Learning from clients: A qualitative investigation of psychotherapists' reactions to negative verbal feedback.
To explore how therapists experience, react to, and learn from negative feedback from their clients. Eighteen experienced therapists' written descriptions of episodes where they had received negative verbal feedback from clients were analyzed according to the Consensual Qualitative Research methodology. Receiving feedback was experienced as challenging, but educational. Learning was manifested in different ways: (a) Immediately Applied Learning-therapists improved the following therapy process by changing their behavior with the client, (b) Retrospectively Applied Learning-therapists made changes in their way of working with subsequent clients, and (c) Non-Applied Learning-new ideas generated by the experience had not been translated into behavior. We compared cases describing these manifestations of learning and found differences in the nature of the feedback and how therapists understood, reacted, and responded to it. The therapists benefitted from obtaining and being open to specific feedback from their clients, regulating their own emotional reactions, accommodating dissatisfied clients, and considering how they themselves contributed to negative therapy processes.


[An improvement in the accuracy of determining the titer of staphylococcal alpha-antitoxin].
The modification of the titration technique involves addition (in microvolumes) of various solvent quantities to equal blood serum volumes, followed by levelling of liquid volumes, and then addition of equal toxin doses. Serum dilutions: No. 1 - 1: 0.5 of toxin working dose, etc., provide a registration scale with 1 U interval. This modification makes the method more accurate and simple.


Health matters in Texas.
Physicians who testified before legislative committees presented an aggressive public health agenda to shield Texans from cigarette smoke, protect them from vaccine-preventable diseases, curb the obesity rate, and support cancer prevention and research. Thanks to their voices and the work of the Texas Medical Association and the Texas Public Health Coalition, the 2013 Texas Legislature got the message and passed many key bills that will help physicians accomplish some of those goals.


Dual-Graphene Rechargeable Sodium Battery.
Sodium (Na) ion batteries are attracting increasing attention for use in various electrical applications. However, the electrochemical behaviors, particularly the working voltages, of Na ion batteries are substantially lower than those of lithium (Li) ion batteries. Worse, the state-of-the-art Na ion battery cannot meet the demand of miniaturized in modern electronics. Here, we demonstrate that electrochemically exfoliated graphene (EG) nanosheets can reversibly store (PF6- ) anions, yielding high charging and discharging voltages of 4.7 and 4.3 V vs. Na+ /Na, respectively. The dual-graphene rechargeable Na battery fabricated using EG as both the positive and negative electrodes provided the highest operating voltage among all Na ion full cells reported to date, together with a maximum energy density of 250 Wh kg-1 . Notably, the dual-graphene rechargeable Na microbattery exhibited an areal capacity of 35 μAh cm-2 with stable cycling behavior. This study offers an efficient option for the development of novel rechargeable microbatteries with ultra-high operating voltage and high energy density.


European results of matched unrelated donor bone marrow transplantation for chronic myeloid leukemia. Impact of HLA class II matching. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
We have retrospectively analyzed the impact of prognostic factors on the outcome of serologically HLA-matched unrelated donor (UD) BMT for CML. For this purpose, we have studied a cohort of 366 patients transplanted in Europe between January 1985 and December 1994. The median age of the 211 males and 155 females was 34 years; 238 patients were transplanted in first chronic phase and 116 in advanced phases. The median interval from diagnosis to BMT was 827 days. GVHD prophylaxis consisted of CsA and MTX in 202 patients or of ex vivo or in vivo T cell depletion (TCD) in 129. Recently, DNA-based methods of HLA-class II typing have been used to improve donor selection. We obtained complete data on 300 donor/recipient (D/R) pairs. Among them, we have identified three groups of patients, according to specific HLA-DRB1 D/R compatibility. Two hundred and ten patients received marrow from donors identical for HLA-DRB1 (group 1). Thirty-one patients received BMT from a donor who was HLA-DRB1 mismatched (group 2) and 59 from a donor in whom specific HLA-DRB1 typing was not performed (group 3). The overall survival was 37 +/- 3% at 2 years and leukemia-free survival (LFS) was 31 +/- 3%. In univariate analysis, five variables had a favorable effect on LFS: transplant in first chronic phase (P = 0.0001), time interval from diagnosis to BMT shorter than the median (P = 0.01), prophylaxis of GVHD without TCD (P + 0.001), acute GVHD < grade III (P = 0.0009) and HLA-DRB1 D/R matching (P = 0.0001). Transplant-related mortality (TRM) was 49 +/- 4% in group 1, 79 +/- 8% in group 2 and 80 +/- 6% in group 3 (P = 0.0001). Multivariate analysis confirmed that HLA-DRB1 matching was the most significant factor influencing survival (P = 0.04), LFS (P = 0.013) and TRM (P = 0.0049). From these results, we have defined a 'good risk' group, ie patients transplanted in first chronic phase, from an HLA-DRB1 matched donor, without TCD as prophylaxis against GVHD. The 2 year LFS, TRM and relapse incidence for this group were 51 +/- 5%, 47 +/- 5% and 2 +/- 2%, respectively. This suggests that the long-term outcome of patients with favorable prognostic features can approach that of patients transplanted from geno-identical siblings. In contrast, the TRM for patients transplanted for advanced disease from non HLA-DRB1-identical donors was 94%. Such a high TRM clearly indicates that UD BMT is not justifiable for these individuals.


Negative pressure therapy: a viable option for general surgical management of the open abdomen.
Management of the open abdomen (OA) is challenging for surgeons and requires experienced medical teamwork. The need for improvements in temporary abdominal closure methods has led to the development of a negative-pressure therapy (NPT; ABThera OA NPT, KCI USA, Inc, San Antonio, TX). The authors present a 19-patient case series documenting their use of NPT for OA management in nontraumatic surgery. All received NPT until the fascia was considered ready for closure. Of 19 patients, 17 (89.5%) achieved fascial closure with a Kaplan-Meier (KM) median time to closure of 6 days. Mean hospital and intensive care unit stays were 32.1 and 26.6 days, respectively. During their hospitalization, 5 patients (26.3%) died, with a KM median time to mortality of 53 days. These findings demonstrate effective use of NPT for managing the OA in critically ill patients, and this has led the authors to use it in their general surgery practice.


Nanostructured gold architectures formed through high pressure-driven sintering of spherical nanoparticle arrays.
We have demonstrated pressure-directed assembly for preparation of a new class of chemically and mechanically stable gold nanostructures through high pressure-driven sintering of nanoparticle assemblies at room temperature. We show that under a hydrostatic pressure field, the unit cell dimension of a 3D ordered nanoparticle array can be reversibly manipulated allowing fine-tuning of the interparticle separation distance. In addition, 3D nanostructured gold architecture can be formed through high pressure-induced nanoparticle sintering. This work opens a new pathway for engineering and fabrication of different metal nanostructured architectures.


Drug education in tune.
America's impassioned involvement with music has found its way into the schools. A great song is complete in itself and needs nothing more to enhance it. The nose-thumbing spirit of Vietnam protesters in the seventies was reflected in the music of American songwriters of that period which included John Prine. Written in the traditional folk music style, John Prine's "Sam Stone" follows the storyline of a Vietnam veteran addicted to heroin and his tragic death. This article examines the heroin-related lyricism and music of "Sam Stone" as a teaching method in drug education.


Front view and panoramic side view videoscope lens system design.
A novel structure of a rigid panoramic endoscope is designed and presented. The inspected target field is imaged on the sensor by an optical lens with a dynamic mechanical module. A microgear and motor are used to drive the dynamic lens components, and a compensation element is used in the system to correct the aberrations due to the protective cylindrical endoscope cover. A long depth of field navigator lens is attached to image the front side. The design details are presented and results are shown.


Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip.
Congenital disorders of glycosylation (CDG) comprise a clinically and biochemically heterogeneous group of monogenetic-inherited, multisystemic diseases that affect the biosynthesis of N- and/or O-glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic-orientated GDP-mannose:Man(3-4) GlcNAc(2)-PP-dolichol alpha-1,2-mannosyltransferase (ALG11), who presented an accumulation of shortened dolichol-linked oligosaccharides leading to CDG-Ip (ALG11-CDG). Here we describe an improved metabolic labeling method that allowed the identification of three new CDG-Ip cases that were missed so far in routine diagnostics. Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life.


Central nervous system congenital anomalies: a prospective neurosurgical observational study from Nigeria.
This is a prospective observational study on the profile of central nervous system (CNS) anomalies in a neurosurgical unit in Ikeja, Nigeria. All cases of CNS anomalies seen by the authors in 1 year, January to December 2005, were analyzed. Descriptive variables include some demographics of the patients and their parents; profiles of CNS anomalies, cranial or spinal, neural tube defects (NTD) or others; presence of associated anomalies; and rate of surgical correction of these anomalies. Sixty-one cases were recorded, approximately 64% of our total pediatric neurosurgical output. Forty-one cases were males, 20 females, with a male to female ratio of approximately 2 to 1. The age at presentation ranged from 2 days to 60 months (mean 5.6 months) and the majority of the parents were young (the mean ages of the fathers and mothers were 35 years and 28 years, respectively), and low income earners (70%). The cases comprised cranial (61%) and spinal (39%) anomalies, or 54% of NTD versus others. The cranial lesions were mainly congenital primary hydrocephalus in 44% of cases, encephalocele in 28%, and microcephaly in 17%. The spinal lesions were spinal dysraphism in more than 90%; all in the lumbosacral region. Seventy percent of the NTD had associated cranial or other system anomalies, mainly secondary hydrocephalus in 65%. The surgical correction rate of all of these cases was 38%. NTD were significantly more likely to present early, be associated with other anomalies and undergo surgical correction in this series (P < 0.001). CNS congenital anomalies are under-reported in Nigeria and other developing countries. A call is made for the establishment of nationwide efforts to fully clarify the epidemiology of this silent epidemic.


