Does Community Outsourcing Improve Timeliness of Care for Veterans With Obstructive Sleep Apnea?
Providing timely access to care has been a long-standing priority for the Veterans Affairs Healthcare System. Recent strategies to reduce long wait times have focused on purchasing community care by a fee-for-service model. Whether outsourcing Veterans Affairs (VA) specialty care to the community improves access is unclear. We compared time from referral to treatment among Veterans whose care was provided by VA versus community care purchased by the VA, using obstructive sleep apnea as an example condition. This was a retrospective cohort study of Northern California Veterans seeking sleep apnea care through the San Francisco VA Healthcare System between 2012 and 2018. We used multivariable linear regression with propensity score matching to investigate the relationship between time to care delivery and care setting (VA provided vs. VA-purchased community care). A total of 1347 Northern California Veterans who completed sleep apnea testing within the VA and 88 Veterans who completed sleep apnea testing in the community had complete data for analysis. Among Northern California Veterans with obstructive sleep apnea, outsourcing of care to the community was associated with longer time from referral to therapy (mean±SD, 129.6±82.8 d with VA care vs. 252.0±158.8 d with community care, P<0.001) and greater loss to follow-up. These findings suggest that purchasing community care may lead to care fragmentation and not improve wait times nor improve access to subspecialty care for Veterans.


The galanin and galanin receptor subtypes, its regulatory role in the biological and pathological functions.
The multitalented neuropeptide galanin was first discovered 30 years ago but initially no biologic activity was found. Further research studies discovered the presence of galanin in the brain and some peripheral tissues, and galanin was identified as a modulator of neurotransmission in the central and peripheral nervous system. Over the last decade there were performed very intensive studies of the neuronal actions and also of nonneuronal actions of galanin. Other galanin family peptides have been described, namely galanin, galanin-like peptide, galanin-message associated peptide and alarin. The effect of these peptides is mediated through three galanin receptors subtypes, GalR1, GalR2 and GalR3 belonging to G protein coupled receptors, and signaling via multiple transduction pathways, including inhibition of cyclic AMP/protein kinase A (GalR1, GalR3) and stimulation of phospholipase C (GalR2). This also explains why one specific molecule of galanin can be responsible for different roles in different tissues. The present review summarizes the information currently available on the relationship between the galaninergic system and known pathological states. The research of novel galanin receptor specific agonists and antagonists is also very promising for its future role in pharmacological treatment. The galaninergic system is important target for current and future biomedical research.


Pediatric cutaneous angiosarcomas: a clinicopathologic study of 10 cases.
Cutaneous angiosarcomas are rare tumors, which predominantly arise in the sun-exposed skin of the head and neck of adult and elderly patients. Rarely, these tumors can be seen in children. We identified cutaneous angiosarcomas in 10 children and assessed clinical (patient age, tumor site, tumor size, and tumor focality) and histologic features including growth pattern (vasoformative vs. solid), mitotic rate (mitotic figures per 10 high power field), necrosis (present vs. absent), and cell shape (epithelioid vs. nonepithelioid). Tumors predominated in the lower extremities (6 of 10) of female patients (2 male and 8 female); age at diagnosis ranged from 1.5 months to 15 years. Four patients had preexisting conditions: congenital hemihypertrophy of the contralateral limb, the Aicardi syndrome, congenital lymphedema, and congenital hemangioma treated with radiation therapy. Tumors were located in the lower extremity (6), flank (1), elbow (1), and buccal mucosa (1), and ranged in size from 0.6 to 6.5 cm. Eight cases showed predominantly epithelioid morphology, 1 case showed mixed epithelioid and spindled morphology and 1 case was entirely spindled. Mitotic activity ranged from 1 to 55 mitotic figures per 10 high power field. Necrosis was seen in 5 cases. Clinical follow-up was obtained for 9 patients: 4 died of disease (range, 12 to 49 mo; mean, 25 mo) and 5 patients were alive without disease (18 mo to 28 y). Five patients had metastatic disease; sites of involvement included the lung, soft tissue, lymph node, pleura, liver, and bone. Cutaneous angiosarcomas in children are rare tumors, which are commonly associated with a preexisting condition, suggesting a greater role for genetics as opposed to environmental factors in the pathogenesis of these tumors.


Brain functional segregation, handedness and cognition in situs inversus totalis: A replication study.
Situs inversus totalis (SIT) is a rare congenital anomaly in which the arrangement of the visceral organs is completely left-right mirrored. A previous study by our lab suggests that SIT (N = 15) correlated with more heterogeneous asymmetrical brain organization and increased left-handedness. In addition, visceral reversal correlated with poorer cognitive performance, especially when hemisphere organization was atypical. The current study sought to replicate these findings in a larger sample. We scanned 23 volunteers with SIT as well as an equal number of controls with usual organ arrangement, and used fMRI to determine their hemisphere dominance for two left hemisphere functions (language and manual praxis) and two right hemisphere functions (spatial attention and face recognition). Effects of SIT etiology were explored by pooling data from the original cohort with the replication sample. Our results reveal that each of those four cognitive functions demonstrated the expected population dominance in SIT, albeit they were less pronounced - but not significantly so - compared to controls. Unusual patterns of hemispheric crowding and mirror-reversal of functional brain organization was observed more often in SIT (48%) than in the controls (30%), but this difference also did not reach statistical significance. However, left-handedness was found to be significantly more common in SIT (26%) than in the overall population (10.6%). Finally, cognitive ability, as assessed by a neuropsychological test battery, was not associated with organ situs or hemisphere organization. Taken together, our data adds to the growing evidence that the determinants of visceral and neural asymmetries are largely independent from one another and that complete situs inversus does not co-occur with an obligatory transposition of the brain's functional architecture. There nevertheless might be instances in which (genetic) mechanisms could simultaneously cause complete visceral reversal and atypical brain laterality.


Improving data quality control in quality improvement projects.
The results of many quality improvement (QI) projects are gaining wide-spread attention. Policy-makers, hospital leaders and clinicians make important decisions based on the assumption that QI project results are accurate. However, compared with clinical research, QI projects are typically conducted with substantially fewer resources, potentially impacting data quality. Our objective was to provide a primer on basic data quality control methods appropriate for QI efforts. Data quality control methods should be applied throughout all phases of a QI project. In the design phase, project aims should guide data collection decisions, emphasizing quality (rather than quantity) of data and considering resource limitations. In the data collection phase, standardized data collection forms, comprehensive staff training and a well-designed database can help maximize the quality of the data. Clearly defined data elements, quality assurance reviews of both collection and entry and system-based controls reduce the likelihood of error. In the data management phase, missing data should be quickly identified and corrected with system-based controls to minimize the missing data. Finally, in the data analysis phase, appropriate statistical methods and sensitivity analysis aid in managing and understanding the effects of missing data and outliers, in addressing potential confounders and in conveying the precision of results. Data quality control is essential to ensure the integrity of results from QI projects. Feasible methods are available and important to help ensure that stakeholder's decisions are based on accurate data.


Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior.
Prenatal phthalate exposure has been associated with behavioral problems and lower performance on measures of cognitive ability in children. However, the potential effect of phthalate exposure during the sensitive preconception period is unknown. To estimate the association of maternal and paternal preconception urinary phthalate metabolite concentrations with child behavior and evaluate potential modification by child sex. We used data from 166 children (111 singletons, 26 pairs of twins, and 1 set of triplets) born to 134 mothers and 100 fathers participating in a prospective preconception cohort study of subfertile couples from the Massachusetts General Hospital Fertility Center. We estimated mean maternal and paternal preconception exposures by averaging individual phthalate metabolite concentrations in multiple urine samples collected before pregnancy. We assessed children's behavior at 2-9 years of age by parent report using the Behavior Assessment System for Children-2 (BASC-2). We estimated the covariate-adjusted association between individual phthalate metabolite concentrations and the sum of di(2-ethylhexyl) phthalate metabolites (∑ DEHP) and behavior scores, and evaluated differences in associations by child sex using linear regression with Generalized Estimating Equations. Models were further adjusted for prenatal phthalate concentrations in sensitivity analyses. Each loge-unit increase in maternal and paternal preconception concentrations of ∑DEHP was associated with a 2.0 (95% CI: - 3.2, - 0.7) and 1.8 (95% CI: - 3.1, - 0.4) point decrease in BASC-2 internalizing behavior scores among all children, respectively. We observed sex-specific associations for some phthalate biomarkers: among boys, maternal monoisobutyl phthalate (MiBP) was positively associated with externalizing behaviors, and paternal MiBP and mono-n-butyl phthalate were positively associated with internalizing behaviors. In this cohort, paternal and maternal preconception concentrations of some phthalate biomarkers were associated with specific aspects of child behavior, even after adjustment for prenatal concentrations. While additional research is warranted to confirm these results, our findings suggest that the preconception period of exposure may be a critical window for offspring neurodevelopment.


The bacterial protein YopJ abrogates multiple signal transduction pathways that converge on the transcription factor CREB.
Bacterially encoded proteins are known to affect eukaryotic signalling pathways and thus cell growth and differentiation. The enteric pathogen Yersinia pseudotuberculosis (YP) can translocate Yersinia outer proteins (Yops) into eukaryotic cells. Recently, MKK proteins have been identified as tentative targets of YopJ-mediated inhibition of ligand receptor-dependent signal transduction in mammalian cells. These results prompted us to assess whether multiple signal transduction pathways and their downstream target genes would also be subject to regulation by YopJ. Here, we show that YopJ effectively blocks the lipopolysaccharide (LPS) receptor, the interleukin (IL)-1beta receptor and the UVC-induced activation of the transcription receptor cAMP response element-binding protein (CREB). In addition, by abrogating the phosphorylation of CREB and thus activating protein (AP)-1-dependent transcription, YopJ can block LPS-induced clonal expansion that is associated with an adaptive immune response. Thus, YopJ interferes with multiple pathways converging on the transcription factor CREB. Our data are discussed in the context of YopJ acting as an antagonist to circumvent innate and adaptive immune responses at multiple levels.


