Declining Transmission and Immunity to Malaria and Emerging Artemisinin Resistance in Thailand: A Longitudinal Study.
Reductions in malaria transmission decrease naturally acquired immunity, which may influence the emergence of Plasmodium falciparum artemisinin-resistant phenotypes and genotypes over time. Antibodies specific for P. falciparum antigens were determined in uncomplicated hyperparasitemic malaria patients over a 10-year period of declining malaria transmission and emerging artemisinin resistance in northwestern Thailand. We investigated the association between antibody levels and both parasite clearance time (PCt½) and artemisinin resistance-associated kelch13 genotypes over time. Immunity to P. falciparum declined prior to 2004, preceding the emergence of artemisinin resistance-associated genotypes and phenotypes (maximum mean change in antibody level per year: anti-MSP142 = -0.17; 95% confidence interval [CI] = -.31 to -.04; P = .01). In this period of declining immunity, and in the absence of kelch13 mutations, PCt½ increased. Between 2007 and 2011, levels of antibodies fluctuated, and higher antibody levels were associated with faster PCt½ (maximum yearly change in PCt½, in hours: EBA140rII = -0.39; 95% CI = -.61 to -.17; P < .001). Understanding the impact of changing transmission and immunity on the emergence of artemisinin resistance is important particularly as increased malaria control and elimination activities may enhance immunological conditions for the expansion of artemisinin-resistant P. falciparum.


Cystatin C is Better than Serum Creatinine for Estimating Glomerular Filtration Rate to Detect Osteopenia in Chronic Kidney Disease Patients.
Recent studies have reported that loss of bone mass is associated with renal function decline and increased fracture risks in chronic kidney disease (CKD) patients. The aim of this study was to investigate the best estimated glomerular filtration rate (eGFR) equation to detect osteopenia in CKD patients. This was a cross-sectional study, and 780 patients aged 50 years or above were classified into normal bone mass or osteopenia groups according to the -1.0 of T-scores at total hip and femur neck. Comparisons of area under the receiver operating characteristic (ROC) curves (AUC) were performed to investigate significant differences among three eGFR formulas: Modification of Diet in Renal Disease, CKD-Epidemiology Collaboration (EPI) creatinine, and CKD-EPI cystatin C (CKD-EPI-Cys). The mean age was 61 years old and the proportion of females was 37.3%. The total hip osteopenia group showed lower CKD-EPI-Cys eGFR levels (osteopenia group, 33.3±19.0 mL/min/1.73 m²; normal group, 48.1±26.2 mL/min/1.73 m², p<0.001). In multiple logistic regression analysis, CKD-EPI-Cys eGFR was independently associated with osteopenia at the total hip (per 1 mL/min/1.73 m² increase, odds ratio 0.98, 95% confidence interval 0.97-0.99, p=0.004) after adjusting for confounding variables. ROC curve analyses indicated that CKD-EPI-Cys shows the largest AUC for osteopenia at the total hip (AUC=0.678, all p<0.01) and the femur neck (AUC=0.665, all p<0.05). Decreased renal function assessed by CKD-EPI-Cys equation correlates with osteopenia better than creatinine-based methods in CKD patients, and the CKD-EPI-Cys formula might be a useful tool to assess skeletal-related event risks.


Efficacy and Safety of Berberine Alone for Several Metabolic Disorders: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Background: Metabolic activity is the basic life activity of organisms and the fundamental for maintaining body functions. With the improvement of living standards, the incidence of metabolic disorder is also increasing. At present, most of the clinical treatment strategies and meta-analysis for metabolic disorder uncover that combined medicines with berberine ameliorate several metabolic disorders. However, evidence to disclose the therapeutic effect of berberine treatment alone and the possible factors affecting the efficacy is limited. Therefore, we have formulated strict inclusion criteria and selected more reliable data for meta-analysis through more refined screening strategies to provide evidence and guidance for clinical decision-making and understand the effect of berberine treatment alone and the factors affecting its efficacy. Methods and results: Using meta-analysis of "Cochrane Handbook for Systematic Reviews of Interventions" as guidelines, we searched PubMed, GeenMedical, Cochrane library, and china national knowledge infrastructure (CNKI) for trials reporting clinical treatment data of berberine. Another 417 trials were included through other sources to increase confidence in results. Among the 1,660 related documents retrieved from the four databases, 18 eligible documents were selected for analysis. Given the differences in trial design and measurement units, we used the standardized mean difference (SMD) method to eliminate the differences and then summarize the data for analysis. The main factors are triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), homeostasis model assessment-insulin resistance (HOMA-IR), and fasting plasma glucose (FPG). Random-effect model analysis was performed: TG (SMD: 0.94; 95%CI: 0.49,1.38; p = 0.00), TC (SMD: 1.06; 95%CI: 0.64, 1.48; p = 0.00), LDL (SMD: 1.77; 95%CI: 1.11,2.44; p = 0.00), HDL (SMD: -1.59; 95%CI: -2.32, -0.85; p = 0.00), HOMA-IR (SMD: 1.25; 95%CI: 0.25,2.24; p = 0.01), and FPG (SMD: 0.65; 95%CI: 0.28,1.03; p = 0.00). This study aimed to conduct a systematic review and meta-analysis of the literature to evaluate the therapeutic effect of berberine singly on metabolic diseases. Conclusion: Berberine can improve obesity and hyperlipidemia by reducing TG, TC, and LDL and increasing HDL; reduce insulin resistance to improve type Ⅱ diabetes; and prevent diabetic encephalopathy.


Real-Time Embedded Eye Image Defocus Estimation for Iris Biometrics.
One of the main challenges faced by iris recognition systems is to be able to work with people in motion, where the sensor is at an increasing distance (more than 1 m) from the person. The ultimate goal is to make the system less and less intrusive and require less cooperation from the person. When this scenario is implemented using a single static sensor, it will be necessary for the sensor to have a wide field of view and for the system to process a large number of frames per second (fps). In such a scenario, many of the captured eye images will not have adequate quality (contrast or resolution). This paper describes the implementation in an MPSoC (multiprocessor system-on-chip) of an eye image detection system that integrates, in the programmable logic (PL) part, a functional block to evaluate the level of defocus blur of the captured images. In this way, the system will be able to discard images that do not have the required focus quality in the subsequent processing steps. The proposals were successfully designed using Vitis High Level Synthesis (VHLS) and integrated into an eye detection framework capable of processing over 57 fps working with a 16 Mpixel sensor. Using, for validation, an extended version of the CASIA-Iris-distance V4 database, the experimental evaluation shows that the proposed framework is able to successfully discard unfocused eye images. But what is more relevant is that, in a real implementation, this proposal allows discarding up to 97% of out-of-focus eye images, which will not have to be processed by the segmentation and normalised iris pattern extraction blocks.


Methanolic leaf extract of Gymnema sylvestre augments glucose uptake and ameliorates insulin resistance by upregulating glucose transporter-4, peroxisome proliferator-activated receptor-gamma, adiponectin, and leptin levels in vitro.
The present study was undertaken to evaluate the effect of methanolic leaf extract of Gymnema sylvestre (MLGS) on glucose transport (GLUT) and insulin resistance in vitro. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) and GLUT-4 expression were assessed in L6 myotubes for concluding the GLUT activity, and adiponectin and leptin expression was studied in 3T3 L1 murine adipocyte cell line to determine the effect of MLGS (250-750 μg/ml) on insulin resistance. The findings of the experiments have demonstrated a significant and dose-dependent increase in glucose uptake in all the tested concentrations of MLGS, further the glucose uptake activity of MLGS (750 μg/ml) was at par with rosiglitazone (50 μg/ml). Concomitantly, MLGS has shown enhanced GLUT-4 and PPAR-γ gene expressions in L6 myotubes. Furthermore, cycloheximide (CHX) had completely abolished the glucose uptake activity of MLGS when co-incubated, which further confirmed that glucose uptake activity of MLGS was linked to enhanced expression of GLUT-4 and PPAR-γ. In addition, in another experimental set, MLGS showed enhanced expression of adiponectin and leptin, thus confirms the ameliorative effect of MLGS on insulin resistance. These findings suggest that MLGS has an enhanced glucose uptake activity in L6 myotubes, and ameliorate the insulin resistance in 3T3 L1 murine adipocyte cell line in vitro.


Binding of an RNA trafficking response element to heterogeneous nuclear ribonucleoproteins A1 and A2.
Heterogeneous nuclear ribonucleoprotein (hnRNP) A2 binds a 21-nucleotide myelin basic protein mRNA response element, the A2RE, and A2RE-like sequences in other localized mRNAs, and is a trans-acting factor in oligodendrocyte cytoplasmic RNA trafficking. Recombinant human hnRNPs A1 and A2 were used in a biosensor to explore interactions with A2RE and the cognate oligodeoxyribonucleotide. Both proteins have a single site that bound oligonucleotides with markedly different sequences but did not bind in the presence of heparin. Both also possess a second, specific site that bound only A2RE and was unaffected by heparin. hnRNP A2 bound A2RE in the latter site with a K(d) near 50 nm, whereas the K(d) for hnRNP A1 was above 10 microm. UV cross-linking assays led to a similar conclusion. Mutant A2RE sequences, that in earlier qualitative studies appeared not to bind hnRNP A2 or support RNA trafficking in oligodendrocytes, had dissociation constants above 5 microm for this protein. The two concatenated RNA recognition motifs (RRMs), but not the individual RRMs, mimicked the binding behavior of hnRNP A2. These data highlight the specificity of the interaction of A2RE with these hnRNPs and suggest that the sequence-specific A2RE-binding site on hnRNP A2 is formed by both RRMs acting in cis.


