing neurosurgery, particularly vascular and oncological neurosurgery. Two investigators independently and systematically searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrail.Gov, and Web of Science to identify relevant studies respecting the criteria for inclusion and exclusion published up to June 30, 2022. The outcomes of our research included mortality rate, length of stay, modified Rankin Score, delay in care, Glasgow outcome scale, and major complications. The risk of bias was assessed using the Methodological Index for Non-randomized Studies (MINORS) checklist. Two investigators independently and systematically searched 1378 results from MEDLINE, EMBASE, Cochrane database, ClinicalTrail.Gov, and Web of Science and extracted the detailed data from 13 studies that met the review's eligibility criteria. Two articles reported on patients with intracerebral hemorrhages, five on patients with subarachnoid hemorrhages, four on patients undergoing surgery for neuro-oncology, and in two studies the patients' conditions were unspecified. A total of 26,831 patients were included in our research. The number who died was significantly increased in the COVID-19 pandemic group (OR 1.52, 95% CI 1.36-1.69, P < 0.001). No significant difference was found between the two groups in terms of length of stay (SMD - 0.88, 95% CI - 0.18-0.02, P = 0.111), but it differed between regions, according to our subgroup analysis. Compared to the pre-pandemic group, the number who died was significantly increased in the COVID-19 pandemic group. Meanwhile, the effect of the pandemic on clinical outcomes in people undergoing neurosurgery might differ in different regions, according to our subgroup analysis.


In silico evaluation of some commercially available terpenoids as spike glycoprotein of SARS-CoV-2 - inhibitors using molecular dynamic approach.
Coronavirus, an extremely contagious infections disease had a harmful effect on the world's population. It is a family of enveloped, single-stranded, positive-strand RNA viruses of Nidovirales order belongs to coroviridae family. At present, worldwide several lakhs of deaths and several billions of infections have been reported. Hence, the focus of the present study was to assess the SARS-CoV-2 enzyme inhibitory potential of certain commercially available terpenoids using Lamarckian genetic algorithm as a working principle and molecular dynamic studies was also performed. AutoDock 4.2 software was used to perform the computational docking calculations of terpenoids against SARS-CoV-2 enzyme. The terpenoids such as, Andrographolide, Betulonic acid, Erythrodiol, Friedelin, Mimuscopic acid, Moronic acid, and Retinol were selected based on the drug likeness properties. Remdesivir a well-known anti-viral drug was selected as the standard drug. Molecular dynamic simulation studies were carried using Desmond module of Schrodinger Suite. In the current study we observed that, Friedelin was exhibited excellent SARS-CoV-2 enzyme inhibitory potential than the standard drug and other selected terpenoids. Friedelin and the standard Remdesivir was undergone the molecular dynamic studies and Friedelin showed a good number of hydrogen bonds over the simulation time of 100 ns. Based on the in silico computational evaluation, it can be concluded that Friedelin could be worthwhile terpenoid against SARS-CoV-2 spike protein. A further study on Friedelin is required to develop a potential chemical entity against the management of COVID disease.Communicated by Ramaswamy H. Sarma.


Phase II study of docetaxel plus cisplatin as a second-line combined therapy in patients with advanced gastric carcinoma.
We conducted a pilot phase II study to evaluate the efficacy and safety of docetaxel and cisplatin as a combination second-line therapy for advanced gastric cancer. Between 2000 and 2003, 30 patients were enrolled into this study. Chemotherapy consisted of 60 mg/m2 of docetaxel followed by 60 mg/m2 of cisplatin. This regimen was repeated at least three times at 3-week intervals. The overall response rate was 26.7%. The median time to disease progression was 4.5 months. The median survival time was 13 months from the start of the first-line therapy and 6 months from the second-line therapy. With respect to toxicity, the major adverse effect was leukopenia, which reached grades 3-4 in 26.7%. Non-hematological toxicities were usually moderate, and no deaths were attributable to the adverse effects of the drugs. This combination therapy was effective as a second-line treatment for advanced gastric cancer with acceptable toxic side-effects.


