African-American men and intention to adhere to recommended follow-up for an abnormal prostate cancer early detection examination result.
To assess the intention of African-American men to have the recommended follow-up in the event of an abnormal prostate cancer early detection examination and to identify the variables that help to explain adherence intention. In the spring of 1995, we selected a random sample of 548 African-American men who were patients at the University of Chicago Health Service. The sample included men who were 40 to 70 years of age, did not have a personal history of prostate cancer, and had a working telephone number. A total of 413 men who completed the telephone survey received an invitation to consider undergoing a prostate cancer early detection examination. The survey provided data on personal background characteristics, knowledge, attitudes, and beliefs related to prostate cancer and early detection. Respondents were asked whether they would choose to have the recommended follow-up in the event of an abnormal early detection examination result. Univariate and multivariate analyses of intention to have follow-up were performed. An intention to have the recommended follow-up was reported by 77% of the survey respondents. The results of multivariate analyses revealed that the intention to have the follow-up was positively associated with education beyond high school (odds ratio [OR] 1.9); perceived self-efficacy related to prostate cancer screening (OR 2.1); the belief that prostate cancer can be cured (OR 3.3); the belief that prostate cancer screening should be done in the absence of prostate problems (OR 2.3); and physician support for prostate cancer screening (OR 2.1). African-American men who have a high school education or less may be at risk of nonadherence to recommended follow-up. Adherence also may be low among men who do not have favorable views of early detection or do not perceive strong physician support for early detection. Research is needed to determine whether intention and other factors predict actual adherence to follow-up in this population group.


P2X(7) receptor-mRNA and -protein in the mouse retina; changes during retinal degeneration in BALBCrds mice.
A combined real-time PCR/immunohistochemistry study was carried out to investigate whether P2X(7) receptors, known to induce apoptosis and necrosis, may be causally related to the process of retinal degeneration in BALBCrds mice. In the retinae of BALBCrds mice, P2X(7) receptor-mRNA was the highest at an age of 20-40 days, and declined afterwards. At the same time, the P2X(7) receptor-message was constantly low in the retina of control BALBC mice until postnatal day 100. The receptor-mRNA in total brain tissue of both strains of mice was comparable with that of BALBCrds retinae. Double immunofluorescence in combination with laser scanning microscopy was used to study the distribution of P2X(7) receptor-immunoreactivity (IR) on neurons and different glial cell types of the retina. An exclusively neuronal localization of P2X(7)-IR in the ganglion cell layer was found by using either anti-neuronal nuclei or microtubule associated protein-2 as neuronal markers. There was a slight age-dependent decrease in the abundance of neuronal P2X(7)-IR both in BALBCrds or BALBC mice. P2X(7)-IR failed to co-localize with any of the non-neuronal markers used to stain microglial or Müller glial cells. No P2X(7) receptor-IR was found in the retinal ganglion cell layer of P2X(7)(-/-) animals, when compared with the control littermates. Hence, we suggest that, in BALBCrds mice, an early up-regulation of neuronal P2X(7) receptors may cause injury of retinal neurons and thereby functionally contribute to the retinal damage.


The JAK-STAT signaling pathway: input and output integration.
Universal and essential to cytokine receptor signaling, the JAK-STAT pathway is one of the best understood signal transduction cascades. Almost 40 cytokine receptors signal through combinations of four JAK and seven STAT family members, suggesting commonality across the JAK-STAT signaling system. Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. Using the examples of the IL-6 and IL-10 receptors, I will discuss how diverse outcomes in gene expression result from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors. I also consider receptor preferences by different STATs and interpretive problems in the use of STAT-deficient cells and mice. Finally, I consider how the suppressor of cytokine signaling (SOCS) proteins regulate the quality and quantity of STAT signals from cytokine receptors. New data suggests that SOCS proteins introduce additional diversity into the JAK-STAT pathway by adjusting the output of activated STATs that alters downstream gene activation.


Validity and Reliability of the Pictures of Facial Affect (POFA) in Healthy People and Patients with Essential Tremor in the Turkish Population.
This study aimed to conduct the validity and reliability of the (Pictures of Facial Affect) POFA test for the Turkish population and contribute to increasing the number of tests that are still insufficient in our country. This descriptive, randomized controlled study was conducted in two steps, namely Step 1 (Pilot Study and Validity Studies) and Step 2 (Reliability Study Step). The number of participants was planned regarding the original study by which the POFA test was developed. The EYES test was also used for comparison. In the pilot study, the most widely identified emotions from 47 of 110 photos in the POFA test were chosen as the new POFA picture set to be used in the reliability and validity study under the name "POFA Test Short Form". A total of 100 participants, including 82 healthy volunteers and 18 essential tremor (ET) patients, were enrolled in the first step of the study. Another cohort of 22 healthy volunteers was enrolled in the second step of the study for test-retest reliability analysis. A significant positive correlation was found between the total POFA Test Short Form and EYES Test scores in the healthy volunteer group in terms of criterion-related validity (r=0.44, p<0.01). There were statistically significant differences between healthy volunteers and ET groups regarding EYES Total, POFA Total, POFA Sadness, POFA Anger, and POFA Neutral scores. It was observed that the 47-item POFA Test Short Form total score showed skewness and kurtosis, which demonstrated suitability for clinical use. The POFA Test Short Form was found to be a valid and reliable assessment tool in the Turkish population to be used in studies on emotion recognition and was shown to be beneficial for the discrimination of healthy individuals and ET patients.


Clinically available intracorporeal left ventricular assist devices.
There are now 3 commercially approved intracorporeal left ventricular assist devices (LVADs). Product similarities include (1) LV apex, to pump, to ascending aorta flow patterns, (2) excellent hemodynamic support with reversal of heart failure and neurohormone/cytokine milieu, and (3) the requirement of major surgery for device implantation and later explantation, with or without transplant. Two electrically powered models allow a tether-free existence and hospital discharge. All complications are being addressed, and in the past decade, device failure and thromboemboli have been reduced. Infection continues to be an obstacle to more widespread adoption of therapy. Despite pre-LVAD shock, most patients (65% to 78% by Food and Drug Administration data) survive until transplant (averaging 80 to 96 days of LVAD support), and posttransplant survival is equal to nonbridged patients. As the problem of infection is reduced, more widespread LVAD use can be anticipated.


[Pancreatic mucinous cystadenoma with atypical clinical presentation].
We present a 33-year-old patient with atypical clinical course of pancreatic mucinous cystadenoma. The tumor had connection with pancreatic ductal system and led to bleeding into cystic cavity. This contributed to incorrect preoperative diagnosis of post-necrotic cyst. The final diagnosis of mucinous cystadenoma was established after histological examination. Distal pancreatectomy excluded incorrect treatment.


[Genesis of specific multisite Medical Intervention Plans in the Brussels Capital Region].
After the november 19th 2015 Paris terrorist attacks, there was a clear need to update the Medical Intervention Plans (MIP) for Mass Casualty Events (MCE) in the Brussels Capital Region (BCR), because they only offered a response to single-site MCE in a peace-time context. We compared the organisation and the resources of the BCR and cities like Paris and Lille, we discussed with our french colleagues and formed a Multisite Attack Task-force that produced a specific multisite MIP, which had to be put to use only a few days after its creation.


School Scoliosis Screenings: Family Experiences and Potential Anxiety After Orthopaedic Referral.
Cross-sequential study design that used data from Texas Scottish Rite Hospital for Children (TSRHC). Examine anxiety symptoms and family experiences subsequent to school scoliosis screening (SSS) referrals. Use of SSS remains controversial. Prior research suggested that SSS programs may result in anxiety for both children and parents. Unfortunately, no study has examined the SSS referral processes and anxiety in families. Study consisted of 2 groups-patients/parents from TSRHC evaluated for Adolescent Idiopathic Scoliosis (AIS) (n = 27) and control participants/parents (n = 27) between ages 9 and 17. All participants completed the primary outcome measure (State-Trait Anxiety Inventory) before and after the scoliosis evaluation or controlled wait time. Parents also rated experience and satisfaction with SSS. Compared with the control group, children/parents in patient group experienced significantly elevated levels of state-anxiety at preappointment. Children/parents in the patient group not diagnosed with AIS experienced a significant decline in state-anxiety. Children/parents in the patient group diagnosed with AIS continued to report elevated levels of anxiety. The control group remained consistent, reporting of low levels of anxiety pre to post. More than half (55.5%) of families indicated they received no information from the school about scoliosis. A third of the families who received information indicated it did not adequately address their concerns. Nonetheless, most families reported overall satisfaction with SSS. This study suggested that children and parents referred through the SSS program experienced significantly elevated levels of state-anxiety. This supports the subjective concerns of anxiety experiences in families voiced by researchers previously. However, families deemed the costs of the SSS referral process as worth the benefits. Though challengers of SSS programs were accurate in observing anxiety in families, it may not constitute significant burden to eliminate SSS programs altogether. Improvements to the current system may be warranted. 3.