Norms of online expressions of emotion: Comparing Facebook, Twitter, Instagram, and WhatsApp.
The main aim of this study was to examine the norms of expressing emotions on social media. Specifically, the perceived appropriateness (i.e. injunctive norms) of expressing six discrete emotions (i.e. sadness, anger, disappointment, worry, joy, and pride) was investigated across four different social media platforms. Drawing on data collected in March 2016 among 1201 young Dutch users (15-25 years), we found that positive expressions were generally perceived as more appropriate than negative expressions across all platforms. In line with the objective of the study, some platform differences were found. The expression of negative emotions was rated as most appropriate for WhatsApp, followed by Facebook, Twitter, and Instagram. For positive emotion expression, perceived appropriateness was highest for WhatsApp, followed by Instagram, Facebook, and Twitter. Additionally, some gender differences were found, while age showed little variations. Overall, the results contribute to a more informed understanding of emotion expression online.


[Peritoneal dialysis outcome. The Andalusian Registry Peritoneal Dialysis: 1999-2008].
In this study we show the results derived from the processing of the data of the Registry of the patients on peritoneal dialysis that initiated renal replacement therapy in Andalucía between January of 1999 and December of 2008. All the information comes from the base of the Registry of Renal Patients of the Andalucia s Health Service. The results show demographic data, distribution by provinces, etiology of the end stage renal disease, reason for election of the peritoneal dialysis, inclusion or not in list of renal transplant, catheter data, withdraws and their causes, and peritonitis data of 2008. We also analyze in the report, from 1999-2008: annual incidence, diabetes, automatic peritoneal dialysis and peritonitis incidence. Finally we have studied patient and technique survival and factors affecting mortality on peritoneal dialysis, the initial comorbid conditions and its impact in the patient s survival.


[Human biomonitoring investigations of organochlorine compounds -- PCB, DDE, HCB, beta- and gamma-HCH, PCDD/PCDF, Dioxin-like PCB's and polybrominated biphenyl ethers].
Although PCB and PCB-containing materials are not processed for a long time, PCB is under discussion again and again caused by the pollution of indoor environments. To objectify the discussion, the dates of the PCB-biomonitoring, the organochlorine-compounds (DDE, HCB, beta-/gamma -HCH, PCDD/PCDF) and the polybrominated biphenyl ethers concerning the investigations within the project "Sentinel Health Departments" in Baden-Wurttemberg are represented. Additionally results from children from Kazakhstan (Aral-Sea area) and from teachers which are working in PCB polluted schools as well as from a long term investigated test person are reported. Blood concentrations of the following compounds decreased from 1996/97 to 2002/03: the sum of the concentration of PCB 138,153 and 180 decreased from 0.46 microg/L to 0.20 microg/L, DDE from 0.32 microg/L to 0.17 microg/, HCB from 0.20 microg/L to 0.08 microg/L, beta-HCH below the level of detection, I-TEQ NATO to 4.8 pg/g blood fat, TEQ WHO (without PCB) to 5.5 pg/g blood fat, PCB 126 to 18,8,pg/g blood fat and PCB 169 to 12.8 pg/g blood fat. The influence of breast feeding and the gender on the level of the pollution is conspicious. No local correlations were found in Baden-Wurttemberg, but they were found in comparison with the results of Kazakhstan (Aral-Sea area). The difficulty to produce time series while the analyzing pollutants are more and more decreasing, as well as the change of the calculation base of the summation of parameters like I-TEQ NATO to TEQ WHO are discussed.


Use of praziquantel for treatment of Diphyllobothrium sp infection in a dog.
Eggs of a tapeworm, Diphyllobothrium sp (probably D dendriticum), were detected in feces of a healthy, 5-month-old, Siberian Husky. The dog acquired its infection in northern Canada while consuming a diet that included raw salmonid fish. Such fish serve as intermediate hosts for Diphyllobothrium spp. The infection was successfully eliminated by oral administration of a single dose of praziquantel (7.5 mg/kg of body weight.


Correlation of glucocorticoid receptor binding sites on MMTV proviral DNA with hormone inducible transcription.
Steroid hormones, when complexed to their receptors, recognize and bind specific DNA sequences and subsequently induce increased levels of transcription. The mechanisms of steroid hormone action were analyzed by constructing chimeric DNA molecules from portions of mouse mammary tumor virus envelope and long terminal repeat (LTR) regions ligated to the thymidine kinase (tk) gene of herpes simplex virus. This construction allowed the tk gene to be expressed in a hormone-responsive fashion upon transfection into Ltk- cells. Comparison of transcription data with in vitro binding data showed that hormone-responsive transcription can be directly correlated to the presence of steroid hormone receptor binding sites on the DNA. There are at least two such receptor binding sites in the LTR region, one between -202 and -137 and another between -137 and -50 base pairs from the RNA cap site, as well as a site near the 5' end of the envelope region. These results strengthen the hypothesis that steroid-receptor complexes regulate genes primarily by binding to DNA sites near the promoter region and thereby modulate transcription.


Current best clinical practices for monitoring of interstitial lung disease.
Interstitial lung diseases (ILDs) are a heterogeneous group of inflammatory and/or fibrotic conditions with variable outcome and often a dismal prognosis. Since many ILDs are progressive in nature, monitoring of signs and symptoms of progression is essential to inform treatment decisions and patient counseling. Monitoring of ILDs is a multimodality process and includes all aspects of the disease, e.g. measurement of pulmonary function and exercise capacity, symptom registration and quality of life (QoL), imaging, comorbidities and/or involvement of other organs to assess disease activity, symptom burden, treatment effects, adverse events, the need for supportive and palliative care, and lung transplantation. For this narrative review, we searched the PUBMED database to identify articles relevant for monitoring ILDs, including pulmonary function tests, exercise capacity, imaging, telemedicine, symptoms, and QoL. Due to the high heterogeneity of the ILDs and their disease course, an individualized multimodality approach must be applied. Future strategies include use of telemedicine for home monitoring of lung function and symptoms, use of artificial intelligence to support automatized guidance of patients, computerized evaluation of ILD changes on imaging, and new imaging tools with less radiation dosage.


The complications of high tibial osteotomy: closing- versus opening-wedge methods.
We compared the incidence and severity of complications during and after closing- and opening-wedge high tibial osteotomy used for the treatment of varus arthritis of the knee, and identified the risk factors associated with the development of complications. In total, 104 patients underwent laterally based closing-wedge and 90 medial opening-wedge high tibial osteotomy between January 1993 and December 2006. The characteristics of each group were similar. All the patients were followed up for more than 12 months. We assessed the outcome using the Hospital for Special Surgery knee score, and recorded the complications. Age, gender, obesity (body mass index > 27.5 kg/m(2)), the type of osteotomy (closing versus opening) and the pre-operative mechanical axis were subjected to risk-factor analysis. The mean Hospital for Special Surgery score in the closing and opening groups improved from 73.4 (54 to 86) to 91.8 (81 to 100) and from 73.8 (56 to 88) to 93 (84 to 100), respectively. The incidence of complications overall and of major complications in both groups was not significantly different (p = 0.20 overall complication, p = 0.29 major complication). Logistic regression analysis adjusting for obesity and the pre-operative mechanical axis showed that obesity remained a significant independent risk factor (odds ratio = 3.23) of a major complication after high tibial osteotomy. Our results suggest that the opening-wedge high tibial osteotomy can be an alternative treatment option for young patients with medial compartment osteoarthritis and varus deformity.


Evaluation of Vascular Endothelial Growth Factor Gene Expression in Recellularized Liver Tissue by Mouse Embryo Fibroblast.
The aim of the present study was to evaluate alterations in the vegf gene expression as an angiogenic factor in mouse embryo fibroblasts seeded on the decellularized liver fragments. Liver tissue samples (n = 10) collected from adult male mice were randomly divided into decellularized and native control groups. Tissues were decellularized by treating with 1% Triton X-100 and 0.1% SDS for 24 hours and assessed by H&E staining and SEM. Then DNA content analysis and toxicity tests were performed. By centrifugation, DiI-labeled mouse embryo fibroblasts were seeded on each scaffold and cultured for one week. The recellularized scaffolds were studied by H&E staining, SEM, and LSCM. After RNA extraction and cDNA synthesis, the expression of the vegf gene in these samples was investigated using real-time RT-PCR. Our observations showed that the decellularized tissues had morphology and porous structure similar to the control group, and their DNA content significantly reduced (p < 0.05) and reached to 4.12% of the control group. The MTT test indicated no significant cellular toxicity for the decellularized scaffolds. Light microscopy, SEM, and LSCM observations confirmed the attachment and penetration of embryonic fibroblast cells on the surface and into different depths of the scaffolds. There was no statistically significant difference in terms of vegf gene expression in the cultured cells in the presence and absence of a scaffold. The reconstructed scaffold had no effect on vegf gene expression. Decellularized mouse liver tissue recellularized by embryonic fibroblasts could have an application in regenerative medicine.


High number of HPAI H5 virus infections and antibodies in wild carnivores in the Netherlands, 2020-2022.
In October 2020, a new lineage of a clade 184.108.40.206b HPAI virus of the H5 subtype emerged in Europe, resulting in the largest global outbreak of HPAI to date, with unprecedented mortality in wild birds and poultry. The virus appears to have become enzootic in birds, continuously yielding novel HPAI virus variants. The recently increased abundance of infected birds worldwide increases the probability of bird-mammal contact, particularly in wild carnivores. Here, we performed molecular and serological screening of over 500 dead wild carnivores and sequencing of RNA positive materials. We show virological evidence for HPAI H5 virus infection in 0.8%, 1.4%, and 9.9% of animals tested in 2020, 2021, and 2022 respectively, with the highest proportion of positives in foxes, polecats and stone martens. We obtained near full genomes of 7 viruses and detected PB2 amino acid substitutions known to play a role in mammalian adaptation in three sequences. Infections were also found in without neurological signs or mortality. Serological evidence for infection was detected in 20% of the study population. These findings suggests that a high proportion of wild carnivores is infected but undetected in current surveillance programmes. We recommend increased surveillance in susceptible mammals, irrespective of neurological signs or encephalitis.