The preparation and composition of HIDA.
The compositions of four "brands" of Tc-HIDA-dimethyl HIDA (Sorin Biomedica), diethyl HIDA (Solco), diethyl HIDA (The Radiochemical Centre), and para-butyl HIDA (Sorin Biomedica)--were investigated at varying times after their preparation from "instant kits", by using Sephadex gel column chromatography. Up to three peaks of activity were seen in each chromatogram, representing free reduced technetium, the monocomplex, and the biscomplex of Tc-HIDA respectively. In all cases the free reduced technetium component diminished to reach a plateau at less than 4% of total activity, by 1 h. In both "brands" of diethyl HIDA there was a transformation from the monocomplex to the biscomplex which took about one hour. The rate of this transformation was increased by raising the temperature of incubation, or by agitation during incubation. In the para-butyl HIDA this transformation was again noted, but was incomplete. In the dimethyl HIDA the monocomplex form was not seen. There was no noticeable disintegration of any Tc-HIDA complex up to 6 h. It is suggested that HIDA should be incubated for 1 h after preparation, before use, to achieve a stable composition.


ERPs and chronometry of face recognition: following-up Seeck et al. and George et al.
Seeck et al. found that event-related potentials (ERPs) evoked by repeated and non-repeated face photographs differ as early as 50-70ms post-onset. They thus suggested that faces are recognized at these latencies, in contrast with current opinions in ERP literature. However, the similar latencies obtained by George et al. for stimuli not perceived as faces suggest that Seeck et al.'s differences could index repetition rather than face recognition per se. To address this issue, we used matched faces of known and unknown persons. We found the earliest differences between the ERPs to these faces between 76 and 130 ms. These results, which are consistent with other data, suggest that the differentiation of faces takes approximately 100 ms of processing time in humans.


The effect of fucoidan from brown seaweed Sargassum wightii on WSSV resistance and immune activity in shrimp Penaeus monodon (Fab).
The polysaccharide-fucoidan was extracted from brown seaweed Sargassum wightii and characterized through FT-IR and (13)C &(1)H NMR analysis. The extracted fucoidan was supplemented with pellet diets at three different concentrations (0.1, 0.2 and 0.3%). The fucoidan supplemented diets were fed to Penaeus monodon for 45 days, then challenged with WSSV and the mortality percentage was recorded daily up to 21 days. During the challenge test, the control group showed 100% mortality within 10 days, but in the experimental groups, the mortality percentage (51-72% within 21 days) was decreased considerably (P < 0.05) with respect to the concentrations of fucoidan. The reduction in mortality percentage of experimental groups over control group was ranged from 50.81 to 68.06%. During challenge experiment, the immunological parameters such as THC, prophenoloxidase activity, respiratory burst activity, superoxide dismutase activity and phagocytic activity were measured before injection of WSSV (0 day) and after the injection of WSSV on 10th and 21st days, respectively. All the immunological parameters of experimental groups were significantly (P < 0.05) increased than control group. RT-PCR analysis confirmed the considerable reduction of WSSV DNA copy numbers with respect to the concentration of fucoidan. It was concluded that P. monodon fed with fucoidan of S. wightii supplemented diet had enhanced the innate immunity and increased resistance against WSSV infection.


Surgical treatment of male urinary incontinence.
Between January 1975 and December 1981 we treated 34 men with urinary incontinence with surgical intercavernous embedding of the bulboperineal urethra along its entire length. The etiology of incontinence was sphincteric damage following either prostatectomy (30 cases) or pelvic trauma (4 cases). All patients had complete neurologic integrity of the detrusor, 25 (75 per cent) had complete urinary continence, 5 (15 per cent) experienced considerable improvement, while 4 were failures. Followup ranged from 7 years to 4 months. Details of the surgical procedure are described, preoperative and postoperative management is emphasized and results are presented.