Reduced field-of-view MRI using outer volume suppression for spinal cord diffusion imaging.
A spin-echo single-shot echo-planar imaging (SS-EPI) technique with a reduced field of view (FOV) in the phase-encoding direction is presented that simultaneously reduces susceptibility effects and motion artifacts in diffusion-weighted (DW) imaging (DWI) of the spinal cord at a high field strength (3T). To minimize aliasing, an outer volume suppression (OVS) sequence was implemented. Effective fat suppression was achieved with the use of a slice-selection gradient-reversal technique. The OVS was optimized by numerical simulations with respect to T(1) relaxation times and B(1) variations. The optimized sequence was evaluated in vitro and in vivo. In simulations the optimized OVS showed suppression to <0.25% and approximately 3% in an optimal and worst-case scenario, respectively. In vitro measurements showed a mean residual signal of <0.95% +/- 0.42 for all suppressed areas. In vivo acquisition with 0.9 x 1.05 mm(2) in-plane resolution resulted in artifact-free images. The short imaging time of this technique makes it promising for clinical studies.


Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Leukoencephalitis Following COVID-19: Systematic Review and Meta-synthesis.
Since the onset of the COVID-19 pandemic, a growing number of reports have described cases of acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) following infection with COVID-19. Given their relatively rare occurrence, the primary objective of this systematic review was to synthesize their clinical features, response to treatments, and clinical outcomes to better understand the nature of this neurologic consequence of COVID-19 infection. Patients with a history of COVID-19 infection were included if their reports provided adequate detail to confirm a diagnosis of ADEM or AHLE by virtue of clinical features, radiographic abnormalities, and histopathologic findings. Cases purported to be secondary to vaccination against COVID-19 or occurring in the context of a preexisting relapsing CNS demyelinating disease were excluded. Case reports and series were identified via PubMed on May 17, 2021, and 4 additional cases from the authors' hospital files supplemented the systematic review of the literature. Summary statistics were used to describe variables using a complete case analysis approach. Forty-six patients (28 men, median age 49.5 years, 1/3 >50 years old) were analyzed, derived from 26 case reports or series originating from 8 countries alongside 4 patient cases from the authors' hospital files. COVID-19 infection was laboratory confirmed in 91% of cases, and infection severity necessitated intensive care in 67%. ADEM occurred in 31 cases, whereas AHLE occurred in 15, with a median presenting nadir modified Rankin Scale score of 5 (bedridden). Anti-MOG seropositivity was rare (1/15 patients tested). Noninflammatory CSF was present in 30%. Hemorrhage on brain MRI was identified in 42%. Seventy percent received immunomodulatory treatments, most commonly steroids, IV immunoglobulins, or plasmapheresis. The final mRS score was ≥4 in 64% of patients with adequate follow-up information, including 32% who died. In contrast to ADEM cases from the prepandemic era, reported post-COVID-19 ADEM and AHLE cases were often advanced in age at onset, experienced severe antecedent infection, displayed an unusually high rate of hemorrhage on neuroimaging, and routinely had poor neurologic outcomes, including a high mortality rate. Findings are limited by nonstandardized reporting of cases, truncated follow-up information, and presumed publication bias.


[Competence and work identity--an evaluation of Norwegian continuing education in psychiatric nursing].
Mental health services are in transition. The question is to what extent professional training programmes within the health and social sectors have taken into consideration claims and expectations on professionals following this organizational transition. The purpose of this descriptive study was, by means of a semi-structured questionnaire, to evaluate Norwegian postgraduate programmes of psychiatric nursing with respect to what extent they had met the psychiatric nurses' need for competence in their clinical work. Only few evaluations of this type are reported from Scandinavia, and, consequently, it is important to conduct such studies to elucidate strengths and weaknesses in existing programmes. In all 154 psychiatric nurses participated (response rate 48%). The study revealed that psychiatric nurses perceived their training as significant to their practice--and that their professional identity and competence had been strengthened. This was connected to the possibility of studying their own professional field in depth--and to clarify their field of responsibility. Thus, the respondents regarded an alteration of the postgraduate programme in an interdisciplinary direction as unfortunate. Such an alteration might contribute to a weakening of their specific competence and professional perspective. The respondents held that productive interdisciplinary co-operation presupposes a multi-disciplinary approach. The postgraduate programmes seem definitely to qualify psychiatric nurses for working in psychiatric institutions, but their training is also relevant for working in the community health services.


C,N-bipyrazole receptor grafted onto a porous silica surface as a novel adsorbent based polymer hybrid.
A simple heterogeneous synthesis of pure adsorbent based polymer hybrid made by condensing a functionalized C,N-bipyrazole with a 3-glycidoxypropyl-trimethoxysilane silylant agent, previously anchored on a silica surface was developed. The formed material (SG2P) was characterized through elemental analysis, FT-IR spectroscopy, (13)C NMR of solid state, scanning electron microscope (SEM), and was studied and evaluated by determination of the surface area using the BET equation, the adsorption and desorption capability using the isotherm of nitrogen and B.J.H. pore sizes. The new material exhibits good thermal stability determined by thermogravimetry curves and good chemical stability was examined in various acidic and buffer solutions (pH 1-7). The binding and adsorption abilities of SG2P were investigated for Hg(2+), Cd(2+), Pb(2+), Zn(2+), K(+), Na(+) and Li(+) cations and compared to the results of classical liquid-liquid extraction with the unbound C,N-bipyrazole compound. The grafting at the surface of silica does not affect complexing properties of the ligand and the SG2P exhibits a high selectivity toward Hg(2+) ion with no complexation being observed towards zinc and alkali metals. The extracted and the complexing cation percentages were determined by atomic absorption measurements.


Interactions between sulforaphane and apigenin in the induction of UGT1A1 and GSTA1 in CaCo-2 cells.
The isothiocyanate, sulforaphane and the flavonoid, apigenin modulate gene expression including phase II detoxifying enzymes, such as glutathione S-transferases (GST) and UDP-glucuronosyltransferases (UGT). Using undifferentiated CaCo-2 cells, we have examined the interactions between sulforaphane and apigenin in the regulation of UGT and GST expression. We show that apigenin induces UGT1A1 transcription (4-fold) but not GSTA1, and that sulforaphane induces both UGT1A1 (3.7-fold) and GSTA1 (2.8-fold) transcription in both dose- and time-dependent manners. The combination of sulforaphane and apigenin resulted in a synergistic induction of UGT1A1 mRNA up to 12-fold, although this interaction was not seen for GSTA1. Nuclear factor kappa B (NF-kappaB) mRNA was induced by apigenin and sulforaphane (2.5- and 2-fold, respectively). NF-kappaB translocation inhibitor SN50 and phosphatidylinositol 3-kinase (PI3) inhibitor LY294002 decreased the induction of GSTA1 by sulforaphane almost to baseline level. However, the MEK inhibitor PD98059 enhanced significantly the induction of GSTA1 by sulforaphane. This suggests that NF-kappaB and PI3-kinase signaling pathways play a role in GSTA1 gene expression. Conversely, the induction of UGT1A1 transcription by sulforaphane was totally abolished by PD98059, although PD98059 slightly enhanced (20%) the induction of UGT1A1 by apigenin implying that the induction of UGT1A1 by sulforaphane is mediated by MAPK/extracellular signal-regulated kinase kinase, whereas UGT1A1 induction by apigenin may be associated with NF-kappaB translocation since the NF-kappaB translocation inhibitor, SN50 enhanced the induction of UGT by apigenin. The results show that UGT1A1 and GSTA1 are regulated by sulforaphane through different signal transduction pathways and the differences in the mechanisms of modulation of UGT1A1 transcription by sulforaphane and apigenin resulted in a synergistic effect between these two compounds in the induction of UGT1A1.