Effect of Selected Music Soundtracks on Cardiac Vagal Control and Complexity Assessed by Heart Rate Variability.
Listening to music is experimentally associated with positive stress reduction effect on human organisms. However, the opinions of therapists about this complementary non-invasive therapy are still different. The aim of our study was to investigate the effect of selected passive music therapy frequencies without vocals on selected cardio-vagal and complexity indices of short-term heart rate variability (HRV) in healthy youth, in terms of calming the human. 30 probands (15 male, averaged age: 19.7+/-1.4 years, BMI: 23.3+/-3.8 kg/m2) were examined during protocol (Silence baseline, Music 1 (20-1000 Hz), Silence 1, Music 2 (250-2000 Hz), Silence 2, Music 3 (1000-16000 Hz), and Silence 3). Evaluated HRV parameters in time, spectral, and geometrical domains represent indices of cardio-vagal and emotional regulation. Additionally, HRV complexity was calculated by approximate entropy and sample entropy (SampEn) and subjective characteristics of each phase by Likert scale. the distance between subsequent R-waves in the electrocardiogram (RR intervals [ms]) and SampEn were significantly higher during Music 3 compared to Silence 3 (p=0.015, p=0.021, respectively). Geometrical cardio-vagal index was significantly higher during Music 2 than during Silence 2 (p=0.006). In the subjective perception of the healthy youths evaluated statistically through a Likert scale, the phases of music were perceived significantly more pleasant than the silent phases (p<0.001, p=0.008, p=0.003, respectively). Our findings revealed a rise of cardio-vagal modulation and higher complexity assessed by short-term HRV indices suggesting positive relaxing effect music especially of higher frequency on human organism.


Temporary vaccine recommendations and provider compliance: a survey of pediatric practices during the 2003-2004 pneumococcal conjugate vaccine shortage.
Heptavalent pneumococcal conjugate vaccine was in short supply from December 2003 to August 2004. The Centers for Disease Control and Prevention with the American Academy of Pediatrics and the American Academy of Family Physicians made recommendations to providers to withhold third and fourth doses of heptavalent pneumococcal conjugate vaccine to ensure availability for those at highest risk. Previous studies of vaccine shortages have demonstrated that provider compliance with temporary recommendations is low. The objective of this study was to collect timely data about awareness and adherence to temporary recommendations and current supply status of heptavalent pneumococcal conjugate vaccine in pediatric practices. A 2-phase telephone survey of pediatric practices was conducted during a 10-week period during the 2003-2004 heptavalent pneumococcal conjugate vaccine shortage. Immunization nurses at randomly selected sites with physician-members of the American Academy of Pediatrics were asked a series of questions. In both study phases, >90% of participating practices were aware of the recommendations and reported adhering to the recommendations. In phase 1, practices with insufficient supply were more likely to implement recommendations than practices with sufficient supply. Participants identified health departments and Wyeth Vaccines as the most common sources of information. At least 65% of the practices in each phase reported use of tracking systems for children who missed doses. Most pediatric practices surveyed were aware of the shortage and were implementing the heptavalent pneumococcal conjugate vaccine recommendations. Simplified recommendations and collaborative efforts to develop and widely disseminate interim recommendations may result in increased compliance by providers.


Neuro- and immunomodulatory steroids and other biochemical markers in drug-naive schizophrenia patients and the effect of treatment with atypical antipsychotics.
Serum levels of neuro- and immunomodulatory adrenal steroids together with selected hormonal, lipid and other relevant biochemical parameters were investigated to examine the differences between first-episode schizophrenia patients and age-matched healthy subjects, and the effect of treatment with atypical antipsychotics. The patient´s group consisted of 22 drug-naive patients (13 men and 9 women), diagnosed with schizophrenia according to ICD-10 criteria, before and after six-months treatment with atypical antipsychotics of olanzapine or non-olanzapine type. Biochemical markers included steroids cortisol, dehydroepiandrosterone, its sulfate, 7-hydroxylated metabolites of dehydroepiandrosterone, prolactin, thyrotropin, free thyroxine, autoantibodies against thyroid peroxidase and thyroglobulin, glucose levels, four major lipid parameters, homocysteine and three other aminothiols. Steroids, prolactin and thyroid parameters were determined by radioimmunoassays, the other markers by standard biochemical methods. Significantly lower dehydroepiandrosterone sulfate and of 7α-hydroxy- dehydroepiandrosterone levels than in controls were found in male patients. In the female group, the only difference in steroid spectra was significantly higher cortisolemia in the patients. The patients had also higher titres of autoantibodies against thyroid peroxidase. Compared to controls, the patients displayed worse lipid spectra, and higher homocysteinemia. Medication did not lead to significant changes in the parameters, with the exception of expected increase in prolactin levels in non-olanzapine treated subgroups. Lower levels of 7α-hydroxydehydroepiandrosterone, abundant especially in brain, determined for the first time in schizophrenia patients, are in agreement with recent opinion of their neuroprotective and immunoprotective role. High levels of autoantibodies against thyroid peroxidase in the patients support the autoimmunity hypothesis of schizophrenia.


Hypoxia-responsive nanoparticle based drug delivery systems in cancer therapy: An up-to-date review.
Hypoxia is a salient feature observed in most solid malignancies that holds a pivotal role in angiogenesis, metastasis and resistance to conventional cancer therapeutic approaches, and thus enables cancer progression. However, the typical characteristics of hypoxic cells such as low oxygen levels and highly bio-reductive environment can offer stimuli-responsive drug release to aid in tumor-specific chemo, radio, photodyanamic and sonodynamic therapies. This approach based on targeting the poorly oxygenated tumor habitats offers the prospective to overcome the difficulties that arises due to heterogenic nature of tumor and could be possibly used in the design of diagnostic as well as therapeutic nanocarriers for targeting various types of solid cancers. Consequently, hypoxia triggered nanoparticle based drug delivery systems is a rapidly progressing research area in developing effective strategies to combat drug-resistance in solid tumors. The present review presents the recent advances in the development of hypoxia-responsive nanovehicles for drug delivery to heterogeneous tumors. The initial sections of the article provides insights into the development of hypoxia in growing cancer and its role in disease progression. The current limitations and the future prospective of hypoxia-stimulated nanomachines for cancer treatment are also discussed.


An NLRP3 inflammasome-triggered cytokine storm contributes to Streptococcal toxic shock-like syndrome (STSLS).
Infection with the Streptococcus suis (S. suis) epidemic strain can cause Streptococcal toxic shock-like syndrome (STSLS), which is characterized by a cytokine storm, dysfunction of multiple organs and a high incidence of mortality despite adequate treatment. Despite some progress concerning the contribution of the inflammatory response to STSLS, the precise mechanism underlying STSLS development remains elusive. Here, we use a murine model to demonstrate that caspase-1 activity is critical for STSLS development. Furthermore, we show that inflammasome activation by S. suis is mainly dependent on NLRP3 but not on NLRP1, AIM2 or NLRC4. The important role of NLRP3 activation in STSLS is further confirmed in vivo with the NLRP3 inhibitor MCC950 and nlrp3-knockout mice. By comparison of WT strain with isogenic strains with mutation of various virulence genes for inflammasome activation, Suilysin is essential for inflammasome activation, which is dependent on the membrane perforation activity to cause cytosolic K+ efflux. Moreover, the mutant strain msly (P353L) expressing mutagenic SLY without hemolytic activity was unable to activate the inflammasome and does not cause STSLS. In summary, we demonstrate that the high membrane perforation activity of the epidemic strain induces a high level of NLRP3 inflammasome activation, which is essential for the development of the cytokine storm and multi-organ dysfunction in STSLS and suggests NLRP3 inflammasome as an attractive target for the treatment of STSLS.


A central role for TOR signalling in a yeast model for juvenile CLN3 disease.
Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases.


[Leaf consumption by herbivores in mangroves of the Dagua river estuary, Pacific coast of Colombia].
Herbivore leaf consumption of various mangrove species in relation to environmental factors and leaf hardness were studied in the Dagua river estuary, Colombia. Leaf consumption and damage were assessed by measuring the percentage of area attacked by herbivores, distinguishing between consumption and damage. The species that suffered the highest consumption, such as Avicennia germinans (Avicenniaceae) and Laguncularia racemosa (Combretaceae), had softer leaves and less herbivore species when compared with Rhizophora spp. (Rhizophoraceae) and Pelliciera rhizophorae (Theaceae). The abundance and diversity of leaf grazing and its variability among mangrove species in the Dagua River estuary, show the importance of the trophic dynamics of live vegetable matter, in spite of their relatively low contribution to removing organic matter.


Hypoxia-inducible factor and bacterial infections in chronic obstructive pulmonary disease.
COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non-antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia-inducible factor (HIF)-1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF-1α expression can upregulate the platelet-activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR-dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF-1α in augmenting PAFR-dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia-induced inflammation, HIF-1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.


Controlled attenuation parameter and magnetic resonance spectroscopy-measured liver steatosis are discordant in obese HIV-infected adults.
Hepatic steatosis is common in HIV-infected individuals. Magnetic resonance spectroscopy (MRS) is the preferred noninvasive method for hepatic steatosis measurement but is expensive. Controlled attenuation parameter (CAP) also assesses hepatic steatosis and is conveniently performed concomitantly with transient elastography. We aimed to assess the accuracy of CAP in the setting of HIV infection. Cross-sectional study. CAP and MRS were performed in 82 study participants (39 HIV monoinfected; seven hepatitis C virus (HCV) monoinfected; 21 HIV/HCV coinfected; 15 with neither infection). We used concordance correlation coefficients to compare log-transformed and standardized CAP and MRS values and linear regression to examine factors associated with CAP and MRS-measured hepatic steatosis (MRS-HS). The accuracy of CAP to detect at least mild hepatic steatosis, defined as MRS-liver fat fraction more than 0.05, and the factors associated with discordance between CAP and MRS were evaluated. Overall, CAP-measured hepatic steatosis and MRS-HS correlated moderately well (rc = 0.63; P < 0.001), and correlation was strongest in the HIV-monoinfected group (rc = 0.67; P < 0.001). Body composition factors (higher BMI, waist circumference, visceral and abdominal subcutaneous adipose tissue) and insulin resistance were significantly associated with both greater CAP-measured hepatic steatosis and MRS-HS. Using a validated CAP cut-off of at least 238 dB/m, sensitivity and specificity for at least mild hepatic steatosis were 84% and 75% in the entire cohort; 89% and 80% in the HIV-monoinfected group. Participants with higher body composition parameters were more likely to be misclassified as having hepatic steatosis by CAP. Our findings suggest CAP is an acceptable noninvasive surrogate for hepatic steatosis in HIV-infected individuals but may overestimate hepatic steatosis prevalence, especially in individuals with high BMI. Evaluation of factors that improve CAP accuracy and determination of optimal cut-offs are warranted.