Haemostatic efficacy and inflammatory response of a novel beta-chitin patch in a cerebral small vessel injury model - A pilot study.
Rapid and efficacious haemostasis is paramount in neurosurgery. Assessing the efficacy and short- and long-term safety of haemostatic agents utilised within cerebral tissue is essential. This pilot study investigates the haemostatic efficacy and long-term safety of a novel beta-chitin patch against traditionally used agents, bipolar and Floseal, within cerebral tissue. Eighteen Merino sheep underwent standardised distal cortical vessel injury via temporal craniotomy. Sheep were randomised to receive 2 mls Floseal, 2 cm novel beta-chitin patch, or bipolar cautery to manage bleeding. All sheep underwent cerebral magnetic resonance imaging (MRI) at three months, before euthanasia and brain harvesting for histological assessment. Beta-chitin demonstrated a trend towards a faster mean time to haemostasis (TTH) compared to Floseal (223.3 ± 199 s v. 259.8 ± 186.4 s), albeit non-significant (p = 0.234). Radiologically, cerebrocortical necrosis (p = 0.842) and oedema (p = 0.368) were noted slightly more frequently in the beta-chitin group. Histologically, severe fibrotic (p = 0.017) and granulomatous changes at the craniotomy sites were only present in the beta-chitin group (p = 0.002). Neuronal degeneration was seen in all with Floseal, but beta-chitin showed a trend towards more severe reaction when present. Bipolar use predominantly showed an inflammatory cortical reaction with substantial microvascular proliferation, and Floseal showed worse severity and depth of subpial oedema, however no statistical significance was reached. All haemostats controlled bleeding, with beta-chitin demonstrating a non-inferior TTH compared to Floseal. However, it resulted in intense granulomatous and fibrotic changes, including degenerative neuronal reactions. More extensive studies are needed to assess these trends, to make further clinical inferences.


Predicting mortality after hospitalisation for COPD using electronic health records.
Few prognostic models exist for patients hospitalised with chronic obstructive pulmonary disease (COPD); most are based on small cohorts enroled by specialists in academic centres. Electronic health records (EHRs) provide an opportunity to develop more representative models, although they may not record some variables used in existing models. for this retrospective cohort study, using EHRs, we identified 17,973 patients with an unplanned hospitalisation for COPD (in any diagnostic position) in the Glasgow area between 2011 and 2017. Patients with known lung cancer were excluded. EHR were linked to prior admissions, community prescribing and laboratory data. A pragmatic, parsimonious multivariable model was developed to predict 90-day mortality. we identified 12 variables strongly related to prognosis, including age, sex, length of index hospitalisation stay, prior diagnosis of cancer (excluding lung cancer) or dementia, prescription of oxygen or digoxin, neutrophil/lymphocyte ratio and serum chloride, urea, creatinine and albumin. The model achieved excellent calibration with reasonable discrimination (area under the curve: 0.806; 95% CI: 0.792-0.820). A risk-score was developed and an electronic risk-calculator is provided. a small number of variables, including prescriptions and laboratory data obtained from routine EHRs predict 90-day mortality after a hospitalisation for COPD. The risk-calculator provided might prove useful for service-evaluation and audit, to guide clinical management and to risk-stratify and select patients to be invited to participate in clinical research.


Development and performance of a next generation sequencing (NGS) assay for monitoring of mixed chimerism.
The aim of this study was to evaluate the performance of a novel NGS-based assay to monitor mixed chimerism (MC) and compare its technical capacity to established techniques for chimerism analysis. Artificial and clinical samples with increasing amounts of patient DNA were compared using real-time PCR detection of indels and SNP, fragment analysis of short-tandem repeats (STR) and NGS analysis of indels. Real-time PCR displayed excellent sensitivity (>0,01%) but poor accuracy (>20 CV% at MC > 20%), while fragment analysis exhibited good accuracy (<5 CV% at MC > 20%) with limited sensitivity (>2,5%). In contrast, NGS chimerism demonstrated a sensitivity (>0,1%) equal to real-time PCR and an accuracy equal or better than STR analysis throughout an extensive range of mixed chimerism (0,1 - 100%). To evaluate performance of the separate techniques for chimerism determination, 75 retrospective patient monitoring samples (3-7 weeks post-HSCT) with low (<5%), intermediate (5-20%) or high mixed chimerism (>20%) were analyzed. The between run precision for the NGS assay varied from 0,72% (>20% MC) to 7,38% (MC < 5%). In conclusion, NGS displayed a combination of high sensitivity with good accuracy in both artificial and clinical chimerism samples.