Effects of Cr, W, and Mo on the High Temperature Oxidation of Ni-Based Superalloys.
The oxidation behavior of Ni-9.5Co-(8~12)Cr-(2.5~5.5)Mo-(4~8)W-3Al-5Ti-3Ta-0.1C-0.01B alloys was investigated at 850 °C and 1000 °C The mass change, the phase of oxides, and the cross-sectional structure of specimens were analyzed after cyclic oxidation tests. The oxide scale was composed mainly of Cr2O3 and NiCr2O4, but NiO, TiO2, and CrTaO4 were also found. Al2O3 was formed beneath the Cr oxide layer. The Cr oxide layer and internal Al oxide acted as barriers to oxidation at 850 °C, while Al oxide was predominantly protective at 1000 °C. Cr increased the mass gain after oxidation test at both temperatures. Mo increased the oxidation rate at 850 °C but decreased the oxidation rate at 1000 °C. W slightly increased the mass gain at 850 °C but did not produce a significant effect at 1000 °C. The effects of Cr, Mo, W, and the temperature were discussed as well as the volatilization of oxides, the valence number of elements, and diffusion retardation.


Two epizootics of lymphocytic choriomeningitis virus occurring in laboratory mice despite intensive monitoring programs.
Two epizootics of lymphocytic choriomeningitis virus in mice occurred within two months in one research facility consisting of several widely separated rooms. These outbreaks developed despite intensive institutional monitoring policies designed to prevent introduction and spread of lymphocytic choriomeningitis virus. Evidence derived from serological and virological assays and interviews with the concerned investigators suggested that a single transplantable tumor carried in mice may have been responsible for spread of the virus. However, the tumor was not contaminated with lymphocytic choriomeningitis virus at the time of its introduction into the mouse facility. The origin of the virus responsible for the outbreaks was not definitively established although data supported an hypothesis that the virus was introduced into the research facility by a wild or feral mouse. Virus spread from infected mice to humans did not occur, as measured by serological tests. However, a large and valuable animal facility was depopulated for safety reasons. Absorption of sera with lymphocytic choriomeningitis virus antigen proved a necessary and reliable method for confirming specificity of lymphocytic choriomeningitis virus fluorescence-positive reactions.


Prevalence, Predictors, and Clinical Presentation of Acute Pericardial Effusion Following Percutaneous Coronary Intervention.
Background: Iatrogenic pericardial effusion (PE) has been demonstrated to lead to cardiac injury as a sign of systemic inflammatory response. Objectives: This study sought to determine the anatomical characteristics and clinical presentation associated with PE after percutaneous coronary intervention (PCI) by using echocardiography. Methods: The clinical outcomes of all patients with coronary artery disease who underwent PCI from July 2014 to December 2018 were evaluated. The quantitative and qualitative analyses of PE were performed. The associations between the presence of PE and procedural factors were also evaluated. Results: A total of 882 patients were enrolled. PE was found in 144 patients (16.3%) and was mostly located in the anterior pericardium at low amounts. The serum levels of high-sensitive C-reaction protein before PCI and troponin T in the group with PE after PCI were significantly higher than those in the group without PE (p < 0.0001). The presence of PE was associated with the procedural time (OR = 1.02, p = 0.035) and the degree of interventional complexity (multiple vessels OR = 1.89, p = 0.014; chronic total occlusion OR = 2.04, p = 0.005; and PCI with rotational atherectomy OR = 1.15, p = 0.011) independent of the number of culprit vessels and stents. During 1-year follow-up, a significantly higher number of cardiac deaths (3) and myocardial infarctions (8) occurred in patients with PE than in patients without PE (P < 0.05). Conclusion: Post-PCI acute PE was frequent, generally mild, mainly asymptomatic, and independently associated with procedural time and complexity. This effusion, which is considered as a cardiac damage marker, could be a predominant clinical sign for long-term prognosis.


Di-μ-acetato-κO:O-bis-{(acetato-κO,O')bis-[3-(1H-imidazol-1-yl-κN)-1-phenyl-propan-1-one]cadmium} tetra-hydrate.
In the mol-ecular structure of the title neutral binuclear complex, [Cd(2)(C(2)H(3)O(2))(4)(C(12)H(12)N(2)O)(4)]·4H(2)O, each Cd(II) atom is six-coordinated and exhibits a distorted octa-hedral geometry. Three O atoms from two acetate ions and one monodentate 3-(1H-imidazol-1-yl-κN(3))-1-phenyl-propan-1-one (L) ligand form the equatorial plane, while the bridging-O atom forming the longer Cd-O distance,and the N atom of the second L ligand, forming the longer Cd-N distance, occupy axial positions with an N-Cd-O angle of 170.77 (7)°. Inter-molecular O-H⋯O hydrogen bonds exist between the lattice water mol-ecules and the acetate ions of adjacent mol-ecules, resulting in a two-dimensional supra-molecular structure.


Predictive factors of pathologic complete response of HER2-positive breast cancer after preoperative chemotherapy with trastuzumab: development of a specific predictor and study of its utilities using decision curve analysis.
The aim of this study was to assess the Institut Gustave Roussy/M.D. Anderson Cancer Center (IGR/MDACC) nomogram in predicting pathologic complete response (pCR) to preoperative chemotherapy in a cohort of human epidermal growth factor receptor 2 (HER2)-positive tumors treated with preoperative chemotherapy with trastuzumab. We then combine clinical and pathological variables associated with pCR into a new nomogram specific to HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. Data from 270 patients with HER2-positive tumors treated with preoperative chemotherapy with trastuzumab at the Institut Curie and at the Georges François Leclerc Cancer Center were used to assess the IGR/MDACC nomogram and to subsequently develop a new nomogram for pCR based on multivariate logistic regression. Model performance was quantified in terms of calibration and discrimination. We studied the utility of the new nomogram using decision curve analysis. The IGR/MDACC nomogram was not accurate for the prediction of pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab, with poor discrimination (AUC = 0.54, 95% CI 0.51-0.58) and poor calibration (p = 0.01). After uni- and multivariate analysis, a new pCR nomogram was built based on T stage (TNM), hormone receptor status, and Ki67 (%). The model had good discrimination with an area under the curve (AUC) at 0.74 (95% CI 0.70-0.79) and adequate calibration (p = 0.93). By decision curve analysis, the model was shown to be relevant between thresholds of 0.3 and 0.7. To the best of our knowledge, ours is the first nomogram to predict pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. To ensure generalizability, this model needs to be externally validated.


Case report: Altered pre-mRNA splicing caused by intronic variant c.1499 + 1G > A in the SLC4A4 gene.
Proximal renal tubular acidosis (pRTA) with ocular abnormalities is an autosomal recessive disease caused by variants in the Solute Carrier Family 4 Member 4 (SLC4A4) gene. Patients present with metabolic acidosis and low plasma bicarbonate concentration (3∼17 mmol/L). In addition, they are often accompanied by ocular abnormalities, intellectual disability, and growth retardation. The patient underwent whole exome sequencing (WES) and bioinformatics analysis of variant pathogenicity in this study. Then, a minigene assay was conducted to analyze the splicing site variant further. Compound heterozygous variants in the SLC4A4 gene (NM_003759.3), c.145C > T (p.Arg49*) and c.1499 + 1G > A, were detected by WES. The minigene assay showed an mRNA splicing aberration caused by the c.1499 + 1G > A variant. Compared with the wild type, the mutant type caused 4-base insertion between exons 10 and 11 of SLC4A4 after expression in HEK293 cells. In conclusion, the c.1499 + 1G > A variant in the SLC4A4 gene may be one of the genetic causes in the patient. Moreover, our study provides the foundation for future gene therapy of such pathogenic variants.


Ethanol exposure during development reduces resident aggression and testosterone in rats.
Ethanol exposure during development has been shown to alter social behaviors in people, but the range of deficits is not clear. Using an animal model of Fetal Alcohol Spectrum Disorders, inter-male aggression and testosterone levels were examined in adult rats. Rats were exposed to ethanol during the entire prenatal period and from postnatal day 2 through 10. Ethanol was administered via intragastric intubation. Two other groups consisted of a nontreated control and an intubated control group that was exposed to the administration procedures but not ethanol. Both offensive and defensive aggression were examined in experimental residents and intruders under three different housing conditions for the resident males: (1) with another male, (2) with a pregnant female, and (3) with a female and litter fathered by the experimental animal. When housed with a female and litter, ethanol-exposed rats displayed reduced offensive aggression compared to control groups under the same condition. Defensive aggression in the non-experimental intruders was reduced in this same condition. There were no differences in duration of non-aggressive social behaviors among the groups in any of the housing conditions. Testosterone levels were reduced in ethanol-exposed rats compared to controls. In summary, ethanol exposure over the combined prenatal and postnatal periods reduces aggressive behavior in a condition where aggressive behavior is normally seen. This reduction may be related to lower testosterone levels.


Murine CD4 T cells selected in a highly disparate xenogeneic porcine thymus graft do not show rapid decay in the absence of selecting MHC in the periphery.
CD4 repopulation can be achieved in T cell-depleted, thymectomized mice grafted with xenogeneic porcine thymus tissue. These CD4 T cells are specifically tolerant of the xenogeneic porcine thymus donor and the recipient, but are positively selected only by porcine MHC. Recent studies suggest that optimal peripheral survival of naive CD4 T cells requires the presence of the same class II MHC in the periphery as that of the thymus in which they were selected. These observations would suggest that T cells selected on porcine thymic MHC would die rapidly in the periphery, where porcine MHC is absent. Persistent CD4 reconstitution achieved in mice grafted with fetal porcine thymus might be due to increased thymic output to compensate for rapid death of T cells in the periphery. Comparison of CD4 T cell decay after removal of porcine or murine thymic grafts ruled out this possibility. No measurable role for peripheral murine class II MHC in maintaining the naive CD4 pool originating in thymic grafts was demonstrable. However, mouse class II MHC supported the conversion to, survival, and/or proliferation of memory-type CD4 cells selected in fetal porcine thymus. Thus, the same MHC as that mediating positive selection in the thymus is not critical for maintenance of the memory CD4 cell pool in the periphery. Our results support the interpretation that xenogeneic thymic transplantation is a feasible strategy to reconstitute CD4 T cells and render recipients tolerant of a xenogeneic donor.