Rotation of a submerged finite cylinder moving down a soft incline.
A submerged finite cylinder moving under its own weight along a soft incline lifts off and slides at a steady velocity while also spinning. Here, we experimentally quantify the steady spinning of the cylinder and show theoretically that it is due to a combination of an elastohydrodynamic torque generated by flow in the variable gap, and the viscous friction on the edges of the finite-length cylinder. The relative influence of the latter depends on the aspect ratio of the cylinder, the angle of the incline, and the deformability of the substrate, which we express in terms of a single scaled compliance parameter. By independently varying these quantities, we show that our experimental results are consistent with a transition from an edge-effect dominated regime for short cylinders to a gap-dominated elastohydrodynamic regime when the cylinder is very long.


Control system modification of an electromechanical pulsatile total artificial heart.
A reliable control system is one of the most important characteristics of the electromechanical pulsatile total artificial heart (TAH). Obtaining an error-free procedure is essential for a successful in vivo implantation. To avoid any malfunction of the electrical control system, a modification of the previously designed controller was made to ensure stable pumping without the Hall effect sensor missensing. The installation position of the Hall effect sensor was changed from the top of the housing to the central piece with small magnets being installed in the stabilizer rods. The usage of the Hall effect sensor was chosen as an electrical switch. An in vitro one month running test of the TAH demonstrated adequate hydrodynamic performance with a completely error-free pumping characteristic. The total efficiency of the TAH was 12.6 +/- 1.4% at an 8 L/min outflow and 10.7 +/- 1.0% at a 6 L/min outflow condition.


Factors Affecting Social Health from Young Adults' Perspective: A Qualitative Study.
Factors affecting social health, especially in young adults, are among the most important research priorities. Knowledge of social factors affecting young adults' health will lead to understand them in the social context. The present study is aimed to explain the perspective of young adults on social factors affecting health. In the present qualitative content analysis study, semi-structured open interviews were conducted through targeted sampling of young volunteers aged 18-30 who were selected from Tehran Province. Interviews were recorded, transcribed, and analyzed. The inclusion criteria for participants were willingness to participate in the study and ability to express their personal experiences. Twenty-one data were collected through collection was done with individual in-depth interviews. Using this qualitative approach, the present study was conducted to identify factors affecting social health from the perspective of young adults. The analysis led to the extraction of three main categories, each with two or three subcategories: expectations regarding the community, expectations regarding the family, and expectations regarding infrastructures. Our findings shown that social support considered as effective elements in providing social health of young adults. The evidence on controlling factors should be considered in promoting the social health of specific target groups. The results of the present study could be used for better planning of interventions in youth social health domains.


Pioglitazone improves potassium channel remodeling induced by angiotensin II in atrial myocytes.
It has been demonstrated that atrial electrical remodeling contributes toward atrial fibrillation (AF) maintenance, and that angiotensin II (AngII) is involved in the pathogenesis of atrial electrical remodeling. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists have been shown to inhibit atrial electrical remodeling, but the underlying mechanisms are poorly understood. In the present study we investigated the regulating effects of PPAR-g agonist on AngII-induced potassium channel remodeling in atrial myocytes. Whole-cell patch-clamp technique was used to record transient outward potassium current (Ito), ultra-rapid delayed rectifier potassium (Ikur), and inward rectifier potassium current (Ik1). Real-time PCR was used to assess potassium channel subunit mRNA expression. Compared with the control group, AngII reduced Ito and Ikur current density as well as amplified Ik1 current density, which were partially prevented by pioglitazone. Furthermore, pioglitazone alleviated the downregulation of Ito subunit (Kv 4.2) and Ikur subunit (Kv 1.5), as well as the upregulation of Ik1 subunit (Kir 2.1 and Kir 2.2) mRNA expression stimulated by AngII. These results suggest that pioglitazone exhibits a beneficial effect on AngII-induced potassium channel remodeling. PPAR-γ agonists may be potentially effective up-stream therapies for AF.


Identification of Prostaglandin F2 Receptor Negative Regulator (PTGFRN) as an internalizable target in cancer cells for antibody-drug conjugate development.
Antibody-drug conjugates (ADC) are effective antibody-based therapeutics for hematopoietic and lymphoid tumors. However, there is need to identify new targets for ADCs, particularly for solid tumors and cancers with unmet needs. From a hybridoma library developed against cancer cells, we selected the mouse monoclonal antibody 33B7, which was able to bind to, and internalize, cancer cell lines. This antibody was used for identification of the target by immunoprecipitation and mass spectrometric analysis, followed by target validation. After target validation, 33B7 binding and target positivity were tested by flow cytometry and western blot analysis in several cancer cell lines. The ability of 33B7 conjugated to saporin to inhibit in vitro proliferation of PTFRN positive cell lines was investigated, as well as the 33B7 ADC in vivo effect on tumor growth in athymic mice. All flow cytometry and in vitro internalization assays were analyzed for statistical significance using a Welsh's T-test. Animal studies were analyzed using Two-Way Analysis of Variance (ANOVA) utilizing post-hoc Bonferroni analysis, and/or Mixed Effects analysis. The 33B7 cell surface target was identified as Prostaglandin F2 Receptor Negative Regulator (PTGFRN), a transmembrane protein in the Tetraspanin family. This target was confirmed by showing that PTGFRN-expressing cells bound and internalized 33B7, compared to PTGFRN negative cells. Cells able to bind 33B7 were PTGFRN-positive by Western blot analysis. In vitro treatment PTGFRN-positive cancer cell lines with the 33B7-saporin ADC inhibited their proliferation in a dose-dependent fashion. 33B7 conjugated to saporin was also able to block tumor growth in vivo in mouse xenografts when compared to a control ADC. These findings show that screening antibody libraries for internalizing antibodies in cancer cell lines is a good approach to identify new cancer targets for ADC development. These results suggest PTGFRN is a possible therapeutic target via antibody-based approach for certain cancers.


STZ-induced diabetes in SHR and renovascular hypertensive rats: dissociation between changes in arterial pressure and vascular collagen synthesis.
Streptozotocin (STZ)-induced diabetes depresses the rate of vascular collagen synthesis in the spontaneously hypertensive rat (SHR), but it also reduces arterial pressure (SAP) in this strain. We investigated this phenomenon further by comparing the SHR with the renovascular hypertensive (RVH) rat, because diabetes does not affect SAP in the latter model of hypertension. Renovascular hypertension was induced by clipping the left renal artery of Wistar-Kyoto (WKY) rats; sham-operated WKY were included as normotensive controls. Collagen synthesis of arterial tissue in vitro was quantified as prolyl hydroxylase activity and the rate of radioactive proline incorporation into collagen. Arterial collagen synthesis of nondiabetic SHR and RVH animals was elevated compared to that of the nonhypertensive WKY controls. STZ-induced diabetes (8 weeks) reduced SAP of SHR, but had no effect on SAP of either RVH or normotensive WKY rats. However, diabetes significantly depressed vascular collagen synthesis of both SHR and RVH rats, and, less consistently, of the WKY. The results strongly suggest that STZ-induced diabetes in SHR impairs arterial collagen synthesis independent of associated changes in arterial pressure.


Actinidia arguta (Sieb. et Zucc.) Planch. ex Miq.: A Review of Phytochemistry and Pharmacology.
Actinidia arguta (Siebold & Zucc.) Planch ex Miq. (A. arguta) is a highly valued vine plant belonging to the Actinidia lindl genus. It is extensively utilized for its edible and medicinal properties. The various parts of A. arguta serve diverse purposes. The fruit is rich in vitamins, amino acids, and vitamin C, making it a nutritious and flavorful raw material for producing jam, canned food, and wine. The flowers yield volatile oils suitable for essential oil extraction. The leaves contain phenolic compounds and can be used for tea production. Additionally, the roots, stems, and leaves of A. arguta possess significant medicinal value, as they contain a wide array of active ingredients that exert multiple pharmacological and therapeutic effects. These effects include quenching thirst, relieving heat, stopping bleeding, promoting blood circulation, reducing swelling, dispelling wind, and alleviating dampness. Comprehensive information on A. arguta was collected from scientific databases covering the period from 1970 to 2023. The databases used for this review included Web of Science, PubMed, ProQuest, and CNKI. The objective of this review was to provide a detailed explanation of A. arguta from multiple perspectives, such as phytochemistry and pharmacological effects. By doing so, it aimed to establish a solid foundation and propose new research ideas for further exploration of the plant's potential applications and industrial development. To date, a total of 539 compounds have been isolated and identified from A. arguta. These compounds include terpenoids, flavonoids, phenolics, phenylpropanoids, lignin, organic acids, volatile components, alkanes, coumarins, anthraquinones, alkaloids, polysaccharides, and inorganic elements. Flavonoids, phenolics, alkaloids, and polysaccharides are the key bioactive constituents of A. arguta. Moreover, phenolics and flavonoids in A. arguta exhibit remarkable antioxidant, anti-inflammatory, and anti-tumor properties. Additionally, they show promising potential in improving glucose metabolism, combating aging, reducing fatigue, and regulating the immune system. While some fundamental studies on A. arguta have been conducted, further research is necessary to enhance our understanding of its mechanism of action, quality evaluation, and compatibility mechanisms. A more comprehensive investigation is highly warranted to explore the mechanism of action and expand the range of drug resources associated with A. arguta. This will contribute to the current hot topics of anti-aging and anti-tumor drug research and development, thereby promoting its further development and utilization.