Sleep Disturbances and Emotional and Behavioral Difficulties Among Preschool-Aged Children.
Sleep disturbances and mental health problems are highly comorbid and bidirectionally correlated across childhood. The association between the natural history of sleep disturbances and the transition of mental health problems has not been quantified. To examine the association between the natural history of sleep disturbances and resolved and incident emotional and behavioral difficulties (EBDs). This cohort study used data from the Shanghai Children's Health, Education and Lifestyle Evaluation-Preschool (SCHEDULE-P), a prospective and population-based longitudinal cohort study of children enrolled in preschools in Shanghai, China, from November 10 to 24, 2016. A total of 20 324 children aged 3 to 4 years were recruited from the junior class of 191 kindergartens, of whom 17 233 (84.8%) participated in the 2-year follow-up. A multilevel regression model was used to evaluate the association between the development of sleep disturbances and the occurrence of resolved and incident EBDs. The data analysis spanned from August 4, 2021, to October 31, 2023. Sleep disturbances were assessed using the Children's Sleep Habit Questionnaire; EBDs were assessed using the Strengths and Difficulties Questionnaire. Occurrence of incident and resolved EBDs at the 2-year follow-up. The cohort included 17 182 participants, with a mean (SD) age of 3.73 (0.29) years at enrollment; 52.0% were boys. The prevalence of EBDs at school entry and graduation years was 27.8% and 18.7%, respectively, while the prevalence of sleep disturbances was 41.3% and 31.5%, respectively. Among those with EBDs at the entry year, 35.0% maintained stability in the graduation year, while sleep disturbances were stable in 50.0% of those with sleep disturbances. After controlling for confounding factors, the odds ratio (OR) for resolved EBDs was lower in the incident sleep disturbance (ISD) group (OR, 0.50 [95% CI, 0.41-0.62]; P < .001) and stable sleep disturbance (SSD) group (OR, 0.47 [95% CI, 0.40-0.56]; P < .001) compared with the group with no sleep disturbances. The ORs for incident EBDs among the ISD group (OR, 2.58 [95% CI, 2.22-3.01]; P < .001) and SSD group (OR, 2.29, [95% CI, 1.98-2.64]; P < .001) were higher than among the group with no sleep disturbances. In this prospective cohort study, the natural history of sleep disturbances among preschool-aged children was associated with both resolved and incident EBDs. Routine screening and precise intervention for sleep disturbances may benefit the psychosocial well-being of this population.


Operational diagnosis of endogenous depression. II. Comparison of 8 different operational diagnoses.
The comparison of 8 different operational diagnoses (OPD) of endogenous depression in a group of 173 inpatients with operationally diagnosed depressive syndromes shows a rather low agreement between the different diagnoses. Whereas in most comparisons there is a significant association between the different diagnoses (chi 2) the chance-corrected agreement is poor (kappa less than 0.50) in nearly all comparisons. These values cannot guarantee a comparability of results found in patient samples which are diagnosed as endogenous depressions by different OPD. The simultaneous application of competing OPD (polydiagnosis) seems to be an approach suited to overcome this problem and allow comparability of research results of endogenously depressed patient samples.


Prediction of biological sensors appearance with ARIMA models as a tool for Integrated Pest Management protocols.
Powdery mildew caused by Uncinula necator and Downy mildew produced by Plasmopara viticola are the most common diseases in the North-West Spain vineyards. Knowledge of airborne spore concentrations could be a useful tool in the Integrated Pest Management protocols in order to reduce the number of pesticide treatments, applied only when there is a real risk of infection. The study was carried out in a vineyard of the D. O. Ribeiro, in the North-West Spain, during the grapevine active period 2004-2012. A Hirts-type volumetric spore-trap was used for the aerobiological monitoring. During the study period the annual total U. necator spores amount ranged from the 578 spores registered in 2007 to the 4,145 spores sampled during 2008. The highest annual total P. viticola spores quantity was observed in 2010 (1,548 spores) and the lowest in 2005 (210 spores). In order to forecast the concentration of fungal spores, ARIMA models were elaborated. The most accurate models were an ARIMA (3.1.3) for U. necator and (1.0.3) for P. viticola. The possibility to forecast the spore presence 72 hours in advance open an important horizon for optimizing the organization of the harvest processes in the vineyard.


Platelet membrane alterations induced by the local anesthetic dibucaine.
Tertiary amine local anesthetics modify a variety of platelet membrane-related functions. The present study explored dibucaine (DB)-induced inhibition of platelet cohesion by examining structural and functional alterations of the human platelet membrane glycoprotein IIb-IIIa complex (GPIIb-IIIa) and platelet Ca2+ homeostasis. Complete inhibition of ADP-induced aggregation was achieved five minutes after platelet exposure to 0.10 to 0.25 mmol/L of DB when fibrinogen binding was reduced by 50%. At higher concentrations of DB (approximately 1 mmol/L), ADP-induced fibrinogen binding was completely blocked. Scatchard analysis revealed loss of high-affinity binding sites in addition to reduction in Bmax. In contrast, chymotrypsin-treated platelets sustained 50% inhibition of fibrinogen binding when incubated with 0.4 to 0.5 mmol/L DB, and kinetic analysis showed that the high-affinity platelet-fibrinogen interactions were reduced but not absent. Fibrinogen binding to chymotrypsin-treated platelets could not be completely inhibited even at high DB concentrations (1 mmol/L). The inhibition of fibrinogen binding to chymotrypsin-treated platelets correlated with changes in binding of a monoclonal antibody (10E5) specific for an epitope on the GPIIb-IIIa complex. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and radioelectroimmunoassay of DB-treated platelets, however, showed no evidence of a reduction or degradation of GP IIb or IIIa. Platelet incubation with DB (five minutes, 0.1 to 1.0 mmol/L) was also accompanied by: increased platelet membrane-associated Ca2+ involving low-affinity binding sites [Kd = 5 X 10(-5) mol/L-]; increased 45Ca2+ uptake which correlated with degradation of actin-binding protein (ABP) and digestion of GPIb as visualized on periodic-acid Schiff (PAS)-stained SDS gels and as inferred from decreased binding of a monoclonal antibody (6D1) directed against this glycoprotein; and enhanced Ca2+ exchange. Thus, exposure of platelets to DB results in membrane-related alterations that may contribute to inhibition of platelet cohesion: Decreased fibrinogen receptor exposure by traditional agonists and diminished accessibility of the GPIIb-IIIa complex to extracellular ligands correlate with DB-induced inhibition of platelet aggregation; and increased calcium uptake and exchange across the platelet membrane likely leads to activation of the calcium-dependent protease(s) which was previously shown to correlate with DB-induced inhibition of ristocetin-induced platelet agglutination.


Correction to: Identification of novel Y chromosome encoded transcripts by testis transcriptome analysis of mice with deletions of the Y chromosome long arm.
Following publication of the original article [1], the following error was reported: The actin control panel in Fig. 3 of this paper is reproduced from Fig. 7 of Touré et al, 2004 [2] by kind permission of the Genetics Society of America. Touré et al, 2004 used Northern blotting to show that the Y-linked genes Ssty1 and Ssty2 have reduced expression in a range of mouse genotypes with deletions on the Y chromosome long arm. This paper shows that two novel genes, Sly and Asty are also present on mouse Yq and have reduced expression in these deleted genotypes. A further companion paper was published in Human Molecular Genetics (Ellis et al, 2005 [3]) showing that X-linked genes are upregulated in the various deleted genotypes. Since two of the genotypes concerned are sterile and very hard to generate, all the Northern blot experiments in these papers were performed on a single membrane that was stripped and re-probed with a range of different X- and Y-linked genes. The same beta-actin loading control image thus necessarily applies to all the data presented, and was shown in all three papers. We regret that this was not mentioned appropriately in the Methods and figure legends at the time of publication.


Improving performance of an accountable care organization on a quality measure assessing β-blocker use in systolic heart failure.
The implementation and outcomes are described for a clinical pharmacist-generated initiative to improve the performance of a Medicare Pioneer accountable care organization (ACO) quality measure evaluating the percentage of patients at least 18 years of age with heart failure and a left ventricular ejection fraction (LVEF) of less than 40% who are prescribed with an evidence-based β-blocker (carvedilol, metoprolol succinate, or bisoprolol). Atrius Health clinical pharmacists developed several educational documents to facilitate appropriate prescribing of evidence-based therapies in patients with heart failure. After educating clinicians, clinical pharmacists reviewed patient charts to determine eligibility for initiating or switching to evidence-based β-blocker therapy. Medicare Pioneer ACO patients 18-85 years of age with heart failure and a current or prior LVEF of less than 40% were reviewed. Patients had a current prescription for metoprolol tartrate, atenolol, or no β-blocker. Patients were considered ineligible if they had a documented contraindication or intolerance to β-blocker therapy or were clinically unstable. Recommendations to initiate or switch to an appropriate β-blocker were sent electronically by a clinical pharmacist to an eligible patient's treating physician before a scheduled office visit. In approximately three months, 48 patients underwent chart review by a clinical pharmacist. Performance improved by 8% after the implementation, with 82% of eligible patients achieving the quality measure in 2014-an increase from 74% in 2013. The performance on a Medicare Pioneer ACO quality measure evaluating β-blocker use in systolic heart failure improved in a one-year period after a clinical pharmacist-generated initiative was implemented at Atrius Health practice sites.


Stretching Interventions in Children With Cerebral Palsy: Why Are They Ineffective in Improving Muscle Function and How Can We Better Their Outcome?
Hyper-resistance at the joint is one of the most common symptoms in children with cerebral palsy (CP). Alterations to the structure and mechanical properties of the musculoskeletal system, such as a decreased muscle length and an increased joint stiffness are typically managed conservatively, by means of physiotherapy involving stretching exercises. However, the effectiveness of stretching-based interventions for improving function is poor. This may be due to the behavior of a spastic muscle during stretch, which is poorly understood. The main aim of this paper is to provide a mechanistic explanation as to why the effectiveness of stretching is limited in children with CP and consider clinically relevant means by which this shortcoming can be tackled. To do this, we review the current literature regarding muscle and tendon plasticity in response to stretching in children with CP. First, we discuss how muscle and tendon interact based on their morphology and mechanical properties to provide a certain range of motion at the joint. We then consider the effect of traditional stretching exercises on these muscle and tendon properties. Finally, we examine possible strategies to increase the effectiveness of stretching therapies and we highlight areas of further research that have the potential to improve the outcome of non-invasive interventions in children with cerebral palsy.


