Intracranial cavity volumes: a new method and its potential applications.
Variations of brain weights and volumes often reflect pathological states. However, these parameters are more meaningful when related to intracranial volume. The most useful derived parameter is the difference between intracranial volume and brain volume expressed as a percentage (potential intracranial space). In patients with cerebral atrophy the potential intracranial space will be large, whereas in patients with space occupying lesions or brain swelling the potential intracranial space will shift towards 0%. Previously described techniques to determine intracranial volume have been unsatisfactory for routine application in the autopsy room. The technique described herein is based on the production of a permanent polyurethane cast of the cranial cavity. The casts can be formed in about 20 min with little modification of standard autopsy technique. Duplicate casts were made in twenty-seven unselected cases and in all cases there was less than 2% error in duplicate cast volumes. The cast provides a permanent record of the size and shape of the cranial cavity and can be used to determine intracranial volume or other intracranial dimension. The usefulness of the derived parameter, potential intracranial space, is evident in some of the cases studied.


Oral impacts on daily performances and recent use of dental services in schoolchildren.
To explore whether oral impacts on daily performances are related to recent use of dental services among children and whether oral impacts on specific daily performances are more strongly related to recent use of dental services. Data from a cross-sectional survey, including 805 11-12-year-old children attending four randomly selected schools in Lima (Peru), were used. The child version of the oral impacts on daily performances (Child-OIDP) was used to assess prevalence, intensity, and extent of oral impacts. Use of dental services was assessed by self-reports of last dental visit and reason for the visit. Associations of the prevalence, intensity, and extent of oral impacts with use of dental services were tested in logistic regression models. Children with oral impacts were 1.99 (95% CI: 1.17-3.37) times more likely to have used dental services recently than their counterparts. The intensity and extent of oral impacts were linearly associated with children's use of dental services. Difficulties in eating were the only type of oral impacts on daily performances associated with use of dental services, independent of children's demographic characteristics, and impacts on other performances. Oral impacts on daily performances were related to recent use of dental services among these schoolchildren.


Elaboration of the preliminary Rheumatoid Arthritis Impact of Disease (RAID) score: a EULAR initiative.
Current response criteria in rheumatoid arthritis (RA) usually assess only three patient-reported outcomes (PROs): pain, functional disability and patient global assessment. Other important PROs such as fatigue are not included. To elaborate a patient-derived composite response index for use in clinical trials in RA, the RA Impact of Disease (RAID) score. Ten patients identified 17 domains or areas of health relevant for inclusion in the score, then 96 patients (10 per country in 10 European countries) ranked these domains in order of decreasing importance. The seven most important domains were selected. Instruments were chosen for each domain after extensive literature research of psychometric properties and expert opinion. The relative weight of each of the domains was obtained from 505 patients who were asked to "distribute 100 points" among the seven domains. The average ranks of importance of these domains were then computed. The RAID score includes seven domains with the following relative weights: pain (21%), functional disability (16%), fatigue (15%), emotional well-being (12%), sleep (12%), coping (12%) and physical well-being (12%). Weights were similar across countries and across patient and disease characteristics. Proposed instruments include the Health Assessment Questionnaire and numerical ratings scales. The preliminary RAID score is a patient-derived weighted score to assess the impact of RA. An ongoing study will allow the final choice of questionnaires and assessment of validity. This score can be used in clinical trials as a new composite index that captures information relevant to patients.


Problematic and risky sexual behaviour under the influence of alcohol among university students.
The objective of this research was to determine the prevalence of problematic and risky sexual behaviour after alcohol consumption and the correlation between this prevalence and sex, behavioural factors, problematic drinking, and alcohol consumption characteristics. A survey of students was carried out at four faculties. Data were gathered via internet and self-administered paper-pencil questionnaires. The analysis employed Pearson's chi-squared test, gross odds ratios and logistic regression to calculate the adjusted odds ratios (OR) and their confidence interval (CI). Problematic drinking was detected by the CAGE test. Sixteen percent of students reached the CAGE score of 2, which indicates a potential threat of addiction, while 6% of students reached even higher problematic scores (3 or 4). Among those respondents who did drink alcohol, 23% had unprotected sex and 21% had sex which they later regretted. There were some differences between male and female respondents with men reporting more instances of risky behaviour. Among university students, problematic and risky sexual behaviour after alcohol use is associated with sex, the intensity of problematic drinking, first drunkenness, the place of alcohol use, and attitude to alcohol use. Problematic drinking and risky sexual behaviour after alcohol consumption exist among students and deserve special attention and response in the form of suitable measures. Problematic and risky sexual behaviour after alcohol consumption among university students is associated with behavioural factors and characteristics of alcohol use that allow a targeted approach to preventive efforts.


A novel polymorphism of the human CD40 receptor with enhanced function.
CD40 signaling is critical for innate and adaptive immunity against pathogens, and the cytoplasmic domain of CD40 is highly conserved both within and between species. A novel missense single nucleotide polymorphism (SNP) in the cytoplasmic domain of CD40 at position 227 (P227A) was identified, which resides on a conserved ancestral haplotype highly enriched in persons of Mexican and South American descent. Functional studies indicated that signaling via human (h) CD40-P227A stably expressed in several B-cell lines led to increased phosphorylation of c-Jun, increased secretion of the pro-inflammatory cytokines interleukin (IL)-6 and TNF-alpha, and increased Ig production, compared with wild-type hCD40. Cooperation between hCD40-P227A signaling and B-cell receptor (BCR)- or Toll-like receptor 9 (TLR9)-mediated signaling was also enhanced, resulting in elevated and synergistic production of IL-6 and Ig. We have thus identified a novel genetic variant of hCD40 with a gain-of-function immune phenotype.


Alcohol and white matter development--a review.
This is a review of the literature on the effects of alcohol on white matter development. For many years, human and animal studies have reported the vulnerability of developing white matter to the effects of alcohol. However, until recently, studies on alcohol and white matter were limited by existing technology. New technology documenting the presence of neurotransmitter receptors and ion channels on glial cells now provides a new focus for research on alcohol and white matter development. New research using new technology should enlarge our knowledge of the role of glial cells in brain damage associated with alcohol exposure during development.


Healing ethno-racial trauma in Latinx immigrant communities: Cultivating hope, resistance, and action.
Latinx immigrants living in the United States often experience the negative effects of systemic oppression, which may lead to psychological distress, including ethno-racial trauma. We define ethno-racial trauma as the individual and/or collective psychological distress and fear of danger that results from experiencing or witnessing discrimination, threats of harm, violence, and intimidation directed at ethno-racial minority groups. This form of trauma stems from a legacy of oppressive laws, policies, and practices. Using an intersectionality framework, this article discusses the complex ways in which interlocking systems of oppression (e.g., racism, ethnocentrism, nativism, sexism) and anti-immigrant policies impact Latinxs individuals, families, and communities. The article also presents a framework to stimulate healing from ethno-racial trauma titled, HEART (Healing Ethno And Racial Trauma). Grounded in the principles of Liberation Psychology and trauma-informed care, the framework is composed of four phases. Each phase is accompanied by a goal to assist clinicians in helping individuals, families, and communities to achieve growth, wellness, and healing. The main objective of each phase is for Latinx immigrants to find relief, gain awareness, and cope with systemic oppression while encouraging resistance and protection from the external forces that cause ethno-racial trauma. Overall, our intention and hopeful expectation is that the content presented in this article serves as a call to action for psychologists to make psychology a Sanctuary Discipline by using and integrating intersectionality theory, trauma-informed care, and Liberation Psychology into policy, research, and practice with Latinx immigrants. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Predictive factors for preoperative serum levels of sialy Lewis(x), sialyl Lewis(a) and sialyl Tn antigens in gastric cancer patients.
Preoperative serum levels of sialyl Lewis(a) (CA19-9), sialyl Lewis(x) (SLX) and sialyl Tn (STN) antigens in 180 patients with gastric cancer were examined to establish predictive factors for serum levels of these antigens compared with carcinoembryonic antigen (CEA). The patients were divided into low and high antigen groups. Multivariate logistic regression analysis revealed the following independent predictive factors for high antigen levels [odds ratio]: liver metastasis for CA19-9 [4.40], SLX [9.90], STN [39.65] and CEA [5.14]; peritoneal dissemination for SLX [4.78] or STN [13.01]; venous invasion for CEA [3.56]; lymph node metastasis for CA19-9 [4.51]. In addition, high CA19-9 levels were independently related to lymph node metastasis in patients with stage I or II tumors. In conclusion, high serum levels of CA19-9, SLX and STN are associated with liver metastasis, while high serum levels of SLX and STN are associated with peritoneal dissemination. In addition, high serum CA19-9 levels may represent an independent predictor for lymph node metastasis.


Catabolism of neurotensin in interstitial fluid of the rat stomach.
The catabolism of neurotensin (NT) was studied in the gastric submucosa of the conscious rat using a novel technique to obtain a dialysate of interstitial fluid. A microdialysis fiber system was surgically implanted into the gastric submucosa, and 2 days later experiments were commenced on conscious animals. Isotope-labeled NT was administered to the tissue, and a dialysate of the submucosal interstitial fluid was collected. In the dialysate, NT and catabolites of NT formed in the interstitial fluid were identified and quantitated by high-pressure liquid chromatography. The catabolism of 125I-NT-(1-13) and [3H]NT-(1-13) was studied as was the further breakdown of the major catabolites. NT-(1-13) was, regardless of the type of label, catabolized mainly into NT-(1-8), NT-(9-13), NT-(1-11), and free tyrosine. None of the catabolites formed is known to possess significant biological activity. NT-(9-13) was rapidly cleared, whereas the amino-terminal fragments NT-(1-8) and NT-(1-11) were more resistant to degradation. The biological half-life of neurotensin in the gastric submucosa of the rat was between 9 and 15 min.


Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure.
To test whether plasma interleukin-1 receptor antagonist or variants within the gene encoding for interleukin-1ra (IL1RN), or proteins involved in regulating interleukin-1β levels or interleukin-1β response, are associated with pediatric acute respiratory distress syndrome or outcomes in mechanically ventilated children with parenchymal lung disease. Prospective cohort study. Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622). Children 2 weeks to 17 years old treated with invasive mechanical ventilation for acute airways and/or parenchymal lung disease. Three-hundred seventy-eight of 549 patients had pediatric acute respiratory distress syndrome; DNA and plasma were obtained from 523 of 549 and 480 of 549 patients, respectively. Plasma interleukin-1ra was highest on the day of intubation (day 0) and decreased over the subsequent 3 days (p < 0.0001). Interleukin-1ra level was higher in patients with pediatric acute respiratory distress syndrome than those without pediatric acute respiratory distress syndrome (p < 0.0001). Multivariable regression analysis of data across all days demonstrated a significant association of interleukin-1ra (odds ratio, 1.30; 95% CI, 1.10-1.52; p = 0.002) and day (p < 0.05) with pediatric acute respiratory distress syndrome, independent of age and Pediatric Risk of Mortality-III score. Analysis on individual days indicated that plasma interleukin-1ra levels were associated with pediatric acute respiratory distress syndrome on days 0 and 2, independent of age and Pediatric Risk of Mortality-III score (p = 0.04 and 0.003, respectively), however did not quite reach significance on days 1 and 3 (p = 0.06 and 0.07, respectively). Interleukin-1ra was independently associated with mortality on day 1 (p = 0.02). Interleukin-1ra also correlated with length of mechanical ventilation, measures of oxygenation, and PICU length of stay. No genetic variants were associated with pediatric acute respiratory distress syndrome. Plasma interleukin-1ra is associated with pediatric acute respiratory distress syndrome, PICU length of stay, length of mechanical ventilation, and mortality in children with acute respiratory failure requiring mechanical ventilation.


New Insights into the Oenological Significance of Candida zemplinina: Impact of Selected Autochthonous Strains on the Volatile Profile of Apulian Wines.
In this investigation, we explored the oenological significance of Candida zemplinina (syn. Starmerella bacillaris) isolates from Apulian grape musts. Moreover, we provide the first evidence of the impact of different C. zemplinina strains on the wine aromatic properties tested as monocultures. We described the diversity of C. zemplinina strains isolated from grapes and the variability of 'volatile' phenotypes associated with this intraspecific variability. Thirty-three isolates were characterized at strain level by PCR-based approach and, among these, 16 strains were identified and then tested by microfermentation tests carried out in grape must. Analyzed strains were low producers of acetic acid and hydrogen sulphide, not able to decarboxylate a panel of representative amino acids, whereas they showed fructophilic character and significant glycerol production. Volatile profiles of produced wines were investigated by gas chromatography-mass spectrometry. The Odor Activity Values of all molecules were calculated and 12 compounds showed values above their odor thresholds. Two selected strains (35NC1 and 15PR1) could be considered as possible starter cultures since they were able to positively affect the sensory properties of obtained wine. This report firstly supplies evidence on the strain-specific impact of different C. zemplinina strains on the final aroma of produced wines.


Synthesis of Silver Nanoparticles by Leaf Extract of Cucumis melo L. and Their In Vitro Antidiabetic and Anticoccidial Activities.
In this study, silver nanoparticles were synthesized using Cucumis melo L. leaf extract via a green synthesis approach and their potential against diabetes and coccidiosis was tested under in vitro conditions. The phytochemical components in the leaf extract reacted with silver nitrate in solution and yielded C. melo-silver nanoparticles (Cm-AgNPs). The synthesis of AgNPs was confirmed via UV-visible spectroscopy by obtaining a peak at 440 nm. The nanoparticles were characterized by their morphology, crystallinity, and the presence of functional groups. In vitro α-amylase and α-glucosidase inhibition assays were carried out at different concentrations in the range of 20 to 100 μg/mL of Cm-AgNPs. The Cm-AgNPs exhibited enzyme inhibitory activity in a concentration-dependent manner. As the concentration of Cm-AgNPs increased the inhibitory activities were also increased linearly and the highest inhibition was observed at 100 μg/mL. The effectiveness of Cm-AgNPs against Eimeria tenalla was assessed by an in vitro 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay using Madin-Darby bovine kidney (MDBK) cell lines. The results revealed that the viability of the oocysts and further sporulation were decreased with the increased concentration of Cm-AgNPs. The AgNPs synthesized from the C. melo leaf extract have shown promising potential against diabetes and coccidiosis, and they could be used in biomedical applications.


Implementation of inpatient and outpatient tobacco-cessation programs.
Two programs in which pharmacists have an active role in the provision of tobacco-cessation education are described. An algorithm for tobacco- cessation education was created for use in an inpatient tobacco-cessation program. Patient education handouts were created, and the content of each handout varied by the patient's level of readiness to make a quit attempt. Doctor of pharmacy students who were assigned to the general internal medicine clerkship rotation at the hospital provided tobacco-cessation education to patients. During monthly rotations, these students assess the smoking status of each patient, gauge the patient's readiness to quit, and provide brief tobacco-cessation education to those who smoke. Patients who are willing to quit smoking are asked if they can be contacted by a representative of the health system's tobacco-cessation program. This program includes a series of three group classes focusing on behavior modification and pharmacotherapy provided at a discounted price. An outpatient tobacco-cessation clinic was initiated to provide all patients of the network an opportunity to participate and have access to tobacco-cessation services. The clinic consists of group and individual classes using the principles and interventions highlighted in national clinical practice guidelines. All referred patients must attend an initial one-on-one visit with the clinical pharmacist before enrollment into the group class. During this visit, general medical information is collected, and the patient's stage of change and willingness to set a quit date are determined. A medication review for drug-smoking interactions is conducted, individual goals are discussed, and a care plan is created. Tobacco-cessation services were implemented by pharmacists working in inpatient and outpatient settings.


Nanostructures of complexes formed by calf thymus DNA interacting with cationic surfactants.
Synchrotron small-angle X-ray scattering was used to study the nanostructures of the complexes formed by calf thymus DNA interacting with cationic lipids (or surfactants) of didodecyldimethylammonium bromide (DDAB), cetyltrimethylammonium bromide (CTAB), and their mixture with a zwitterionic lipid of 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHGPC). The effects of lipid/DNA ratios, DNA chain flexibility, lipid topology, and neutral lipid mixing on the nanostructures of DNA-lipid complexes were investigated. The complexes between double-stranded DNA (dsDNA) and double-tailed DDAB formed a bilayered lamellar structure, whereas the complexes between dsDNA and single-tailed CTAB preferred a structure of 2D hexagonal close packing of cylinders. With single stranded DNA (ssDNA) interacting with CTAB, the complexes showed a Pm3n cubic structure due to the different chain flexibility between dsDNA and ssDNA. The lipid molecules bound by rigid dsDNA like to form cylindrical micelles, whereas lipids bound to flexible ssDNA could form spherical or short cylindrical micelles. The addition of the neutral single-chained PHGPC lipids to the CTAB lipids could induce a structural transition of dsDNA-lipid complexes from a 2D hexagonal to a multi-bilayered lamellar structure. The parallel DNA strands were intercalated in the water layers of lamellar stacks of the mixed lipid bilayers. The DNA-DNA spacing depended on the ratios of charged lipid to neutral lipid, and charged lipid to DNA, respectively.


Drug Development Against Metastatic Cancers.
While combinational diagnostic and treatment strategies over the past decades have significantly improved the overall survival of cancer patients, metastatic cancer remains a leading cause of death in developed countries. The lack of successful treatment strategies for the disease is in large part due to the complexity of the metastatic transformation, which embodies extensive cellular and extracellular alterations, enabling metastatic cancer cells to reach and colonize other organs. The mode of action for the majority of anti-cancer drugs used in clinics today is primarily tumor growth inhibition. While they are effective in destroying cancer cells, they fall short in blocking metastasis. Here we discuss the evolution of past and current anti-cancer drug development, the limits of current strategies, and possible alternative approaches for future drug development against metastatic cancers.


Operation of a brain-computer interface walking simulator for individuals with spinal cord injury.
Spinal cord injury (SCI) can leave the affected individuals with paraparesis or paraplegia, thus rendering them unable to ambulate. Since there are currently no restorative treatments for this population, novel approaches such as brain-controlled prostheses have been sought. Our recent studies show that a brain-computer interface (BCI) can be used to control ambulation within a virtual reality environment (VRE), suggesting that a BCI-controlled lower extremity prosthesis for ambulation may be feasible. However, the operability of our BCI has not yet been tested in a SCI population. Five participants with paraplegia or tetraplegia due to SCI underwent a 10-min training session in which they alternated between kinesthetic motor imagery (KMI) of idling and walking while their electroencephalogram (EEG) were recorded. Participants then performed a goal-oriented online task, where they utilized KMI to control the linear ambulation of an avatar while making 10 sequential stops at designated points within the VRE. Multiple online trials were performed in a single day, and this procedure was repeated across 5 experimental days. Classification accuracy of idling and walking was estimated offline and ranged from 60.5% (p = 0.0176) to 92.3% (p = 1.36×10-20) across participants and days. Offline analysis revealed that the activation of mid-frontal areas mostly in the μ and low β bands was the most consistent feature for differentiating between idling and walking KMI. In the online task, participants achieved an average performance of 7.4±2.3 successful stops in 273±51 sec. These performances were purposeful, i.e. significantly different from the random walk Monte Carlo simulations (p<0.01), and all but one participant achieved purposeful control within the first day of the experiments. Finally, all participants were able to maintain purposeful control throughout the study, and their online performances improved over time. The results of this study demonstrate that SCI participants can purposefully operate a self-paced BCI walking simulator to complete a goal-oriented ambulation task. The operation of the proposed BCI system requires short training, is intuitive, and robust against participant-to-participant and day-to-day neurophysiological variations. These findings indicate that BCI-controlled lower extremity prostheses for gait rehabilitation or restoration after SCI may be feasible in the future.