Neuroprotective effect of erythropoietin on hypoxic-ischemic brain injury in neonatal rats.
Erythropoietin (Epo) prevents ischemia and hypoxia-induced neuronal death in vitro. Recent studies have shown that this cytokine also has in vivo neuroprotective effects in cerebral and spinal ischemia in adult rodents. In this study, we aimed to investigate the effect of systemically administered recombinant human Epo on infarct volume and apoptotic neuronal death in a newborn rat hypoxic-ischemic brain injury model. Our results showed that a single dose of intraperitoneal Epo treatment (1,000 U/kg) significantly decreased the mean infarct volume as compared to the control group. In contrast to the Epo-treated group, histopathological examination by positive terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling of the affected brain in control animals revealed widespread neuronal injury associated with numerous apoptotic cells. Morphometric analysis to determine the extent of damage quantitatively ascertained that the mean infarct volume was significantly lower in the Epo-treated group (p < 0.003). These results suggest the beneficial neuroprotective effect of Epo in this model of neonatal hypoxic-ischemic brain injury. To our knowledge, this is the first study that demonstrates a protective effect of Epo against hypoxia-ischemia in the developing brain.


Immunocytochemical evidence for the presence of somatostatin-like immunoreactive nerves in human dental pulp.
Specific antiserum to somatostatin was used for the immunocytochemical detection of this neuropeptide in human dental pulp. Immunoreactive axon varicosities were observed in the radicular as well as coronal pulp. Fibers displaying somatostatin-like immunoreactivity were detectable within radicular nerve trunks and were found to be associated mainly with blood vessels. Nevertheless, positive fibers with no apparent relation to blood vessels were also observed. No pulp cell was found to be immunoreactive. Previous physiological studies demonstrated that somatostatin may function as a regulatory peptide in feline dental pulp via a pre-synaptic inhibition of substance P release from sensory nerve terminals. It is tempting to speculate that such a mechanism may also be effective in human teeth and may be of value in the regulation of pulpal blood flow and in situations when sensory nerve fibers are activated, e.g., during pulpal inflammation.


Membrane Electromechanics in Biology, with a Focus on Hearing.
Cells are ion conductive gels surrounded by a ~5-nm-thick insulating membrane, and molecular ionic pumps in the membrane establish an internal potential of approximately -90 mV. This electrical energy store is used for high-speed communication in nerve and muscle and other cells. Nature also has used this electric field for high-speed motor activity, most notably in the ear, where transduction and detection can function as high as 120 kHz. In the ear, there are two sets of sensory cells: the "inner hair cells" that generate an electrical output to the nervous system and the more numerous "outer hair cells" that use electromotility to counteract viscosity and thus sharpen resonance to improve frequency resolution. Nature, in a remarkable exhibition of nanomechanics, has made out of soft, aqueous materials a microphone and high-speed decoder capable of functioning at 120 kHz, limited only by thermal noise. Both physics and biology are only now becoming aware of the material properties of biomembranes and their ability to perform work and sense the environment. We anticipate new examples of this biopiezoelectricity will be forthcoming.


Feeble object detection of underwater images through LSR with delay loop.
Feeble object detection is a long-standing problem in vision based underwater exploration work. However, because of the complicated light propagation situation and high background noise, underwater images are highly degraded. Noise is not always detrimental. Logical stochastic resonance (LSR) can be a useful tool for amplifying feeble signals by utilizing the constructive interplay of noise and a nonlinear system. In the present study, an appropriate LSR structure with a delay loop is proposed to process a low-quality underwater image for enhancing the vision detection accuracy of underwater feeble objects. Ocean experiments are conducted to demonstrate the effectiveness of the proposed structure. We also give explicit numerical results to illustrate the relationship between the structure of LSR and the correct detection probability. Methods presented in this paper are quite general and can thus be potentially extended to other applications for obtaining better performance.


Pyrrolizidine alkaloids in honey and bee pollen.
A total of 3917 honey samples and 119 'bee pollen' samples (pollen collected by honeybees) were analysed for pyrrolizidine alkaloids (PAs). Some 0.05 M sulphuric acid was used for extraction followed by a clean-up step by means of solid-phase extraction. Separation and detection was achieved by target analysis using an LC-MS/MS system. PAs were found in 66% of the raw honeys (bulk honey not yet packaged in containers for sale in retail outlets) and in 94% of honeys available in supermarkets (retail honey). A total of 60% of the bee pollen samples were PA positive. The PA pattern was used to identify the potential origin of the PAs in honey, which was verified for the genus Echium by relative pollen analysis. The results give an estimate of the impact of PA-containing plants belonging to the genera Echium, Senecio and, to a certain extent, Eupatorium on PA levels in honey and can serve as a decision basis for beekeepers in order to find the most suitable location for the production of honey and bee pollen low in PAs.


Challenging the maximum flow rate: a new index of voiding dysfunction in men with benign prostatic enlargement.
To present the theoretical development and clinical relevance of a new index of voiding dysfunction (D) based purely on free uroflow (FF), to assist in the management of patients with benign prostatic enlargement (BPE), and to compare its merits against the maximum flow rate (Q(max)). In the Valentini-Besson-Nelson (VBN) micturition model for men, two variables characterize urethral obstruction, i.e. the prostatic urethral counter-pressure pucp and the detrusor force coefficient k. D can be obtained from a FF assuming a normal detrusor (k = 1). Clinically, multiple FF from patients entered in a double-blind pharmacological trial provided variations of D over time. D values were also compared before and after transurethral resection of the prostate (TURP). In 137 patients with BPE from several institutions, D was more precise than Q(max) because D is independent of volume and of perturbations of short duration during the flow. The change in D was proportionate to the invasiveness of treatment; the mean (SD) decrease after TURP was 14.6 (8.7) cmH(2)O, vs 8.1 (5.4) cmH(2)O after 90 days of alpha-blocker intake. Retrospectively, the range of D fitted with the clinician's decision, i.e. pharmacological trial (16-31 cmH(2)O) vs TURP (27-46 cmH(2)O; P < 0.001). The new index (D), deduced from the VBN analysis of only FF, is responsive to treatment. This simple calculation offers an insight into the voiding status of a patient with BPE beyond that obtained by Q(max) alone.


General anesthetic versus light sedation: effect on pediatric endoscopy wait times.
Wait times are an important measure of health care system effectiveness. There are no studies describing wait times in pediatric gastroenterology for either outpatient visits or endoscopy. Pediatric endoscopy is performed under light sedation or general anesthesia. The latter is hypothesized to be associated with a longer wait time due to practical limits on access to anesthesia in the Canadian health care system. To identify wait time differences according to sedation type and measure adverse clinical outcomes that may arise from increased wait time to endoscopy in pediatric patients. The present study was a retrospective review of medical charts of all patients <18 years of age who had been assessed in the pediatric gastroenterology clinic and were scheduled for an elective outpatient endoscopic procedure at McMaster Children's Hospital (Hamilton, Ontario) between January 2006 and December 2007. The primary outcome measure was time between clinic visit and date of endoscopy. Secondary outcome measures included other defined waiting periods and complications while waiting, such as emergency room visits and hospital admissions. The median wait time to procedure was 64 days for general anesthesia patients and 22 days for patients who underwent light sedation (P<0.0001). There was no significant difference between the two groups with regard to the number of emergency room visits or hospital admissions, both pre- and postendoscopy. Due to the lack of pediatric anesthetic resources, patients who were administered general anesthesia experienced a longer wait time for endoscopy compared with patients who underwent light sedation. This did not result in adverse clinical outcomes in this population.


[Hemostasis and rheologic properties of blood in patients with minor strokes].
The hemostasis and rheological properties of the blood were studied in 88 patients with minor stroke (MS), 26 with transient disorders of the cerebral circulation (TDCC), and in 34 patients with stroke with minimum residual symptoms (SMRS). It has been established that disturbances of the hemostasis and rheological properties of the blood are one of the pathogenetic factors with respect to MS. In terms of severity and reversibility the latter occupies an intermediate position between TDCC and SMRS.


Septic pulmonary embolism: Is it an underestimated diagnosis?
Non-thrombotic pulmonary embolism, an uncommon entity, is defined as the embolization of tissues, microorganisms, air, or foreign material. One subset in this non-thrombotic category is septic pulmonary embolism (SPE) that refers to embolism of microorganisms with or without a thrombotic mantle into the pulmonary vasculature. This condition is often recognized on the basis of imaging with a clinical correlation. Unfortunately, data regarding the pathological features are meager. This has prompted to review such cases at autopsy. To study the pathological features of SPE at autopsy. Ten-year (2012 to 2021) autopsy records of the hospital were retrospectively reviewed. The diagnosis was based on the identification of acute necrotizing pulmonary arteritis with peri-bronchoarterial consolidation. These cases were analyzed with reference to the demographics, clinical characteristics, and pulmonary/extrapulmonary findings at autopsy. Nil. According to the inclusion criterion, 19 cases demonstrated the presence of SPE. There were 11 men and 8 women with a mean age of 32.1 years. The major source of infection included infection arising from skin and musculo-skeletal system (11 patients, 59.7%). The common clinical presentation included fever, dyspnea, chest pain, hemoptysis, and altered sensorium. The cause of death was mainly due to septicemia and/or confluent lung consolidations. A large number of bacterial colonies were seen in all; Candida species were also identified in two cases. Other lung findings included diffuse alveolar damage, fresh arterial thrombosis, infarction, arterial pseudo-aneurysms, abscess formation, and pyogenic pleuritis. Presence of an extrapulmonary infection with persistent fever, bacteremia, and pulmonary complaints should raise suspicion for this entity, particularly in resource-poor settings, to prevent grave pulmonary complications.