Congenital microvillous inclusion disease presenting as antenatal bowel obstruction.
Prenatal ultrasound has led to confidence in the antenatal diagnosis of intestinal obstruction allowing counseling and birth planning. We describe a male infant of a diabetic mother who had an antenatal diagnosis of distal bowel obstruction. This baby was subsequently found not to have bowel obstruction, but a congenital enteropathy - microvillous inclusion disease. The antenatal scans had demonstrated polyhydramnios as well as multiple fluid-filled dilated loops of bowel in the fetal abdomen. To our knowledge, similar prenatal ultrasound findings have not been previously described in this condition. The baby was delivered in a pediatric surgical center and postnatally there was no evidence of bowel obstruction either clinically or on abdominal X-ray. This baby initially fed well, but became collapsed and acidotic on his third day, having lost 26% of his birth weight due to excessive stool loss. The diagnosis of microvillous inclusion disease was made by electron microscopy of a small bowel biopsy. Congenital microvillous inclusion disease is a very rare inherited enteropathy with high mortality and morbidity. This condition, and other enteropathies, should be considered in cases in which antenatally diagnosed bowel obstruction is not confirmed after birth.


A strategy for probing the function of noncoding RNAs finds a repressor of NFAT.
Noncoding RNA molecules (ncRNAs) have been implicated in numerous biological processes including transcriptional regulation and the modulation of protein function. Yet, in spite of the apparent abundance of ncRNA, little is known about the biological role of the projected thousands of ncRNA genes present in the human genome. To facilitate functional analysis of these RNAs, we have created an arrayed library of short hairpin RNAs (shRNAs) directed against 512 evolutionarily conserved putative ncRNAs and, via cell-based assays, we have begun to determine their roles in cellular pathways. Using this system, we have identified an ncRNA repressor of the nuclear factor of activated T cells (NFAT), which interacts with multiple proteins including members of the importin-beta superfamily and likely functions as a specific regulator of NFAT nuclear trafficking.


Growth phase in relation to ketoconazole and miconazole susceptibilities of Candida albicans.
The antifungal imidazoles miconazole and ketoconazole inhibit synthesis of essential cell membrane components. Furthermore, miconazole can exert direct physicochemical cell membrane damage at relatively high levels, but ketoconazole cannot. Experiments were designed to explain our previous observation that concentrations of miconazole capable of causing direct membrane damage were no more active against Candida albicans than equimolar levels of ketoconazole. When stationary-phase cells were inoculated into medium containing either drug at 3.8 X 10(-5) M, fungistatic effects were indistinguishable. If, however, such cultures were incubated 3 h before drug addition, differences were remarkable. After 3 h, miconazole caused a 99% reduction in CFU per milliliter within 20 min, but ketoconazole again was only fungistatic. The immediate onset, rapidity, and magnitude of the miconazole effect were indicative of direct lethal cell damage. Miconazole concentrations as low as 1.0 X 10(-5) M were similarly active. It was concluded that C. albicans undergoes phenotypic changes during the growth cycle that coincidentally confer susceptibility or resistance to the lethal direct membrane damage effect of miconazole. The fungistatic or metabolic effects of ketoconazole or low-level miconazole appeared to be independent of growth phase.


Mobile-Based Analysis of Malaria-Infected Thin Blood Smears: Automated Species and Life Cycle Stage Determination.
Microscopy examination has been the pillar of malaria diagnosis, being the recommended procedure when its quality can be maintained. However, the need for trained personnel and adequate equipment limits its availability and accessibility in malaria-endemic areas. Rapid, accurate, accessible diagnostic tools are increasingly required, as malaria control programs extend parasite-based diagnosis and the prevalence decreases. This paper presents an image processing and analysis methodology using supervised classification to assess the presence of malaria parasites and determine the species and life cycle stage in Giemsa-stained thin blood smears. The main differentiation factor is the usage of microscopic images exclusively acquired with low cost and accessible tools such as smartphones, a dataset of 566 images manually annotated by an experienced parasilogist being used. Eight different species-stage combinations were considered in this work, with an automatic detection performance ranging from 73.9% to 96.2% in terms of sensitivity and from 92.6% to 99.3% in terms of specificity. These promising results attest to the potential of using this approach as a valid alternative to conventional microscopy examination, with comparable detection performances and acceptable computational times.


How human brucellosis incidence in urban Kampala can be reduced most efficiently? A stochastic risk assessment of informally-marketed milk.
In Kampala, Uganda, studies have shown a significant incidence of human brucellosis. A stochastic risk assessment involving two field surveys (cattle farms and milk shops) and a medical record survey was conducted to assess the risk of human brucellosis infection through consumption of informally marketed raw milk potentially infected with Brucella abortus in Kampala and to identify the best control options. In the cattle farm survey, sera of 425 cows in 177 herds in the Kampala economic zone were sampled and tested for brucellosis using a competitive enzyme-linked immunosorbent assay (CELISA). Farmers were interviewed for dairy information. In the milk shop surveys, 135 milk sellers in the urban areas were interviewed and 117 milk samples were collected and tested using an indirect enzyme-linked immunosorbent assay (IELISA). A medical record survey was conducted in Mulago National Referral Hospital for serological test results. A risk model was developed synthesizing data from these three surveys. Possible control options were prepared based on the model and the reduction of risk was simulated for each scenario. Overall, 12.6% (6.8-18.9: 90%CI) of informally marketed milk in urban Kampala was contaminated with B.abortus at purchase and the annual incidence rate was estimated to be 5.8 (90% CI: 5.3-6.2) per 10,000 people. The best control option would be the construction of a milk boiling centre either in Mbarara, the largest source of milk, or in peri-urban Kampala and to ensure that milk traders always sell milk to the boiling centre; 90% success in enforcing these two options would reduce risk by 47.4% (21.6-70.1: 90%CI) and 82.0% (71.0-89.0: 90%CI), respectively. This study quantifies the risk of human brucellosis infection through informally marketed milk and estimates the incidence rate in Kampala for the first time; risk-based mitigation strategies are outlined to assist in developing policy.


Saccades from torsional offset positions back to listing's plane.
Rapid eye movements include saccades and quick phases of nystagmus and may have components around all three axes of ocular rotation: horizontal, vertical, and torsional. In this study, we recorded horizontal, vertical, and torsional eye movements in normal subjects with their heads upright and stationary. We asked how the eyes are brought back to Listing's plane after they are displaced from it. We found that torsional offsets, induced with a rotating optokinetic disk oriented perpendicular to the subject's straight ahead, were corrected during both horizontal and vertical voluntary saccades. Thus three-dimensional errors are synchronously reduced during saccades. The speed of the torsional correction was much faster than could be accounted for by passive mechanical forces. During vertical saccades, the peak torsional velocity decreased and the time of peak torsional velocity was delayed, as the amplitude of vertical saccades increased. In contrast, there was no consistent reduction of torsional velocity or change in time of peak torsional velocity with an increase in the amplitude of horizontal saccades. These findings suggest that 1) the correction of stimulus-induced torsion is neurally commanded and 2) there is cross-coupling between the torsional and vertical but not between the torsional and horizontal saccade generating systems. This latter dichotomy may reflect the fact that vertical and torsional rapid eye movements are generated by common premotor circuits located in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). When horizontal or vertical saccade duration was relatively short, the torsional offset was not completely corrected during the primary saccade, indicating that although the saccade itself is three-dimensional, saccade duration is determined by the error in the horizontal or the vertical, but not by the error in the torsional component.


Attachment Styles of Dermatological Patients in Europe: A Multi-centre Study in 13 Countries.
Attachment styles of dermatological outpatients and satisfaction with their dermatologists were investigated within the framework of a multicentre study conducted in 13 European countries, organized by the European Society for Dermatology and Psychiatry. Attachment style was assessed with the Adult Attachment Scale. Patient satisfaction with the dermatologist was assessed with an 11-degree scale. A total of 3,635 adult outpatients and 1,359 controls participated in the study. Dermatological outpatients were less able to depend on others, were less comfortable with closeness and intimacy, and experienced similar rates of anxiety in relationships as did the controls. Participants who had secure attachment styles reported stressful life events during the last 6 months significantly less often than those who had insecure attachment styles. Patients with secure attachment styles tended to be more satisfied with their dermatologist than did insecure patients. These results suggest that secure attachment of dermatological outpatients may be a protective factor in the management of stress.