Magnetic Resonance Imaging-Defined Prostate-Specific Antigen Density Significantly Improves the Risk Prediction for Clinically Significant Prostate Cancer on Biopsy.
To evaluate the predictive value of magnetic resonance imaging (MRI)-defined prostate-specific antigen (PSA) density and MRI interpretation for the detection of clinically significant prostate cancer (PCa). We retrospectively reviewed our institutional database of men who received prostate MRI prior to biopsy at our institution between September 2014 and December 2016, excluding those on active surveillance (n = 372). Logistic regression models to predict clinically significant PCa on biopsy were developed using (1) MRI-defined PSA density; (2) PSA alone; and (3) the Prostate Cancer Prevention Trial (PCPT) risk calculator. Additional logistic regression models were then generated by combining the previous clinical variables with MRI interpretation (ie, prostate imaging reporting and data system [PI-RADS] classification): (1) MRI-defined PSA density + MRI interpretation; (2) PSA + MRI interpretation; and (3) PCPT + MRI interpretation. Receiving operator characteristic curves for each of the 6 models were generated, and the area under the curves (AUC) were compared. MRI-defined PSA density (AUCPSAD = 0.77) significantly outperformed the PSA (AUCPSA = 0.66, P < .01) and PCPT models (AUCPCPT = 0.70, P < .01). When combined with MRI interpretation (ie, PI-RADS classification), the MRI-defined PSA density model (AUCPSAD + MRI = 0.80) significantly outperformed the PSA (AUCPSA + MRI = 0.75, P < .01) and PCPT models (AUCPCPT + MRI = 0.76, P = .01). In addition to the PI-RADS classification, prebiopsy multiparametric magnetic resonance imaging also provides an accurate assessment of prostate volume. By utilizing this additional data to determine MRI-defined PSA density, we find that risk discrimination for clinically significant PCa on biopsy can be significantly improved.


CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia.
Taxanes are a leading cause of severe and often permanent chemotherapy-induced alopecia. As the underlying pathobiology of taxane chemotherapy-induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell-rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy-induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy-induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell-protective therapy in taxane-based oncotherapy, and provides preclinical proof-of-principle in a healthy human (mini-) organ that G1 arrest therapy can limit taxane-induced tissue damage.


Medical cannabis and stigma: A qualitative study with patients living with chronic pain.
To explore the ways in which stigma is experienced, and what strategies are used to manage stigma among patients using medical cannabis to ease suffering from chronic pain. Various jurisdictions have legalised medical cannabis in recent decades. Despite increasing prevalence and more liberal attitudes towards medical cannabis, it is possible that patients who use medical cannabis experience stigma. A phenomenological qualitative study. Fifteen patients living with chronic pain and licensed by the Israeli Ministry of Health to use medical cannabis to treat pain symptoms for at least 1 year participated in semi-structured interviews. Transcribed data were analysed using thematic analysis to identify themes related to stigma. The manuscript is in correspondence to SRQR EQUATOR checklist. Expressions of stigma were more related to 'felt' than 'enacted' stigma. Stigma related to decisions to delay onset of medical cannabis treatment and the ways in which participants managed medical cannabis use during their everyday lives. Participants dissociated themselves from recreational cannabis users, by presenting themselves as responsible normative individuals and engaging in a form of normalisation known as 'normification', emphasising their own discrete and controlled medical cannabis use and cannabis' benefits. Patients experienced 'felt' stigma which had consequences for their self-presentations and medical cannabis use. This suggests that medical cannabis is not normalised in Israel and interventions may be needed to handle stigma related to medical cannabis. The findings emphasise the effects of 'felt' stigma on patients. Aiming to increase the effectiveness of medical cannabis treatment and reducing harms, we suggest that particular focus should be placed on managing stigma at the intrapersonal level. In addition, there may be a need to address stigma at the societal level including social interactions with friends, family and medical personnel.


A study on oliguric standard in the elderly.
Water deprivation test was done in 44 healthy elderly persons, 26 were male, and 18 were female. They were deprived of the intake of water for 25 hours. The results showed that the maximal renal concentration function both in the elderly males and females was 887 +/- 91 mmol/L and 888 +/- 127 mmol/L respectively. The renal excretion of waste products in 24 hours both in the elderly males and females was 815 + 170 mmol/d and 620 + 132 mmol/d respectively. On the basis of point estimation, the minimal essential urine volume per day in the elderly males and females was 926 ml/d and 708 ml/d respectively, if the daily urine volume of the elderly is less than this level, then, the metabolic products generated per day can not be excreted by the kidney, and it would result in disorders of internal environment. Therefore, the oliguric standard in elderly males and females must be less than 926 ml/d and 708 ml per day respectively.


Narcolepsy: new understanding of irresistible sleep.
Recently, low levels of a newly identified neuropeptide, hypocretin 1, were described in the cerebrospinal fluid of patients with narcolepsy. This neurochemical finding furthers our understanding of this enigmatic sleep disorder typically characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Narcolepsy appears to be fundamentally related to abnormally regulated rapid eye movement sleep. The diagnosis of this disorder remains challenging because of multiple other conditions that can cause daytime sleepiness and the difficulties in recognizing cataplexy based on patient report. The role of hypocretins in narcolepsy is unclear but intriguing because the cell bodies are restricted to the lateral hypothalamus, a brain region long associated with sleep regulation, with neuronal widespread projections to areas including the locus ceruleus, ventral tegmental area, amygdala, and dorsal raphe. Hypocretins potentially modulate the activity of monoamines and acetylcholine, and therefore their absence leads to the multiple symptoms of narcolepsy. This article reviews the current understanding of the diagnosis and treatment of narcolepsy and discusses the possible implications of the hypocretin discovery.


A Complementary Isothermal Amplification Method to the U.S. EPA Quantitative Polymerase Chain Reaction Approach for the Detection of Enterococci in Environmental Waters.
We report a novel molecular assay, based on helicase-dependent amplification (HDA), for the detection of enterococci as markers for fecal pollution in water. This isothermal assay targets the same Enterococcus 23S rRNA gene region as the existing quantitative polymerase chain reaction (qPCR) assays of U.S. Environmental Protection Agency Methods 1611 and 1609 but can be entirely performed on a simple heating block. The developed Enterococcus HDA assay successfully discriminated 15 enterococcal from 15 non-enterococcal reference strains and reliably detected 48 environmental isolates of enterococci. The limit of detection was 25 target copies per reaction, only 3 times higher than that of qPCR. The applicability of the assay was tested on 30 environmental water sample DNA extracts, simulating a gradient of fecal pollution. Despite the isothermal nature of the reaction, the HDA results were consistent with those of the qPCR reference. Given this performance, we conclude that the developed Enterococcus HDA assay has great potential as a qualitative molecular screening method for resource-limited settings when combined with compatible up- and downstream processes. This amplification strategy can pave the way for developing a new generation of rapid, low-cost, and field-deployable molecular diagnostic tools for water quality monitoring.


Sli15(INCENP) dephosphorylation prevents mitotic checkpoint reengagement due to loss of tension at anaphase onset.
The mitotic checkpoint, also known as the spindle assembly checkpoint, delays anaphase onset until all chromosomes have reached bipolar tension on the mitotic spindle [1-3]. Once this is achieved, the protease separase is activated to cleave the chromosomal cohesin complex, thereby triggering anaphase. Cohesin cleavage releases tension between sister chromatids, but why the mitotic checkpoint now remains silent is poorly understood. Here, using budding yeast as a model, we show that loss of sister chromatid cohesion at anaphase onset would engage the mitotic checkpoint if this was not prevented by concomitant separase-dependent activation of the Cdc14 phosphatase. Cdc14, in turn, inactivates the mitotic checkpoint by dephosphorylating Sli15(INCENP), a subunit of the conserved Aurora B kinase complex that forms part of the proposed chromosomal tension sensor. Dephosphorylation-dependent relocation of Sli15(INCENP) from centromeres to the central spindle during anaphase is seen in organisms from yeast to human [4-8]. Our results suggest that Sli15(INCENP) dephosphorylation is part of an evolutionarily conserved mechanism that prevents the mitotic checkpoint from reengaging when tension between sister chromatids is lost at anaphase onset.


Incorporating FLT3 inhibitors into acute myeloid leukemia treatment regimens.
FMS-Like-Tyrosine kinase-3 (FLT3) mutations are found in about 30% of cases of acute myeloid leukemia and confer an increased relapse rate and reduced overall survival. Targeting of this tyrosine kinase by direction inhibition is the focus of both preclinical and clinical research in AML. Several molecules in clinical development inhibit FLT3 with varying degrees of specificity. Preclinical models suggest that these compounds enhance the cytotoxicity of conventional chemotherapeutics against FLT3 mutant leukemia cells. The pharmacodynamic interactions between FLT3 inhibitors and chemotherapy appear to be sequence dependent. When the FLT3 inhibitor is used prior to chemotherapy, antagonism is displayed, while if FLT3 inhibition is instituted after to exposure to chemotherapy, synergistic cytotoxicity is seen. The combination of FLT3 inhibitors with chemotherapy is also complicated by potential pharmacokinetic obstacles, such as plasma protein binding and p-glycoprotein interactions. Ongoing and future studies are aimed at incorporating FLT3 inhibitors into conventional induction and consolidation therapy specifically for patients with FLT3 mutant AML.


[Importance of chemical mediators for the pathogenesis and treatment of hemicrania].
The vascular mechanism of migraine attacks--intracranial vasoconstriction during the prodromal stage and passive vasodilatation of extracranial arteries during the painful phase--has been confirmed by modern methods. In addition, number of humoral factors--plasmakinin, serotonin, histamine--intervene in the chain of events that culminates in migraine headache. In addition to these three humoral mediators, the part played by tyramine in migraine of alimentary origin, the precipitating effect of oestrogen decrease in menstrual migraine and the hypothetical role of prostaglandins and prolactin are discussed. The multifactorial mechanism of migraine accounts for the very variable profiles of effective anti-migraine drugs.