Hospital falls prevention with patient education: a scoping review.
Hospital falls remain a frequent and debilitating problem worldwide. Most hospital falls prevention strategies have targeted clinician education, environmental modifications, assistive devices, hospital systems and medication reviews. The role that patients can play in preventing falls whilst in hospital has received less attention. This critical review scopes patient falls education interventions for hospitals. The quality of the educational designs under-pinning patient falls education programmes was also evaluated. The outcomes of patient-centred falls prevention programs were considered for a range of hospital settings and diagnoses. The Arksey and O'Malley (2005) framework for scoping reviews was adapted using Joanna Briggs Institute and PRISMA-ScR guidelines. Eight databases, including grey literature, were searched from January 2008 until February 2020. Two reviewers independently screened the articles and data were extracted and summarised thematically. The quality of falls prevention education programs for patients was also appraised using a modified quality metric tool. Forty-three articles were included in the final analysis. The interventions included: (i) direct face-to-face patient education about falls risks and mitigation; (ii) educational tools; (iii) patient-focussed consumer materials such as pamphlets, brochures and handouts; and (iv) hospital systems, policies and procedures to assist patients to prevent falls. The included studies assessed falls or education related outcomes before and after patient falls prevention education. Few studies reported incorporating education design principles or educational theories. When reported, most educational programs were of low to moderate quality from an educational design perspective. There is emerging evidence that hospital falls prevention interventions that incorporate patient education can reduce falls and associated injuries such as bruising, lacerations or fractures. The design, mode of delivery and quality of educational design influence outcomes. Well-designed education programs can improve knowledge and self-perception of risk, empowering patients to reduce their risk of falling whilst in hospital.


Co-circulation of paramyxo- and influenza viruses in pigeons in Egypt.
In recent years, avian influenza virus (AIV) and Newcastle disease virus (NDV) have caused large-scale outbreaks in many countries, including Egypt. The culling and vaccination strategies have failed to control both viruses in Egypt. In this study, we investigated the outbreaks of nervous manifestations and deaths in pigeons between 2013 and 2015. The H5N1 subtype of the highly pathogenic avian influenza virus and pigeon paramyxovirus-1, an antigenic variant of NDV, were found to be the cause; AIV and pigeon paramyxovirus-1 were isolated from 61.3% (19/31) and 67.8% (21/31) of tested pigeons, respectively. Co-infection with both viruses was detected in 51.6% of pigeons (16/31). The AIV sequences showed PQGEKRRKKR/GLF motif at the haemagglutinin gene cleavage site, which is typical of the highly pathogenic H5N1 subtype. The phylogenetic tree showed that the highly pathogenic avian influenza belonged to clade 22.214.171.124. The NDV sequences carried one of the three motifs, 112GKQGRL117, 112KRQKRF117 or 112RRQKRF117, at the fusion protein cleavage site and were classified as genotypes I, VI and II in NDV-class II, respectively. This indicated that different genotypes of NDV can circulate simultaneously among pigeons. Further analysis revealed the clustering of some sequences in sub-genotypes Ia and VIb.2. To the best of our knowledge, these sub-genotypes have not been previously reported from pigeons in Egypt. Our results should serve as a base for future studies on both viruses in Egypt.


Defective interfering particles of encephalomyocarditis virus.
Encephalomyocarditis (EMC) virus and five temperature-sensitive mutants of EMC virus were serially passed numerous times in HeLa, L929 and BHK-21 cells. Equilibrium centrifugation in CsCl density gradients of virus and electrophoresis of virus RNA from many of the high number passages indicated the presence of standard EMC virus and particles containing RNA of lower molecular weight. Three virus isolates with high passage number were able to interfere with the replication of the standard virions in mixed infections. We believe our results show the generation of defective interfering particles of EMC virus.


Two-Dimensional Electron Gas at the Spinel/Perovskite Interface: Suppression of Polar Catastrophe by an Ultrathin Layer of Interfacial Defects.
Two-dimensional electron gas (2DEG) at the interface between two insulating perovskite oxides has attracted much interest for both fundamental physics and potential applications. Here, we report the discovery of a new 2DEG formed at the interface between spinel MgAl2O4 and perovskite SrTiO3. Transport measurements, electron microscopy imaging, and first-principles calculations reveal that the interfacial 2DEG is closely related to the symmetry breaking at the MgAl2O4/SrTiO3 interface. The critical film thickness for the insulator-to-metal transition is approximately 32 Å, which is twice as thick as that reported on the widely studied LaAlO3/SrTiO3 system. Scanning transmission electron microscopy imaging indicates the formation of interfacial Ti-Al antisite defects with a thickness of ∼4 Å. First-principles density functional theory calculations indicate that the coexistence of the antisite defects and surface oxygen vacancies may explain the formation of interfacial 2DEG as well as the observed critical film thickness. The discovery of 2DEG at the spinel/perovskite interface introduces a new material platform for designing oxide interfaces with desired characteristics.


Efficient and stable acidic CO2 electrolysis to formic acid by a reservoir structure design.
Electrochemical synthesis of valuable chemicals and feedstocks through carbon dioxide (CO2) reduction in acidic electrolytes can surmount the considerable CO2 loss in alkaline and neutral conditions. However, achieving high productivity, while operating steadily in acidic electrolytes, remains a big challenge owing to the severe competing hydrogen evolution reaction. Here, we show that vertically grown bismuth nanosheets on a gas-diffusion layer can create numerous cavities as electrolyte reservoirs, which confine in situ-generated hydroxide and potassium ions and limit inward proton diffusion, producing locally alkaline environments. Based on this design, we achieve formic acid Faradaic efficiency of 96.3% and partial current density of 471 mA cm-2 at pH 2. When operated in a slim continuous-flow electrolyzer, the system exhibits a full-cell formic acid energy efficiency of 40% and a single pass carbon efficiency of 79% and performs steadily over 50 h. We further demonstrate the production of pure formic acid aqueous solution with a concentration of 4.2 weight %.


Characterization of mice deficient in the Src family nonreceptor tyrosine kinase Frk/rak.
Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Although developmental expression patterns and functional overexpression in vitro have associated these kinases with growth suppression and differentiation, their physiological functions remain largely unknown. We therefore generated mice carrying a null mutation in iyk, the mouse homolog of Frk/rak. We report here that frk/rak(-/-) mice are viable, show similar growth rates to wild-type animals, and are fertile. Furthermore, a 2-year study of health and survival did not identify differences in the incidence and spectrum of spontaneous tumors or provide evidence of hyperplasias in frk/rak(-/-) epithelial tissues. Histological analysis of organs failed to reveal any morphological changes in epithelial tissues that normally express high levels of Frk/rak. Ultrastructural analysis of intestinal enterocytes did not identify defects in brush border morphology or structural polarization, demonstrating that Frk/rak is dispensable for intestinal cytodifferentiation. Additionally, frk/rak-null mice do not display altered sensitivity to intestinal damage induced by ionizing radiation. cDNA microarray analysis revealed an increase in c-src expression and identified subtle changes in the expression of genes regulated by thyroid hormones. Significant decreases in the circulating levels of T3 but not T4 hormone are consistent with this observation and reminiscent of euthyroid sick syndrome, a stress-associated clinical condition.


Pathogenesis, neuroimaging and management in children with cerebral palsy born preterm.
With advances in obstetric and perinatal management, the incidence of intraventricular hemorrhage in premature infants has declined, while periventricular leukomalacia remains a significant concern. It is now known that brain injury in children born preterm also involves neuronal-axonal disease in supratentorial and infratentorial structures. The developing brain is especially vulnerable to white matter (WM) injury from 23 to 34 weeks gestation when blood vessels serving the periventricular WM are immature. Oligodendrocyte progenitors, which are beginning to form myelin during this time, are susceptible to attack from oxygen free radicals, glutamate, and inflammatory cytokines. Advances in imaging techniques such as diffusion tensor imaging provide a more complete picture of the location and extent of injury. Effective management of children born preterm with cerebral palsy is predicated on an understanding of sequential links from etiological antecedents to brain neuropathology as revealed with neuroimaging techniques to clinical phenotypes, toward focused interventions with measurable outcomes.


Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson's disease.
The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine, Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found that the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD.


Perturbation of the normal immune system in patients with CLL.
Immune dysregulation is a cardinal feature of chronic lymphocytic leukemia (CLL) from its early stage and worsens during clinical observation, even in absence of disease progression. Although the mechanisms remain unclear, new insights are emerging into the complex relationship between the CLL clone and its immune environment. T cells are increased in early-stage disease and show progressive accumulation and exhaustion. The mechanisms that drive this expansion may include auto-antigens involved in the original clonal expansion. In addition, chronic viral infections such as cytomegalovirus generate huge virus-specific immune responses, which are further expanded in CLL. Attention is now focused largely on the direct immunosuppressive properties of the tumor. Remarkably, CLL clones often have features of the recently described regulatory B cells producing immunosuppressive IL-10. Better knowledge of the regulatory properties intrinsic to CLL cells may soon become more important with the switch from chemotherapy-based treatments, which trade control of CLL with further impairment of immune function, to the new agents targeting CLL B-cell receptor-associated signaling. Treatment with these new agents is associated with evidence of immune recovery and reduced infectious complications. As such, they offer the prospect of immunologic rehabilitation and a platform from which to ultimately replace chemotherapy.


Diagnostic yield of genetic testing in children diagnosed with autism spectrum disorders at a regional referral center.
The aim was to systematically review genetic testing guidelines in the evaluation of children with autism spectrum disorders (ASDs). The Clinical Report published by the American Academy of Pediatrics (AAP)(1) recommended individualizing the workup, including karyotype and specific DNA testing for fragile X syndrome. A recent publication reported higher rates of abnormalities on CGH microarray (CMA) testing on children with ASD.(2) The medical records of 507 children seen through the Kirch Developmental Services Center were abstracted for genetic testing and factors associated with this testing. Abnormalities were found on karyotype in 2.3% and in DNA for fragile X in 0.04%. The author concludes that the diagnostic yield of the genetic testing was low in this population. Furthermore, their findings support the theory that CMA can be considered as part of the initial genetic screening in children with ASD in most situations. Future studies will need to be done prospectively to evaluate children in a standard fashion.