A suppressor mutation in the alpha-phycocyanin gene in the light/glucose-sensitive phenotype of the psbK-disruptant of the cyanobacterium Synechocystis sp. PCC 6803.
psbK encodes a small transmembrane component of PSII. Here we report that the psbK-disruptant of Synechocystis sp. PCC 6803 cannot survive under photomixotrophic conditions of light and glucose after transient growth, while the wild type is able to grow. A spontaneous yellow-green mutant that recovered the sustained growth under the same conditions was isolated from the psbK-disruptant. Instead of recovery, the mutant largely lost photoautotrophic growth. By phenotype complementation, the mutation was identified in cpcA as a sequence replacement with a close downstream segment, generating an inverted repeat of 23 bp. The mutant phenotype was characterized by (i) the complete loss of alpha- and beta-phycocyanin; (ii) increased accumulation of PSII; and (iii) greatly reduced transcripts harboring cpcA in abundance and in size. The inverted repeat generated in cpcA probably led to the early termination of transcription. A possible mechanism for such a mutation is discussed.


[Ethnic differences between pre-trial suspected offenders].
Black and minority ethnic (BME) patients with a severe psychiatric disorder are compulsory admitted to psychiatric hospitals more often than Dutch native patients. To describe ethnic differences with regard to (1) the prevalence of psychiatric disorders, (2) the degree to which 'suspects' are considered to be accountable for their actions and (3) recommended treatment for reported pre-trial suspects. 14,540 pre-trial reports in the Netherlands between 2000 and 2006 with a known ethnicity were assessed. Dutch native, Western, Turkish, Moroccan, Surinamese, Antillean, and other non-Western defendants were compared with chi-square tests and logistic regression models. Psychotic and behavioural disorders were more prevalent among bme suspects, whereas all other psychiatric disorders occurred less frequently in the BME group. Compared to Dutch native suspects, BME suspects were more often deemed to be fully accountable for their actions. Antillean, Moroccan, Surinamese, and other non-Western suspects were more often recommended for compulsory admission to a psychiatric hospital or received no treatment and much less out-patient treatment. There were no ethnic differences with regard to the frequency with which suspects were recommended for compulsory admission to a penitentiary hospital or with regard to medication. Compared to Dutch native suspects, BME suspects are, on one hand, more often deemed accountable for their actions but, on the other hand, are more often recommended for compulsory admission to a psychiatric hospital.


[Refractory hypotension during anesthesia in a patient treated with angiotensin receptor blockers].
A 66-year-old woman treated with valsartan, an angiotensin II receptor blocker, and diuretics was scheduled for surgery to remove a pelvic mass. Both drugs were withdrawn 24 hours before anesthetic induction. Combined general and epidural anesthesia was provided. When hypotension developed and was refractory to fluid replacement and phenylephrine administration, terlipressin, a vasopressin receptor antagonist, was infused and outcome was favorable. Anesthetized patients treated with angiotensin II receptor blockers to control hypertension may experience hypotensive events that are refractory to standard treatment but that respond to vasopressin receptor antagonists.


Early MRI findings in stab wound of the cervical spine: two case reports.
MR imaging was found to be the most sensitive modality for the detection of spinal cord abnormalities in the acutely injured spine. Although it is reported that traumatic pneumomyelogram indicates a base-of-skull or middle cranial fossa fracture and is almost certainly associated with intracranial subarachnoid air, early MR imaging may demonstrate subarachnoid air in penetrating trauma of the spinal cord without head injury. We report two cervical-spine stab-wound cases, one of which had subarachnoid air on early MR findings.


Advances in indolo[2,3-a]carbazole chemistry: design and synthesis of protein kinase C and topoisomerase I inhibitors.
Indolo[2,3-a]carbazoles, their pyrrolo[3,4-c]anellated variants and structurally closely related bisindolylmaleimides represent a biologically highly interesting class of natural compounds which are potential anticancer agents. According to the ongoing literature new and efficient synthetic methods yield a great variety of these compounds which have been reported in detail. The biological activities and the inhibitory activities against the target enzymes protein kinase C and topoisomerase I are also discussed including structure activity relationships. A molecular binding model of the protein kinase C inhibitors with the target enzyme at the atomic level is presented and supported by X-ray crystallographic structures and by molecular modelling studies.


Reduced Absorption and Impaired Translocation Endows Glyphosate Resistance in Amaranthus palmeri Harvested in Glyphosate-Resistant Soybean from Argentina.
Amaranthus palmeri S. Watson is probably the worst glyphosate-resistant (GR) weed worldwide. The EPSPS (5-enolpyruvylshikimate-3-phosphate-synthase) gene amplification has been reported as the major target-site-resistance (TSR) mechanism conferring resistance to glyphosate in this species. In this study, TSR and non-target-site-resistance (NTSR) mechanisms to glyphosate were characterized in a putative resistant A. palmeri population (GRP), harvested in a GR soybean crop from Argentina. Glyphosate resistance was confirmed for the GRP population by dose-response assays. No evidence of TSR mechanisms, as well as glyphosate metabolism, was found in this population. Moreover, a susceptible population (GSP) that absorbed about 10% more herbicide than the GRP population was evaluated at different periods after treatment. The GSP population translocated about 20% more glyphosate to the remainder of the shoots and roots at 96 h after treatment than the control, while the GRP population retained 62% of herbicide in the treated leaves. This is the first case of glyphosate resistance in A. palmeri involving exclusively NTSR mechanisms.


Multiple Giant Splenic Artery Aneurysms Causing Sinistral (Left-Sided) Portal Hypertension.
Background. Splenic artery aneurysm is the most common type of visceral aneurysms. They are usually asymptomatic and have a potential for rupture and therefore life-threatening hemorrhage. It is rare for them to cause sinistral portal hypertension. Case Report. A 23-year-old female patient presented to our clinic with gastric varices, splenomegaly, pancytopenia, and normal liver functions. She was thus diagnosed with left-sided portal hypertension. Radiologic evaluation showed splenomegaly, splenic vein obstruction, and multiple aneurysms along the splenic artery ranging from 2.5 cm to 7 cm. Splenic artery aneurysm was thought to be the cause of portal hypertension and hypersplenism. We decided splenectomy is the best course of treatment. Pancytopenia could not be corrected preoperatively despite the transfusion treatment. Surgical exploration revealed multiple aneurysms deeply embedded in pancreas. Thrombocyte and erythrocyte transfusion was performed after splenic artery ligation to correct pancytopenia before further intervention. Splenic artery, spleen, and distal pancreas were resected en bloc. Patient's blood parameters became normal within first postoperative day. Patient had an uneventful postoperative course and was discharged without incident. Conclusion. Splenic artery aneurysms are rare but potentially life-threatening incidents. Therefore, it is important to know the unusual presentations and prepare accordingly.


[Tissue-specific nucleoprotein complexes].
A method of isolation of native nucleorprotein complexes from cattle cerebral cortex, thymus, and liver was developed. Compositions of these complexes were studied by means of gel-chromatography and ion-exchange chromatography. These preparations were shown to consist of several fractions of proteins and their complexes differ by molecular mass and electro-chemical properties. Native nucleoprotein complexes revealed high tissue specific activity, which was not species-specific.


UVB irradiation-enhanced zinc oxide nanoparticles-induced DNA damage and cell death in mouse skin.
UV-induced reactive oxygen species (ROS) have been implicated in photocarcinogenesis and skin aging. This is because UV-induced ROS can induce DNA damage that, if unrepaired, can lead to carcinogenesis. Sunscreens contain UV attenuators, such as organic chemical and/or physical UV filters, which can prevent all forms of damage from UV irradiation. In recent years, the effective broad-spectrum UV attenuation properties of ZnO-nanoparticles (ZnO-NPs) have made them attractive as active components in sunscreens and other personal care products. As the use of ZnO-NPs in sunscreens is on the rise, so is public concern about their safety, particularly with exposure to sunlight. Therefore, in the present study, using various experimental approaches, we investigated the possible toxic effects resulting from exposure to UVB and ZnO-NPs in primary mouse keratinocytes (PMKs) as well as in the skin of SKH-1 hairless mice. The findings of the present study demonstrated that co-exposure to UVB and ZnO-NPs: (1) translocated the ZnO-NPs into the nucleus of PMKs; (2) caused enhanced generation of ROS; (3) induced more severe DNA damage as evident by alkaline comet assay and immunocytochemistry for γ-H2AX and 8-hydroxy-2'-deoxyguanosine (8-OHdG); and (4) subsequently caused much more pronounced cell death in PMKs. Further, to elucidate the physiological relevance of these in vitro findings, SKH-1 hairless mice were topically treated with ZnO-NPs and after 30min irradiated with UVB (50mJ/cm(2)). Interestingly, we found that co-exposure of ZnO-NPs and UVB caused increased oxidative DNA damage and cell death, indicated by immunostaining for 8-OHdG and TUNEL assay in sections of exposed mouse skin. Thus, collectively, our findings suggest that UVB exposure increases ZnO-NPs-mediated oxidative stress and oxidative damage, thereby enhancing ZnO-NPs-induced cell death.