The next level of radiology peer review: enterprise-wide education and improvement.
It is essential to the future of radiology that our profession own and embrace the objectives and methodology of peer review. The authors describe a natural evolution of peer review away from measurement and error identification toward the goal of performance improvement for the entire profession by allowing everyone to learn from the mistakes of everyone else. This can be accomplished by a comprehensive program of reviewer education, cross-platform anonymous prospective data collection, third-party expert arbitration, and meaningful sharing of results with the entire body of radiologists and residency programs. Such a system would require robust informatics and leadership from provincial and state as well as national radiologist associations. In so doing, apprehension and risk for the individual radiologist could be minimized, while ensuring that everyone benefits from others' mistakes, thereby measurably reducing errors across the entire enterprise. Seldom, and only in cases of significant and immediate patient risk, would an individual's identity and performance ever need to be made visible, even to the administrators of the program.


Selected psychiatric symptoms associated with rate of cognitive decline in patients with Alzheimer's disease.
We examined the relation between selected psychiatric symptoms and the average rate of decline in different areas of cognition in patients with Alzheimer's disease. Measures of decline were computed by determining patients' average rates of decline on the underlying factors of the Mini-Mental State Examination (MMSE). Patients with agitation or wandering declined more rapidly on the total MMSE score than did patients without either symptom. The Following Commands factor accounted for almost all of this decline. The findings suggest a relation between the presence of certain behavioral problems in Alzheimer's disease and decline in particular cognitive areas.


Overcoming 'ageism' bias in the treatment of hypercholesterolaemia : a review of safety issues with statins in the elderly.
Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.


Aromatic diosmatricyclic nitrogen-containing compounds.
Aromatic diosmatricyclic nitrogen-containing compounds are prepared from Os(VI) complex OsH6(PiPr3) by double 1,3-C-H bond activation of aromatic six-membered cycles with imino substituents meta disposed.


Blockage of FOXP3 transcription factor dimerization and FOXP3/AML1 interaction inhibits T regulatory cell activity: sequence optimization of a peptide inhibitor.
Although T regulatory cells (Treg) are essential for the prevention of autoimmune diseases, their immunoregulatory function restrains the induction of immune responses against cancer. Thus, development of inhibitors of FOXP3, a key transcription factor for the immunosuppressive activity of Treg, might give new therapeutic opportunities. In a previous work we identified a peptide (named P60) able to enter into the cells, bind to FOXP3, and impair Treg activity in vitro and in vivo. Here we show that P60 binds to the intermediate region of FOXP3 and inhibits its homodimerization as well as its interaction with the transcription factor AML1. Alanine-scanning of P60 revealed the relevance of each position on FOXP3 binding, homodimerization, association with AML1 and inhibition of Treg activity. Introduction of alanine at positions 2, 5 and 11 improved the activity of the original P60, whereas alanine mutations at positions 1, 7, 8, 9, 10 and 12 were detrimental. Multiple mutation experiments allowed us to identify peptides with higher FOXP3 binding affinity and stronger biological activity than the original P60. Head to tail macrocyclization of peptide P60-D2A-S5A improved Treg inhibition and enhanced anti-tumor activity of anti-PD1 antibodies in a model of hepatocellular carcinoma. Introduction of a D-aminoacid at position 2 augmented significantly microsomal stability while maintained FOXP3 binding capacity and Treg inhibition in vitro. In vivo, when combined with the cytotoxic T-cell epitope AH1, it induced protection against CT26 tumor implantation. This study provides important structure-function relationships essential for further drug design to inhibit Treg cells in cancer.


Adrenergic Modulation With Photochromic Ligands.
Adrenoceptors are ubiquitous and mediate important autonomic functions as well as modulating arousal, cognition, and pain on a central level. Understanding these physiological processes and their underlying neural circuits requires manipulating adrenergic neurotransmission with high spatio-temporal precision. Here we present a first generation of photochromic ligands (adrenoswitches) obtained via azologization of a class of cyclic amidines related to the known ligand clonidine. Their pharmacology, photochromism, bioavailability, and lack of toxicity allow for broad biological applications, as demonstrated by controlling locomotion in zebrafish and pupillary responses in mice.


Elevated Epstein-Barr Virus Antibody Level is Associated with Cognitive Decline in the Korean Elderly.
Chronic viral infection is implicated in cognitive decline and Alzheimer's disease (AD). Our goal was to identify biomarkers for the development of amnestic mild cognitive impairment (aMCI) from cognitively normal state. To accomplish this, we analyzed plasma IgG levels against Epstein-Barr virus (EBV) and herpes simplex virus 1 (HSV-1) in study subjects with incident aMCI (Converter) and normal cognitive function (NC Control) who did or did not convert from cognitively normal state to aMCI during the 2-year follow-up period, respectively. The Converter group exhibited elevated levels of anti-EBV IgG antibodies in the post-follow-up phase (aMCI state) compared to the pre-follow-up phase (cognitively normal state), but not the NC Control group. In contrast, the total IgG level was not significantly changed over the follow-up period. Moreover, elevated anti-EBV IgG levels were significantly associated with CDR scales and total CERAD scores in the Converter group. These results suggest that EBV infection or its related host immune response is linked to cognitive decline. Thus, an EBV antibody level may be used as a potential biomarker for assessing the risk of aMCI development, implying a role for chronic EBV infection in AD pathogenesis.


Explanatory pragmatism: a context-sensitive framework for explainable medical AI.
Explainable artificial intelligence (XAI) is an emerging, multidisciplinary field of research that seeks to develop methods and tools for making AI systems more explainable or interpretable. XAI researchers increasingly recognise explainability as a context-, audience- and purpose-sensitive phenomenon, rather than a single well-defined property that can be directly measured and optimised. However, since there is currently no overarching definition of explainability, this poses a risk of miscommunication between the many different researchers within this multidisciplinary space. This is the problem we seek to address in this paper. We outline a framework, called Explanatory Pragmatism, which we argue has two attractive features. First, it allows us to conceptualise explainability in explicitly context-, audience- and purpose-relative terms, while retaining a unified underlying definition of explainability. Second, it makes visible any normative disagreements that may underpin conflicting claims about explainability regarding the purposes for which explanations are sought. Third, it allows us to distinguish several dimensions of AI explainability. We illustrate this framework by applying it to a case study involving a machine learning model for predicting whether patients suffering disorders of consciousness were likely to recover consciousness.


Treatment of chromoblastomycosis with itraconazole.
The results of long-term itraconazole therapy in 10 patients with active chromoblastomycosis due to F. pedrosoi were reported. Therapy consisted of 100 or 200 mg/day of itraconazole, the length of therapy depending on the patient's response (12 to 24 months). This new triazole proved effective in reducing the number, size, and severity of the lesions in nine of the patients. Those patients with minor involvement profited more from therapy and were cured; patients with moderate involvement achieved either minor or major improvement. In most cases, signs and symptoms began to improve after 6 months of therapy. Mycological tests (in which tissue samples were treated with potassium hydroxide and cultured) became negative in six patients, but the fungus was eradicated in only three patients. Itraconazole produced no side effects. In spite of the need for long-term therapy, this new azole derivative effectively controls the disease.


Characterization of the transcription-initiation site and of the promoter region within the 5' flanking region of the human aldolase C gene.
Several aldolase C clones from a human genomic library have been identified using a mouse aldolase C cDNA as a hybridization probe. The most complete fragment of the clones identified is 14 kb long and contains the complete aldolase C gene. The nucleotide sequence analysis of more than 5 kb includes the intron/exon organization structure of the gene and the 3' and 5' flanking regions. Although no human cDNA is yet available, a canonical polyadenylation signal at the 3' end of the gene indicates the proximity of the poly(A) addition site. We have analyzed the 5' noncoding region by S1 mapping and primer-extension experiments. The transcription-initiation sites for the human aldolase C gene in brain tissue was located about 1300 bp upstream from the methionine initiation codon. Preliminary functional assays of the promoter by transfection into rat glioma cells have indicated that promoter elements lie between positions -161 and -416 from the start point of transcription.


Isolation and quantitation of ecologically important phloroglucinols and other compounds from Eucalyptus jensenii.
Eucalyptus jensenii has not been explored for its phytoconstituents except for its essential oil although a formylated phloroglucinol compound jensenone has been the focus of several ecological studies. i) To optimise the extraction conditions for preparative scale isolation of jensenone and other secondary metabolites from leaves. (ii) To develop an RP-HPLC method for simultaneous determination of phloroglucinols and other compounds in Eucalyptus leaves. Jensenone and other compounds were isolated from acetone extract using VLC over TLC grade silica. HPLC quantitation of isolated compounds was undertaken on a C₁₈-column using acetonitrile-water (2% formic acid) gradient elution. Extraction conditions for isolation of jensenone were optimised and more than 99% pure jensenone was obtained in a yield of 2.1% from the dried leaves. Ten phloroglucinol compounds, including a new nuclear methylated phloroglucinol named 4-O-demethyl miniatone, and two triterpenoids were also isolated. A RP-HPLC method was developed for simultaneous quantitation of phloroglucinols and other compounds in different extracts of E. jensenii leaves. A total of 19 compounds reported from different species of Eucalyptus was separated by this method. The method described for isolation of jensenone is a simple, rapid and low-cost procedure amenable to the preparative scale. A new monomeric phloroglucinol compound was isolated and characterised from the acetone extract of E. jensenii leaves. The HPLC method developed can be applied successfully to different eucalypt matrices for precise and accurate determination of 19 secondary metabolites belonging to different chemical classes.