Fast training of recurrent networks based on the EM algorithm.
In this work, a probabilistic model is established for recurrent networks. The expectation-maximization (EM) algorithm is then applied to derive a new fast training algorithm for recurrent networks through mean-field approximation. This new algorithm converts training a complicated recurrent network into training an array of individual feedforward neurons. These neurons are then trained via a linear weighted regression algorithm. The training time has been improved by five to 15 times on benchmark problems.


Functional, structural, and neuronal alterations in urinary bladder during diabetes: investigations of a mouse model.
Urinary bladder dysfunction is a common complication in diabetes, but the mechanisms involved are undefined and treatment options are limited. Murine models provide opportunities to utilize transgenic technologies for bladder research and here we investigate the functional, structural and neuronal aspects of the bladder in a mouse model of type-1 diabetes. Mice were injected with streptozotocin (150 mg/kg) or vehicle and studied at 5 weeks. Increases in blood glucose and total urine output were observed. In vitro cystometry showed a 2-fold increase in bladder capacity and compliance and decreased intravesical plateau pressure in diabetics versus controls. Bladder structure and composition were evaluated by digital imaging; region-specific changes included increased smooth muscle and urothelium and no change in collagen content. Alterations in cholinergic, adrenergic and nitric oxide-related functional responsiveness were also observed. The prevalence of cholinergic and adrenergic neuronal tracts was determined by immunohistochemistry: decreased vesicular acetylcholine transferase was observed in smooth muscle, whereas tyrosine hydroxylase was increased in the lamina propria, demonstrating a 'neuronal remodeling' shift toward pro-relaxant neuronal pathways. These studies demonstrate that this mouse model of diabetes exhibits important features of urinary bladder remodeling that are similar to the findings in humans and other animal models and will therefore be useful for further mechanistic investigations.


Grey matter changes in motor conversion disorder.
To detect anatomical differences in areas related to motor processing between patients with motor conversion disorder (CD) and controls. T1-weighted 3T brain MRI data of 15 patients suffering from motor CD (nine with hemiparesis and six with paraparesis) and 25 age- and gender-matched healthy volunteers were compared using voxel-based morphometry (VBM) and voxel-based cortical thickness (VBCT) analysis. We report significant cortical thickness (VBCT) increases in the bilateral premotor cortex of hemiparetic patients relative to controls and a trend towards increased grey matter volume (VBM) in the same region. Regression analyses showed a non-significant positive correlation between cortical thickness changes and symptom severity as well as illness duration in CD patients. Cortical thickness increases in premotor cortical areas of patients with hemiparetic CD provide evidence for altered brain structure in a condition with presumed normal brain anatomy. These may either represent premorbid vulnerability or a plasticity phenomenon related to the disease with the trends towards correlations with clinical variables supporting the latter.


Effect of a chloride channel blocker on bullfrog corneal epithelium.
The effect of the chloride channel blocker, diphenylamine-2-carboxylate (DPC), was investigated on the bullfrog cornea epithelium using microelectrodes. Perfusion of 2 X 10(-4) M DPC on the tear side resulted in a 44% reduction of the corneal transepithelial potential difference (TEP) and a 9% reduction in corneal conductance. The cornea epithelial cells hyperpolarized 7.2 +/- 1.5 mV, and the apical fractional resistance increased 35% (n = 8 tissues). The basolateral potential difference depolarized 5.5 +/- 1.8 mV. The relative apical conductance decreased 29%, whereas relative changes of basolateral membranes increased 56% with prolonged DPC exposure, indicating that the DPC inhibition was acting at the apical cell membrane. DPC-treated corneas could be stimulated with isoproterenol (10(-6) M), indicating that the DPC inhibition could be reversed with the stimulation of chloride conductance. The DPC inhibitory effect was dependent on basolateral chloride. Intracellular chloride activity increases with DPC, indicating that the integrity of the basolateral chloride entry mechanism was not altered. The DPC inhibitory action was due to a reduction in apical chloride conductance.


Mapping ligand interactions with the hyperpolarization activated cyclic nucleotide modulated (HCN) ion channel binding domain using a soluble construct.
Hyperpolarization activated cyclic nucleotide modulated (HCN) ion channel currents are activated by hyperpolarization and modulated in response to changes in cytosolic adenosine 3',5'-cyclic monophosphate (cAMP) concentrations. A cDNA chimera combining the rat HCN2 cyclic nucleotide binding domain and the DNA binding domain of the cAMP receptor protein (CRP) from E. coli and the histidine tag (HCN2/CRP) was expressed and purified. The construct is capable of forming only non-ligand dependent dimers because the C-linker region of the channel is not present in this construct. The construct binds 8-[[2-[(fluoresceinylthioureido) amino] ethyl] thio] adenosine-3',5'-cyclic monophosphate (8-fluo cAMP) with a Kd of 0.299 microM as determined with a monomer binding model. The Ki values of 20 ligands related to cAMP were measured in order to determine the properties necessary for a ligand to bind to the HCN2 binding domain. This is the first report of cAMP and gunaosine 3',5'-cyclic monophosphate (cGMP) affinities to the HCN2 binding domain being equivalent, even though they modulate the channel with a 10-fold difference in K0.5. Furthermore, the array of ligands measured allows the preference rank order for each purine ring position to be determined: position 1, H > NH2 > O; position 2, NH2 > Cl > H > O; position 6, NH2 > Cl > H > O; and position 8, NH2 > Cl > H > O. Finally, the ability of HCN2/CRP to bind cyclic nucleotide pyrimidine rings at concentrations approximately 1.33 times greater than cAMP suggests that ribofuranose is key for binding.


Genome Analysis of Planctomycetes Inhabiting Blades of the Red Alga Porphyra umbilicalis.
Porphyra is a macrophytic red alga of the Bangiales that is important ecologically and economically. We describe the genomes of three bacteria in the phylum Planctomycetes (designated P1, P2 and P3) that were isolated from blades of Porphyra umbilicalis (P.um.1). These three Operational Taxonomic Units (OTUs) belong to distinct genera; P2 belongs to the genus Rhodopirellula, while P1 and P3 represent undescribed genera within the Planctomycetes. Comparative analyses of the P1, P2 and P3 genomes show large expansions of distinct gene families, which can be widespread throughout the Planctomycetes (e.g., protein kinases, sensors/response regulators) and may relate to specific habitat (e.g., sulfatase gene expansions in marine Planctomycetes) or phylogenetic position. Notably, there are major differences among the Planctomycetes in the numbers and sub-functional diversity of enzymes (e.g., sulfatases, glycoside hydrolases, polysaccharide lyases) that allow these bacteria to access a range of sulfated polysaccharides in macroalgal cell walls. These differences suggest that the microbes have varied capacities for feeding on fixed carbon in the cell walls of P.um.1 and other macrophytic algae, although the activities among the various bacteria might be functionally complementary in situ. Additionally, phylogenetic analyses indicate augmentation of gene functions through expansions arising from gene duplications and horizontal gene transfers; examples include genes involved in cell wall degradation (e.g., κ-carrageenase, alginate lyase, fucosidase) and stress responses (e.g., efflux pump, amino acid transporter). Finally P1 and P2 contain various genes encoding selenoproteins, many of which are enzymes that ameliorate the impact of environmental stresses that occur in the intertidal habitat.


Focus on: ethnicity and the social and health harms from drinking.
Alcohol consumption is differentially associated with social and health harms across U.S. ethnic groups. Native Americans, Hispanics, and Blacks are disadvantaged by alcohol-attributed harms compared with Whites and Asians. Ethnicities with higher rates of risky drinking experience higher rates of drinking harms. Other factors that could contribute to the different effects of alcohol by ethnicity are social disadvantage, acculturation, drink preferences, and alcohol metabolism. This article examines the relationship of ethnicity and drinking to (1) unintentional injuries, (2) intentional injuries, (3) fetal alcohol syndrome (FAS), (4) gastrointestinal diseases, (5) cardiovascular diseases, (6) cancers, (7) diabetes, and (8) infectious diseases. Reviewed evidence shows that Native Americans have a disproportionate risk for alcohol-related motor vehicle fatalities, suicides and violence, FAS, and liver disease mortality. Hispanics are at increased risk for alcohol-related motor vehicle fatalities, suicide, liver disease, and cirrhosis mortality; and Blacks have increased risk for alcohol-related relationship violence, FAS, heart disease, and some cancers. However, the scientific evidence is incomplete for each of these harms. More research is needed on the relationship of alcohol consumption to cancers, diabetes, and HIV/AIDS across ethnic groups. Studies also are needed to delineate the mechanisms that give rise to and sustain these disparities in order to inform prevention strategies.


Mycobacterium marinum MMAR_2380, a predicted transmembrane acyltransferase, is essential for the presence of the mannose cap on lipoarabinomannan.
Lipoarabinomannan (LAM) is a major glycolipid in the mycobacterial cell envelope. LAM consists of a mannosylphosphatidylinositol (MPI) anchor, a mannan core and a branched arabinan domain. The termini of the arabinan branches can become substituted with one to three α(1→2)-linked mannosyl residues, the mannose cap, producing ManLAM. ManLAM has been associated with a range of different immunomodulatory properties of Mycobacterium tuberculosis during infection of the host. In some of these effects, the presence of the mannose cap on ManLAM appears to be crucial for its activity. So far, in the biosynthesis of the mannose cap on ManLAM, two enzymes have been reported to be involved: a mannosyltransferase that adds the first mannosyl residue of the mannose caps to the arabinan domain of LAM, and another mannosyltransferase that elongates the mannose cap up to three mannosyl residues. Here, we report that a third gene is involved, MMAR_2380, which is the Mycobacterium marinum orthologue of Rv1565c. MMAR_2380 encodes a predicted transmembrane acyltransferase. In M. marinum ΔMMAR_2380, the LAM arabinan domain is still intact, but the mutant LAM lacks the mannose cap. Additional effects of mutation of MMAR_2380 on LAM were observed: a higher degree of branching of both the arabinan domain and the mannan core, and a decreased incorporation of [1,2-(14)C]acetate into the acyl chains in mutant LAM as compared with the wild-type form. This latter effect was also observed for related lipoglycans, i.e. lipomannan (LM) and phosphatidylinositol mannosides (PIMs). Furthermore, the mutant strain showed increased aggregation in liquid cultures as compared with the wild-type strain. All phenotypic traits of M. marinum ΔMMAR_2380, the deficiency in the mannose cap on LAM and changes at the cell surface, could be reversed by complementing the mutant strain with MMAR_2380. Strikingly, membrane preparations of the mutant strain still showed enzymic activity for the arabinan mannose-capping mannosyltransferase similar to that of the wild-type strain. Although the exact function of MMAR_2380 remains unknown, we show that the protein is essential for the presence of a mannose cap on LAM.