Humoral immune response following a third SARS-CoV-2 mRNA vaccine dose in solid organ transplant recipients compared with matched controls.
Solid organ transplant (SOT) recipients have shown suboptimal antibody response following COVID-19 vaccination. Several risk factors for the diminished response have been identified including immunosuppression and older age, but the influence of different comorbidities is not fully elucidated. This case-control study consisted of 420 Danish adult SOT recipients and 840 sex- and age-matched controls, all vaccinated with a third homologous dose of either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. The primary outcome was differences in humoral immune response. The secondary outcome was breakthrough infections. Additionally, we looked for factors that could predict possible differences between the two groups. Response rate increased from 186/382 (49%) to 275/358 (77%) in SOT recipients and remained on 781/790 (99%) to 601/609 (99%) in controls following a third vaccine dose. SOT recipients had significantly lower median antibody concentrations after third dose compared to controls (332.6 BAU/ml vs 46,470.0 BAU/ml, p <0.001). Lowest median antibody concentrations were seen in SOT recipients with liver disease (10.3 BAU/ml, IQR 7.1-319) and diabetes (275.3 BAU/ml, IQR 7.3-957.4). Breakthrough infections occurred similarly frequent, 150 (40%) among cases and 301 (39%) among controls (p = 0.80). A third COVID-19 vaccine dose resulted in a significant increase in humoral immunogenicity in SOT recipients and maintained high response rate in controls. Furthermore, SOT recipients were less likely to produce antibodies with overall lower antibody concentrations and humoral immunity was highly influenced by the presence of liver disease and diabetes. The prevalence of breakthrough infections was similar in the two groups.


Acid-Mediated Kidney Injury Across the Spectrum of Metabolic Acidosis.
Metabolic acidosis affects about 15% of patients with chronic kidney disease. As kidney function declines, the kidneys progressively fail to eliminate acid, primarily reflected by a decrease in ammonium and titratable acid excretion. Several studies have shown that the net acid load remains unchanged in patients with reduced kidney function; the ensuing acid accumulation can precede overt metabolic acidosis, and thus, indicators of urinary acid or potential base excretion, such as ammonium and citrate, may serve as early signals of impending metabolic acidosis. Acid retention, with or without overt metabolic acidosis, initiates compensatory responses that can promote tubulointerstitial fibrosis via intrarenal complement activation and upregulation of endothelin-1, angiotensin II, and aldosterone pathways. The net effect is a cycle between acid accumulation and kidney injury. Results from small- to medium-sized interventional trials suggest that interrupting this cycle through base administration can prevent further kidney injury. While these findings inform current clinical practice guidelines, large-scale clinical trials are still necessary to prove that base therapy can limit chronic kidney disease progression or associated adverse events.


Aleukemic Myeloid Leukemia Cutis with a Kikuchi Disease-Like Inflammatory Pattern in Myelodysplastic Syndrome.
Myeloid leukemia cutis (MLC) is a rare disease characterized by the infiltration of neoplastic myeloid, myelomonocytic, or monocytic precursors into the skin, producing clinically nonspecific-appearing papules, nodules, plaques, or purpura that necessitate biopsy for definitive diagnosis. In general, it is considered an extramedullary manifestation of acute myeloid leukemia (AML) similar to myeloid sarcoma, also known as a chloroma. MLC often develops in patients with an established diagnosis of AML and is only rarely seen before the onset of systemic disease. Even more rarely, some patients are found to have an underlying nonleukemic bone marrow disease, such as a myelodysplastic syndrome (MDS). It is in these latter settings that the somewhat perplexing terminology aleukemic leukemia cutis (ALC) has been used widely. As may be imagined, establishing a diagnosis of ALC can be problematic and typically requires a high index of suspicion with careful integration of clinical, histopathological, and laboratory data. Once a diagnosis of ALC is made, a complete hematologic workup, including assessment of the patient's bone marrow, is essential because a diagnosis of MLC (with or without systemic leukemia) generally indicates a poor prognosis. When discovered in a patient with MDS, MLC has been suggested to herald progression toward more advanced disease. We present a rare case of so-called aleukemic myeloid leukemia cutis in an 82-year-old man subsequently diagnosed as having MDS without progression to overt AML. This case also illustrates a seemingly rare Kikuchi disease-like inflammatory pattern that obscured the underlying leukemic infiltrate in the skin, delaying its recognition.


Perinatal outcome of primiparous teenagers in northern Namibia.
Internationally, teenagers are at risk for pregnancy-related morbidity and mortality. We assessed the obstetric and perinatal outcomes of teenage pregnancies compared with their older counterparts in northern Namibia. We made a retrospective study using birth records from February 2002 to August 2002. The data collected included perinatal mortality, delivery mode, birth weight, in-hospital days and frequency of antenatal care (ANC) attendance. They were compared with primiparous women in different age groups (n = 612). No differences were found in obstetric and perinatal outcomes between the three different age groups. Overall ANC attendance was high. The perinatal outcome for pregnant teenagers was comparable with their older counterparts in northern Namibia. In this region, ANC succeeds in reaching pregnant teenagers and teenage pregnancies are not at an increased risk for obstetric complications.


Molecular mechanisms of 33-mer gliadin peptide oligomerisation.
The proteolytic resistant 33-mer gliadin peptide is an immunodominant fragment in gluten and responsible for the celiac disease and other gluten-related disorders. Meanwhile, the primary structure of the 33-mer is associated with the adaptive immune response in celiac patients, and the structural transformation of the 33-mer into protofilaments activates a primordial innate immune response in human macrophages. This means that accumulation, oligomerisation and structural transformation of the 33-mer could be the unknown first event that triggers the disease. Herein, we reveal the early stepwise mechanism of 33-mer oligomerisation by combining multiple computational simulations, tyrosine cross-linking, fluorescence spectroscopy and circular dichroism experiments. Our theoretical findings demonstrated that the partial charge distribution along the 33-mer molecule and the presence of glutamine that favours H-bonds between the oligomers are the driving forces that trigger oligomerisation. The high content of proline is critical for the formation of the flexible PPII secondary structure that led to a β structure transition upon oligomerisation. Experimentally, we stabilised the 33-mer small oligomers by dityrosine cross-linking, detecting from dimers to higher molecular weight oligomers, which confirmed our simulations. The relevance of 33-mer oligomers as a trigger of the disease as well as its inhibition may be a novel therapeutic strategy for the treatment of gluten-related disorders.


Expression of fatty acid and lipid biosynthetic genes in developing endosperm of Jatropha curcas.
Temporal and spatial expression of fatty acid and lipid biosynthetic genes are associated with the accumulation of storage lipids in the seeds of oil plants. In jatropha (Jatropha curcas L.), a potential biofuel plant, the storage lipids are mainly synthesized and accumulated in the endosperm of seeds. Although the fatty acid and lipid biosynthetic genes in jatropha have been identified, the expression of these genes at different developing stages of endosperm has not been systemically investigated. Transmission electron microscopy study revealed that the oil body formation in developing endosperm of jatropha seeds initially appeared at 28 days after fertilization (DAF), was actively developed at 42 DAF and reached to the maximum number and size at 56 DAF. Sixty-eight genes that encode enzymes, proteins or their subunits involved in fatty acid and lipid biosynthesis were identified from a normalized cDNA library of jatropha developing endosperm. Gene expression with quantitative reverse-transcription polymerase chain reaction analysis demonstrated that the 68 genes could be collectively grouped into five categories based on the patterns of relative expression of the genes during endosperm development. Category I has 47 genes and they displayed a bell-shaped expression pattern with the peak expression at 28 or 42 DAF, but low expression at 14 and 56 DAF. Category II contains 8 genes and expression of the 8 genes was constantly increased from 14 to 56 DAF. Category III comprises of 2 genes and both genes were constitutively expressed throughout endosperm development. Category IV has 9 genes and they showed a high expression at 14 and 28 DAF, but a decreased expression from 42 to 56 DAF. Category V consists of 2 genes and both genes showed a medium expression at 14 DAF, the lowest expression at 28 or 42 DAF, and the highest expression at 56 DAF. In addition, genes encoding enzymes or proteins with similar function were differentially expressed during endosperm development. The formation of oil bodies in jatropha endosperm is developmentally regulated. The expression of the majority of fatty acid and lipid biosynthetic genes is highly consistent with the development of oil bodies and endosperm in jatropha seeds, while the genes encoding enzymes with similar function may be differentially expressed during endosperm development. These results not only provide the initial information on spatial and temporal expression of fatty acid and lipid biosynthetic genes in jatropha developing endosperm, but are also valuable to identify the rate-limiting genes for storage lipid biosynthesis and accumulation during seed development.