Anticonvulsant effect of flupirtine in an animal model of neonatal hypoxic-ischemic encephalopathy.
Research studies suggest that neonatal seizures, which are most commonly associated with hypoxic-ischemic injury, may contribute to brain injury and adverse neurologic outcome. Unfortunately, neonatal seizures are often resistant to treatment with current anticonvulsants. In the present study, we evaluated the efficacy of flupirtine, administered at clinically relevant time-points, for the treatment of neonatal seizures in an animal model of hypoxic-ischemic injury that closely replicates features of the human syndrome. We also compared the efficacy of flupirtine to that of phenobarbital, the current first-line drug for neonatal seizures. Flupirtine is a KCNQ potassium channel opener. KCNQ channels play an important role in controlling brain excitability during early development. In this study, hypoxic-ischemic injury was induced in neonatal rats, and synchronized video-EEG records were acquired at various time-points during the experiment to identify seizures. The results revealed that flupirtine, administered either 5 min after the first electroclinical seizure, or following completion of 2 h of hypoxia, i.e., during the immediate reperfusion period, reduced the number of rats with electroclinical seizures, and also the frequency and total duration of electroclinical seizures. Further, daily dosing of flupirtine decreased the seizure burden over 3 days following HI-induction, and modified the natural evolution of acute seizures. Moreover, compared to a therapeutic dose of phenobarbital, which was modestly effective against electroclinical seizures, flupirtine showed greater efficacy. Our results indicate that flupirtine is an extremely effective treatment for neonatal seizures in rats and provide evidence for a trial of this medication in newborn humans.


Construction of tissue-engineered human corneal endothelium for corneal endothelial regeneration using a crosslinked amniotic membrane scaffold.
Descemet's membrane endothelial keratoplasty (DMEK) may provide fast visual rehabilitation in the therapy of corneal endothelial disorders. However, due to shortage of donated corneas, how to construct a corneal endothelial substitute with powerful functions that can be used for DMEK is still unsolved. Herein, we introduced the method of corneal crosslinking (CXL) and conjugated the components of native Descemet's membrane (DM) to improve the mechanical properties and the biocompatibility of denuded amniotic membrane (dAM), further assessed their effects on cell adhesion, proliferation, YAP translocation, and metabolic activity in human corneal endothelial (HCE) cells. Using modified crosslinked dAM (mcdAM) and non-transfected HCE cells, we constructed a tissue-engineered HCE (TE-HCE) and evaluated its functions in cat and monkey models as well. Our results showed that the mechanical properties of mcdAM were improved effectively by CXL, and the adhesion, proliferation, and YAP translocation of HCE cells were dose-dependently improved after ECM modification. The combination of 0.01 mg/mL laminin with 0.1 mg/mL fibronectin showed the highest efficacy. Then, the TE-HCE was constructed in vitro, with a high density of 3612 ± 243 cells/mm2. Results of DMEK in animal models showed that corneal transparency was maintained, accompanied with normal morphology and histological structure of the regenerated corneal endothelium. Therefore, CXL combined with DM-mimic-coating methods could effectively improve the mechanical properties of dAM and enhance the biocompatibility with HCE cells. The constructed TE-HCE had normal histological structure and functioned well in animal models via DMEK, which could be used as a promising powerful equivalent of HCE. STATEMENT OF SIGNIFICANCE: Using high-quality corneal endothelium and an appropriate endothelial keratoplasty is the most effective way for the treatment of corneal endotheliopathy. Descemet's membrane endothelial keratoplasty (DMEK) which can provide better visual acuity, lower immunological rejection rates, and improved graft survival is an ideal surgery at present. However, due to the shortage of donated corneas, it is urgent to find an equivalent substitute of corneal endothelial donor which is suitable for the DMEK surgery to solve the problem of corneal endothelial regeneration. Herein, we introduced the clinical cornea-crosslinking and Descemet's membrane-mimic-coating methods to build the modified crosslinked denuded amniotic membrane scaffold and further constructed a high-quality corneal endothelial functional substitute that can be used in DMEK surgery.


Savings for visuomotor adaptation require prior history of error, not prior repetition of successful actions.
When we move, perturbations to our body or the environment can elicit discrepancies between predicted and actual outcomes. We readily adapt movements to compensate for such discrepancies, and the retention of this learning is evident as savings, or faster readaptation to a previously encountered perturbation. The mechanistic processes contributing to savings, or even the necessary conditions for savings, are not fully understood. One theory suggests that savings requires increased sensitivity to previously experienced errors: when perturbations evoke a sequence of correlated errors, we increase our sensitivity to the errors experienced, which subsequently improves error correction (Herzfeld et al. 2014). An alternative theory suggests that a memory of actions is necessary for savings: when an action becomes associated with successful target acquisition through repetition, that action is more rapidly retrieved at subsequent learning (Huang et al. 2011). In the present study, to better understand the necessary conditions for savings, we tested how savings is affected by prior experience of similar errors and prior repetition of the action required to eliminate errors using a factorial design. Prior experience of errors induced by a visuomotor rotation in the savings block was either prevented at initial learning by gradually removing an oppositely signed perturbation or enforced by abruptly removing the perturbation. Prior repetition of the action required to eliminate errors in the savings block was either deprived or enforced by manipulating target location in preceding trials. The data suggest that prior experience of errors is both necessary and sufficient for savings, whereas prior repetition of a successful action is neither necessary nor sufficient for savings.


The Use of Preventive Health Care in Asian Americans: The Cross-level Interactions between Individual and Neighborhood Factors in the United States.
The present study explored how individual- and neighborhood-level factors contribute to predicting the use of preventive health care in a sample of Asian Americans. The cross-level interaction between individual- and neighborhood-level factors was also examined. We found a significant interaction between individual-level health insurance coverage and neighborhood health care providers' availability. Those who were uninsured and living in areas with limited health care provider availability (bottom 20%) were the most disadvantaged. This study adds to the growing literature on the effect of neighborhood-level factors on health care as sources of disparities. For health care policy, identifying individuals without health insurance coverage and living in a neighborhood with limited health care providers should be a priority to diminish disparities in access to care.


The glutaredoxin ATGRXS13 is required to facilitate Botrytis cinerea infection of Arabidopsis thaliana plants.
Botrytis cinerea is a major pre- and post-harvest necrotrophic pathogen with a broad host range that causes substantial crop losses. The plant hormone jasmonic acid (JA) is involved in the basal resistance against this fungus. Despite basal resistance, virulent strains of B. cinerea can cause disease on Arabidopsis thaliana and virulent pathogens can interfere with the metabolism of the host in a way to facilitate infection of the plant. However, plant genes that are required by the pathogen for infection remain poorly described. To find such genes, we have compared the changes in gene expression induced in A. thaliana by JA with those induced after B. cinerea using genome-wide microarrays. We have identified genes that are repressed by JA but that are induced by B. cinerea. In this study, we describe one candidate gene, ATGRXS13, that encodes for a putative glutaredoxin and that exhibits such a crossed expression. In plants that are infected by this necrotrophic fungus, ATGRXS13 expression was negatively controlled by JA and TGA transcription factors but also through a JA-salicylic acid (SA) cross-talk mechanism as B. cinerea induced SA production that positively controlled ATGRXS13 expression. Furthermore, plants impaired in ATGRXS13 exhibited resistance to B. cinerea. Finally, we present a model whereby B. cinerea takes advantage of defence signalling pathways of the plant to help the colonization of its host.


Statins in Chronic Kidney Disease-Effects on Atherosclerosis and Cellular Senescence.
Chronic kidney disease (CKD) is a serious health problem that can affect various systems in the human body. Renal failure promotes mechanisms of premature cellular aging and also features of generalized inflammation in the body, which translates into a close relationship between kidney dysfunction and cardiovascular disease (CVD). As kidney function deteriorates, cardiovascular risk and mortality increase in this group of patients. Oxidative stress and inflammation are two closely related processes that initiate a vicious cycle by activating each other. Together with aging, they represent the key factors that cause and exacerbate CVD in CKD. Patients with CKD are particularly vulnerable to the accumulation of aging endothelial cells, vascular smooth muscle and macrophages, increasing the risk of atherosclerosis. Several mechanisms are known that can lead to the progression of the aforementioned problems, such as the accumulation of uremic toxins, persistent inflammation, impaired lipid and electrolyte metabolism, nitric oxide (NO) deficiency, the increased production of reactive oxygen species (ROS) and damage to deoxyribonucleic acid (DNA) and mitochondria. According to research, we can distinguish a group of drugs that effectively counteract the negative effects of CKD-statins. This is a group of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase and affect a number of cellular processes and pathways, resulting in the overall slowing of atherosclerosis and cellular aging.


AGL61 interacts with AGL80 and is required for central cell development in Arabidopsis.
The central cell of the female gametophyte plays a role in pollen tube guidance and in regulating the initiation of endosperm development. Following fertilization, the central cell gives rise to the seed's endosperm, which nourishes the developing embryo within the seed. The molecular mechanisms controlling specification and differentiation of the central cell are poorly understood. We identified AGL61 in a screen for transcription factor genes expressed in the female gametophyte. AGL61 encodes a Type I MADS domain protein, which likely functions as a transcription factor. Consistent with this, an AGL61-green fluorescent protein fusion protein is localized to the nucleus. In the context of the ovule and seed, AGL61 is expressed exclusively in the central cell and early endosperm. agl61 female gametophytes are affected in the central cell specifically. The morphological defects include an overall reduction in size of the central cell and a reduced or absent central cell vacuole. When fertilized with wild-type pollen, agl61 central cells fail to give rise to endosperm. In addition, synergid- and antipodal-expressed genes are ectopically expressed in agl61 central cells. The expression pattern and mutant phenotype of AGL61 are similar to those of AGL80, suggesting that AGL61 may function as a heterodimer with AGL80 within the central cell; consistent with this, AGL61 and AGL80 interact in yeast two-hybrid assays. Together, these data suggest that AGL61 functions as a transcription factor and controls the expression of downstream genes during central cell development.


[Modern nosology and the pathomorphism of kidney diseases].
In studies of the Bright disease the most promising have proved to be functional-physiological and immunological lines, genetic, morphological and enzymological investigations. Achievements of nephrology in studies of nosological forms have made it possible to describe new disorders, to give different interpretation of the diseases existed earlier, and to fractionate the "monolith" nosological forms, which complicates the development of classificational forms of kidney diseases. Singling out of individual disease is impeded, moreover, by the pathomorphosis of kidney diseases, a phenomenon particularly noticeable during the last decade, which not infrequently is difficult to be distinguished from pathology of therapy. The existing classifications of kidney diseases do not meet any longer theoretical and practical needs of current nephrology. In elaborating rational classificational schemes one should be guided not by one but by several principles, including etiological, pathogenetic, clinical, and structural ones, hereditary pathology being considered quite separately.