Reasons for hospitalisation of HIV-infected patients in ICUs - a single-centre observational study.
There are no Polish data regarding the reasons for and incidence of ICU hospitalisations of HIV-infected patients. The aim of the study was to determine the reasons for and incidence of hospitalisations of HIV-infected patients in the Department of Anaesthesiology and Intensive Therapy of the Dr W. Biegański Regional Specialist Hospital in Łódź in the years 2010-2014. Preliminary research enabled to identify all the patients with laboratory-confirmed HIV, including those hospitalised in the ICU. Patients` medical records were analysed. Analysis involved epidemiological data, underlying diagnosis, coexisting diseases and conditions, as well as biochemical, hematologic, virusologic, bacteriologic, mycologic and immunologic tests. In the years 2010-2014, new HIV infections were diagnosed in 224 individuals; 8 of them required ICU hospitalization (10 hospitalisations) - 5 men (62.5%) and 3 women (37.5%). The age of patients ranged from 24 to 46 years. All the patients were diagnosed with AIDS. Three of them died. The patients with HIV constituted 1.30% of all patients hospitalised in the ICU over the period of 5 years. Low number of HIV-infected patients hospitalised in the ICU in the years 2010-2014 was associated with low HIV incidence rates in the Łódź province and generally available modern antiretroviral therapy rather than restrictive admission policy. Reasons for admission as well as coexisting diseases and conditions, including opportunistic infections, of patients hospitalised in the ICU in 2010-2014 are similar to those in West European countries and the United Stated.


Effect of Tamm-Horsfall urinary glycoprotein on phagocytosis and killing of type I-fimbriated Escherichia coli.
Human polymorphonuclear leukocytes (PMN) ingest type I (mannose sensitive) fimbriated Escherichia coli even in the absence of antibody, complement, or other serum opsonins. Our studies suggest that the Tamm-Horsfall urinary glycoprotein (THP) interferes with serum-independent ingestion. Electron micrographs showed that dissolved THP adhered to type I fimbriae and formed a pseudocapsule around bacteria bearing type I fimbriae. Phase-variant bacteria grown on blood agar neither expressed fimbriae nor bound THP. Affinity column chromatography demonstrated mannose-sensitive binding between purified type I fimbriae and purified THP. The ability of human PMN to bind and ingest type I-fimbriated E. coli was diminished if the bacteria had been coated by exposure to THP at physiologic concentrations. At 1 h, PMN were associated with an average of 2.62 uncoated bacteria, but with only 0.18 coated bacteria (P less than 0.001). alpha-Methyl mannoside blocked the observed effect of THP on binding and phagocytosis in a dose-dependent fashion: increased mannoside led to increased blocking. PMN preincubated with THP were able to bind and phagocytose normally. There did not appear to be any significant clumping of bacteria in suspension to account for these effects. Bactericidal assays with leukocytes in suspension demonstrated protection of THP-coated bacteria. At 1 h, PMN killed 42% of noncoated E. coli (a decrease of 0.24 log), but the number of THP-coated bacteria increased by 75% (an increase of 0.24 log). These observations may partially explain the virulence of E. coli in the bladder and kidney, where serum activity is low and THP is abundant.


Shame regulation in personality pathology.
Drawing on extant work on shame and emotion regulation, this article proposes that three broad forms of maladaptive shame regulation strategies are fundamental in much of personality pathology: Prevention (e.g., dependence, fantasy), used preemptively, lessens potential for shame; Escape (e.g., social withdrawal, misdirection) reduces current or imminent shame; Aggression, used after shame begins, refocuses shame into anger directed at the self (e.g., physical self-harm) or others (e.g., verbal aggression). This article focuses on the contributions of shame regulation to the development and maintenance of personality pathology, highlighting how various maladaptive shame regulation strategies may lead to personality pathology symptoms, associated features, and dimensions. Consideration is also given to the possible shame-related constructs necessitating emotion regulation (e.g., shame aversion and proneness) and the points in the emotion process when regulation can occur.


Observational studies: a review of study designs, challenges and strategies to reduce confounding.
There are several methods in which one can assess the relationship between an intervention and an outcome. Randomized controlled trials (RCTs) are considered as the gold standard for evaluating interventions. However, for many questions of clinical importance, RCTs would be impractical or unethical. Clinicians must rely on observational studies for the best available evidence when RCTs are unavailable. This article provides an overview of observational research designs to facilitate the understanding and appraising of their validity and applicability in clinical practice. Major methodological issues of observational studies including selection bias and confounding are also discussed. In addition, strategies to minimize these problems in the design and analytical phases of a study are highlighted. Knowledge of the strengths, weaknesses and recent methodological advances in observational studies can assist clinicians to make informed decisions about whether a particular observational study would provide useful information to enhance patient care.


Diagnostic performance of body mass index to identify obesity as defined by body adiposity: a systematic review and meta-analysis.
We performed a systematic review and meta-analysis of studies that assessed the performance of body mass index (BMI) to detect body adiposity. Data sources were MEDLINE, EMBASE, Cochrane, Database of Systematic Reviews, Cochrane CENTRAL, Web of Science, and SCOPUS. To be included, studies must have assessed the performance of BMI to measure body adiposity, provided standard values of diagnostic performance, and used a body composition technique as the reference standard for body fat percent (BF%) measurement. We obtained pooled summary statistics for sensitivity, specificity, positive and negative likelihood ratios (LRs), and diagnostic odds ratio (DOR). The inconsistency statistic (I2) assessed potential heterogeneity. The search strategy yielded 3341 potentially relevant abstracts, and 25 articles met our predefined inclusion criteria. These studies evaluated 32 different samples totaling 31 968 patients. Commonly used BMI cutoffs to diagnose obesity showed a pooled sensitivity to detect high adiposity of 0.50 (95% confidence interval (CI): 0.43-0.57) and a pooled specificity of 0.90 (CI: 0.86-0.94). Positive LR was 5.88 (CI: 4.24-8.15), I (2)=97.8%; the negative LR was 0.43 (CI: 0.37-0.50), I (2)=98.5%; and the DOR was 17.91 (CI: 12.56-25.53), I (2)=91.7%. Analysis of studies that used BMI cutoffs >or=30 had a pooled sensitivity of 0.42 (CI: 0.31-0.43) and a pooled specificity of 0.97 (CI: 0.96-0.97). Cutoff values and regional origin of the studies can only partially explain the heterogeneity seen in pooled DOR estimates. Commonly used BMI cutoff values to diagnose obesity have high specificity, but low sensitivity to identify adiposity, as they fail to identify half of the people with excess BF%.


Assessment of serum antioxidant status in patients with silicosis.
Prolonged exposure to silica dust causes an imbalance in the generation of free radicals and in the antioxidant system, thereby inducing oxidative stress. The antioxidant status of 113 silicosis patients and 116 control subjects without silicosis was examined. Serum superoxide dismutase (SOD) activity and serum levels of malondialdehyde (MDA) and glutathione (GSH) were significantly higher in silicosis patients than in controls. The GSH level in patients with stage I silicosis was higher than that in patients with other stages, but there was no difference in serum MDA level and SOD activity between disease stages. The GSH level of patients who worked with air drills was significantly lower than that of patients in other occupations, whereas the MDA level was significantly elevated in patients who used air drills. Serum SOD activity did not differ significantly according to the occupational group. It is concluded that the measurement of serum SOD, GSH and MDA levels could be beneficial in the clinical evaluation of serum antioxidant status in silicosis patients.


Efficient synthesis of nucleic acids heavily modified with non-canonical ribose 2'-groups using a mutantT7 RNA polymerase (RNAP).
A T7 RNAP mutant (Y639F) which eliminates discrimination of the chemical character of the NTP ribose 2'-group, facilitates incorporation of non-canonicalsubstrates into nucleic acids. However, transcripts containing a high percentage of non-canonical NMPs are poorly extended due to effects of the 2'-substituents on the transcript:template hybrid conformation. We tested the addition of compounds that stabilize A-type helix geometry to the reaction. High concentrations of polyamines, together with other changes in reaction conditions, greatly increased the synthesis of transcripts heavily substituted with non-canonical ribose 2'-groups. Template structures that facilitate promoter opening increased the efficiency of reactions where non-canonical substrates were incorporated during transcription of +1 to +6.


Complex-anisotropy-induced pattern formation in bistable media.
A construct of anisotropy in bistable media is adopted to characterize the effects of anisotropy on pattern formation by means of anisotropic line tension. A velocity curvature relation is further derived to account for the anisotropic wave propagations. Stability analysis of transverse perturbations indicates that a sufficiently strong complex anisotropy can induce dynamical instabilities and even lead to a breakup of the wave patterns. Numerical simulations show that complex anisotropy can induce rich spatiotemporal behaviors in bistable media. The results of analysis and simulations demonstrate that this method successfully incorporates complex anisotropy into the reaction diffusion model and has general significance.


Inhibitory activity against epidermal growth factor receptor (EGFR) based on single point mutations of active site residues.
Epidermal growth factor receptors belong to the ErbB family of receptor tyrosine kinases (TKs) involved in the proliferation of normal and malignant cells. EGFR has attracted considerable attention as a target for cancer therapy. The findings reported herein are believed to provide some novel insights into the design of effective drugs for the therapeutic treatment of EGFR-related cancers. In particular, it is shown using sophisticated computational tools in a systematic way that the affinity of a wide spectrum of thiazolo[4,5-d]pyrimidine analogs can be carefully tuned up by seeking the desired goal in the structural modifications of EGFR, such as single point mutations of the critical EGFR residues in the active site. It is also demonstrated that a large number of the small ligand molecules can be efficiently divided into subgroups of the structurally similar ligands and that every such a subgroup has its unique inhibitory activity signature. The protein engineering approach, as quite reproducible, is proposed to be a viable partner to experiment in addressing a variety of issues, including investigation of clinically important mutations, development of drug resistance, identification of the most promising anti-cancer drug candidates, etc.