A dicentric iso (Y) chromosome in an infertile male.
A dicentric Y chromosome was detected in a 30-year-old azoospermic male patient who was found to be mosaic for 45,X/46,X,dic Y(qter----p11::p11----qter). The dicentric iso (Y) chromosome was identified conclusively with C-banding, G-banding and Q-banding techniques. The relationship of structural abnormalities of the Y chromosome and azoospermia is discussed.


Circulating level of microRNA-142-5p is a potential biomarker for predicting in-stent restenosis: a case-control study.
Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers. In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR. Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively. The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.


[Adhesion in Corynebacterium diphtheriae].
The study of 8 C. diphtheriae strains of different origin revealed that these strains were capable of inducing the agglutination of trypsinized sheep red blood cells (SRBC). Toxigenic strains gravis isolated from diphtheria patients were more active in their adhesion to SRBC than toxigenic strains gravis isolated from carriers. The latter were, in their turn, more active than nontoxigenic strains mitis. No fimbriae were detected on the cell surface by electron microscopy.


Calcium transport by isolated anterior and posterior Malpighian tubules of Drosophila melanogaster: roles of sequestration and secretion.
Ca(2+) transport was examined in isolated Malpighian tubules (MTs) of adult Drosophila melanogaster. All segments of both anterior and posterior MTs have substantial capacity to transport Ca(2+) and to play a role, therefore, in calcium homeostasis and elimination of excess dietary Ca(2+). Approximately 85% of Ca(2+) which enters the tubule is sequestered, and approximately 15% is secreted in soluble form into the tubule lumen. Tubules secreting fluid at maximal rates can remove an amount of Ca(2+) equal to the whole animal calcium content in approximately 9 h. Distal segments of the pair of anterior MTs can sequester the same amount of Ca(2+) in <2 h. Functional advantages of high Ca(2+) turnover rates are discussed. Transepithelial Ca(2+) secretion is increased by treatments which depolarize the transepithelial potential (thapsigargin, high K(+)), or acidify the secreted fluids (bicarbonate-free salines). The effects of pharmacological reagents and variations in bathing saline ionic composition indicate that the processes of secretion and sequestration are controlled independently, and that diltiazem-sensitive Ca(2+) channels are an important component of sequestration. The contribution of some form of apical Ca(2+) pump is evaluated.


Candida gosingica sp. nov., an anamorphic ascomycetous yeast closely related to Scheffersomyces spartinae.
During surveys on yeast diversity in forest soils from Taiwan and Thailand, ten yeast strains isolated from different samples were found to have similar molecular and physiological characteristics. Sequence analysis of small subunit (SSU) rDNA, the D1/D2 domain of large subunit (LSU) rDNA and internal transcribed spacer (ITS)-5.8S rDNA demonstrated that these strains were closely related to Scheffersomyces spartinae. The novel strains could be differentiated from S. spartinae by a 0.9 % sequence divergence (5 substitutions, 0 gaps) in the D1/D2 domain of LSU rDNA, a 1.5 % divergence (8 substitutions, 0 gaps) in the ITS-5.8S rDNA and a 0.7 % divergence (12 substitutions, 2 gaps) in the SSU rDNA. The novel strains also showed specific patterns of electrophoretic karyotypes that differed from that of S. spartinae. Therefore, a novel yeast species, Candida gosingica sp. nov., is proposed to accommodate these strains. The type strain SJ7S11(T) (=BCRC 23194(T)=CBS 11433(T)) was assigned and deposited in the Bioresource Collection and Research Center (BCRC), Food Industry Development and Research Institute, Hsinchu, Taiwan, and Centraalbureau voor Schimmelcultures (CBS), Utrecht, The Netherlands.


Chitosan and its role in ocular therapeutics.
From the past few decades, tremendous awareness has been laid on the use of natural polymers in ocular drug delivery. Chitosan, a modified natural carbohydrate polymer, has number of applications in the field of ophthalmics and attracted a great deal of attention of scientific community, academicians and environmentalists due to its unique features. Chitosan has been explored for the delivery of drugs, genes, biotechnological products, proteins and peptides to the target site within ocular tissues. Chitosan being a polycationic in nature interacts with the polyanionic surface of ocular mucosa through hydrogen bonding /ionic interactions and enhance the mucoadhesive effect of formulation. Sustained and controlled ocular delivery can be achieved with chitosan based formulations like chitosan gels, inserts, chitosan coated liposome/niosome and chitosan nanoparticles. This review discussed various aspects related to chitosan and chitosan based formulations particularly developed for ocular therapeutics. The fate and toxicological consideration related to chitosan, resulting with its interaction to ocular tissues, has also been summed up in addition.


The long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B. The Long-Term Follow-up Investigator Group. The European Study Group on Viral Hepatitis (EUROHEP). Executive Team on Anti-Viral Treatment.
This study was performed to evaluate the long-term effects of interferon-alpha 2a (IFN-alpha 2a) vs no treatment in patients with chronic hepatitis B and to determine whether viral clearance, following therapy or occurring spontaneously, was sustained. Patients originating from three previously published multicentre, randomized, controlled trials were analysed. Information about survival and response during long-term follow-up was available in 340 (73%) and 308 (66%) of 469 randomized patients respectively. Response to therapy (viral clearance) was defined as: loss of hepatitis B virus (HBV) DNA and loss of hepatitis B e antigen (HBeAg) and improvement in alanine aminotransferase level. Scheduled treatment-free follow-up was 12 months in all studies. Median long-term follow-up time after inclusion in the individual studies was 4.7 years (range: 0.2-7.5 years). Viral clearance after IFN-alpha 2a, or occurring spontaneously, was sustained in 70 out of 80 evaluable patients (88%) who were responders at the end of the original trials and 21 (30%) lost hepatitis B surface antigen (HBsAg). A total of 80 patients received (re)treatment during the long-term follow-up period and 33% of them responded, irrespective of previous treatment category. Overall response rate was not significantly affected by gender, sexual inclination or ethnic origin. Durability of response did not depend upon ethnic origin or presence of cirrhosis. At the end of the original trial periods, 253 patients were histologically evaluated and 22 (9%) had histologically confirmed progression to cirrhosis. During long-term follow-up an additional five patients developed cirrhosis. Hepatocellular carcinoma developed in three patients (1%): in one patient during the follow-up period of the original trial and in two patients (one untreated) during the long-term follow-up period. Ten of 25 deaths were liver-related (hepatocellular carcinoma in three, gastrointestinal bleeding in two and liver failure in five). The distribution of clinical events (progression to cirrhosis, hepatocellular carcinoma and liver-related deaths) was unrelated to original treatment category and response to treatment. Hence, 90% of responding patients will, irrespective of treatment category, have a sustained response. At least 30% of responding patients will eventually lose HBsAg. For a number of reasons, the present patient population and observation period are insufficient to establish a presumed beneficial effect of IFN-alpha 2a on disease progression and survival.


Regulation of tyrosine hydroxylase phosphorylation in PC12 pheochromocytoma cells by elevated K+ and nerve growth factor. Evidence for different mechanisms of action.
A specific antiserum was used to compare phosphorylation of tyrosine hydroxylase (TH) (EC 22.214.171.124, tyrosine 3-monooxygenase) as regulated by elevated K+ and nerve growth factor (NGF) in cultured PC12 pheochromocytoma cells. Exposure of cultures to either elevated K+ or to NGF significantly enhanced the incorporation of [32P]orthophosphate into TH. The effect of elevated K+ was evident at 10 mM and was maximal by 40-80 mM. Increased phosphorylation of TH was detected at 0.1 nM (3 ng/ml) NGF and reached a maximal level by 0.3-1 nM (10-30 ng/ml) NGF. Elevated K+ showed a biphasic time course of action with one maximum of phosphorylation at about 30 sec of exposure and a second after about 10 min of exposure. In contrast, the NGF effect showed an initial lag of several minutes followed by a monophasic increase in phosphorylation to reach a plateau. Both treatments enhanced TH activity, but in each case the time courses of this did not strictly correlate with that of phosphorylation. The effect of elevated K+ on TH phosphorylation required the presence of extracellular Ca2+ and was suppressed by trifluoperazine (100 microM). N-(6-Aminohexyl)-5-(chloronaphthalene)-1-sulfonamide (W-7) (100 microM), a potent inhibitor of calmodulin activity, also blocked the enhancement of phosphorylation by elevated K+, whereas N-(6-aminohexyl)-1-(naphthalene)sulfonamide (W-5) (100 microM), a less potent analogue of W-7, did not. In contrast to these findings, the increase in TH phosphorylation brought about by NGF did not require extracellular Ca2+, and was only slightly affected by trifluoperazine or W-7. When TH phosphorylated under various conditions (control medium, elevated K+, NGF) was subjected to peptide mapping after exposure to Staphylococcus aureus protease V8, multiple phosphorylated peptides were observed. Elevated K+ and NGF each produced increases in labeling of each of the peptides. However, the relative degree of labeling of different peptides was distinct for each condition. These data suggest that elevated K+ and NGF bring about rapid enhancement of the phosphorylation of TH by means of different mechanisms.