BCG vaccine-induced lupus vulgaris.
A case of intradermal BCG vaccination was complicated by a lupus-like tuberculosis cutis progressive for over 30 years. The patient had been vaccinated twice with BCG in the affected site. A review of other BCG vaccine-induced cases of lupus vulgaris indicates that the incidence of this complication is markedly increased following multiple BCG vaccinations, but is rare following a single BCG vaccination. In our patient a skin biopsy specimen was characteristic for lupus vulgaris. Acid-fast stains from the tissue and cultures from the affected site were negative. The patient was successfully treated with rifampin.


Investigation of Pertussis Cases in a Texas County, 2008-2012.
Within the past 25 years, there has been a dramatic increase in the incidence of pertussis cases in the United States. As such, this investigation reports on the high-risk groups and describes risk factors of pertussis cases in a large Texas county. This study was a cross-sectional analysis of data collected by health department employees using the Texas Department of State Health Service's Pertussis Case Track Record, which is the standard investigation form for collecting vital information on pertussis cases. We extracted and analyzed county-level data for a 5-year period (2008-2012). The study population at risk included all current residents in this county, and cases included all who were clinically diagnosed as having confirmed or probable pertussis cases that were reported to the health department according to the Centers for Disease Control and Prevention case definition. The vaccination status of a case was defined as fully vaccinated, partially vaccinated, or not vaccinated. A total of 198 probable and confirmed pertussis cases were included in this analysis. Most of the cases were infants younger than 1 year old (n = 107). The largest category of cases was not vaccinated and of the rest, 32.8% were partially vaccinated, 17.2% had unknown vaccination status, and 13.1% were fully vaccinated. Only 48 (24.2%) sources of exposure were identified and they included fathers (14.6%), sisters (14.6%), brothers (14.6%), other children (14.6%), and mothers (12.5%). Many sources of exposure (n = 26, 54.1%) were unaware of their vaccination history. Hispanics accounted for 84.5% of cases in the younger than 1 year old group and 88.9% of cases were in the 1 to 2 years old group. With respect to race/ethnicity and vaccination status of the cases, 39.46% of Hispanics, 32% of whites, and 50% of blacks were reported to be unvaccinated. Increasing pertussis vaccination coverage among children, as well as providing booster shots to adults with special attention on the Hispanic population, may prove to be an effective strategy for health departments.


Clinical performance and caries inhibition of resin-modified glass ionomer cement and amalgam restorations.
The authors clinically examined two restorative materials to evaluate their effectiveness in Class II restorations in primary molars and their ability to inhibit recurrent caries. Forty subjects, each in need of two Class II restorations in primary molars, took part in this study. Each patient received one Class II restoration of resin-modified glass ionomer cement and one of amalgam. The authors evaluated the restorations at six-month, one-year, two-year and three-year recall appointments. On exfoliation, teeth with experimental restorations were retrieved and microscopically examined for inhibition of demineralization at restoration margins. The results of the clinical evaluation demonstrated no significant differences between the resin-modified glass ionomer cement restorations and the amalgam restorations (P < .05). Polarized light microscopic examination of the returned teeth that were restored as a part of this study indicated that the resin-modified glass ionomer cement had significantly less enamel demineralization at restoration margins than did amalgam (P < .0001). The resin-modified glass ionomer cement functioned clinically as well as amalgam for Class II restorations in primary molars. However, the resin-modified glass ionomer exhibited significantly less enamel demineralization at restoration margins than did amalgam. Resin-modified glass ionomer cement restorative material functions well for Class II restorations in primary molars and exhibits less recurrent caries at restoration margins than does amalgam.


Pulmonary embolism with endovascular thrombolysis for thrombosed hemodialysis arteriovenous access .
Acute thrombosis of hemodialysis (HD) arteriovenous access is an urgent problem for HD patients and is commonly managed by endovascular thrombolysis. Pulmonary embolism (PE) is a recognized complication of HD access thrombosis and thrombolysis but the risk and outcomes are unclear. This study aims to determine the incidence, predictors, and outcomes of PE after endovascular thrombolysis of HD arteriovenous access in patients presenting with acute thrombosis. A single-center retrospective study was performed for all adult chronic kidney disease patients undergoing arteriovenous access thrombolysis between January 1, 2012, and December 31, 2014. Investigation for PE with CT pulmonary angiography or ventilation/perfusion scintigraphy (V/Q scan) was performed as clinically directed by the managing clinicians. In cases diagnosed with PE, the pulmonary embolism severity index (PESI) was calculated. A total of 48 (median age 68) patients underwent 74 thrombolysis procedures. Thrombolysis techniques were divided into pharmacological (44.6%), mechanical (17.6%), or pharmacomechanical (37.8%). Clinical success was achieved in 56/74 (75.7%) of procedures. Five episodes of thrombolysis for access thrombosis (6.8%) were associated with clinically symptomatic PE. The PESI score ranged from 51 to 127. All patients with PE were managed with 3 - 6 months of anticoagulation and recovered clinically. There were no statistically significant differences in baseline characteristics, methods of thrombolysis, or clot burden in patients that developed a PE. There is a clinically significant risk of symptomatic PE after arteriovenous access thrombolysis for access thrombosis in HD patients. .


Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice.
Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe-/- mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe-/- mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe-/- mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD.


Cytogenetics of human oocytes, zygotes, and embryos after in vitro fertilization.
Chromosome errors, inherited or arising de novo during gametogenesis and transmitted at fertilization to the conceptus, may be a major cause of embryonic mortality. The in vitro fertilization and embryo transfer (IVF/ET) procedure provides extra material--oocytes, zygotes, and embryos--to investigate the contribution of chromosomal abnormality to implantation failure. This paper reviews the results of cytogenetic studies on such material. Estimates from a total of 1120 oocytes from 11 studies give an overall proportion of chromosomal abnormality of 35%. Single and multiple nullisomies and disomies are found, involving nonrandom chromosome gain or loss. Hypohaploid complements are more frequent than hyperhaploid complements. The higher rate of chromosome loss of hypohaploid karyotypes was found to be largely artifactual. The estimated overall frequency of aneuploidy is 13%. In embryos the level of chromosomal abnormality is 23%-40%. Errors of fertilization are responsible for a substantial number of triploid embryos, many of which develop into mosaics. Factors extrinsic to the conceptus, such as infertility, advanced maternal age, and ovarian hyperstimulation, may increase the level of chromosomal abnormality. More refined methods for accurately recognizing and selecting chromosomally normal embryos for transfer are needed to improve the success rate of this reproductive technology.


Using the payback framework to evaluate the outcomes of pilot projects supported by the Georgia Clinical and Translational Science Alliance.
The Clinical and Translational Science Awards (CTSA) program of the National Center for Advancing Translational Sciences (NCATS) seeks to improve population health by accelerating the translation of scientific discoveries in the laboratory and clinic into practices for the community. CTSAs achieve this goal, in part, through their pilot project programs that fund promising early career investigators and innovative early-stage research projects across the translational research spectrum. However, there have been few reports on individual pilot projects and their impacts on the investigators who receive them and no studies on the long-term impact and outcomes of pilot projects. The Georgia CTSA funded 183 pilot projects from 2007 to 2015. We used a structured evaluation framework, the payback framework, to document the outcomes of 16 purposefully-selected pilot projects supported by the Georgia CTSA. We used a case study approach including bibliometric analyses of publications associated with the selected projects, document review, and investigator interviews. These pilot projects had positive impact based on outcomes in five "payback categories": (1) knowledge; (2) research targeting, capacity building, and absorption; (3) policy and product development; (4) health benefits; and (5) broader economic benefits. Results could inform our understanding of the diversity and breadth of outcomes resulting from Georgia CTSA-supported research and provide a framework for evaluating long-term pilot project outcomes across CTSAs.


Genesis of a New Generation of Telepractitioners: The COVID-19 Pandemic and Pediatric Speech-Language Pathology Services.
Purpose In March 2020, the COVID-19 pandemic caused a worldwide shift from in-person care to synchronous videoconferencing or telehealth. Many barriers to remote service delivery were eliminated, effectively creating a new generation of telepractitioners. This study chronicles changes in speech-language pathology clinicians' use and perceptions of telehealth with pediatric populations. Method The Telehealth Services: Pediatric Provider Survey was created in multiple steps and then distributed broadly through social media and professional community sites. Respondents were speech-language pathologists and speech-language pathology assistants in a variety of employment settings from across the country and abroad who were serving primarily pediatric clients (n = 269). Survey questions sought to capture changes in speech-language pathology clinicians' experiences with and perceptions of telehealth before, during, and predictions after the COVID-19 pandemic. Analyses identified factors that influenced the use of telehealth services before and after March 2020 (COVID-19). Results Survey results documented the dramatic increase in telehealth use from before March 2020 to October 2020. The reasons pediatric speech-language pathology clinicians used telehealth during the pandemic were mostly a result of employer mandates or lowering infection risk for both client and clinician; however, over time, pediatric speech-language pathology clinicians increased their telehealth proficiency and discovered the benefits of telehealth. Conclusion The adoption of telehealth and the rapid improvement in proficiency is a testament to the resiliency of providers and has long-term effects on the use of telehealth into the future. Supplemental Material https://doi.org/10.23641/asha.15183690.