[Genetic study of the Penta E locus and identification of rare alleles].
OBJECTIVE To study the genetic polymorphisms of Penta E locus in Fujian Han population. METHODS Polymorphisms of the Penta E locus in 851 unrelated individuals were analyzed using polymerase chain reaction-short tandem repeat (PCR-STR). The mutation rate of rare alleles was analyzed in 494 paternity identification cases (in a total of 674 meiosis). RESULTS Twenty-six alleles were identified for the Penta E locus, with their frequencies ranging from 0.0006 to 0.1528. There were 7 rare alleles, among which Penta E-28.4 ([AAAGA]29) was identified for the first time. Genetic parameters of the Penta E locus in Fujian Han population were obtained, including PIC= 0.91, PE= 0.817, PD= 0.986, and mutation rate= 0.0015. CONCLUSION The Penta E locus is highly polymorphic and has a low mutation rate in Fujian Han population. It also has a good prospect in genetics applications. DNA sequencing is a good method for identifying rare alleles.


Refusal of viral testing during the SARS-CoV-2 pandemic.
Widespread testing for the respiratory syndrome coronavirus-2 (SARS-CoV-2) will represent an important part of any strategy designed to safely reopen societies from lockdown. Healthcare settings have the potential to become reservoirs of infectivity, and therefore many hospital trusts are beginning to carry out routine screening of staff and patients. This could promote the effective cohorting of patients and reduce the rate of nosocomial infection. However, for various reasons, some individuals may refuse this testing. Here we highlight this as an emergent ethicolegal issue which we expect to become increasingly relevant as testing becomes ubiquitous. We explore this position from an ethical and legal perspective, determining whether refusal of testing is acceptable under UK law. Individual patients refusing testing could undermine a hospital's testing strategy; therefore clinicians and policy makers must prospectively determine the best course of action if this were to occur.


Fish contamination by polychlorobiphenyls: the mass spectrometric ortho effect in a new and easy gas chromatography-mass spectrometry method for the analysis of the seven indicators. The case of Bluefin Tuna.
A simple instrumental procedure was developed to carry out the not simple analysis of PCBs in fish samples. PCBs with the same degree of chlorination (the isomers) are expected to be totally indistinguishable among them by all existing detectors and by all existing mass spectrometers, and there is no apparent solution in those frequent cases where two isomers chromatographically coelute. Generally such coelutions are solved by means of multidimensional GC, but it is a complex technique impractical for most laboratories. The present research focuses on the seven important "indicator PCBs" by using the mass spectrometer in an innovative way. The "mass spectrometric ortho effect" was usefully exploited in addressing coelutions between isomers. Other new important observations on mass spectra were decisive in solving the apparent problem arising from coelutions between higher chlorinated PCBs with the lower chlorinated ones when low-resolution MS is used. With the proposed procedure, the seven indicators are analyzed in a simple way and with a degree of accuracy never observed with the conventional gas chromatography. The method was applied to some Bluefin Tuna fish samples of big size suspected to have not negligible levels of PCBs due to the high position of this species in the food chain. The supposition was partly confirmed. On the basis of the results here obtained, the recently introduced EU Regulation on six of the seven indicators shows one critical point: in the present paper, an amendment to the Regulation is proposed. A number of important validation measures are reported.


Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia.
Schizophrenia is a severe psychiatric illness characterised by disturbance of thought, hallucination and delusions.(1) Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and in particular an excessive activation of glutamate receptors seems to be related to the disruption of neuronal ionic gradients leading to excitotoxicity.(2-7) Numerous findings suggested that the kainate ionotropic glutamate receptors are primarily involved in this mechanism. Recently it has been demonstrated that the GRIK3 gene encoding for the ionotropic glutamate receptor kainate 3 contains a functional polymorphism (T928G) leading to the substitution of a serine with an alanine in position 310 of the protein sequence.(8-11) We performed an association study between the ser310ala GRIK3polymorphism and schizophrenia in a sample of 99 schizophrenic patients and 116 controls. We found a significant difference in the genotype distribution and in particular considering the ala allele as dominant (P = 0.0105, odds ratio (OR) 2.031, 95% confidence interval (CI) 1.177-3.504). This finding suggests a potential role for GRIK3 for susceptibility to schizophrenia.


Synthesis and coordination chemistry of phosphine oxide decorated dibenzofuran platforms.
A four-step synthesis for 4,6-bis(diphenylphosphinoylmethyl)dibenzofuran (4) from dibenzofuran and a two-step synthesis for 4,6-bis(diphenylphosphinoyl)dibenzofuran (5) are reported along with coordination chemistry of 4 with In(III), La(III), Pr(III), Nd(III), Er(III), and Pu(IV) and of 5 with Er(III). Crystal structure determinations for the ligands, 4·CH(3)OH and 5, the 1:1 complexes [In(4)(NO(3))(3)], [Pr(4)(NO(3))(3)(CH(3)CN)]·0.5CH(3)CN, [Er(4)(NO(3))(3)(CH(3)CN)]·CH(3)CN, [Pu(4)Cl(4)]·THF and the 2:1 complex [Nd(4)(2)(NO(3))(2)](2)(NO(3))(2)·(H(2)O)·4(CH(3)OH) are described. In these complexes, ligand 4 coordinates in a bidentate POP'O' mode via the two phosphine oxide O-atoms. The dibenzofuran ring O-atom points toward the central metal cations, but in every case it is more than 4 Å from the metal. A similar bidentate POP'O' chelate structure is formed between 5 and Er(III) in the complex, {[Er(5)(2)(NO(3))(2)](NO(3))·4(CH(3)OH)}(0.5), although the nonbonded Er···O(furan) distance is reduced to ∼3.6 Å. The observed bidentate chelation modes for 4 and 5 are consistent with results from molecular mechanics computations. The solvent extraction performance of 4 and 5 in 1,2-dichloroethane for Eu(III) and Am(III) in nitric acid solutions is described and compared against the extraction behavior of n-octyl(phenyl)-N,N-diisobutylcarbamoylmethyl phosphine oxide (OΦDiBCMPO) measured under identical conditions.


Biocontrol of Phytophthora Blight and Anthracnose in Pepper by Sequentially Selected Antagonistic Rhizobacteria against Phytophthora capsici.
We previously developed a sequential screening procedure to select antagonistic bacterial strains against Phytophthora capsici in pepper plants. In this study, we used a modified screening procedure to select effective biocontrol strains against P. capsici; we evaluated the effect of selected strains on Phytophthora blight and anthracnose occurrence and fruit yield in pepper plants under field and plastic house conditions from 2007 to 2009. We selected four potential biocontrol strains (Pseudomonas otitidis YJR27, P. putida YJR92, Tsukamurella tyrosinosolvens YJR102, and Novosphingobium capsulatum YJR107) among 239 bacterial strains. In the 3-year field tests, all the selected strains significantly (P < 0.05) reduced Phytophthora blight without influencing rhizosphere microbial populations; they showed similar or better levels of disease suppressions than in metalaxyl treatment in the 2007 and 2009 tests, but not in the 2008 test. In the 2-year plastic house tests, all the selected strains significantly (P < 0.05) reduced anthracnose incidence in at least one of the test years, but their biocontrol activities were variable. In addition, strains YJR27, YJR92, and YJR102, in certain harvests, increased pepper fruit numbers in field tests and red fruit weights in plastic house tests. Taken together, these results indicate that the screening procedure is rapid and reliable for the selection of potential biocontrol strains against P. capsici in pepper plants. In addition, these selected strains exhibited biocontrol activities against anthracnose, and some of the strains showed plant growth-promotion activities on pepper fruit.


Risk Assessment of Mycotoxins in Stored Maize Grains Consumed by Infants and Young Children in Nigeria.
Maize is a major complimentary food for infants (0-4years) and young children (5-12years) in Nigeria. In this study, we assessed the risk of exposure of infants and young children (IYC) to some major mycotoxins in stored maize grains from five agro-ecological zones of Nigeria. The probable daily intake approach was employed to determine exposure to five mycotoxins while the margin of exposure (MOE) and population at risk of primary hepatocellular carcinoma approaches were used to characterize the risk of consuming aflatoxin contaminated maize. Infants and young children in the Derived Savannah zone are more exposed to aflatoxins, ochratoxins, and zearalenone while those in the Northern Guinea Savanna zone are mainly exposed to deoxynivalenol and fumonisins. The mean national MOE for infants and children were 0.12 and 0.3 respectively while the risk of developing primary liver cancer was estimated at 152.7 and 61.1 cancer/year/100,000 population of infants and children, respectively. Infants and young children consuming mycotoxin contaminated maize in Nigeria are therefore vulnerable to the adverse health effects. Mycotoxin contamination of maize is still a challenge in Nigeria; mitigation efforts should target the value chain and stricter tolerable limits should be enforced.


GPs' recognition of death in the foreseeable future and diagnosis of a fatal condition: a national survey.
Nowadays, palliative care is considered as a care continuum that may start early in the course of the disease. In order to address the evolving needs of patients for palliative care in time, GPs should be aware in good time of the diagnosis and of the imminence of death. The aim of the study was to gain insight into how long before a non-sudden death the diagnosis of the disease ultimately leading to death is made and on what kind of information the diagnosis is based. In addition, we aimed to explore when, and based on what kind of information, GPs become aware that death of a patient will be in the foreseeable future. A written questionnaire focusing on the GPs' experiences with their last patient who died non-suddenly was sent to a random representative sample of 850 GPs in the Netherlands. The data were analysed of the 297 GPs who responded. 76% of the reported cases were cancer patients and 24% were patients with another non-sudden cause of death. The diagnosis was made only in the last week of life for 15% of the non-cancer patients and 1% of the patients with cancer. GPs were most likely to have been informed of the diagnosis by the medical specialist, although particularly in the case of non-cancer patients GPs also relied on their own assessment of the diagnosis or on other information sources.The GP remained unaware that the patient would die in the foreseeable future until the last week of life in 26% of the non-cancer group, while this was the case for only 6% of the cancer patients. GP's awareness was most likely to be based on the GP's own observations of problems and/or symptoms. The GP often only becomes aware of a fatal diagnosis and of death in the foreseeable future at a late stage in the disease trajectory, particularly in the case of non-cancer patients. It can be assumed that if the diagnosis and the nearing death are only recognised at a late stage, palliative care is either started at a very late stage or not at all.