Ectopic expression of Hmgn2 antagonizes mouse erythroid differentiation in vitro.
Hmgn2 (high mobility group nucleosomal 2), a ubiquitous nucleosome-binding protein that unfolds chromatin fibres and enhances DNA replication, reportedly regulates differentiation of epithelial and mesenchymal cells. To investigate how Hmgn2 regulates HC (haemopoietic cell) differentiation, we quantified Hmgn2 expression in HCs of mouse FL (fetal liver) during erythroid differentiation. Hmgn2 expression levels were >10-fold higher in immature erythroid progenitors than in mature erythroid cells, suggesting that Hmgn2 antagonizes erythroid differentiation. To address this issue, Hmgn2 were transfected into both Friend erythroleukaemia cells and FL HCs. There was a 3.3-fold decrease in relatively mature c-Kit(+)/CD71(+) erythroid cells, a 2.9-fold increase in immature c-Kit(+)/CD71(-) erythroid cells in transfected Friend cells, a 1.1-fold decrease in relatively mature CD71(+)/Ter119(+) erythroid cells, and a 1.7-fold increase in relatively immature c-Kit(+)/CD71(+) erythroid cells in FL HCs accompanied by down-regulation of genes encoding the erythroid transcription factors, Gata1 and Klf1. Two days after Hmgn2 transfection of Friend erythroleukaemia cells, the number of S-phase cells increased, whereas the number of cells in G(1) decreased, while that of mitotic cells remained unchanged. We conclude that ectopic expression of Hmgn2 antagonizes mouse erythroid differentiation in vitro, which may be due to enhancement of DNA replication and/or blocking entry of mitosis at S-phase.


Controllable Synthesis and Characterization of AuPd Nanowire Networks with High Electrocatalytic Performance.
A simple and efficient method is proposed for the synthesis of bimetallic AuPd nanowire networks (NWs) with tunable compositions by using KBr as a structure-directing agent and NaBH₄ as a reducing agent. TEM, XRD and XPS results show that the AuPd NWs have a unique one-dimensional network structure. Electrochemical tests indicate that the AuPd NWs catalysts have excellent electrocatalytic activity and durability for methanol oxidation due to the special one-dimensional nanostructure and many structural defects at the junction. The Au1Pd1 NWs show better catalytic activity, which is 2.03 times higher than that of the commercial Pd/C catalyst.


p53-driven lipidome influences non-cell-autonomous lysophospholipids in pancreatic cancer.
Adaptation of the lipid metabolism participates in cancer pathogenesis, facilitating energy storage and influencing cell fate and control of molecular signalling. The tumour suppressor protein p53 is a molecular hub of cell metabolism, supporting antioxidant capabilities and counteracting oncogene-induced metabolic switch. Despite extensive work has described the p53-dependent metabolic pathways, a global profiling of p53 lipidome is still missing. By high-throughput untargeted lipidomic analysis of pancreatic ductal adenocarcinoma (PDAC) cells, we profile the p53-dependent lipidome, revealing intracellular and secreted lysophospholipids as one of the most affected class. Lysophospholipids are hydrolysed forms of phospholipids that results from phospholipase activity, which can function as signalling molecules, exerting non-cell-autonomous effects and instructing cancer microenvironment and immunity. Here, we reveal that p53 depletion reduces abundance of intracellular lysophosphatidyl-choline, -ethanolamine and -serine and their secretion in the extracellular environment. By integrating this with genomic and transcriptomic studies from in vitro models and human PDAC patients, we identified potential clinically relevant candidate p53-dependent phospholipases. In particular PLD3, PLCB4 and PLCD4 expression is regulated by p53 and chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) indicates a direct transcriptional control on their chromatin accessible genomic loci. Consistently, PLD3, PLCB4 and PLCD4 expression correlates with p53 mutational status in PDAC patients, and these genes display prognostic significance. Overall, our data provide insights into lipidome rewiring driven by p53 loss and identify alterations of lysophospholipids as a potential molecular mechanism for p53-mediated non-cell-autonomous molecular signalling that instructs cancer microenvironment and immunity during PDAC pathogenesis.


Glyphosate-Eating Fungi: Study on Fungal Saprotrophic Strains' Ability to Tolerate and Utilise Glyphosate as a Nutritional Source and on the Ability of Purpureocillium lilacinum to Degrade It.
Glyphosate is the most commonly used herbicide worldwide. Its improper use during recent decades has resulted in glyphosate contamination of soils and waters. Fungal bioremediation is an environmentally friendly, cost effective, and feasible solution to glyphosate contamination in soils. In this study, several saprotrophic fungi isolated from agricultural environments were screened for their ability to tolerate and utilise Roundup in different cultural conditions as a nutritional source. Purpureocillium lilacinum was further screened to evaluate the ability to break down and utilise glyphosate as a P source in a liquid medium. The dose-response effect for Roundup, and the difference in toxicity between pure glyphosate and Roundup were also studied. This study reports the ability of several strains to tolerate 1 mM and 10 mM Roundup and to utilise it as nutritional source. P. lilacinum was reported for the first time for its ability to degrade glyphosate to a considerable extent (80%) and to utilise it as a P source, without showing dose-dependent negative effects on growth. Pure glyphosate was found to be more toxic than Roundup for P. lilacinum. Our results showed that pure glyphosate toxicity can be only partially addressed by the pH decrease determined in the culture medium. In conclusion, our study emphasises the noteworthy potential of P. lilacinum in glyphosate degradation.


Use of photoaffinity probes containing poly(ethylene glycol) spacers for topographical mapping of the cholecystokinin receptor complex.
To further define the structure of the pancreatic cholecystokinin (CCK) receptor and the topographical distance relationships between its subunits, we developed a series of monofunctional photoaffinity probes in which a fixed receptor-binding domain was separated from a photolabile nitrophenylacetamido group by defined lengths of a flexible spacer. The well-characterized CCK receptor radioligand 125I-D-Tyr-Gly-[(Nle28,31)CCK-26-33] provided the receptor-binding component of the probes, while the polymer poly(ethylene glycol) (2, 4, 7, and 10 monomer units long) was used as the spacer. The patterns of affinity labeling of rat pancreatic plasma membranes were examined as a function of spacer length. This ranged from 7.3 to 16.2 A, as calculated by root-mean-square end-to-end distances and validated experimentally by time-resolved fluorescence resonance energy transfer measurements. All probes in the series specifically labeled the Mr = 85,000-95,000 glycoprotein with Mr = 42,000 core, which has been proposed to contain the hormone recognition site. In addition, when the spacer length reached 16.2 A, membrane proteins of Mr = 80,000 and Mr = 40,000 were specifically labeled. The product of endo-beta-N-acetylglucosaminidase F digestion of the Mr = 80,000 protein was Mr = 65,000, similar to a protein previously identified in affinity labeling experiments using a CCK-33-based probe. These observations are consistent with the Mr = 85,000-95,000 pancreatic protein representing the hormone-binding subunit of the CCK receptor, while proteins of Mr = 80,000 and Mr = 40,000 may represent noncovalently associated subunits sited within 16.2 A of the binding domain.(ABSTRACT TRUNCATED AT 250 WORDS)


Imaging brain tissue architecture across millimeter to nanometer scales.
Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanometer synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS uses fixation-compatible extracellular labeling and optical imaging, including stimulated emission depletion or expansion microscopy, to comprehensively delineate cellular structures. It enables three-dimensional reconstruction of single synapses and mapping of synaptic connectivity by identification and analysis of putative synaptic cleft regions. Applying CATS to the mouse hippocampal mossy fiber circuitry, we reconstructed and quantified the synaptic input and output structure of identified neurons. We furthermore demonstrate applicability to clinically derived human tissue samples, including formalin-fixed paraffin-embedded routine diagnostic specimens, for visualizing the cellular architecture of brain tissue in health and disease.


Multiple Migrated Superior Vena Cava Stents With Cardiac Injury - A Stepwise Open Cardiotomy Strategy to Mitigate Potential Fatality.
Iatrogenic injuries with migrated interventional stents can sometimes be life-threatening. The interventional retrieval management is generally the treatment of choice, as surgical procedures carry a high mortality risk with only a few cases reported. We report a patient with two stents migrated into the right atrium from superior vena cava resulting in cardiac perforation. She was successfully treated using pericardiocentesis followed by surgical intervention with rapid post-operative resolution of symptoms. The technique presented here substantiates the steps for a safe and effective removal of these multiple displaced stents with minimal postprocedural complications.


The endocannabinoid system in invertebrates.
What is the role of the cannabinoid system in invertebrates and can it tell us something about the human system? We discuss in this review the possible presence of the cannabinoid system in invertebrates. Endocannabinoid processes, i.e., enzymatic hydrolysis, as well as cannabinoid receptors and endocannabinoids, have been identified in various species of invertebrates. These signal molecules appear to have multiple roles in invertebrates; diminishing sensory input, control of reproduction, feeding behavior, neurotransmission and antiinflammatory actions. We propose that since this system worked so well, it was retained during evolution, and that invertebrates can serve as a model to study endogenous cannabinoid signaling.


Asteraceae Artemisia campestris and Artemisia herba-alba Essential Oils Trigger Apoptosis and Cell Cycle Arrest in Leishmania infantum Promastigotes.
We report the chemical composition and anti-Leishmania and antioxidant activity of Artemisia campestris L. and Artemisia herba-alba Asso. essential oils (EOs). Our results showed that these extracts exhibit different antioxidant activities according to the used assay. The radical scavenging effects determined by DPPH assay were of IC50 = 3.3 mg/mL and IC50 = 9.1 mg/mL for Artemisia campestris and Artemisia herba-alba essential oils, respectively. However, antioxidant effects of both essential oils, determined by ferric-reducing antioxidant power (FRAP) assay, were in the same range (2.3 and 2.97 mg eq EDTA/g EO, resp.), while the Artemisia herba-alba essential oil showed highest chelating activity of Fe2+ ions (27.48 mM Fe2+). Interestingly, we showed that both EOs possess dose-dependent activity against Leishmania infantum promastigotes with IC50 values of 68 μg/mL and 44 μg/mL for A. herba-alba and A. campestris, respectively. We reported, for the first time, that antileishmanial activity of both EOs was mediated by cell apoptosis induction and cell cycle arrest at the sub-G0/G1 phase. All our results showed that EOs from A. herba-alba and A. campestris plants are promising candidates as anti-Leishmania medicinal products.