Serial measurement of circulating immune complexes in myocardial infarction.
To study the changes in the quantity of circulating immune complexes in myocardial infarction two serial investigations were performed in 45 and 63 patients, respectively. For the detection of circulating immune complexes in the first series, two methods, a complement consumption test and a Clq-solubility test were used. In the second series, a polyethylene glycol (PEG)-precipitation assay was added to these methods. The incidence of circulating immune complexes was studied on the first, third, seventh, 14th, and 21st day. On the first day the complexes were detected in 59% of the patients. Their occurrence increased in the further samplings to 77%, but from the seventh day their concentration decreased and on the 21st day they were detected in 63%. Three types of changes in the level of circulating immune complexes could be shown. In type I immune complexes were detected in the first days after the onset of the infarction, then, after a gradual decrease, the results became negative. In type II immune complexes appeared in the second to third week and their quantity did not alter during the entire observation period. In type III the circulating immune complexes could be detected throughout the whole period of the study. These changes in their concentration were frequently associated with the clinical course of the disease.


Mutations in FIE, a WD polycomb group gene, allow endosperm development without fertilization.
A fundamental problem in biology is to understand how fertilization initiates reproductive development. Higher plant reproduction is unique because two fertilization events are required for sexual reproduction. First, a sperm must fuse with the egg to form an embryo. A second sperm must then fuse with the adjacent central cell nucleus that replicates to form an endosperm, which is the support tissue required for embryo and/or seedling development. Here, we report cloning of the Arabidopsis FERTILIZATION-INDEPENDENT ENDOSPERM (FIE) gene. The FIE protein is a homolog of the WD motif-containing Polycomb proteins from Drosophila and mammals. These proteins function as repressors of homeotic genes. A female gametophyte with a loss-of-function allele of fie undergoes replication of the central cell nucleus and initiates endosperm development without fertilization. These results suggest that the FIE Polycomb protein functions to suppress a critical aspect of early plant reproduction, namely, endosperm development, until fertilization occurs.


Hyperbaric oxygen therapy for radiation cystitis in patients with prostate cancer: a long-term follow-up study.
To assess the safety and efficacy of hyperbaric oxygen (HBO) for treating radiation cystitis a long-term follow-up study was done in patients with prostate cancer, the second most common malignancy in Japan. A total of 38 patients at an age of 68 ± 8 years with radiation cystitis following irradiation of prostate cancer were treated with HBO at 2 absolute atmospheric pressures for 90 min daily. The average number of HBO treatment sessions in each patient was 62 ± 12. The follow-up period was 11.6 ± 3.7 years. We evaluated objective and subjective symptoms periodically with special reference to the initiation timing of HBO therapy. High efficacy ratios of objective and subjective findings were obtained at 2 and 4 (79-95%) years, respectively. After 7 years' follow-up, these ratios decreased slightly (72-83%) but still remained stable thereafter (75-88%) without any serious accident. Comparison of late morbidity scores before and 11.6 years after HBO therapy showed significant improvement (p < 0.0005). Twenty-eight patients (74%) obtained nonrecurrent outcome. They had received 18% lower (p < 0.001) radiation dosage than recurrent patients. The interval between the onset of hematuria and start of HBO treatment in nonrecurrent patients was 30% shorter (p < 0.001) than that of recurrent patients. We elucidated the long-term safety and beneficial effect of HBO therapy of radiation cystitis in patients with prostate cancer. Early application of HBO treatment after the onset of hematuria appears to produce favorable outcome.


Immunohistochemical localization in the rat brain of the precursor for thyrotropin-releasing hormone.
A rabbit antiserum to a peptide sequence present in the precursor for thyrotropin-releasing hormone (proTRH), deduced from cloned amphibian-skin complementary DNA, was raised by immunization with the synthetic decapeptide Cys-Lys-Arg-Gln-His-Pro-Gly-Lys-Arg-Cys (proTRH-SH). Immunohistochemical studies on rat brain tissue showed staining of neuronal perikarya in the parvicellular division of the paraventricular nucleus of the hypothalamus and the raphe complex of the medulla, identical to that already described for thyrotropin-releasing hormone (TRH). Immunostaining was abolished by preincubation with proTRH-SH (10(-6)M) but not TRH (10(-5)M). Both TRH precursor and TRH were located in neurons of the paraventricular nucleus. However, in contrast to the findings for TRH, no staining was observed in axon terminals of the median eminence. These results suggest that a TRH precursor analogous to that reported in frog skin is present in the rat brain and that TRH in the mammalian central nervous system is a product of ribosomal biosynthesis.


Idiotypy of human anti-Candida albicans antibodies: recurrence, presence of a cross-reactive autoanti-idiotypic-like activity, and role in the induction of specific in vitro antibody response.
Rabbit anti-idiotypic antibodies (L12) were raised against human anti-mannan of Candida albicans (CA) antibodies isolated from the serum of a normal donor. The absorbed anti-idiotypic antiserum bound to donor anti-CA mannan antibodies but not to control immunoglobulins. Binding was inhibited by CA mannan but not by other polysaccharide antigens. L12 was shown to cross-react with anti-CA mannan-isolated antibodies or with anti-CA antibody-containing sera from individuals unrelated to the donor. IgG fraction isolated from the donor serum was repeatedly absorbed on CA mannan Sepharose to remove anti-mannan antibodies. This IgG fraction (named autoanti-idiotypic fraction) blocked, in a dose-dependent fashion, the binding of rabbit anti-idiotype to donor anti-CA mannan antibodies. Moreover, this CP-depleted IgG fraction cross-reacted with public idiotypic determinants of unrelated anti-CA mannan antibodies. Finally, L12 induced sensitized lymphocytes to produce anti-CA mannan antibodies in vitro in the absence of antigen.


Possible association between thyroid autoimmunity and Menière's disease.
Various aetiopathological mechanisms have been postulated to be at the root of Menière's disease (MD), and some data suggest that there may be also an underlying autoimmune factor. In fact, Menière patients manifest certain characteristics that are typical of autoimmune involvement association of particular human leucocyte antigen haplotypes, the presence of antibodies against internal ear antigens. In this study, we evaluated the association between thyroid autoimmunity and MD in a non-selected group of patients. We recruited 50 consecutive MD patients and two groups as controls: group A, 82 healthy volunteers; and group B, 50 subjects suffering from acute unilateral peripheral vestibulopathy. All subjects were submitted to instrumental assessment of cochlear-vestibular function and analysis of thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, anti-TSH receptor antibody (TR-Ab), anti-thyroperoxidase antibody (TPO-Ab) and anti-thyroglobulin antibody (Tg-Ab) in the blood. The prevalence of autoimmune thyroiditis in group B [6/50 (12%); 66.7% TPO-Ab and 33.3% Tg-Ab] was superimposable with the healthy controls [6/82 (7%); 66.7% TPO-Ab and 33.3% Tg-Ab]. In contrast, 38% of the MD patients (P = 0.0001 versus group A and group B) had significant autoantibody levels (68.4% TPO-Ab; 15.8% TPO-Ab + TR-Ab; 10.5% Tg-Ab; 5.2% TPO-Ab + Tg-Ab). Furthermore, 14% of the MD patients were hyperthyroid under l-thyroxine therapy, while no dysfunction was seen in the control groups. Overall, our data demonstrate a significant association between MD and thyroid autoimmunity, which suggests that an autoimmune factor is involved in the aetiopathogenesis of this disease. These findings suggest that it should be useful to submit MD patients to multi-disciplinary clinical investigation.


Lyn but not Fyn kinase controls IgG-mediated systemic anaphylaxis.
Anaphylaxis is a rapid, life-threatening hypersensitivity reaction. Until recently, it was mainly attributed to histamine released by mast cells activated by allergen crosslinking (XL) of FcεRI-bound allergen-specific IgE. However, recent reports established that anaphylaxis could also be triggered by basophil, macrophage, and neutrophil secretion of platelet-activating factor subsequent to FcγR stimulation by IgG/Ag complexes. We have investigated the contribution of Fyn and Lyn tyrosine kinases to FcγRIIb and FcγRIII signaling in the context of IgG-mediated passive systemic anaphylaxis (PSA). We found that mast cell IgG XL induced Fyn, Lyn, Akt, Erk, p38, and JNK phosphorylation. Additionally, IgG XL of mast cells, basophils, and macrophages resulted in Fyn- and Lyn-regulated mediator release in vitro. FcγR-mediated activation was enhanced in Lyn-deficient (knockout [KO]) cells, but decreased in Fyn KO cells, compared with wild-type cells. More importantly, Lyn KO mice displayed significantly exacerbated PSA features whereas no change was observed for Fyn KO mice, compared with wild-type littermates. Intriguingly, we establish that mast cells account for most serum histamine in IgG-induced PSA. Taken together, our findings establish pivotal roles for Fyn and Lyn in the regulation of PSA and highlight their unsuspected functions in IgG-mediated pathologies.


Promoter hypermethylation of progesterone receptor isoform B (PR-B) in adenomyosis and its rectification by a histone deacetylase inhibitor and a demethylation agent.
Adenomyosis is a fairly common gynecologic disease with unknown pathogenesis. We sought to investigate as to whether the promoter of progesterone receptor isoform B (PR-B) is hypermethylated in adenomyosis and to investigate the treatment of ectopic endometrial stromal cells with trichostatin A (TSA), a histone deacetylase inhibitor (HDI), and 5-aza-2-deoxycytidine (ADC), a demethylation agent, on PR-B gene and protein expression, and on cell viability. Ectopic endometrial tissue specimens were obtained from 9 women with adenomyosis whereas control endometrial tissue samples were obtained from 8 women with surgically diagnosed benign ovarian cysts but without any clinical history of endometriosis/adenomyosis/ myoma. Endometrial stromal cells were isolated, purified, cultured, and analyzed by methylation-specific polymerase chain reaction (PCR), real-time reverse transcriptase PCR (RT-PCR), and Western blot analysis, cell viability assays, and fluorescence-activated cell sorting. We found that none of the normal endometrial stromal cells had PR-B promoter methylation. In contrast, 2 out of 3 ectopic endometrial stromall cells had PR-B hypermethylation (P < .05). The treatment with both TSA and ADC elevated PR-B gene and protein expression in ectopic, but not in normal, endometrial stromal cells. Both TSA and ADC treatment dose-dependently reduced cell viability of ectopic endometrial stromal cells. Trichostatin A and ADC treatment also suppressed the cell cycle progression in ectopic endometrial stromal cells. Thus, this study provides the first piece of evidence that adenomyosis has epigenetic aberration and may also be an epigenetic disease amenable to rectification by pharmacological means. This perspective may shed new light onto the pathogenesis of adenomyosis and lead to novel ways to treat the disease.