ECHO-11 as a respiratory virus: quantitation of infection in man.
Through a series of controlled experiments in volunteers, quantitative aspects of infection, illness, and immunity to ECHO-11 virus were studied. ECHO-11 is a transmissable viral infection in man and equally infectious to the upper respiratory and the intestinal tracts. The rate of infection was directly related to the dose of virus exposure, but any infectious dose of virus produced illness in only about one-third of the infected subjects. The infectious dose for man varied over a billionfold range. Larger challenge doses caused no difference in the local symptoms at the portal of entry or in the peak severity of illness, but symptoms were more diverse and prolonged after a higher dose. Persons with asymptomatic infections became just as heavily infected as ill persons. In respiratory secretions from natural infection, the titer of infectious virus was found to be about 10(2) median infective doses in tissue culture (TCID(50))/ml. At this level, up to 40% of exposed contacts could be infected per milliliter of secretion. The observed rate of spread was 24%. This low-dose inoculum caused illness in 12% of volunteers but failed to elicit a significant antibody response in 93% or immunity to reinfection and another illness upon rechallenge. Larger doses of virus produced a longer excretion of virus and a significant increase in serum-neutralizing antibody. Nasal antibody was infrequently found. The principal effect of antibody was to decrease virus excretion and to shorten illness; it reduced the rate but did not prevent infection. Attempts to produce an asymptomatic enteric infection which would induce immunity failed.The characteristics of respiratory transmission with mild disease, recurrent infection, and illness without a detectable antibody response or solid immunity to reinfection, satisfy the epidemiologic conditions to establish ECHO-11 virus as one of the causes of the common cold.


Effects of temperature and fatigue on the electromechanical delay components.
Neuromuscular activation can be influenced by both muscle temperature (Tm) and fatigue. To assess the effects of Tm and fatigue on the electromechanical delay (EMD), 15 participants performed voluntary isometric contractions of different intensities under neutral (TmN), low (TmL), and high (TmH) Tm, before and after a fatiguing exercise. During contraction, electromyogram (EMG), mechanomyogram (MMG), and force (F) were recorded from the biceps brachii muscle. The EMD and the latencies between EMG and MMG (Δt EMG-MMG, which includes the electrochemical processes of EMD) and between MMG and F (Δt MMG-F, which includes the mechanical processes of EMD) were calculated. TmL increased only Δt EMG-MMG, both before and after fatigue. Fatigue lengthened EMD, Δt EMG-MMG, and Δt MMG-F under all Tm to a similar extent. While fatigue increased all EMD components, muscle cooling affected only the electrochemical but not the mechanical processes of EMD.


Comparison of dwell time and complications between peripheral venous catheters and midline catheters in infants weighing ≥ 1500 g at birth.
Newborns in the neonatal intensive care unit (NICU) often require infusion therapy immediately after admission. In such cases, the catheter must be selected according to the condition of the neonate. The aim of this study was to compare the performance of a peripheral venous catheter (PVC) in terms of dwell time, number of catheter replacements required, and complication rate with that of a midline catheter (MC) in neonates weighing ≥1500 g and requiring care in a NICU. The study had a retrospective observational design and included neonates with a birthweight of ≥1500 g who were admitted to a level III NICU between April 2019 and May 2021 and received infusion therapy via a PVC or MC. Patient, maternal, and infusion-related data were collected from the medical records. The outcomes were compared between the PVC and MC groups according to type of catheter used. Univariate analyses of the infusion-related data demonstrated that neonates in the MC group (n = 52) had significantly longer dwell times, required fewer catheter replacements, and had a greater probability of completing therapy with less risk of extravasation than those in the PVC group (n = 54). These findings confirm that the MC has advantages over the PVC, including a longer dwell time, fewer catheter replacements, and less risk of extravasation in newborns with a birthweight of ≥1500 g.


Percutaneous radiofrequency ablation of adrenal metastases from hepatocellular carcinoma: a single-center experience.
The prognosis of adrenal metastases (AM) from hepatocellular carcinoma (HCC) with surgical contraindication was poor. This study evaluated the feasibility, safety and treatment efficacy of percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) for the local treatment of AM originated from HCC. A retrospective study was carried out on 22 patients (21 male and 1 female, mean age, 53.0 ± 13.0 years) who had single AM (mean diameter, 4.0 ± 1.8 cm, range, 1.7-8.0 cm) originated from HCC and received US-guided percutaneous RFA at our institution. The diagnosis was established on typical radiologic findings. The primary technical success was defined as the tumour being completely ablated in the first RFA session. The secondary technical success was defined as tumour residual left from the first ablation was completely ablated by a second ablation session. Local tumour progression (LTP) and overall survival (OS) were estimated by using Kaplan-Meier analysis. A total of 25 ablation sessions were performed. The primary technical success and the secondary technical success were 77.3% (17 of 22) and 86.4% (19 of 22), respectively, with the major complication rate at 4.5% (1 of 22). The median follow-up period after RFA was 10 months (3-55 months). During the follow-up period, five patients were detected LTP. The LTP at 3, 6, and 12 months were 15.8, 26.3, and 26.3%, respectively. Nine patients died of distant extra-adrenal metastases and another five of liver failure due to HCC. The OS at 6, 12, 24 months after RFA for AM were at 79.7, 52.6, and 32.9%, respectively. Percutaneous US-guided RFA in the treatment of AM originated from HCC is feasible, safe and effective.


The vascular pedicle of the heart and the vena azygos. Part I: The normal subject.
The widths of the systemic vessels extending from the thoracic inlet to the heart (the vascular pedicle) and of the azygos vein were measured in 83 normal volunteers and 42 patients with cardiac disease. Mean vascular pedicle width ( VPW ) (erect) was 48 +/- 5.0 mm and correlated well with body weight (r = 0.64) and surface area (r = 0.62). Rotation to the left reduced VPW and to the right increased it. Inspiration and expiration caused little change. The supine VPW increased an average of 20% (47 +/- 37% to the compliant venous right side and 7 +/- 48% to the less compliant arterial left). Supine azygos width (AW) increased 105 +/- 47%. Mean erect AW was 5.14 +/- 1.36 mm. AW did not correlate significantly with anthropomorphic characteristics. Because VPW correlates with the patient's physique, its normality can be estimated within clinically useful limits by inspection. Since AW has no such correlation, serial changes are of more value than initial absolute values.


The webspinning sawfly genus Neurotoma (Hymenoptera, Pamphiliidae) of South Korea: Neurotoma silla sp. nov. and a key to species.
Neurotoma silla sp. nov. is described and illustrated from South Korea. It belongs to the N. saltuum subgroup of the N. nemoralis group and is well characterized by the large size, the mostly black body with mostly black antennae and partly pale yellow legs, the densely punctate but nearly glabrous head with smooth interspaces between punctures, and the sharply carinate occipital carina. Six species of Neurotoma are known now from South Korea, including three species endemic to the country. A key to the South Korean species of Neurotoma is given.


Epithelial cell-derived antibacterial peptides human beta-defensins and cathelicidin: multifunctional activities on mast cells.
Antibacterial peptides function as effectors for defense in innate immunity. In mammals, they are implicated in the barrier protection of epithelia where their expression can be induced during infection and inflammation. Over a dozen of antibacterial peptides have been identified in humans. Among these, defensins and cathelicidins have been well characterized. Two types of defensins (alpha- and beta-defensins) are recognized based on the presence of their conserved six cysteine residues, whereas cathelicidins are characterized by a homologous cathelin sequence in the pro-region and a variable antibacterial C-terminal sequence. Human beta-defensins and cathelicidin hCAP18/LL-37 are mainly expressed in epithelial tissues where mast cells are present. Here we review the structure of human beta-defensins and cathelicidin, and describe their multiple activities on mast cells to induce chemotaxis, degranulation and prostaglandin D(2) production, acting through receptors coupled to G-protein-phospholipase C pathway. Thus, in addition to their bactericidal activities, epithelial cell-derived antibacterial peptides may modulate the inflammatory responses by recruiting mast cells to inflammation foci and inducing the degranulation as well as prostaglandin production from this cell population.


Milk fermentation products of L. helveticus R389 activate calcineurin as a signal to promote gut mucosal immunity.
Fermented milks containing probiotic bacteria are a way of delivering bioactive constituents to targets in the gastrointestinal tract. We reported previously that the fermentation of milk at constant pH 6 by L. helveticus R389 increased its content of peptide fractions, and the oral administration of the non-bacterial fraction (FMSpH6) to mice increased total secretory IgA in the intestinal lumen and enhanced the number of IgA and various cytokines producing cells as well as the secretion of IL-6 by small intestine epithelial cells. We also demonstrated that this FMSpH6 was effective for the prevention of Salmonella typhimurium infection in mice. In this work, we studied in mice the impact of the oral administration of the supernatant of milk fermented by L. helveticus R389 on the gut physiology by measuring parameters such as calcium channels and E-cadherin expression, the activation of the biological signal calcineurin and mast and goblet cells, as a way to determine some mechanisms involved in the immunomodulating effects of the milk fermentation products, observed in previous studies. We analyzed the impact of the supernatant of milk fermented by L. helveticus R389 at pH6-controlled on the expression of calcineurin and on the reinforcement of the ephitelial barrier, measuring parameters such as calcium channels and E-cadherin expression and in the reinforcement of the non-specific immunity determining mast cells and goblet cells associated to the gut. We observed an enhanced expression of TRPV6 channels in the duodenum, indicating an improved capacity for dietary Ca2+ uptake. We demonstrated an enhanced expression of calcineurin in the small intestine, able to upregulate immune parameters such as IL-2 and TNF production, with an increase in the number of these cytokines secreting cells. We determined an increase in the number of mucosal mast cells and goblet cells, which would mean an improved state of mucosal surveillance at sites of infection. The oral administration of the supernatant of milk fermented by L. helveticus R389 enhanced the gut mucosal immunity by improving the mechanisms that reinforce the epithelial and non-specific barriers and the gut functioning at sites of infection, with an improvement in the expression of the enzyme calcineurin, an important signal in the network that activates the gut immune system. The results of this work contribute to revealing the mechanisms underlying the immunomodulation of the gut immune function by fermented milks with probiotic bacteria.