Recruitment of the putative transcription-repair coupling factor CSB/ERCC6 to RNA polymerase II elongation complexes.
Cockayne's syndrome (CS) is a disease characterized by developmental and growth defects, sunlight sensitivity, and a defect in transcription-coupled nucleotide excision repair. The two principle proteins involved in CS, CSA and CSB/ERCC6, have been hypothesized to bind RNA polymerase II (Pol II) and link transcription to DNA repair. We have tested CSA and CSB in assays designed to determine their role in transcription-coupled repair. Using a unique oligo(dC)-tailed DNA template, we provide biochemical evidence that CSB/ERCC6 interacts with Pol II molecules engaged in ternary complexes containing DNA and nascent RNA. CSB is a DNA-activated ATPase, and hydrolysis of the ATP beta-gamma phosphoanhydride bond is required for the formation of a stable Pol II-CSB-DNA-RNA complex. Unlike CSB, CSA does not directly bind Pol II.


Behavioural responses of zebrafish larvae to acute ethosuximide exposure.
The anticonvulsant drug ethosuximide has shown diverse anxiety-related activity in rodents, but research in zebrafish is limited. To evaluate the effects of acute ethosuximide exposure on locomotor activity and anxiety-related thigmotaxis behaviours of zebrafish larvae, the activity of AB strain zebrafish larvae at 5 and 7 days postfertilization (dpf) was analysed under normal constant illumination and stressful light-dark transitions. Under constant illumination, ethosuximide at concentrations of 2, 5 and 10 mmol/l increased the distances travelled and intensified locomotor responses to a novel environment. In addition, 40 mmol/l ethosuximide decreased the travel distance and attenuated the locomotor response to darkness. The effects were age related. Under constant illumination, ethosuximide at 40 mmol/l reduced thigmotaxis behaviours in larvae at both ages. Under the light-dark transition, 5 mmol/l ethosuximide reduced thigmotaxis behaviours in 7-dpf larvae. We concluded that under constant lighting, ethosuximide at low concentrations (2, 5 and 10 mmol/l) stimulated the locomotor activity of zebrafish larvae, whereas a high concentration (40 mmol/l) inhibited the activity. Ethosuximide at a low concentration (5 mmol/l) showed anxiolytic effects during the stressful light-dark transition in 7-dpf larvae. The effects of ethosuximide were age and concentration related.


The prognostic significance of ureteral obstruction in patients with recurrent carcinoma of the cervix uteri.
The findings of the present investigation confirm that no patient with total ureteral obstruction by recurrent cancer survived longer than two years after pelvic exenteration. In contrast,ver 50 per cent of those patients with normal intravenous pyelograms are alive with no evidence of disease two to ten years after radical operation. There is no question that all patients with recurrent carcinoma of the cervix uteri who are satisfactory candidates for radical operative procedures should undergo exploration to determine the extent of the disease and the possibility to curative resection. However, when total ureteral obstruction is found to be caused by a tumor, patient survival is so limited as to make pelvic exenteration impractical.


Melancholic Symptoms in Bipolar II Depression and Responsiveness to Lamotrigine in an Exploratory Pilot Study.
In this exploratory pilot study we reanalyzed data from a previous randomized, double-blind, placebo-controlled trial of lamotrigine for bipolar II depression in which lamotrigine was not superior to placebo to determine if splitting the sample into melancholic and nonmelancholic subgroups revealed a significant treatment effect. Adult outpatients (n = 150) in an acute bipolar II depressive episode completed 8 weeks of treatment with lamotrigine (titrated to 200 mg/d) or placebo. Depressive symptoms were assessed at baseline and weekly with the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Åsberg Depression Rating Scale (MADRS). The presence of melancholic depression was determined by baseline responses to the HAMD-17 and MADRS according to the Diagnostic and Statistical Manual of Mental Disorders criteria. Cox regression models stratified by melancholic status were used to predict HAMD-17 and MADRS treatment response. Analysis-of-variance models were used to compare HAMD-17 and MADRS change scores between lamotrigine and placebo groups while testing for interactions by melancholic status. Lamotrigine was associated with higher odds of treatment response compared with placebo in the melancholic subgroup but not in the nonmelancholic subgroup. However, the melancholic subgroup-treatment interactions from the analysis-of-variance models were nonsignificant. Further research is warranted to test the hypothesis that bipolar depression with melancholic symptoms is more responsive to lamotrigine over placebo than nonmelancholic bipolar depression.


Synergistic effect of hyperbaric oxygen therapy with PTH [1-34] on calvarial bone graft in irradiated rat.
To determine the synergistic effect of parathyroid hormone (PTH) [1-34] in combination with hyperbaric oxygen (HBO) on bone graft in a rat calvarial bone defect model under impaired osteogenic conditions. Twenty-four rats were divided into three groups. Localized radiation with a single 12 Gy dose was administered to the calvaria. Four weeks after radiation, calvarial circular defects were created in the parietal bones. All defects were filled with biphasic calcium phosphate. After the bone graft, PTH [1-34] was injected subcutaneously, and HBO was administered. At 6 weeks after the bone graft, the rats were sacrificed, and specimens were harvested. Histomorphometric evaluation showed that the percentage of new bone area was higher in the PTH and PTH/HBO groups than in the control group. The percent residual material area was decreased in the PTH/HBO group compared with the control group. The percentage blood vessel number was highest in the PTH group. Micro-CT evaluation showed that the new bone volume was highest in the PTH/HBO group. The residual material volume was lowest in the PTH/HBO group. Within the limitations of this study, our data indicate that PTH combined with HBO may reverse radiation-induced impairment of bone healing.


Validation of an in vitro potency test for the Cuban hepatitis B vaccine.
Cuban Hepatitis B vaccine is used for immunisation in our country and by other countries. There is a need to harmonise the quality control procedures, mainly the potency tests. Taking into account that the in vivo potency test is more expensive, variable and longer than the alternative methods and that the commercial kits are expensive, we designed an in-house method based on the principle of the previous neutralisation test (using Hepanostika anti-HbsAg kit). This is the same principle used by the Cuban Hepatitis B manufacturer for lot release. The aim of this paper was to validate our in vitro method, to replace the in vivo test in our laboratory. We evaluated validation parameters such as specificity, accuracy, and precision with outstanding results. We also correlated our method with the in vitro test performed by the Cuban manufacturer (r=0.96, p=0.0093) and the method performed by Venezuela using commercial kits (for direct determination of antigen) and we got very good results (r=0.998, p=0.0009). The correlation with the in vivo potency test (using Hepanostika anti-HbsAg kit) was also good (r=0.995, p=0.0008).


The NCK and ABI adaptor genes in catfish and their involvement in ESC disease response.
Adaptor proteins non-catalytic region of tyrosine kinase (NCK) and Abelson interactor (ABI) are crucial for disease response. NCK1 was identified to be a candidate gene for enteric septicemia of catfish (ESC) disease resistance, and was speculated to play similar roles during ESC and enteropathogenic Escherichia coli (EPEC) pathogenicity. ABI1 was reported as a positional candidate gene for bacterial cold water disease (BCWD) resistance in rainbow trout. In this study, three NCK genes and six ABI genes were identified in the channel catfish (Ictalurus punctatus) genome and blue catfish (I. furcatus) transcriptome, and annotated by domain structures, phylogenetic and syntenic analyses. Their expression patterns were examined in the intestine and liver of catfish after challenge with Edwardsiella ictaluri. In the intestine, NCK1, ABI2a, ABI2b, ABI3a were differentially expressed after E. ictaluri infection. In the liver, NCK2a, NCK2b, ABI1b, ABI2a, ABI2b were significantly upregulated in ESC susceptible fish. In general, the NCK and ABI genes, with exception of ABI3a gene and NCK1 gene, were expressed at higher levels in susceptible fish after infection than in control fish, but were expressed at lower levels in resistant fish than in the control fish. Taken together, these results support the notion that NCK and ABI genes are involved in disease processes facilitating pathogenesis of the E. ictaluri bacteria.


Prevalence of traumatic brain injury in cocaine-dependent research volunteers.
There is a high prevalence of traumatic brain injury (TBI) among those with substance dependence. However, TBI often remains undiagnosed in these individuals, due to lack of routine screening in substance use treatment settings or due to overlap in some of the cognitive sequelae (eg impulsivity, disinhibition) of TBI and cocaine dependence. The prevalence of self-reported mild to moderate TBI in a group of cocaine-dependent (n = 95) and a group of healthy volunteers (n = 75) enrolled at the same facility was assessed. Additionally, the relationship between TBI and clinically relevant correlates, including impulsivity, cocaine use history, and treatment outcome in the cocaine-dependent group was also examined. A higher proportion of individuals with cocaine dependence (29.5%) reported having suffered a TBI in their lifetime compared to controls (8%) on a Closed Head Injury scale. Among cocaine users, the average age of sustaining TBI was significantly lower than the age of initiating cocaine use. Presence of TBI was not associated with higher impulsivity on the Barratt Impulsiveness Scale-11 or self-reported years of cocaine use. No differences were noted on treatment outcome for cocaine dependence as measured by treatment effectiveness scores (TES) between cocaine users with TBI and their non-TBI counterparts. These results are the first to highlight the high prevalence of TBI among individuals with cocaine dependence. This study underscores the possible role of TBI history as a risk factor for onset of cocaine use, however, more research is needed to determine the impact of co-morbid TBI as a complicating factor in the substance abuse treatment setting.