Coexistence of leukemic infiltration and extramedullary hematopoeisis in a lymph node: A cytological diagnosis.
Extramedullary hematopoeisis (EMH) occurs when function of the bone marrow is insufficient or destroyed. We report a case of lymph nodal mass in a young patient, diagnosed on fine needle aspiration cytology (FNAC) as infiltration by leukemia along with features of EMH. FNA smears from axillary lymph node revealed lymphoblasts with hand mirror cell and teat cell morphology. Also seen were occasional megakaryocytes and metamyelocytes.


Autonomic control of cerebral blood flow: fundamental comparisons between peripheral and cerebrovascular circulations in humans.
Understanding the contribution of the autonomic nervous system to cerebral blood flow (CBF) control is challenging, and interpretations are unclear. The identification of calcium channels and adrenoreceptors within cerebral vessels has led to common misconceptions that the function of these receptors and actions mirror those of the peripheral vasculature. This review outlines the fundamental differences and complex actions of cerebral autonomic activation compared with the peripheral circulation. Anatomical differences, including the closed nature of the cerebrovasculature, and differential adrenoreceptor subtypes, density, distribution and sensitivity, provide evidence that measures on peripheral sympathetic nerve activity cannot be extrapolated to the cerebrovasculature. Cerebral sympathetic nerve activity seems to act opposingly to the peripheral circulation, mediated at least in part by changes in intracranial pressure and cerebral blood volume. Additionally, heterogeneity in cerebral adrenoreceptor distribution highlights region-specific autonomic regulation of CBF. Compensatory chemo- and autoregulatory responses throughout the cerebral circulation, and interactions with parasympathetic nerve activity are unique features to the cerebral circulation. This crosstalk between sympathetic and parasympathetic reflexes acts to ensure adequate perfusion of CBF to rising and falling perfusion pressures, optimizing delivery of oxygen and nutrients to the brain, while attempting to maintain blood volume and intracranial pressure. Herein, we highlight the distinct similarities and differences between autonomic control of cerebral and peripheral blood flow, and the regional specificity of sympathetic and parasympathetic regulation within the cerebrovasculature. Future research directions are outlined with the goal to further our understanding of autonomic control of CBF in humans.


System Composed of Three Types of Electronic Angular Momenta: A J-S-L Triad in a Photoexcited π-Radical Bis(phthalocyaninato)terbium Single-Molecule Magnet.
Interactions of three different types of electronic angular momenta, namely, spin, orbital, and total angular momenta from different origins in a photoexcited neutral bis(phthalocyaninato)terbium single-molecule magnet (Pc2Tb, where Pc2- denotes a phthalocyaninato anion) have been studied. We have conducted varied-temperature and varied-magnetic-field magnetic circular dichroism (MCD) measurements on the highest occupied molecular orbital-lowest unoccupied molecular orbital electronic transition in the ligand side of the neutral Pc2Tb to reveal the quantum nature of the system composed of a π-radical with a spin angular momentum S, the 4f system with a total angular momentum J, and the cyclic π conjugate system with a photoinduced orbital angular momentum L. We have constructed a new theoretical model that gives a quantitative agreement to the temperature and magnetic field dependence of MCD. The theoretical analysis revealed that the system takes eight quantum states that can be expressed as | J z S z L z⟩ = |±±±⟩, where the three angular momenta are quantized along the fourfold symmetry axis. Thus, we have identified the existence of the magnetic interactions among the three angular momenta and quantitatively determined their magnitudes for the first time.


[Assessment of the hemodynamics of pulmonary artery and right ventricular function in chronic obstructive pulmonary disease with pulmonary hypertension using cardiac magnetic resonance imaging].
To investigate the role of cardiac magnetic resonance imaging (CMRI) in evaluating pulmonary hemodynamics and right ventricular function in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PAH); and the relationship between CMRI parameters and pulmonary function parameters, blood gas analysis parameters and 6-minute walk test (6MWT) parameters in patients with COPD complicated with PAH. Thirty-seven patients were diagnosed with COPD in the department of respiratory and critical care discipline of Ningxia Medical University General Hospital from October 2013 to October 2016, who underwent transthoracic echocardiography (TTE) to measure pulmonary arterial systolic pressure (PASP), and were divided into COPD group and COPD+PAH group according to whether there was PAH [PASP > 40 mmHg (1 mmHg = 0.133 kPa) was defined as PAH]. All patients completed pulmonary function tests [1 second forced expiratory volume to forced vital capacity ratio (FEV1/FVC), FEV1 predicted value (FEV1pred)], blood gas analysis [arterial blood oxygen partial pressure (PaO2), arterial blood carbon dioxide partial pressure (PaCO2)], CMRI examination [relative dilatation of the main pulmonary artery (mPAD), mean pulmonary artery pressure (mPAP), left ventricular ejection fraction (LVEF), right ventricular ejection fraction (RVEF), right ventricular end-diastolic myocardial mass (RVMED), right ventricular end-systolic myocardial mass (RVMES)], and 6MWD [6-minute walk distance (6MWD)] within 1 week. The obtained clinical parameters had been compared between the groups, and correlation was analyzed. Among the 37 patients with COPD, 16 patients were complicated with PAH. There were no significant differences in FEV1/FVC, FEV1pred, PaO2, PaCO2 and other baseline indicators between the two groups. In the COPD group, TTE obtained PASP of 2 patients were normal (PSAP < 40 mmHg), while CMRI measured mPAP were higher than the normal limit (> 25 mmHg). Compared with the COPD group, mPAD, RVEF and 6MWD were significantly decreased in the COPD+PAH group [mPAD: (25.64±5.01)% vs. (44.00±22.52)%, RVEF: 0.525±0.054 vs. 0.592±0.071, 6MWD (m): 319.3±116.5 vs. 408.2±38.0, all P < 0.01], mPAP, RVMED and RVMES were significantly increased [mPAP (mmHg): 28.89±3.16 vs. 20.18±2.43, RVMED (g): 57.19±15.46 vs. 40.71±15.44, RVMES (g): 45.99±11.16 vs. 33.71±13.39, all P < 0.01], and there was no significant differences in LVEF (0.663±0.082 vs. 0.699±0.075, P > 0.05). Correlation analysis showed that mPAD was positively correlated with FEV1/FVC and FEV1pred (r1 = 0.538, P1 = 0.021; r2 = 0.448, P2 = 0.049); RVMED was negatively correlated with PaO2 (r = -0.581, P = 0.015), and positively correlated with PaCO2 (r = 0.592, P = 0.014); 6MWD was positively correlated with RVEF (r = 0.485, P = 0.041), and had no correlation with LVEF (r = 0.271, P = 0.104). Compared with COPD patients, changes in pulmonary hemodynamics and right ventricular function in COPD patients with PAH are related to the severity of airflow limitation. CMRI can early monitor pulmonary hemodynamics and right heart function changes in patients with COPD. Once PAH appears, pulmonary hemodynamics, right heart function and exercise tolerance have changed.


Clinical Outcomes in Patients with Deferred Coronary Lesions according to Disease Severity Assessed by Fractional Flow Reserve.
Data on the clinical outcomes in deferred coronary lesions according to functional severity have been limited. This study evaluated the clinical outcomes of deferred lesions according to fractional flow reserve (FFR) grade using Korean FFR registry data. Among 1,294 patients and 1,628 lesions in Korean FFR registry, 665 patients with 781 deferred lesions were included in this study. All participants were consecutively categorized into 4 groups according to FFR; group 1: ≥ 0.96 (n = 56), group 2: 0.86-0.95 (n = 330), group 3: 0.81-0.85 (n = 170), and group 4: ≤ 0.80 (n = 99). Primary endpoint was major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction, and target vessel revascularization. The median follow-up period was 2.1 years. During follow-up, the incidence of MACE in groups 1-4 was 1.8%, 7.6%, 8.8%, and 13.1%, respectively. Compared to group 1, the cumulative rate by Kaplan-Meier analysis of MACE was not different for groups 2 and 3. However, group 4 had higher cumulative rate of MACE compared to group 1 (log-rank P = 0.013). In the multivariate Cox hazard models, only FFR (hazard ratio [HR], 0.95; P = 0.005) was independently associated with MACE among all participants. In contrast, previous history of percutaneous coronary intervention (HR, 2.37; P = 0.023) and diagnosis of acute coronary syndrome (ACS) (HR, 2.35; P = 0.015), but not FFR, were independent predictors for MACE in subjects with non-ischemic (FFR ≥ 0.81) deferred coronary lesions. Compared to subjects with ischemic deferred lesions, clinical outcomes in subjects with non-ischemic deferred lesions according to functional severity are favorable. However, longer-term follow-up may be necessary.


Dark Opening of Stomates of Vicia faba in CO(2)-free Air: EFFECT OF TEMPERATURE ON STOMATAL APERTURE AND POTASSIUM ACCUMULATION.
Leaf epidermal strips of Vicia faba were floated on 10 millimolar KCl at temperatures of 10 to 45 C for several time periods in the dark. For the duration of the experiment, a jet of water-saturated, CO(2)-free air was passed over the strips. The width of the stomatal aperture was measured microscopically and the potassium content was estimated and expressed as the percentage of area of the guard cell pair stained with cobaltinitrite. Stomatal opening in the dark occurred at temperatures above 35 C. The high temperature aperture reduction previously observed at 45 C in the light was not observed in the dark. Potassium accumulation occurred at all temperatures except 10 C, with a maximum at 45 C, which appeared functionally different from that seen previously in the light.