Inner ear formation during the early larval development of Xenopus laevis.
The formation of the eight independent endorgan compartments (sacculus, utricle, horizontal canal, anterior canal, posterior canal, lagena, amphibian papilla, and basilar papilla) of the Xenopus laevis inner ear is illustrated as the otic vesicle develops into a complex labyrinthine structure. The morphology of transverse sections and whole-mounts of the inner ear was assessed in seven developmental stages (28, 31, 37, 42, 45, 47, 50) using brightfield and laser scanning confocal microscopy. The presence of mechanosensory hair cells in the sensory epithelia was determined by identification of stereociliary bundles in cryosectioned tissue and whole-mounts of the inner ear labeled with the fluorescent F-actin probe Alexa-488 phalloidin. Between stages 28 and 45, the otic vesicle grows in size, stereociliary bundles appear and increase in number, and the pars inferior and pars superior become visible. The initial formation of vestibular compartments with their nascent stereociliary bundles is seen by larval stage 47, and all eight vestibular and auditory compartments with their characteristic sensory fields are present by larval stage 50. Thus, in Xenopus, inner ear compartments are established between stages 45 and 50, a 2-week period during which the ear quadruples in length in the anteroposterior dimension. The anatomical images presented here demonstrate the morphological changes that occur as the otic vesicle forms the auditory and vestibular endorgans of the inner ear. These images provide a resource for investigations of gene expression patterns in Xenopus during inner ear compartmentalization and morphogenesis.


The changing global landscape of health and disease: addressing challenges and opportunities for sustaining progress towards control and elimination of neglected tropical diseases (NTDs).
The drive to control neglected tropical diseases (NTDs) has had many successes but to reach defined targets new approaches are required. Over the last decade, NTD control programmes have benefitted from increased resources, and from effective partnerships and long-term pharmaceutical donations. Although the NTD agenda is broader than those diseases of parasitic aetiology there has been a massive up-scaling of the delivery of medicines to some billion people annually. Recipients are often the poorest, with the aspiration that NTD programmes are key to universal health coverage as reflected within the 2030 United Nations sustainable development goals (SDGs). To reach elimination targets, the community will need to adapt global events and changing policy environments to ensure programmes are responsive and can sustain progress towards NTD targets. Innovative thinking embedded within regional and national health systems is needed. Policy makers, managers and frontline health workers are the mediators between challenge and change at global and local levels. This paper attempts to address the challenges to end the chronic pandemic of NTDs and achieve the SDG targets. It concludes with a conceptual framework that illustrates the interactions between these key challenges and opportunities and emphasizes the health system as a critical mediator.


Prominent occurrence of ribosomes from an uncultured bacterium of the Verrucomicrobiales cluster in grassland soils.
An uncultured bacterium of the Verrucomicrobiales cluster was identified by its 16S rDNA sequence as a major bacterium in Dutch Drentse A grassland soils. Potential metabolic activity of the according organism was estimated by applying direct ribosome isolation from soil and partial amplification of the 16S rRNA via RT-PCR using bacteria-specific primers. Temperature gradient gel electrophoresis separated the amplicons sequence specifically into reproducible fingerprints. One of the fingerprint bands matched with the signal of clone DA101. Southern blot hybridization with a DA101-specific V6 probe confirmed sequence identity. It is the first time that an organism of the Verrucomicrobiales cluster has been indicated as a potential major metabolizer in environmental microbial communities.


Physical activity and risk of renal cell carcinoma.
The role of physical activity in the development of renal cell carcinoma was examined using a population-based case-control study conducted in the province of Ontario. Physical activity was examined in several ways, including by intensity and during various life periods. Frequency-matching by 5-year age groups and sex produced sets of 486 females (133 cases and 353 controls) and 447 males (172 cases, 275 controls). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). After adjusting for age, body mass index and smoking, women who performed relatively high amounts of recent recreational activity (OR = 0.41, 95% CI 0.21-0.82 for the highest vs. lowest quartile of activity, 2 years ago), as well as strenuous recreational activity (OR = 0.40, 95% CI 0.22-0.75), had a reduced risk of developing the disease. In general, moderate recreational activity did not appear to be associated with risk in females. In males, a relatively high frequency of total and moderate recreational activity was associated with reduced risk (total, OR = 0.49, 95% CI 0.27-0.87; moderate, OR = 0.49, 95% CI 0.27-0.89), especially during the teen years. Recreational activity during one's 30s was not associated with cancer risk. There was also no association between occupational activity and cancer risk in females or males. The results of our study, in general, suggest that physical activity may be associated with a decreased risk of developing renal cell carcinoma.


Utilization of inpatient care from private hospitals: trends emerging from Kerala, India.
There is a gap in knowledge on the overall role and characteristics of private health care providers in India. This research is aimed at understanding changes in the consumption of inpatient care services from private hospitals between 1986 and 2004, with a particular focus on equitable outreach. Secondary analysis of National Sample Survey data on the utilization of inpatient care services in Kerala is performed for the periods 1986-87, 1995-96 and 2004. Household survey data are examined to understand the users of the private health system as there are limitations in obtaining reliable data from unregulated private health care providers. The annual hospitalization rate increased from 69 per 1000 population in 1986-87 to 126 per 1000 population by 2004. The proportion of persons seeking care from private rather than government hospitals increased from 55% in 1986-87 to 65% by 2004. Concentration indices revealed that the year 1995-96 witnessed the highest income inequality in hospitalization rates. A decline both in hospitalization rates and in the relative preference for private hospitals over government hospitals among the poorest two quintiles between 1986-87 and 1995-96 indicates that the poor avoided inpatient treatment. The rich-poor divide in care seeking from private hospitals was moderated by 2004. Improvements in the purchasing power of the population, and the strategy of private hospitals in this highly competitive market to generate revenue from the poorer quintiles by offering different pricing options, have reduced the observed rich-poor divide in the consumption of inpatient treatment from this sector. However, while this gap in utilization has closed, the burden of out-of-pocket expenditure is higher among the poor.


18F-FDG PET/CT in Follicular Dendritic Cell Sarcoma With Paraneoplastic Pemphigus as the First Manifestation.
A 48-year-old woman presented with refractory oral ulcers and skin rashes on the palms and trunk, diagnosed as paraneoplastic pemphigus. The chest x-ray revealed a mass in the right lower chest, and the F-FDG PET/CT scan showed the lesion in the right anterior-inferior mediastinum with intense F-FDG uptake, accompanied by right parasternal adenopathy and pleural effusion. The surgical pathology proved a follicular dendritic cell sarcoma, with right parasternal lymph node metastasis.


Current insights into the role of human β-defensins in atopic dermatitis.
Anti-microbial peptides or host defence peptides are small molecules that display both anti-microbial activities and complex immunomodulatory functions to protect against various diseases. Among these peptides, the human β-defensins (hBDs) are localized primarily in epithelial surfaces, including those of the skin, where they contribute to protective barriers. In atopic dermatitis skin lesions, altered skin barrier and immune dysregulation are believed to be responsible for reduced hBD synthesis. Impaired hBD expression in the skin is reportedly the leading cause of increased susceptibility to bacterial and viral infection in patients with atopic dermatitis. Although hBDs have considerable beneficial effects as anti-microbial agents and immunomodulators and may ameliorate atopic dermatitis clinically, recent evidence has also suggested the negative effects of hBDs in atopic dermatitis development. In the current review, we provide an overview of the regulation of hBDs and their role in the pathogenesis of atopic dermatitis. The efforts to utilize these molecules in clinical applications are also described.


Case report: Perilymphatic fistula from a round window microfissure.
A microfissure near the round window niche is an anatomical structure that communicates between middle ear and the ampulla of the posterior semicircular canal. It has been suggested that the microfissure can cause inner ear symptoms; however, the etiology has not yet been confirmed clinically. We report, to our knowledge, the first case of microfissure with complaint of hearing loss and vertigo and improvement in hearing after surgical sealing of the microfissure. A 50-year-old man complained of hearing disturbance, tinnitus with flowing-water sound in the left ear, and a floating sensation upon pushing the left tragus. He had moderate sensorineural hearing loss (43.3 dB) in the left ear for 3 days. His hearing worsened and he complained of severe vertigo. An exploratory tympanotomy was performed 8 days after onset. A microfissure and accumulation of clear fluid in the floor of the round window niche were detected, and leakage point was packed with connective tissue. One month after surgery, his hearing (20.0 dB) and disequilibrium had improved. The inner ear symptoms improved after the surgery in this case, suggesting that the microfissure might have caused the symptoms.


The introduction of the C-22-C-23 ethylenic linkage in ergosterol biosynthesis.
Methods for the chemical synthesis of [23-(3)H(2)]lanosterol, [23,25-(3)H(3)]24-methyldihydrolanosterol and [24,28-(3)H(2)]24-methyldihydrolanosterol are described. It is shown that, in the biosynthesis of ergosterol from [26,27-(14)C(2),23-(3)H(2)]lanosterol by the whole cells of Saccharomyces cerevisiae, one of the original C-23 hydrogen atoms is lost and the other is retained at C-23 of ergosterol. It is also shown that 24-methyldihydrolanosterol is converted into ergosterol in good yield and without prior conversion into a 24-methylene derivative. On the basis of these results possible pathways for the formation of the ergosterol side chain from a 24-methylene side chain are discussed.