A Gut Reaction to SIV and SHIV Infection: Lower Dysregulation of Mucosal T Cells during Acute Infection Is Associated with Greater Viral Suppression during cART.
Selection of a pre-clinical non-human primate (NHP) model is essential when evaluating therapeutic vaccine and treatment strategies for HIV. SIV and SHIV-infected NHPs exhibit a range of viral burdens, pathologies, and responses to combinatorial antiretroviral therapy (cART) regimens and the choice of the NHP model for AIDS could influence outcomes in studies investigating interventions. Previously, in rhesus macaques (RMs) we showed that maintenance of mucosal Th17/Treg homeostasis during SIV infection correlated with a better virological response to cART. Here, in RMs we compared viral kinetics and dysregulation of gut homeostasis, defined by T cell subset disruption, during highly pathogenic SIVΔB670 compared to SHIV-1157ipd3N4 infection. SHIV infection resulted in lower acute viremia and less disruption to gut CD4 T-cell homeostasis. Additionally, 24/24 SHIV-infected versus 10/19 SIV-infected animals had sustained viral suppression <100 copies/mL of plasma after 5 months of cART. Significantly, the more profound viral suppression during cART in a subset of SIV and all SHIV-infected RMs corresponded with less gut immune dysregulation during acute SIV/SHIV infection, defined by maintenance of the Th17/Treg ratio. These results highlight significant differences in viral control during cART and gut dysregulation in NHP AIDS models and suggest that selection of a model may impact the evaluation of candidate therapeutic interventions for HIV treatment and cure strategies.


Apoptosis in different compartments of antrum and corpus mucosa in chronic Helicobacter pylori gastritis. An 18-year follow-up study.
The association of apoptosis was analysed in three different compartments (foveolar cells--FC, proliferating zone--PZ and glandular part--GP) of antrum and corpus mucosa specimens with development of atrophy and the extent of apoptosis as depending on grade of chronic inflammation, activity of gastritis and Helicobacter pylori colonization at two time points of an 18-year follow-up in an adult population from Saaremaa, Estonia, with a high prevalence of H. pylori infection were compared. A total of 68 persons (31 men, 37 women; median age, 39 years in 1979) from a primary sample of 304 subjects, endoscoped in 1979 and reinvestigated by endoscopy and biopsy in 1997, were included in the study. The state of the gastric mucosa and the presence of H. pylori in the antrum and corpus mucosa were assessed in accordance with the Sydney system. The dynamics of apoptotic index (AI) between two time points in 1979 and 1997 was evaluated in antrum biopsies of 49 persons and in corpus biopsies of 64 persons. Apoptosis was measured using terminal deoxyuridine nucleotide nick end labelling (TUNEL) histochemistry. The antrum as well as the corpus of 2/68 persons were H. pylori negative at both time points. Atrophy developed in 9/68 persons in the antrum and in 23/68 in the corpus. In PZ and GP of the corpus mucosa as well as in GP of the antrum mucosa, AI decreased significantly during 18 years compared with initial values (P < 0.05), which was not associated with development of atrophy. In all compartments of the antrum and corpus mucosa, studied at the initial and end points of observation, AI did not reveal a difference in persons with and without development of atrophy (P > 0.05). In the samples of 1979 the highest independent effect on the value of AI in the FC compartment for the antrum was exerted by grade of activity of gastritis (P = 0.01) and in GP by degree of chronic inflammation (P = 0.03), while in the samples of 1997 the highest effect was exerted by grade of H. pylori colonization (P = 0.02 and 0.03 in FC and GP, respectively). For the corpus mucosa AI was most strongly affected also by grade of activity of gastritis in FC compartment (P = 0.02) and by degree of chronic inflammation in PZ (P = 0.04), but not by grade of H. pylori colonization. AI was not associated with development of atrophy, but was largely dependent on grade of activity of gastritis and degree of chronic inflammation; in the antrum mucosa AI depended also on grade of H. pylori colonization.


Similar meltwater contributions to glacial sea level changes from Antarctic and northern ice sheets.
The period between 75,000 and 20,000 years ago was characterized by high variability in climate and sea level. Southern Ocean records of ice-rafted debris suggest a significant contribution to the sea level changes from melt water of Antarctic origin, in addition to likely contributions from northern ice sheets, but the relative volumes of melt water from northern and southern sources have yet to be established. Here we simulate the first-order impact of a range of relative meltwater releases from the two polar regions on the distribution of marine oxygen isotopes, using an intermediate complexity model. By comparing our simulations with oxygen isotope data from sediment cores, we infer that the contributions from Antarctica and the northern ice sheets to the documented sea level rises between 65,000 and 35,000 years ago were approximately equal, each accounting for a rise of about 15 m. The reductions in Antarctic ice volume implied by our analysis are comparable to that inferred previously for the Antarctic contribution to meltwater pulse 1A (refs 16, 17), which occurred about 14,200 years ago, during the last deglaciation.


TSUnet-CC: Temporal Spectrogram Unet embedding Cross Channel-wise attention mechanism for MDD identification.
Automatic detection of major depressive disorder (MDD) with multiple-channel electroencephalography (EEG) signals is of great significance for treatment of the mental diseases. In a U-net network, clear EEG signals are fed to obtain temporal feature tensor through encoder and decoder networks with several convolution operations. Moreover, the clear EEG signals can be converted into multi-scale spectrogram to obtain the rich saliency information and then the spectrogram feature tensor can be extracted by another symmetrical U-net. The temporal and spectrogram feature tensors can provide more comprehensive information, but may also contain redundant information, which may affect the detection of MDD. To deal with such issue, this paper proposed a novel Temporal Spectrogram Unet (TSUnet-CC), which embeds the cross channel-wise attention mechanism for multiple-channel EEGbased MDD identification. We make three novel contributions: 1) multi-scale saliency-encoded spectrogram using Fourierbased approach to capture rich saliency information under different scales, 2) TSUnet network using a symmetrical twostream U-net architecture that learns multiple temporal and spectrogram feature tensors in time and frequency domains, and 3) cross channel-wise block enabling the larger weights of key feature channels that contain MDD information. The leaveone-subject-out experiments show that our proposed TSUnetCC gains high performance with a classification accuracy up to 98.55% and 99.22% in eyes closed and eyes open datasets, which outperformed some state-of-the-art methods and revealed its clinical potential.


Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer.
Despite improvements in prevention and management of colorectal cancer (CRC), uncontrolled tumor growth with metastatic spread to distant organs remains an important clinical concern. Genetic deletion of CD39, the dominant vascular and immune cell ectonucleotidase, has been shown to delay tumor growth and blunt angiogenesis in mouse models of melanoma, lung and colonic malignancy. Here, we tested the influence of CD39 on CRC tumor progression and metastasis by investigating orthotopic transplanted and metastatic cancer models in wild-type BALB/c, human CD39 transgenic and CD39 deficient mice. We also investigated CD39 and P2 receptor expression patterns in human CRC biopsies. Murine CD39 was expressed by endothelium, stromal and mononuclear cells infiltrating the experimental MC-26 tumors. In the primary CRC model, volumes of tumors in the subserosa of the colon and/or rectum did not differ amongst the treatment groups at day 10, albeit these tumors rarely metastasized to the liver. In the dissemination model, MC-26 cell line-derived hepatic metastases grew significantly faster in CD39 over-expressing transgenics, when compared to CD39 deficient mice. Murine P2Y2 was significantly elevated at both mRNA and protein levels, within the larger liver metastases obtained from CD39 transgenic mice where changes in P2X7 levels were also noted. In clinical samples, lower levels of CD39 mRNA in malignant CRC tissues appeared associated with longer duration of survival and could be linked to less invasive tumors. The modulatory effects of CD39 on tumor dissemination and differential levels of CD39, P2Y2 and P2X7 expression in tumors suggest involvement of purinergic signalling in these processes. Our studies also suggest potential roles for purinergic-based therapies in clinical CRC.


Inhibition of endoplasmic reticulum stress is involved in the neuroprotective effect of aFGF in neonatal hypoxic-ischaemic brain injury.
Acidic fibroblast growth factor (aFGF) has been shown to exert neuroprotective effects in experimental models and human patients. In this study, we investigated whether aFGF intranasal-treatment protected against neonatal hypoxic-ischaemic brain injury and evaluated the role of endoplasmic reticulum stress. The Rice-Vannucci model of neonatal hypoxic-ischaemic brain injury was used in 7-day-old rats, which were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia. Intranasal aFGF or vehicle was administered immediately after hypoxic-ischaemic injury (100 ng/g) and then twice a day for 1 week to evaluate the long-term effects. Here we reported that intranasal-treatment with aFGF significantly reduced hypoxic-ischaemic brain infarct volumes and the protective effects were at least partially via inhibiting endoplasmic reticulum stress. In addition, aFGF exerted long-term neuroprotective effects against brain atrophy and neuron loss at 7-day after injury. Our data indicate that therapeutic strategies targeting endoplasmic reticulum stress may be promising to the treatment of neonatal hypoxic-ischaemic brain injury.


Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration.
The carrier molecule that transports dopamine (DA) into dopamine neurons by an electrogenic, Na(+)- and Cl(-)-transport-coupled mechanism is known as the dopamine transporter (DAT). This uptake system is exclusively expressed in DA neurons with significantly higher levels of DAT expression in cells of the substantia nigra pars compacta than those of the ventral tegmental area and arcuate hypothalamic neurons. The expression density of DAT strongly correlates with the extent of DA cell loss in Parkinson's disease (PD). There are also DAT gene polymorphisms associated with PD. These data suggest a role of the DAT in the pathogenesis of PD. Though selective for its respective neurotransmitter, the DAT can also transport synthetic/natural analogues of the transmitter. Should such compounds interact with vital intracellular structures, their penetration into the neuron might have significant consequences. This sequence of toxic events could indeed demonstrated for the synthetic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces selective degeneration of DA neurons characteristic of PD. Dopaminergic toxicity of its active metabolite 1-methyl-4-pyridinium (MPP(+)) is mediated by the DAT through accumulation into DA neurons, where it inhibits mitochondrial complex I activity. Various endogenous and exogenous heterocyclic molecules, which are structurally related to MPTP/MPP(+), such as isoquinolines and beta-carbolines, have been reported to exhibit similar toxic properties on DA cells, which are conferred by their uptake by the DAT. Taken together, there is large body of evidence from morphological, molecular biological and toxicological studies indicating that the DAT might be responsible for the selectivity of DA cell death in PD.


Integrating nanomedicine and imaging.
Biomedical engineering and its associated disciplines play a pivotal role in improving our understanding and management of disease. Motivated by past accomplishments, such as the clinical implementation of coronary stents, pacemakers or recent developments in antibody therapies, disease management now enters a new era in which precision imaging and nanotechnology-enabled therapeutics are maturing to clinical translation. Preclinical molecular imaging increasingly focuses on specific components of the immune system that drive disease progression and complications, allowing the in vivo study of potential therapeutic targets. The first multicentre trials highlight the potential of clinical multimodality imaging for more efficient drug development. In this perspective, the role of integrating engineering, nanotechnology, molecular imaging and immunology to yield precision medicine is discussed.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.


A population-based twin study of the genetic and environmental relationship of major depression, regular tobacco use and nicotine dependence.
Numerous epidemiological studies have reported a positive association between major depression (MD) and regular tobacco use (RU) or nicotine dependence (ND). However, few have used a genetically informative design to assess whether these traits share a common genetic and/or environmental liability. We assessed MD, RU and ND in same-sex twins from the population-based Swedish Twin Registry. In males, we examined both cigarette use and snus (smokeless tobacco) use. We used structural equation modeling to examine the relationship between MD, RU, and ND given RU. The results suggest modest correlations between MD and RU, and between MD and ND. In males, the liability shared between MD and RU is solely genetic for both cigarettes and snus, while MD and ND share both genetic and unique environmental influences. The continuation to ND given RU differed considerably between cigarette and snus users. In females, both MD-RU and MD-ND relationships are partially attributable to genetic and unique environmental correlations. The relationship among MD, RU and ND is at least partially attributable to shared genetic and environmental risk factors. The genetic and environmental correlations between traits are modest. The nature of the shared liability differs by sex, and in males, by the type of tobacco product used. Differences between previous reports and results presented in the current study are suggestive of population differences in how MD and tobacco use inter-relate.


Effect of maternal prenatal food supplementation, gestational weight gain, and breast-feeding on infant growth during the first 24 months of life in rural Vietnam.
Growth faltering among children during the first five years of life is a common problem among low and middle-income countries. The purpose of this study was to determine the effect of a nutrient-rich, food-based supplement given to Vietnamese rural women prior to and/or during pregnancy on the growth of their infants during first 24 months of life and to identify maternal and newborn factors associated with the infant's growth. This prospective cohort study included 236 infants born to mothers who had received nutritional advice or a food supplement from pre-conception to term or from mid-gestation to term as part of a prior randomized controlled trial. Infant anthropometry and feeding information were monitored monthly and the infant weight for age Z-score (WAZ), length for age Z-score (LAZ), and weight for length Z-score (WLZ) were assessed at 6, 12, 18, and 24 months of age using mixed-effects regression modeling. Compared to the non-supplemented mothers, infants born to mothers receiving food supplementation from mid-gestation to term had significantly higher WLZ only at 18 months (p = 0.03) and did not differ in other outcomes. Supplementation from pre-conception to term did not affect infant growth at any time point during the first 24 months. In the entire study cohort, maternal height and gestational weight gain were positively associated with the infant's WAZ and LAZ from 6 to 24 months of age. Programs designed to improve gestational weight gain among women performing demanding physical work throughout a reproductive cycle may improve postnatal infant growth. Trial registration: Registered Clinical Trials.Gov: NCT01235767.


Inhibition of acute inflammation in the periphery by central action of salicylates.
Understanding of the antiinflammatory actions of nonsteroidal drugs is incomplete, but these actions are believed to occur in the periphery, without any contribution from the central nervous system. Recent research on the antipyretic antiinflammatory neuropeptide alpha-melanocyte-stimulating hormone indicates that it can act centrally to inhibit peripheral inflammation; this raises the possibility that other agents, such as nonsteroidal antiinflammatory drugs, may have similar activity. In the present research both lysine acetylsalicylate and sodium salicylate inhibited edema, induced in the mouse ear by topical application of picryl chloride, when injected into the lateral cerebral ventricle. This inhibitory activity on a measure of acute inflammation was not due to escape of the drugs into the periphery, because systemic injection of doses that were effective centrally did not affect inflammation. In contrast, central administration of a dose of indomethacin that was antiinflammatory when given intraperitoneally did not inhibit peripheral inflammation. Thus indomethacin apparently lacks the central antiinflammatory action of the salicylates. This observation, plus our inability to demonstrate either an antiinflammatory effect of intracerebroventricular dexamethasone, a prostaglandin inhibitor, or a pro-inflammatory influence of prostaglandin E2, suggests that prostaglandins are not important to central modulation of inflammation. The results indicate that, in addition to having central influences on fever and pain, salicylates can act within the brain to inhibit acute inflammation in the periphery.


Statistical Analysis of Absenteeism in a University Hospital Center between 2007 and 2019.
To estimate the evolution of compressible absenteeism in a hospital center and identify the professional and sociodemographic factors that influence absenteeism. All hospital center employees have been included over a period of twelve consecutive years (2007 to 2019). Compressible absences and occupational and sociodemographic factors were analyzed using Occupational Health data. Since the distribution of the data did not follow a normal distribution, the number of days of absence was presented as a median (interquartile range (IQR): 1st quartile-3rd quartile), and comparisons were made using non-parametric tests followed by a negative binomial model with zero inflation (ZINB). A total of 16,413 employees were included, for a total of 2,828,599 days of absence, of which 2,081,553 were compressible absences (73.6% of total absences). Overall, 42% of employees have at least one absence per year. Absent employees had a median of 15 (IQR 5-53) days of absence per year, with an increase of a factor of 1.9 (CI95 1.8-2.1) between 2007 and 2019 (p < 0.001). Paramedical staff were most at risk of absence (p < 0.001 vs. all other occupational categories). Between 2007 and 2019, the number of days of absence was multiplied by 2.4 (CI95 1.8-3.1) for administrative staff, 2.1 (CI95 1.9-2.3) for tenured, 1.7 (CI95 1.5-2.0) for those living more than 12 km from the workplace, 1.8 (CI95 1.6-2.0) among women, 2.1 (CI95 1.8-2.6) among those over 50 years of age, 2.4 (CI95 1.8-3.0) among "separated" workers, and 2.0 (CI95 1.8-2.2) among those with at least one child. Paramedical personnel are most at risk of absenteeism. Meanwhile, absenteeism is increasing steadily, and overall, the increase is major for administrative staff. The profile of an employee at risk of absenteeism is a titular employee, living at distance from work, probably female, over 50 years old, separated, and with children. Identifying professionals at risk of absenteeism is essential to propose adapted and personalized preventive measures.


An appetite for meat? Disentangling the influence of animal resemblance and familiarity.
Consumers in modern society are often less exposed to meat that resembles the animal, and thus are less familiar with it, making it difficult to disentangle the influence of these two inputs (familiarity vs. animal resemblance) on meat appetite. Across three studies, we sought to systematically disentangle the impact of familiarity and animal resemblance on meat appetite using inductive (Study 1) and experimental (Studies 2a-2b) approaches. In Study 1 (N = 229) we separated familiarity and animal resemblance into orthogonal dimensions using 28 meat products. Participants provided free associations and rated the products on familiarity, animal resemblance, and appetitive appeal. In Studies 2a and 2b (N = 514) we experimentally examined the independent contributions of familiarity and animal resemblance, using stimuli normed in Study 1. We hypothesized that animal resemblance has its most pronounced influence on appetite when meat products are unfamiliar. Participants' free associations and ratings of the products were in line with this conditional hypothesis (Study1), as were the experimental manipulations of familiarity and animal resemblance (Studies 2a-2b), confirmed by a mini meta-analysis. In all three studies, familiarity had a pervasive influence on appetite. These findings suggest that product familiarity can attenuate the psychological impact that animal reminders have on appetite. Thus, interventions aimed at eliciting animal associations with meat should consider the familiarity of the products employed.