Comparative Inhibitory Effects of Natural Biflavones from Ginkgo against Human CYP1B1 in Recombinant Enzymes and MCF-7 Cells.
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme overexpressed in many tumors and associated with angiogenesis. Ginkgetin, isoginkgetin, sciadopitysin, and amentoflavone, the primary biflavones found in Ginkgo biloba, have excellent anti-inflammatory and anti-tumor effects. However, the effect of biflavones on CYP1B1 activities remains unknown. In this study, 7-ethoxyresorufin O-deethylation (EROD) was used to characterize the activities of CYP1 families. The impacts of four ginkgo biflavones on CYP1B1 activity and the cellular protein expression of CYP1B1 were systematically investigated. The results showed that amentoflavone with six hydroxyl substituents exhibited the most potent selective inhibitory effect on CYP1B1 activity with IC50 of 0.054 µM in four biflavones. Sciadopitysin, with three hydroxyl and three methoxy substituents, had the weakest inhibitory activity against CYP1B1. Ginkgetin and isoginkgetin, both with four hydroxyl and two methoxy substituents, showed similar inhibitory intensity towards CYP1B1 with IC50 values of 0.289 and 0.211 µM, respectively. Kinetic analysis showed that ginkgetin and amentoflavone inhibited CYP1B1 in a non-competitive mode, whereas sciadopitysin and isoginkgetin induced competitive or mixed types of inhibition. Notably, four ginkgo biflavones were also confirmed to suppress the protein expressions of CYP1B1 and AhR in MCF-7. Furthermore, molecular docking studies indicated more hydrogen bonds formed between amentoflavone and CYP1B1, which might explain the strongest inhibitory action towards CYP1B1. In summary, these findings suggested that biflavones remarkably inhibited both the activity and protein expression of CYP1B1 and the inhibitory activities enhanced with the increasing hydroxyl substitution, providing new insights into the anti-tumor potentials of biflavones.


Novel Core-Sheath Cu/Cu2O-ZnO-Fe3O4 Nanocomposites with High-Efficiency Chlorine-Resistant Bacteria Sterilization and Trichloroacetic Acid Degradation Performance.
In order to solve two issues of chlorine-resistant bacteria (CRB) and disinfection byproducts (DBPs) in tap water after the chlorine-containing treatment process, an innovative core-sheath nanostructured Cu/Cu2O-ZnO-Fe3O4 was designed and synthesized. The fabrication mechanism of the materials was then systematically analyzed to determine the component and valence state. The properties of CRB inactivation together with trichloroacetic acid (TCAA) photodegradation by Cu/Cu2O-ZnO-Fe3O4 were investigated in detail. It was found that Cu/Cu2O-ZnO-Fe3O4 displayed excellent antibacterial activity with a relatively low cytotoxicity concentration due to its synergism of nanowire structure, ion release, and reactive oxygen species generation. Furthermore, the Cu/Cu2O-ZnO-Fe3O4 nanocomposite also exhibited outstanding photocatalytic degradation activity on TCAA under simulated sunlight irradiation, which was verified to be dominated by the surface reaction through kinetic analysis. More interestingly, the cell growth rate of Cu/Cu2O-ZnO-Fe3O4 was determined to be 50% and 10% higher than those of Cu/Cu2O and Cu/Cu2O-ZnO after 10 h incubation, respectively, manifesting a weaker cytotoxicity. Therefore, the designed Cu/Cu2O-ZnO-Fe3O4 could be a promising agent for tap water treatment.


Combined flame and electrodeposition synthesis of energetic coaxial tungsten-oxide/aluminum nanowire arrays.
A nanostructured thermite composite comprising an array of tungsten-oxide (WO2.9) nanowires (diameters of 20-50 nm and lengths of >10 μm) coated with single-crystal aluminum (thickness of ~16 nm) has been fabricated. The method involves combined flame synthesis of tungsten-oxide nanowires and ionic-liquid electrodeposition of aluminum. The geometry not only presents an avenue to tailor heat-release characteristics due to anisotropic arrangement of fuel and oxidizer but also eliminates or minimizes the presence of an interfacial Al2O3 passivation layer. Upon ignition, the energetic nanocomposite exhibits strong exothermicity, thereby being useful for fundamental study of aluminothermic reactions as well as enhancing combustion characteristics.


Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials.
KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes. Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed. Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33). MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation.


Hierarchical Nanocapsules of Cu-Doped MoS2@H-Substituted Graphdiyne for Magnesium Storage.
Hierarchical nanocomposites, which integrate electroactive materials into carbonaceous species, are significant in addressing the structural stability and electrical conductivity of electrode materials in post-lithium-ion batteries. Herein, a hierarchical nanocapsule that encapsulates Cu-doped MoS2 (Cu-MoS2) nanopetals with inner added skeletons in an organic-carbon-rich nanotube of hydrogen-substituted graphdiyne (HsGDY) has been developed for rechargeable magnesium batteries (RMB). Notably, both the incorporation of Cu in MoS2 and the generation of the inner added nanoboxes are developed from a dual-template of Cu-cysteine@HsGDY hybrid nanowire; the synthesis involves two morphology/composition evolutions by CuS@HsGDY intermediates both taking place sequentially in one continuous process. These Cu-doped MoS2 nanopetals with stress-release skeletons provide abundant active sites for Mg2+ storage. The microporous HsGDY enveloped with an extended π-conjugation system offers more effective electron and ion transfer channels. These advantages work together to make this nanocapsule an effective cathode material for RMB with a large reversible capacity and superior rate and cycling performance.


[Intravitreal angiostatic treatment of ocular vascular diseases].
Intraocular vascular diseases like neovascular age-related macular degeneration, diabetic macular oedema and retinal vein occlusion are associated with decline in vision if left untreated. Anti-vascular endothelia growth factor (VEGF) agents originally developed for cancer treatment were the beginning of a new treatment regime for intraocular vascular diseases. Ambiguous results exist regarding adverse effects but are considered limited. In the future, anti-VEGF agents are likely to be used for treatment of proliferative diabetic retinopathy, neovascular glaucoma and premature retinopathy.


Combined Orthopaedic and Vascular Injuries With Ischemia: A Multicenter Analysis.
To review a large, multicenter experience to identify the current salvage and amputation rates of these combined injuries and, where possible, the variables that predict amputation. Retrospective. Nine trauma centers. This study involved 199 patients presenting to 9 trauma centers with orthopaedic and vascular injuries resulting in ischemic limbs for whom the orthopaedic service was involved with the decision for salvage versus amputation. We reviewed 199 patients, 17-85 years of age. One hundred seventy-two of the injuries were open. Thirty-eight patients (19%) were treated with amputation upon admission as they were deemed to be unsalvageable. Of the remaining 161 patients who had attempted salvage, 36 (30%) required late amputation. Closed injuries were successfully salvaged in 25 of 27 cases (93%). The highest rate of amputation was in tibia fractures with a combined amputation rate of 62%. In those attempted to be salvaged, 21 of 48 (44%) required amputation. The ischemia time for successful salvage was significantly less, P = 0.03. One hundred twenty-four patients had their definitive vascular repair before the bony reconstruction. There were 15 vascular complications, of which 13 (86%) had the definitive vascular repair performed before the definitive osseous repair, although this was not statistically significant. In this series of combined orthopaedic and vascular injuries, we found a high rate of acute and late amputations. It is possible that other protocols, such as shunting and stabilizing the osseous injury, before vascular repair may benefit limb salvage, although this needs more study. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


In Vitro Propagation of Cannabis sativa L. and Evaluation of Regenerated Plants for Genetic Fidelity and Cannabinoids Content for Quality Assurance.
Cannabis sativa L. (Marijuana; Cannabaceae), one of the oldest medicinal plants in the world, has been used throughout history for fiber, food, as well as for its psychoactive properties. The dioecious and allogamous nature of C. sativa is the major constraint to maintain the consistency in chemical profile and overall efficacy if grown from seed. Therefore, the present optimized in vitro propagation protocol of the selected elite germplasm via direct organogenesis and quality assurance protocols using genetic and chemical profiling provide an ideal pathway for ensuring the efficacy of micropropagated Cannabis sativa germplasm. A high frequency shoot organogenesis of C. sativa was obtained from nodal segments in 0.5 μM thidiazuron medium and 95 % in vitro rhizogenesis is obtained on half-strength MS medium supplemented with 500 mg/L activated charcoal and 2.5 μM indole-3-butyric acid. Inter Simple Sequence Repeats (ISSR) and Gas Chromatography-Flame Ionization Detection (GC-FID) are successfully used to monitor the genetic stability in micropropagated plants up to 30 passages in culture and hardened in soil for 8 months.


[Autologous bone marrow integrating artificial bone and ilium periosteum transplantation for treatment of bone nonunion].
To evaluate the initial clinical effect of the autologous bone marrow integrating artificial bone and ilium periosteum transplantation in treatment of problematic nonunion. From January 2004 to July 2006, 12 patients (13 limbs)with problematic nonunion were treated with autologous bone marrow integrating artificial bone and ilium periosteum. There were 8 males and 4 females, aged 17-58 years old. The position of nonunion were the tibia in 7 limbs, the femur in 3 limbs, the humerus in 2 limbs. The operated number was 1-4, mean 2.5. The time from injury to therapy was 13 months to 9 years, mean 47.6 months. The bone defect distance was 6-30 mm (mean 15 mm) through 1 : 1 X-rays before operation. Eleven limbs were treated by internal fixation (10 limbs by the bone nail and 1 limb by the limited contact-dynamic compression plate), 2 limbs were treated by the external fixation. The X-ray films were taken at 1 day, 1, 3, 6, 9, 12 months after operation to observe fracture union. All patients were followed up for 12-26 months (mean 17.5 months) and achieved union within 4-7 months (mean 6 months). No deformity of rotation, angulation and crispation occurred in 13 limbs, but functional impairment occurred in 6 limbs after union of fracture. Autologous bone marrow integrating artificial bone and ilium periosteum transplantation for treatment of problematic nonunion has the satisfactory result.


Reversing rectangular pulse generator applicable to transient electric birefringence.
An electronic reversing rectangular pulse generator, which can be used for experiments on electric birefringence in macromolecular solutions, was constructed. The performance was very satisfactory when four thyratron tubes of 2D21 or 1G50 type were used. The switching time for pulse reversing was less than 50 ns even without very careful wiring of the circuit. Transient electric birefringence for the common strain and HR strain of tobacco mosaic virus was demonstrated as a preliminary experiment.