Experience of nurses with using eHealth in Gilgit-Baltistan, Pakistan: a qualitative study in primary and secondary healthcare.
To improve the quality of health care in remote parts of Pakistan, a research project was initiated in the mountainous region of Gilgit-Baltistan using information and communication technology to improve patient care and support continuing education of health providers (eHealth). This paper describes the experience of nurses in using eHealth in their routine practices. All health centres of Gilgit-Baltistan, Pakistan using eHealth as part of this study, were taken as a single case. These include four primary healthcare centres, three secondary care centres and one medical centre. In-depth interviews were conducted using semi-structured interview guide to study nurses' perspective about using eHealth, and its perceived impact on their professional lives. According to the respondents, eHealth enhanced access to care for remote communities, and improved quality of health services by providing opportunities for continuing learning. Nurses also appreciated eHealth for reducing their professional isolation, and providing exposure to new knowledge through teleconsultations and eLearning.The responses categorized under six major headings include: gaps in health services prior to eHealth; role of eHealth in addressing these gaps; benefits of eHealth; challenges in eHealth implementation; community's perception about eHealth; and future recommendations. Low-cost and simple eHealth solutions have shown to benefit nurses, and the communities in the remote mountainous regions of Pakistan.


Can Patient Record Summarization Support Quality Metric Abstraction?
We present a pre/post intervention study, where HARVEST, a general-purpose patient record summarization tool, was introduced to ten data abstraction specialists. The specialists are responsible for reviewing hundreds of patient charts each month and reporting disease-specific quality metrics to a variety of online registries and databases. We qualitatively and quantitatively investigated whether HARVEST improved the process of quality metric abstraction. Study instruments included pre/post questionnaires and log analyses of the specialists' actions in the electronic health record (EHR). The specialists reported favorable impressions of HARVEST and suggested that it was most useful when abstracting metrics from patients with long hospitalizations and for metrics that were not consistently captured in a structured manner in the EHR. A statistically significant reduction in time spent per chart before and after use of HARVEST was observed for 50% of the specialists and 90% of the specialists continue to use HARVEST after the study period.


Position statement on West Nile virus: a committee opinion.
Although there is currently no definitive evidence linking West Nile virus (WNV) transmission with reproductive cells, it is recommended that practitioners defer gamete donors who have confirmed or suspected WNV infections. This document was reviewed and reaffirmed by the Practice Committee in August of 2011.


Efficacy and safety of peginterferon alpha-2a/ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C.
Data were examined from a day-to-day clinical practice in Yaounde, Cameroon to evaluate the efficacy and safety of peginterferon alfa-2a and ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C. Ninety adults with chronic hepatitis C (mean age, 53 +/- 8 years; 79% males; 37.8% genotype 1; 23.3% genotype 2; and 38.9% genotype 4) were given at least 12 weeks of combination therapy between February 2003 and August 2007. Of these, 54 completed the treatment and the 24-week follow up. Subsequently, 18 continued treatment and 18 (20%) discontinued the treatment, 6 (6.7%) due to adverse effects. An intention-to-treat analysis showed that 38 (52.8%) had an end-of-treatment virologic response and 34 (47.2%) had a sustained virologic response. Sustained virologic response were significantly higher among patients with hepatitis C virus (HCV) genotype 2 (83.4%) than in those with genotype 1 (31%) or genotype 4 (42.3%) (P < 0.05). Non HCV-2 genotype, pretreatment fibrosis score >2, HCV RNA level >8.0 x 10(5) IU/ml and a non-virologic response at 12 weeks of treatment were associated with poor sustained virologic response (P < 0.05). Thus, HCV can be treated in a Sub-Saharan African country. It indicates that Cameroonian HCV-1 and -4 patients have a poorer sustained virologic response than the published results for Western and Middle-East countries. Virus subtype may influence the treatment outcome, since there is a great genetic diversity within Cameroonian HCV-1 and -4 genotypes.


Thymic selection of immunoglobulin idiotype specific T-cells.
The thymus is the major site for differentiation and maturation of developing T-cells. The diversity in the T-cell repertoire is generated during ontogeny by rearrangements of T-cell receptor gene segments that encode clonally distributed receptors. Most of the newly produced thymocytes that bear alpha beta TCR die in the thymus as a consequence of at least two selective processes. Those that can react to self MHC antigens survive (positive selection), but only if the binding affinity for the same or other self MHC (probably complexed with self peptides) molecules is not too high (negative selection). As a result, each T-cell that has acquired functional competence in the thymus should have a certain degree of self-MHC specificity. Our comprehension of thymic development has been aided by the study of transgenic mice that bear functionally rearranged TCR or Ig lambda light chain genes. To study positive selection we analyzed transgenic mice with alpha beta TCR genes isolated from a T-cell clone specific for an idiotypic peptide of lambda 2(315) (a mutant of the lambda 2 Ig chain) bound to the E(d) MHC class II molecule. The results suggest that positive selection of some thymocytes might be weak, reminiscent of a 'struggle for survival', since the selected population was small and had high levels of transgenic receptor and coreceptor (CD4) molecules. The thymic tolerance mechanism was also investigated using a combination of both TCR and lambda 2(315) transgenic mice. The clonal deletion of Id specific thymocytes was influenced by the production site as well as the concentration of the lambda 2(315) antigen. In conclusion, the interaction avidity of a single thymocyte, which is important for selective processes, might be affected by the expression levels of each interacting component: TCR, CD4 or CD8 and MHC molecule and self antigen.


Communication intervention for individuals with dual sensory and intellectual impairments.
For individuals with dual sensory and intellectual impairments, the lack of effective communication skills places severe limitations on their learning potential and sense of belonging. Educational intervention for this population has recognized the critical need to develop communication skills, yet the complexity of the individual's needs continues to plague progress. Unique needs and situations of individuals in this category, coupled with extremely limited numbers of trained and experienced professionals, challenge the field to develop creative means of addressing this vital issue. Documented case studies provide the field with examples of potential options to employ when addressing the communicative needs of individuals with dual sensory and intellectual impairments. However, these case studies provide partial communication systems that address partial communicative needs. Providing individuals having severe sensory, intellectual, and other disabilities with a true language that can meet all communication needs, both receptive and expressive, is still beyond our grasp. Future efforts with this focus will need to combine early intervention, creative technology, and principles of normalization in order to be successful.


[Modified intracorporeal lithotripsy for cement removal in hip prosthesis exchange operations--experimental principles].
Particularly problematic in total hip revision arthroplasty is the cement removal out of the depth of the femoral canal; it is also costly in time and effort. The extracorporal shock wave lithotripsy proved to be an unsuitable method. With the present paper we proved experimentally a newly developed endoscopically controlled modified intracorporal lithotripter (Swiss Orthoclast) for the removal of bone cement. We tested the efficiency on standardized cement specimens of different manufacturers in vitro. We compared both conventional removing techniques with mallet and chisel and a pneumatically powered chisel with formalin fixed human femora. During these experiments we measured the intrafemoral pressure distally to the cement layer. We achieved a high energy (max. 450 mJ) and a very effective fragmentation of the cement (40 mg fragments calculated on the single impulse of 350 mJ). The endoscopic control ensures a safe control of the cement removal even in the depth of the femoral canal. No bone damage occurred macroscopically and radiologically. No heat or toxic products developed. Using the Swiss Orthoclast the intrafemoral pressure was the lowest possible (7 mbar). Even with hammer and chisel or the pneumatically powered chisel the pressure was too low (max. 55 mbar with mallet and chisel) to cause a fat embolic syndrome. As a result of these experiments we started with clinical trials (with permission of the Ethic commission) to evaluate the practicability of the modified intracorporal lithotripter (Swiss Orthoclast) for cement removal.


[Processing and analysis of ChIP-seq data].
The next-generation sequencing coupled with chromatin immunoprecipitation (ChIP-seq) is becoming a key technology for the study of transcriptional regulation in the context of functional genomics. Due to the overwhelming amount of data generated from ChIP-seq experiments, the ChIP-seq data processing brings many new challenges in the field of bioinformatics. Considering the development of data processing skills largely behind that of the ChIP-seq experiment techniques, it is urgent to give a review on the ChIP-seq data processing for more and more oncoming researchers to build or improve algorithms. This paper provides a brief overview of the ChIP-seq data processing, highlighting the main prob-lems and methods in detail, to allow scientists to understand rapidly and deeply.


[Isotope nephrography in pregnancy].
Emptying disturbances demonstrated by the isotope nephrogram are frequent during pregnancy. For the obstetrician, however, they have only importance, if he can differenciate between changes only due to pregnancy and disturbances with a genuine pathological value. On hand of mean - value curves of radio - nephrograms for each of 50 cases of healthy pregnant women at different ages of pregnancy we try to make a specific judgement of the curves by the introduction of a so-called "Drain-rate A" and attempt to classify the disturbances occurring during normal pregnancy under the term "Gravidity-ING" in order to distinguish them from those with a pathological value.


Malignant nerve-sheath tumor with divergent and glandular differentiation in a dog: a case report.
Malignant nerve-sheath tumor with divergent differentiation including epithelial components was diagnosed in an 8-year-old Labrador retriever. The myelographic, morphologic, and immunohistochemical findings confirmed the diagnosis. The tumor was located in the peripheral nerve roots at the first and second lumbar vertebrae. The dog survived for 161 days after resection of the tumor.


Iron overload induces apoptosis of murine preosteoblast cells via ROS and inhibition of AKT pathway.
This study investigates the inhibitory effect of iron overload on MC3T3-E1 cells and its molecular mechanism. MC3T3-E1 cells were grown under different concentrations of FAC (ferric ammonium citrate), and the WST-8 assay was used to investigate the proliferation of cells following FAC with or without deferasirox. DCFH-DA fluorescence probe was applied to detect the cellular reactive oxygen species (ROS) level. The apoptotic cells were analyzed with Annexin V-FITC/PI and the Hoechst 33258 nuclear staining assay. The JC-1 staining assay was applied to observe the change in the mitochondrial transmembrane potential. The expression levels of caspase-3, PARP, Bcl-2 family proteins, and AKT kinase were detected with the Western blot assay. Iron overload had a cytotoxic effect on MC3T3-E1 cells in a dosage-dependent way and resulted in increasing level of intracellular ROS. Iron overload induced apoptosis in MC3T3-E1 cells via a caspase-dependent mechanism that is accompanied by mitochondria dysfunction and decreased expression of anti-apoptotic proteins. The expression levels of cleaved-caspase-3 and cleaved-PARP were upregulated, while the expression levels of caspase-9, caspase-7, caspase-3, and PARP were downregulated. Phosphorylation of AKT kinase decreased. Iron overload can generate ROS in cells, inhibit AKT kinase and its downstream proteins activity, and subsequently initiate apoptotic events.