Hold it! The influence of lingering rewards on choice diversification and persistence.
Learning to choose adaptively when faced with uncertain and variable outcomes is a central challenge for decision makers. This study examines repeated choice in dynamic probability learning tasks in which outcome probabilities changed either as a function of the choices participants made or independently of those choices. This presence/absence of sequential choice-outcome dependencies was implemented by manipulating a single task aspect between conditions: the retention/withdrawal of reward across individual choice trials. The study addresses how people adapt to these learning environments and to what extent they engage in 2 choice strategies often contrasted as paradigmatic examples of striking violation of versus nominal adherence to rational choice: diversification and persistent probability maximizing, respectively. Results show that decisions approached adaptive choice diversification and persistence when sufficient feedback was provided on the dynamic rules of the probabilistic environments. The findings of divergent behavior in the 2 environments indicate that diversified choices represented a response to the reward retention manipulation rather than to the mere variability of outcome probabilities. Choice in both environments was well accounted for by the generalized matching law, and computational modeling-based strategy analyses indicated that adaptive choice arose mainly from reliance on reinforcement learning strategies. (PsycINFO Database Record


Effect of physical activity intervention based on a pedometer on physical activity level and anthropometric measures after childbirth: a randomized controlled trial.
Pregnancy and childbirth are associated with weight gain in women, and retention of weight gained during pregnancy can lead to obesity in later life. Diet and physical activity are factors that can influence the loss of retained pregnancy weight after birth. Exercise guidelines exist for pregnancy, but recommendations for exercise after childbirth are virtually nonexistent. The aim of this study was to evaluate the effect of physical activity intervention based on pedometer on physical activity level and anthropometric measures of women after childbirth. We conducted a randomized controlled trial in which 66 women who had given birth 6 weeks to 6 months prior were randomly assigned to receive either a 12 week tailored program encouraging increased walking using a pedometer (intervention group, n = 32) or routine postpartum care (control group, n = 34). During the 12-week study period, each woman in the intervention group wore a pedometer and recorded her daily step count. The women were advised to increase their steps by 500 per week until they achieved the first target of 5000 steps per day and then continued to increase it to minimum of 10,000 steps per day by the end of 12th week. Assessed outcomes included anthropometric measures, physical activity level, and energy expenditure per week. Data were analyzed using the paired t-test, independent t-test, Mann-Whitney, chi-square, Wilcoxon, covariance analysis, and the general linear model repeated measures procedure as appropriate. After 12 weeks, women in the intervention group had significantly increased their physical activity and energy expenditure per week (4394 vs. 1651 calorie, p < 0.001). Significant differences between-group in weight (P = 0.001), Body Mass Index (P = 0.001), waist circumference (P = 0.001), hip circumference (P = 0.032) and waist-hip ratio (P = 0.02) were presented after the intervention. The intervention group significantly increased their mean daily step count over the study period (from 3249 before, to 9960 after the intervention, p < 0.001). A physical activity intervention based on pedometer is an effective means to increase physical activity; reducing retention of weight gained during pregnancy and can improve anthropometric measures in postpartum women. ISRCTN: IRCT201105026362N1.


Hospitalized osteoporotic vertebral fracture increases the risk of stroke: a population-based cohort study.
The association between osteoporosis and cardiovascular diseases has been demonstrated. Higher cardiovascular risk has also been correlated with vertebral fractures. However, the association between osteoporotic vertebral fracture and the possibly higher risk of stroke remains uncertain. This study aimed to evaluate the incidence, risk, and type of stroke in patients with osteoporotic vertebral fracture. Patients with osteoporotic vertebral fracture were identified (n = 380) and 10 age- and sex-matched controls per case (comparison group, n = 3795) were chosen from a nationwide representative cohort of 999,997 people from 1998 to 2005. Both groups were followed-up for stroke events for 3 years, matched by propensity scores with adjustments for covariates such as comorbidities (ie, hypertension, diabetes, arrhythmia, or coronary heart diseases) and exposure to medications (ie, aspirin, lipid lowering drug, or nitrates), and assessed by Kaplan-Meier and Cox regression analyses. The incidence rate of stroke in the osteoporotic vertebral fracture group (37.5 per 1000 person-years; 95% confidence interval [CI], 27.5-51.2) was significantly higher than in the comparison group (14.0 per 1000 person-years; 95% CI, 12.0-16.4, p < 0.001). Stroke was more likely to occur in the osteoporotic vertebral fracture patients than in the normal controls (crude hazard ratio [HR] 2.68, 95% CI 1.89-3.79, p < 0.001; adjusted HR 2.71, 95% CI 1.90-3.86, p < 0.001). In conclusion, patients with osteoporotic vertebral fracture have a higher risk of stroke (ie, both ischemic and hemorrhagic) and require stroke prevention strategies.


Outcomes Associated With Resuming Direct Oral Anticoagulant Therapy Following Admission for a Gastrointestinal Bleed.
Although direct oral anticoagulants (DOACs) carry a lower bleeding risk compared with warfarin, gastrointestinal bleeds (GIB) are a known complication. There are limited data observing outcomes associated with resuming DOACs following a GIB. The purpose of this study was to evaluate practice patterns and clinical outcomes of patients admitted with an index GIB while receiving DOAC therapy. This retrospective, single-system study included adult patients receiving DOAC therapy prior to admission and hospitalized with an index GIB between January 1, 2013, and October 31, 2018. Patient exclusion criteria were a history of immune thrombocytopenia purpura or inflammatory bowel disease; discharge to hospice; leaving against medical advice; or death during hospitalization. The primary objective was 90-day readmission for a recurrent GIB. There were 57 patients included for analysis; 37 patients had DOAC therapy held >7 days, 18 patients resumed DOAC therapy within 7 days, and 2 patients switched to warfarin. The majority of patients received rivaroxaban (59.6%) prior to admission for atrial fibrillation (71.9%), were admitted with a major GIB (66.7%), and required a blood transfusion (61.4%). The rates of recurrent GIB were 2.5% (n = 1) and 5.6% (n = 1) for those who had their DOAC held and resumed, respectively (P = 0.83). Mortality within 12 months of discharge occurred in 4 patients (10.8%) who had their DOAC held and 4 patients (22.2%) who resumed DOAC therapy (P = 0.28). Resuming anticoagulation within 7 days of admission for an index GIB was not associated with a recurrent GIB within 90 days of discharge.


Pathological gambling from dopamine agonist and deep brain stimulation of the nucleus tegmenti pedunculopontine.
In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.


The first 1000 cultured species of the human gastrointestinal microbiota.
The microorganisms that inhabit the human gastrointestinal tract comprise a complex ecosystem with functions that significantly contribute to our systemic metabolism and have an impact on health and disease. In line with its importance, the human gastrointestinal microbiota has been extensively studied. Despite the fact that a significant part of the intestinal microorganisms has not yet been cultured, presently over 1000 different microbial species that can reside in the human gastrointestinal tract have been identified. This review provides a systematic overview and detailed references of the total of 1057 intestinal species of Eukarya (92), Archaea (8) and Bacteria (957), based on the phylogenetic framework of their small subunit ribosomal RNA gene sequences. Moreover, it unifies knowledge about the prevalence, abundance, stability, physiology, genetics and the association with human health of these gastrointestinal microorganisms, which is currently scattered over a vast amount of literature published in the last 150 years. This detailed physiological and genetic information is expected to be instrumental in advancing our knowledge of the gastrointestinal microbiota. Moreover, it opens avenues for future comparative and functional metagenomic and other high-throughput approaches that need a systematic and physiological basis to have an impact.


[Lay knowledge about stroke].
The significance of the risk factors and the rapid diagnosis of encephalic vascular disease (EVD) is the reason for this research, where the authors decided to register and analyze the non-medical people knowledge about these risk factors and the symptoms of this group of disease. For this purpose a questionnaire with questions about these facts was applied to 500 voluntaries without pre-selection, 72.6% of them with ages between 16-35 years old, and the answers analyzed by statistical methods. The authors recognized that the risk factors has a good level of knowledge by this population (87.8 % for hypertension, 76.8 % for smoking, 70.8 % for obesity, 68.7 % for sedentary persons, 66.7 % to stress, 66.3 % to alcohol ingest, 60.7 % for fat diet, 59 % to illicit drugs) while the signs and symptoms of EVD has a minor level of knowing and correction: lost sensitivity 70.3 %, headache 64.2 %, twisted mouth 59.5 %, lost or altered speech 57.5 %, dizziness 56 %, syncope 51.7 %, amaurosis 50.3 %, disequilibrium 45 %, deafness 31.2 %, weakness 41.1 %, nervousness 20.7%, chest pain 20.2 %, fatigue 15.3 % and tinnitus 18.9 %. According this data, the authors suggest that the correction or prevention of risk factors as well the precocious medical attention by the recognition of symptoms of EVD must be the object of public health programs.


[Desmoid tumor sensitive to tamoxifen].
Desmoid tumors are the second leading cause of mortality in patients with familial adenomatous polyposis who have undergone proctocolemy. Both medical and surgical treatment of these non-metastasizing but locally aggressive tumors are difficult. A 20-years-old woman consulted 6 years after coloproctectomy for familial adenomatous polyposis. A mesenteric desmoid tumor was found. Resection was not possible. The tumor progressed under sulindac treatment and subocclusion developed. The patient was given tamoxifen, 20 mg/d and the size of the tumor began to regress within a few days together with pain and signs of compression. The treatment was well tolerated for 4.5 years and tumor volume has remained unchanged after a 20-fold reduction compared with the size prior to treatment. The patient has remained symptom-free. In this critical clinical situation, tamoxifen provided rapid and prolonged effect and was well tolerated.