Boronic esters as protective groups in carbohydrate chemistry: processes for acylation, silylation and alkylation of glycoside-derived boronates.
Procedures for selective installation of acyl, silyl ether and para-methoxybenzyl (PMB) ether groups to glycoside substrates have been developed, employing phenylboronic esters as protected intermediates. The sequence of boronic ester formation, functionalization and deprotection can be accomplished with only a single purification step, and the boronic acid component can be recovered and reused after deprotection. Key advances include the identification of reaction conditions for installation of PMB groups in the presence of boronic esters, and the use of the 'phase switching' protocol developed by Hall and co-workers as an efficient method for boronic ester cleavage. The relatively mild conditions for boronate deprotection are tolerant of several functional groups, including esters, silyl ethers, ketals and thioglycosides.


Lost opportunities for intervention: undetected markers for the development of serious juvenile delinquency.
Persistent serious delinquency in young males rarely starts without a history of problem behaviour in childhood. This paper addresses the following questions: (1) At what age does persistent serious offending emerge for the first time? (2) What proportion of persistent serious delinquent boys qualifies for a diagnosis of a disruptive behaviour disorder? (3) What proportion of persistent serious delinquent boys receive help for their behavioural or educational problems, either from mental health professionals or from personnel at school? Eight waves of assessments from the oldest sample (ages 13 to 18.5) of the Pittsburgh Youth Study were used to classify boys as persistent serious violent offenders, persistent serious property offenders, persistent non-serious offenders, and non-offenders based on their self-reports. Juvenile court records, diagnostic information and information about help for mental health problems were used. Almost half of the boys who eventually become a persistent serious offender already have an onset of their serious delinquent behaviour by age 12. Two-thirds of the boys who come to the attention of the juvenile court already had behaviour problems for at least five years, and one-third were diagnosed as having a disruptive behaviour disorder by age 13. However, less than half of the persistent serious delinquents had received any help from either mental health professionals or from personnel in schools. Early behaviour problems and a diagnosis of disruptive behaviour disorder constitute targets for intervention. The relatively low rate of interventions for boys with these problems and who later become persistent serious offenders indicates a high under-utilization of opportunities to prevent serious delinquency by parents and professionals.


Anticonvulsive Effects of Chondroitin Sulfate on Pilocarpine and Pentylenetetrazole Induced Epileptogenesis in Mice.
Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to the extracellular matrix, regulates the intracellular positive ion concentration, and maintains the hypersynchronous epileptiform activity. Therefore, the present study hypothesized an antiepileptic potential of chondroitin sulfate (CS) in pentylenetetrazole-induced kindled epilepsy and pilocarpine-induced status epilepticus in mice. Levels of various oxidative stress markers and inflammatory mediators were estimated in the brain tissue homogenate of mice, and histopathological changes were evaluated. Treatment with valproate (110 mg/kg; i.p.) as a standard drug and chondroitin sulfate (100 & 200 mg/kg, p.o.) significantly (p < 0.01) and dose-dependently prevented the severity of kindled and spontaneous recurrent seizures in mice. Additionally, chondroitin sulfate showed its antioxidant potential by restoring the various biochemical levels and anti-inflammatory properties by reducing NF-kB levels and pro-inflammatory mediators like TNF-alpha, IL-1β, and IL-6, indicating the neuroprotective effect as well as the suppressed levels of caspase-3, which indicated a neuroprotective treatment strategy in epilepsy. The proteoglycan chondroitin sulfate restores the normal physiology and configuration of the neuronal tissue. Further, the molecular docking of chondroitin sulfate at the active pockets of TNF-alpha, IL-1β, and IL-6 showed excellent interactions with critical amino acid residues. In conclusion, the present work provides preclinical evidence of chondroitin sulfate as a new therapeutic approach in attenuating and preventing seizures with a better understanding of the mechanism of alteration in ECM changes influencing abnormal neuronal activities.


Isolation and characterization of somatic cell hybrids with breakpoints spanning 17q22-->q24.
Somatic cell hybrid mapping panels have previously been constructed to assist in the regional assignment of anonymous DNA probes and cloned genes to human chromosome 17. While a substantial number of hybrids are available that subdivide the short arm of this chromosome and the proximal portion of its long arm into specific regions, relatively few exist with breakpoints in the distal portion of the long arm. To increase the resolution of this region, four additional human x rodent somatic cell hybrids have been constructed that include breakpoints spanning the region 17q22-->q24. Hybrid clones carrying the long-arm derivative of chromosome 17 were initially identified by fluorescence in situ hybridization. Hybrids were subsequently screened using the polymerase chain reaction with primer sets representing DNA markers previously mapped to chromosome 17. These hybrids expand the existing somatic cell hybrid panel for the distal portion of the long arm of chromosome 17.


Binding of lysyl oxidase to fibrils of type I collagen.
The binding of highly purified bovine aortic lysyl oxidase to native fibrils of type I collagen has been measured by assay of unbound lysyl oxidase activity in the supernatants of enzyme-collagen mixtures after centrifugation. The apparent binding affinity of lysyl oxidase for native fibrils is quite similar to that for fibrils prepared from pepsin- or chymotrypsin-digested type I collagen, demonstrating that the enzyme binds to the triple-helical portion of collagen molecules. The data also indicate that the enzyme binds predominantly to the fibrillar surface. The results suggest that lysyl oxidase initiates crosslink formation at an early stage in collagen fibrillogenesis.


Prolonged β2-adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1-/- mice.
Prolonged supplementation with the β2-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β2-adrenoceptor (β2-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to-especially diabetic-humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to β1- and β3-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient (UCP1-/-) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1-/- C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1-/- C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in UCP1-/- mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1-/- mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, β2-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans.NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged β2-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the β2-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1-/- mice, indicating that β2-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.


Productivity of older workers: perceptions of employers and employees.
What determines the perceived productivity of the older worker and how does this perception compare to the perception of the productivity of the younger worker? In this study we present evidence based on data from Dutch employers and employees. Productivity perceptions are affected by one's age and one's position in the hierarchy. The young favor the young, the old favor the old, and employers value the productivity of workers less than employees do. However, there are also remarkable similarities across employers and employees. By distinguishing the various dimensions that underlie the productivity of younger and older workers, we tested whether soft qualities and abilities-e.g., reliability and commitment-are just as important as hard qualities-cognitive and physically based skills-in the eyes of both employers and employees. It appears that both employers and employees, young and old, view hard skills as far more important than soft skills.


Pelvic Floor Muscle Training for Urinary Incontinence with or without Biofeedback or Electrostimulation in Women: A Systematic Review.
To determine the effectiveness of pelvic floor muscle training (PFMT) with or without biofeedback or electrostimulation in reducing urinary incontinence and pelvic floor muscle con-traction in non-pregnant women with urinary incontinence. The following electronic databases were searched: PubMed, Cochrane Central, ClinicalTrials.gov, EU Clinical Trials Register, and sources from NICE, FDA, EMA, and SMC (articles only in English, 2000-2021). Search terms were: urinary incontinence, pelvic floor muscle training or exercises, biofeedback, electrostimulation. We used the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) for this systematic review. Relevant articles were selected, data were extracted, and quality was assessed. Data were extracted in predesigned form, followed by narrative synthesis. Following the search, 15 RCTs were retrieved using the strict inclusion and exclusion criteria, assessing 2441 non-pregnant women with urinary incontinence. Of the 15 studies, 7 were low risk, 5 were medium risk, and 3 were high-risk studies. Of the 2441 patients, 970 were in PFMT, 69 were in extracorporeal magnetic innervation (ExMi) or with PFMT + BF, 30 were in electrostimulation (ES), 21 were in whole body vibration training (WBVT), 23 were in pelvic floor muscle + abdominal muscle therapy (PFM + AMT), 326 were in PFMT + biofeedback, 93 were in vaginal cones (VC), 362 were in PFMT + education, 318 were in education, and 229 were in control groups. The most often measures employed were pad tests, bladder diary, and questionnaire on the quality of life. Stress, urge and mixed urinary incontinence were studied. In all RCT, PFMT significantly reduced urinary incontinence, essentially SIU and MUI, when compared with the control group before and after treatment. Overall, out of 997 PFMT or PFMT + education patients, 504 patients (50.5%) showed improvement in urinary incontinence, and 218 became continent (21.8%) (negative pad test). In total, 62% of patients significantly reduced their urinary incontinence or cured it and improved their pelvic floor muscle contraction. All other physiotherapist techniques also significantly reduced urinary leakages, e.g., vaginal cones, biofeedback, ExMI, and WBVT when compared with the control group. There were no significant differences between these methods in reducing the severity of urinary incontinence. PFMT alone or with bio-feedback or electrostimulation was effective in reducing urinary incontinence and improving pelvic floor muscle contraction. PFMT when compared with other interventions such as bio-feedback, VC, and WBVT did not show significant differences but was superior to the control group. RCT studies with similar parameters used for measuring the outcomes need to be included.


Disability Assessment for Patients with Stroke.
This review focuses on six prominent disability instruments designed and used in stroke research. The strengths and limitations of each are reviewed against four criteria which should be considered in selecting among existing instruments: the conceptual scope; the scaling method; its psychometric properties; and the instrument's feasibility. Outcomes measurement is an active area of investigation and the clinical researcher should follow the rehabilitation literature closely to keep abreast of the latest developments.


A consortium, graduate medical education, and Buffalo: defining a common ground.
Regional graduate medical education (GME) consortia are a strategy to align public support for GME with societal goals. One such consortium was established in Buffalo, NY, to pool financial resources, facilitate processing of Accreditation Council for Graduate Medical Education requirements, guarantee quality education, and more appropriately use community resources. Cooperation has attracted external funding from state and federal governments and private foundations, fostering community-wide undergraduate medical education, as well as GME. The American Association of Medical Colleges has identified 36 GME consortia in the United States. New York may lead the nation on a strategy to use consortia for the distribution of all state-appropriated GME support. The relationships fostered by consortial interactions have benefitted family medicine and provided opportunities for leading regional medical education into a primary care-specialty balanced future.