Potential Risks for Seahorse Stock Enhancement: Insight From the Declivity of Genetic Levels With Hatchery Management.
Stock enhancement is one of the potential management strategies for the fishery. To better understand the impaction of stock enhancement, we simulated an experiment for lined seahorse (Hippocampus erectus) and evaluated the genetic structure after stock enhancement. In this study, we found the numbers of alleles (N A ) and heterozygosity (H O ) of stock enhancement strains were lower than those of the wild collections, while the inbreeding coefficient (F IS ) and relatedness index were higher. Within the 3 generations of stock enhancement strain, the N A , H O and polymorphism information content (PIC) didn't change significantly. In addition, the F ST value indicated that the genetic differentiation between the stock enhancement strains and the first wild collection reached an intermediate level, which could lead to substructuring in wild populations. Overall, these findings revealed a potential genetic risk associated with the release of hatchery strains into wild populations.


"We Felt Emotionally Closer:" A Qualitative Study of Couples' Communication about Pornography Use.
Despite much empirical study of the complex association between pornography use and relationship health, little research has been conducted on the quality of communication about pornography use within relationships, which may meaningfully impact its association with relationship health. We used reflexive thematic analysis and behavioral intimacy theory to analyze responses to an online survey in which 146 individuals (77.3% women) in committed relationships described their communication with their partner about pornography use. Themes drawn from participants' responses included: 1) Discussing pornography use is not vulnerable (anymore); (2) Asymmetrical vulnerability within the couple; (3) Disappointment and divergent values present in suppressive events; (4) Sharing the struggle of navigating unwanted pornography use; and (5) Selective reinforcement: encouraging some, but not all, vulnerable behavior, which included two subthemes: (a) Your pornography use is not okay, but I'm glad you told me; and (b) You can use pornography; I just don't need to hear about it. Findings provide guidance to help couples navigate conversations about pornography use in ways that enhance relationship health.


A concise total synthesis of (-)-quinocarcin via aryne annulation.
Described in this report is a rapid asymmetric total synthesis of the tetrahydroisoquinoline antitumor antibiotic (-)-quinocarcin. The sequence employs a mild fluoride-induced aryne annulation developed in our laboratories to build a key isoquinoline-containing intermediate comprising the entire carbon scaffold of the natural product. This intermediate is advanced through six additional steps to the target alkaloid, providing the shortest synthetic route to (-)-quinocarcin reported to date.


[Opioid activity of peptides and wound healing of the skin].
The binding of dalargin, its four analogues and FK-33824, DADLE, met-enkephalin and morphine to peripheral mu- and delta-receptors and to brain receptors has been investigated in comparison with their influence on skin wound healing in rats. It has been shown that only substances with opiate activity, including morphine, stimulated wound healing. No correlation between wound healing effect of peptides and their binding to a definite receptor has been found. Naloxone inhibited wound healing and suppressed opiate peptide-mediated healing process. It is suggested that endogenous opiate peptides are involved in the maintenance of structural homeostasis.


Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells: implications for Parkinson's disease.
It was recently reported that low doses of 6-hydroxydopamine (6-OHDA) induce apoptosis of naive (undifferentiated) and neuronal (differentiated) PC12 cells, and this system has been proposed as an adequate experimental model for the study of Parkinson's disease. The mechanism by which this neurotoxin damages cells is via the production of free radicals. Given that the neurohormone melatonin has been reported 1) to be a highly effective endogenous free radical scavenger, 2) to increase the mRNA levels and the activity of several antioxidant enzymes, and 3) to inhibit apoptosis in other tissues, we have studied the ability of melatonin to prevent the programmed cell death induced by 6-OHDA in PC12 cells. We found that melatonin prevents the apoptosis caused by 6-OHDA in naive and neuronal PC12 cells as estimated by 1) cell viability assays, 2) counting of the number of apoptotic cells, and 3) analysis and quantification of DNA fragmentation. Exploration of the mechanisms used by melatonin to reduce programmed cell death revealed that this chemical mediator prevents the 6-OHDA induced reduction of mRNAs for several antioxidant enzymes. The possibility that melatonin utilized additional mechanisms to prevent apoptosis of these cells is also discussed. Since this endogenous agent has no known side effects and readily crosses the blood-brain-barrier, we consider melatonin to have a high clinical potential in the treatment of Parkinson's disease and possibly other neurodegenerative diseases, although more research on the mechanisms is yet to be done.


Artificial intelligence in osteoarthritis detection: A systematic review and meta-analysis.
As an increasing number of studies apply artificial intelligence (AI) algorithms in osteoarthritis (OA) detection, we performed a systematic review and meta-analysis to pool the data on diagnostic performance metrics of AI, and to compare them with clinicians' performance. A search in PubMed and Scopus was performed to find studies published up to April 2022 that evaluated and/or validated an AI algorithm for the detection or classification of OA. We performed a meta-analysis to pool the data on the metrics of diagnostic performance. Subgroup analysis based on the involved joint and meta-regression based on multiple parameters were performed to find potential sources of heterogeneity. The risk of bias was assessed using Prediction Model Study Risk of Bias Assessment Tool reporting guidelines. Of the 61 studies included, 27 studies with 91 contingency tables provided sufficient data to enter the meta-analysis. The pooled sensitivities for AI algorithms and clinicians on internal validation test sets were 88% (95% confidence interval [CI]: 86,91) and 80% (95% CI: 68,88) and pooled specificities were 81% (95% CI: 75,85) and 79% (95% CI: 80,85), respectively. At external validation, the pooled sensitivity and specificity for AI algorithms were 94% (95% CI: 90,97) and 91% (95% CI: 77,97), respectively. Although the results of this meta-analysis should be interpreted with caution due to the potential pitfalls in the included studies, the promising role of AI as a diagnostic adjunct to radiologists is indisputable.


Vascular cryopreservation in microsurgery.
Cyropreservation of blood vessels has been carried out for some decades with variable results. A rabbit model was used to compare cryopreserved femoral artery allografts (n = 12 arteries), fresh autografts (n = 15 arteries), and fresh allografts (n = 16 arteries) at 1 and 3 months postoperatively. Patency rates were highest in the fresh autografts (86.7 percent), followed by the cryopreserved allografts (66.7 percent at 1 month and 83.3 percent at 3 months) and fresh allografts (62.5 percent at 1 month and 75 percent at 3 months). The fresh allografts showed the greatest alterations in endothelial cells and intima and muscle layer, followed by cryopreserved allografts, and then fresh autografts. Changes observed included pseudoendothelium formation, thickened intima, and thinner muscle layer. Cellular infiltrate appeared on the vessel walls only in the cryopreserved allografts (25 percent), but this did not have an effect on vascular patency. Fresh autografts remain the graft of choice for vascular defects, but cryopreserved allografts serve as the most appropriate option when the former are unavailable.


Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities.
Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments.


Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension.
Pulmonary hypertension induces right ventricular (RV) overload, which is transmitted to cardiomyocytes via integrins that activate intracellular messengers, including focal adhesion kinase (FAK) and neuronal nitric oxide synthase (NOS1). We investigated whether RV hypertrophy (RVH) and RV failure (RVF) were associated with activation of FAK, NOS1, and matrix metalloproteinases (MMPs). Rats were treated without (RVC) or with a low dose of monocrotaline (30mg/kg) to induce RVH, and with a high dose (80mg/kg) to induce RVF. After approximately 30 days, RV function was determined using a combined pressure-conductance catheter. After sacrifice, FAK, NOS1, their phosphorylated forms (FAK-P and NOS1-P), MMP-2, and MMP-9 were quantified in RV myocardium by immunohistochemistry. In RVH and RVF, RV weight/ body weight increased by 36% and 109%, whereas RV ejection fraction decreased by 23% and 57% compared to RVC, respectively. FAK-P and FAK-P/FAK were highest in RVH (2.87+/-0.12 and 2.52+/-0.23 fold compared to RVC, respectively) and slightly elevated in RVF (1.76+/-0.17 and 1.15+/-0.13 fold compared to RVC, respectively). NOS1-P and NOS1-P/NOS1 were increased in RVH (1.63+/-0.12 and 3.06+/-0.80 fold compared to RVC, respectively) and RVF (2.16+/-0.03 and 3.30+/-0.38 fold compared to RVC, respectively). MMP-2 was highest in RVH and intermediate in RVF (3.50+/-0.12 and 1.84+/-0.22 fold compared to RVC, respectively). MMP-9 was elevated in RVH and RVF (2.39+/-0.35 and 2.92+/-0.68 fold compared to RVC, respectively). Activation of FAK in RVH points to an integrin-dependent hypertrophic response of the myocardium. Activation of NOS1 in failing RV suggests a role of excessive NO in the development of failure and activation of MMPs leading to ventricular remodeling.


Nuclear magnetic resonance spectroscopic determination of dicyclomine hydrochloride in tablet, capsule, and injection dosage forms.
A rapid and specific nuclear magnetic resonance (NMR) spectroscopic method was developed for determining dicyclomine hydrochloride in tablet, capsule, and injection dosage forms. The method consists of an extraction step with chloroform, evaporation of the solvent, addition of maleic acid as an internal standard, dissolution of the mixture in deuterated chloroform-deuterated acetone (40 + 60), NMR spectral determination, and integration of the peaks of interest. The concentration of dicyclomine hydrochloride in the dosage form was calculated from the integral values for the peaks of the test compound and the internal standard. The average recovery value +/- the standard deviation (n = 5) of dicyclomine hydrochloride added to synthetic samples was 99.7 +/- 0.9% (coefficient of variation 0.9%). The assay values for various commercial tablets, capsules, and injectables analyzed by using the proposed method differed in all cases by less than 1% from those obtained by using the USP XX titrimetric method. There was no interference from stearate, an excipient found in tablets and capsules, or from chloral hydrate, a preservative found in injectables .