Critical pathways for patients with acute chest pain at low risk.
Critical pathways are predefined protocols that define the crucial steps in evaluating and treating a clinical problem to improve quality of patient care, reduce variability and enhance efficiency. Critical pathways have proliferated for a variety of diagnoses, including evaluation of patients with chest pain, a common and costly complaint. This review will outline the development, implementation, and assessment of critical pathways using as a paradigm our experience with a pathway for patients presenting to the Emergency Department with acute chest pain who are at low risk of myocardial ischemia. The goals of the pathway were to expedite evaluation of low-risk patients and reduce admission rates among these patients and in the cohort overall without compromising outcomes. The pathway was developed by a multidisciplinary team in an iterative process that considered published literature, as well as the experience and consensus of local opinion leaders. Patients at least 30 years old presenting to the Emergency Department of an urban teaching hospital who were pain-free without heart failure or ischemic changes on EKG, but who were not considered appropriate for discharge by the treating physician, were eligible for the critical pathway. The pathway involved one set of creatine kinase-MB enzymes drawn at least 4 hours after pain, a 6 hour observation period after the last episode of pain and exercise testing. Outcomes during evaluation and admission rates were assessed. Clinical outcomes at 7 days and 6 months after evaluation and patient satisfaction at 7 days were also measured. Of 1363 patient visits, 145 (10.6%) were triaged by the pathway: 131 (90.3%) were discharged, 14 (9.7%) were admitted. The overall admission rate decreased from 63% (2898/4595) to 60% (819/1363) [p < 0.05] in comparison to a cohort studied prior to pathway implementation. Pathway patients reported low rates of subsequent cardiac procedures. No deaths or myocardial infarctions were recorded. At 7 days, only 2 respondents (2%) reported going to an Emergency Department since their evaluation. Most respondents (83%) rated their care as very good or excellent. Critical pathways designed to enhance efficiency, reduce variability, and improve the quality of care are becoming increasingly common. Our pathway for evaluation of patients with chest pain at low risk of myocardial ischemia was feasible and safe and was associated with a decline in absolute admission rates. Because of the possibility of concomitant secular trends and the effects of a changing medical environment, further rigorous research on the efficacy of individual pathways is needed.


Efficient Synthesis of Cyclic Carbonates from Unsaturated Acids and Carbon Dioxide and their Application in the Synthesis of Biobased Polyurethanes.
Bio-derived furan- and diacid-derived cyclic carbonates have been synthesized in high yields from terminal epoxides and CO2 . Furthermore, four highly substituted terpene-derived cyclic carbonates were isolated in good yields with excellent diastereoselectivity in some cases. Eleven new cyclic carbonates derived from 10-undecenoic acid under mild reaction conditions were prepared, providing the corresponding carbonate products in excellent yields. The catalyst system also performed the conversion of an epoxidized fatty acid n-pentyl ester into a cyclic carbonate under relatively mild reaction conditions (80 °C, 20 bar, 24 h). This bis(cyclic carbonate) was obtained in high yields and with different cis/trans ratios depending on the co-catalyst used. An allyl alcohol by-product was only observed as a minor product when bis(triphenylphosphine)iminium chloride was used as co-catalyst. Finally, two cyclic carbonates were used as building blocks for the preparation of non-isocyanate poly(hydroxy)urethanes by reaction with 1,4-diaminobutane.


Twelve-month sealant retention in a school-based program using a self-etching primer/adhesive.
Very little independent research has been done on the new self-etching primer/adhesives in dentistry. A recent clinical study compared two sealant application techniques involving self-etching primer adhesives and the traditional phosphoric acid etch. The purpose of this study was to compare these two techniques in an Iowa school-based sealant program. Twelve-month sealant retention data on 208 students from the Des Moines, Iowa, school-based sealant program were analyzed retrospectively. Sealant retention reported at the person level showed that 60 percent of the students who received sealants at the five schools had to be recalled at one year to have one or more surfaces resealed. A logistic regression model at the person level demonstrated that the phosphoric acid technique was six times as likely to have retention of all the sealed tooth surfaces as those sealed with Prompt-L-Pop. In this study, many students had to be recalled to the chair 12 months after sealant application due to incomplete retention. Though sealants were retained in larger numbers with phosphoric acid, overall sealant retention at the tooth level was lower than previously published for clinical studies and school-based programs. Examining retention data at the person level, however, allows program administrators to plan resources more effectively and reevaluate sealant protocol to ensure as few children return for sealant reapplication.


[Research on Cost Control and Rationalization Application Supervision of Medical Equipment Consumables Based on Analytic Hierarchy Process].
To analyze the medical equipment operation data of 44 clinical departments in the hospital from three aspects: materials and consumables, operation and maintenance depreciation, and operation management. To formulate the evaluation standards and scoring criteria for the operation indicators, the lowest score is 0 points, and the highest score is 5 points. Based on the operation indicators of medical equipment, establish a hierarchical structure model, determine the criterion layer and sub-criteria layer, construct a judgment matrix, normalize it, and calculate the weight coefficient. Count equipment operation data in 2021 and 2022. Score according to the assessment standards, assign weights through the analytic hierarchy process, calculate the total score and sort, and making a special analysis on the top 10 departments and departments with a score below 4 points, and formulate a rectification plan. The establishment of index assessment standards and the weight distribution of AHP can effectively enhance the control of equipment operating costs.


Intraindividual variability and short-term change. Commentary.
Interest in the study of intraindividual variability is growing rapidly. The present collection of papers deals with both longer-term, growth and change and shorter-term intraindividual variability. The papers emphasize primarily the former within the context of analyzing large, longitudinal data sets. Also discussed are some key methodological matters. Criteria to help with choosing methods and modeling with missing data are included. A promising direction is toward developing a more systematic and intensive conception of the meaning and significance of the wide variety of manifestations of intraindividual variability and integrating them into theories of aging.


What role for the general practitioner in child protection?
New government guidance on cooperation in child protection confirms the importance of the general practitioner (GP) contribution. While research highlights the concerns of others about their role in the multi-agency process, relatively little is known about the views and experiences of GPs themselves. To examine the understanding that each of the key professional groups had of its own and each other's roles in child protection to identify those factors seen to enhance or inhibit the effective performance of these roles. The research formed part of a larger investigation of the role of health professionals in child protection, which combined case study investigations of child protection networks in three health authority sites with a regional survey of Area Child Protection Committee members. A lack of correspondence was identified between GPs' perception and performance of their role in child protection and the expectations placed upon them by other child protection professionals and government guidance. The study identifies the need for more explicit discussion of the nature and extent of the GP role in local interagency child protection networks.


Activation of permeabilized HL60 cells by vanadate. Evidence for divergent signalling pathways.
The possible role of tyrosine phosphorylation in the activation of granulocytic HL60 cells was examined using vanadate, a phosphotyrosine phosphatase inhibitor. Treatment of permeabilized cells with micromolar concentrations of vanadate resulted in a substantial accumulation of tyrosine-phosphorylated proteins, detected by immunoblotting. At comparable concentrations, vanadate was also found to elicit an NADPH-dependent burst of oxygen utilization. Actin assembly, studied using 7-nitrobenz-2-oxa-1,3-diazole (NBD)-phallacidin, was similarly stimulated by vanadate, though considerably higher concentrations were required to observe this effect. In contrast with these responses, the secretion of lysozyme was not stimulated by vanadate, nor did vanadate affect calcium-induced secretion. Therefore, accumulation of tyrosine-phosphorylated proteins is associated with stimulation of some, but not all, of the responses characteristic of granulocytic cell activation. This indicates that the effects of vanadate are selective and suggests divergence of the signalling pathways leading to the individual effectors.


Deletion distal to the PAX6 coding region reveals a novel basis for familial cosegregation of aniridia and diabetes mellitus.
Analyze cosegregation of aniridia and diabetes to identify genetic criteria for detection and early treatment of diabetes-susceptible aniridia patients. We assessed a two-generation family: three individuals with aniridia, two previously diagnosed as type 2 diabetes. One individual with aniridia, with unknown diabetes status, was evaluated by oral glucose tolerance test. Genetic analysis of aniridia-associated genes was performed on all available family members. Candidate genes were functionally tested by gene silencing in MIN6 pancreatic β-cells. A 25 year old male with aniridia had a diabetic oral glucose tolerance test despite a normal fasting blood glucose. A 484-630 kb deletion ∼120 kb distal to PAIRED BOX 6 (PAX6) showed dominant cosegregation with aniridia and diabetes in all affected family members. The deleted region contains regulatory elements for PAX6 expression and four additional coding regions. Knockdown of two of the deleted genes (Dnajc24 or Immp1l) with Pax6 impaired glucose-stimulated insulin secretion. We demonstrate dominant cosegregation of diabetes and aniridia with a deletion distal to PAX6, which is clinically distinct from the mild glucose intolerance previously reported with PAX6 coding mutations. Asymptomatic aniridia individuals appear at risk of diabetes (and its complications) and could benefit from earlier diagnosis and treatment.


Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation.
Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy. To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed. A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate. In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation.


Cannabinoid receptors in conjunctival epithelium: identification and functional properties.
Preservation of the ocular surface barrier requires complex control of epithelial cell proliferation and inflammation mechanisms. The endocannabinoid system may be regulating these processes. Therefore, the authors explored the presence and properties of cannabinoid receptors (CB1 and CB2) in conjunctival epithelial cells. The authors used immunohistochemistry to detect CB1 and CB2 in normal mouse conjunctiva, human conjunctival cryosections and impression samples, and IOBA-NHC cells, a human conjunctiva-derived cell line. The presence of CB1 and CB2 proteins and transcripts was studied in IOBA-NHC cells by Western blot and RT-PCR, respectively. The authors also used this cell line to assay cannabinoid ligand-induced changes in cAMP levels, cell growth, and tumor necrosis factor-alpha (TNF-alpha)-induced activation of c-jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB). Mouse and human conjunctival epithelial cells displayed CB1 and CB2 proteins and transcripts. Cannabinoid receptor activation decreased cAMP levels in IOBA-NHC cells, and specific CB1 and CB2 antagonists canceled this effect. Cannabinoid ligands also increased cell growth and blocked stress pathways activated by TNF-alpha in vitro. Cannabinoid receptors are present in mouse and human conjunctival cells. Functional responses, such as decreased cAMP levels, proliferation, and modulation of stress signaling pathways, were mediated by CB1 and CB2 stimulation. Thus, these receptors might be involved in the regulation of epithelial renewal and inflammatory processes at the ocular surface.