An assessment of information needs and workflows for emergency service providers and caregivers of children with medical complexity.
The goal of Project Austin, an initiative to improve emergency care for rural children who are medically complex (CMC), is to provide an Emergency Information Form (EIF) to their parents/caregivers, to local Emergency Medical Services, and Emergency Departments. EIFs are standard forms recommended by the American Academy of Pediatrics that provide pre-planned rapid response instructions, including medical conditions, medications, and care recommendations, for emergency providers. Our objective is to describe the workflows and perceived utility of the provided emergency information forms (EIFs) in the acute medical management of CMC. We sampled from two key stakeholder groups in the acute management of CMC: four focus groups with emergency medical providers from rural and urban settings and eight key informant interviews with parents/caregivers enrolled in an emergency medical management program for CMC. Transcripts were thematically analyzed in NVivo© by two coders using a content analysis approach. The thematic codes were combined into a codebook and revised the themes present through combining relevant themes and developing of sub-themes until they reached consensus. All parents/caregivers interviewed were enrolled in Project Austin and had an EIF. Emergency medical providers and parents/caregivers supported the usage of EIFs for CMC. Parents/caregivers also felt EIFs made emergency medical providers more prepared for their child. Providers identified that EIFs helped provide individualized care, however they were not confident the data was current and so felt unsure they could rely on the recommendations on the EIF. EIFs are an easy way to engage parents, caregivers, and emergency medical providers about the specifics of a care for CMC during an emergency. Timely updates and electronic access to EIFs could improve their value for medical providers.


Salivary antibodies, amylase and protein from children with early childhood caries.
The aim of this study was to analyze the organic composition of saliva from children without dental caries and children with early childhood caries (ECC). Two groups of 20 children varying in age from 12 to 47 months were selected: Group I, caries-free children; Group II, children with early childhood caries (ECC). Samples of saliva were collected from each subject and submitted to immunological and biochemical assays. Measurements of total salivary IgA, IgG and IgM were performed by using nephelometric techniques, while total protein concentrations and amylase activity were determined by colorimetric techniques. Comparisons of values between groups were made by using U Mann-Whitney test ( p<0.05). Children with ECC presented significantly higher levels of total salivary IgA and IgG, while the mean values of amylase activity, total protein concentrations and total IgM were similar between the groups. In this study, the presence of ECC was associated with an increase in total salivary IgA.


Naturally occurring antibodies reactive with sperm proteins: apparent deficiency in AIDS sera.
A set of naturally occurring immunoglobulin M (IgM) antibodies that are reactive with a defined subset of proteins in the acrosomal cap region of human sperm has been identified. These antibodies are present in a broad spectrum of human sera from males and females, 1 day to 40 years of age, and are absent or markedly deficient in a large proportion of sera from individuals with the acquired immune deficiency syndrome (AIDS) or at risk for AIDS. The subset of proteins with which the IgM antibodies are reactive includes a factor (or factors) capable of inhibiting lectin-induced T-lymphocyte proliferation. The prevalence of the sperm-reactive IgM antibodies indicates that they are not elicited by sperm. Further, immunoreactivity of the sperm proteins resulting in depletion of specific circulating IgM antibodies, or other interactions between the sperm proteins and elements of the immune system, may be a factor in the suppressed state of the immune system in AIDS.


Optimizing exposure-based CBT for anxiety disorders via enhanced extinction: Design and methods of a multicentre randomized clinical trial.
Exposure-based psychological interventions currently represent the empirically best established first line form of cognitive-behavioural therapy for all types of anxiety disorders. Although shown to be highly effective in both randomized clinical and other studies, there are important deficits: (1) the core mechanisms of action are still under debate, (2) it is not known whether such treatments work equally well in all forms of anxiety disorders, including comorbid diagnoses like depression, (3) it is not known whether an intensified treatment with more frequent sessions in a shorter period of time provides better outcome than distributed sessions over longer time intervals. This paper reports the methods and design of a large-scale multicentre randomized clinical trial (RCT) involving up to 700 patients designed to answer these questions. Based on substantial advances in basic research we regard extinction as the putative core candidate model to explain the mechanism of action of exposure-based treatments. The RCT is flanked by four add-on projects that apply experimental neurophysiological and psychophysiological, (epi)genetic and ecological momentary assessment methods to examine extinction and its potential moderators. Beyond the focus on extinction we also involve stakeholders and routine psychotherapists in preparation for more effective dissemination into clinical practice.