Gas detection by correlation spectroscopy employing a multimode diode laser.
A gas sensor based on the gas-correlation technique has been developed using a multimode diode laser (MDL) in a dual-beam detection scheme. Measurement of CO(2) mixed with CO as an interfering gas is successfully demonstrated using a 1570 nm tunable MDL. Despite overlapping absorption spectra and occasional mode hops, the interfering signals can be effectively excluded by a statistical procedure including correlation analysis and outlier identification. The gas concentration is retrieved from several pair-correlated signals by a linear-regression scheme, yielding a reliable and accurate measurement. This demonstrates the utility of the unsophisticated MDLs as novel light sources for gas detection applications.


Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential.
Tumour acidosis is considered to play a central role in promoting cancer invasion and migration, but few studies have investigated in vivo how tumour pH correlates with cancer invasion. This study aims to determine in vivo whether tumour acidity is associated with cancer metastatic potential. Breast cancer cell lines with different metastatic potentials have been characterised for several markers of aggressiveness and invasiveness. Murine tumour models have been developed and assessed for lung metastases and tumour acidosis has been assessed in vivo by a magnetic resonance imaging-based chemical exchange saturation transfer (CEST) pH imaging approach. The higher metastatic potential of 4T1 and TS/A primary tumours, in comparison to the less aggressive TUBO and BALB-neuT ones, was confirmed by the highest expression of cancer cell stem markers (CD44+CD24-), highlighting their propensity to migrate and invade, coinciding with the measurement obtained by in vitro assays. MRI-CEST pH imaging successfully discriminated the more aggressive 4T1 and TS/A tumours that displayed a more acidic pH. Moreover, the observed higher tumour acidity was significantly correlated with an increased number of lung metastases. The findings of this study indicate that the extracellular acidification is associated with the metastatic potential.


Long-term effects of cyclosporine on renal function in liver transplant recipients.
The long-term effects of cyclosporine on renal function were evaluated in eleven liver transplant recipients over a 6-26-month follow-up period. Renal hemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF]) fell 60% postoperatively, subsequently improved, and stabilized at 45-60% of normal despite continued drug administration. Tubular sodium transport studies during water diuresis suggested that the proximal tubule is a major site of cyclosporine nephrotoxicity. In contrast to the acute effects of cyclosporine on renal function, the fraction of glomerular filtrate reabsorbed in the proximal tubule was less in the patient group while the fractional excretion of sodium, potassium, and phosphate was increased. When the fraction of filtered sodium reabsorbed in the diluting segment was examined as a function of sodium delivery, functional impairment occurred in the diluting segment as well. Eight renal biopsies performed in six patients 4-29 months posttransplantation showed only mild to moderate changes, predominantly vascular, which correlated poorly with corresponding renal function. These data showed that long-term cyclosporine administration produced early and persistent depression of both hemodynamic and tubular function. A functional rather than structural mechanism appears to be more significant during this period of observation.


Potential deleterious impact of dietary salt restriction on cardiovascular risk factors.
Excessive intake of dietary salt is thought to promote hypertension in Western societies, and some have recommended salt restriction for the general population. While such restriction is thought to be innocuous, few studies have examined the impact of dietary salt on cardiovascular risk factors other than blood pressure. In a randomized, placebo-controlled, doubly blinded comparison of one week periods of 20 vs. 208 mEq/d NaCl intake in 27 hypertensives and normotensives, we found that salt restriction had no significant effect on blood pressure (p = 0.45) and a generally adverse impact on risk factors for cardiovascular disease. Stringent, short-term dietary salt restriction caused increases in total and low-density lipoprotein cholesterol that were of borderline significance (p = 0.07). These lipid effects probably resulted from plasma volume contraction, as they were coincident with significant rises in hemoglobin (p = 0.01), hematocrit (p less than 0.001), total protein (p less than 0.01) and albumin (p = 0.01); such changes may act together to increase whole-blood viscosity. In addition, plasma norepinephrine (p = 0.02), fasting plasma insulin (p = 0.02) and glucose-to-insulin ratio (p = 0.01) increased during salt restriction. The potentially adverse impact of dietary salt restriction on the risk factor profile for cardiovascular disease suggests that further studies are necessary before a reduction in dietary salt intake can be prescribed for the general population.


Circannual somatostatin gene and somatostatin receptor gene expression in the early post-natal rat pineal gland.
The origin of somatostatin in the pineal gland is controversial as a double origin - neural in pinealopetal nerve fibers and parenchymal corresponding to locally synthesized peptide - is suggested. We have investigated the ontogeny and possible circadian and circannual variations of somatostatin and somatostatin receptor gene expression in the rat pineal gland using RT-PCR. Somatostatin gene expression was observed in the pineal of animals up to 15 days of postnatal life in autumn and winter, but not in prepubertal or adult rats; no transcript was detected during spring and summer at any age and a circadian rhythm was only detected in 15-day-old rats. In situ hybridization confirmed these results. The transcript of the somatostatin receptor gene (SSTR2) was detected at all ages studied with no seasonal variations in its expression, indicating separate regulatory mechanisms. In conclusion, somatostatin and somatostatin receptor mRNAs are expressed in the neonatal rat pineal with circadian and seasonal variations.


The anterolateral ligament: A cadaveric study in fetuses.
The aim of this study was to determine the presence and morphology of the anterolateral ligament (ALL) of the knee in a sample of fetuses. We hypothesized that the ALL is present in sample fetuses and its origin is not related to repetitive stresses throughout life. Forty fresh-frozen knees from cadaveric fetuses were dissected using a standard technique. The ALL and other structures in the anterolateral compartment of the knee were identified. The details of the femoral and tibial attachments, course and relationships with anatomical structures of the ALL were identified, recorded, and quantitatively characterized. The ALL was identified in 100% of the dissected knees. We found three anatomical patterns regarding the femoral attachment: (1) Proximal and posterior to the fibular collateral ligament (55%); (2) Together with the fibular collateral ligament (25%); and (3). Anterior and distal to it (20%). The ALL was extracapsular with an oblique course attaching into the anterolateral aspect of the tibia, midway between the midpoint of Gerdy's tubercle and the fibular head. The ALL has a strong attachment to the lateral meniscus, creating two fascicles: proximal or meniscofemoral and distal or meniscotibial. The ALL is a constant, extracapsular anatomical structure in the anterolateral compartment of the knee, present from the later prenatal period of life. Its morphology shows three different patterns of femoral attachment in relation to the fibular collateral ligament position, a strong attachment in the lateral meniscus, and a constant tibial attachment. Clin. Anat. 30:625-634, 2017. © 2017 Wiley Periodicals, Inc.


Trapped Electrons and Ions as Particle Detectors.
Electrons and ions trapped with electromagnetic fields have long served as important high-precision metrological instruments, and more recently have also been proposed as a platform for quantum information processing. Here we point out that these systems can also be used as highly sensitive detectors of passing charged particles, due to the combination of their extreme charge-to-mass ratio and low-noise quantum readout and control. In particular, these systems can be used to detect energy depositions many orders of magnitude below typical ionization scales. As illustrations, we suggest some applications in particle physics. We outline a nondestructive time-of-flight measurement capable of sub-eV energy resolution for slowly moving, collimated particles. We also show that current devices can be used to provide competitive sensitivity to models where ambient dark matter particles carry small electric millicharges ≪e. Our calculations may also be useful in the characterization of noise in quantum computers coming from backgrounds of charged particles.


Ventilatory acclimatization in awake guinea pigs raised at high altitude.
To determine if laboratory strains of guinea pigs bred at sea level (SL) are "pre-adapted" to high altitude (HA), we raised litter-matched weanling Hartley guinea pigs for 4 months at SL, intermediate altitude (IA, 1250 m) or HA (3800 m) and exposed them acutely to 100, 21 and 12% inspired O2 at their respective altitude of residence. Control animals raised at SL were also exposed acutely to 10 and 8% inspired O2. In awake spontaneously breathing guinea pigs raised at SL, resting minute ventilation and tidal volume increased significantly when inspired O2 tension fell below about 60 mm Hg. In guinea pigs raised at IA or HA, ventilation was higher at any given inspired O2 tension in direct relationship to the altitude of residence. Resting hematocrit was also higher in animals raised at HA than at SL. We conclude that the pattern of ventilatory acclimatization to HA exposure in Hartley guinea pigs is similar to that in laboratory rats and human lowlanders; therefore laboratory guinea pigs are not pre-adapted and are suitable animals for the study of adaptation to high altitude.


Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation.
Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.


[Structural changes in the chromosomes of the peripheral blood lymphocytes of monkeys subjected to daily long-term irradiation].
During the period that lasted from 4 to 11 years after the cessation of the long-term daily gamma-irradiation the frequency of chromosome rearrangements in peripheral blood lymphocytes of monkeys exceeded the control level. The number of rearrangements did not change significantly at different total irradiation dosses (from 826 to 3677 r). The main type of structural chromosome rearrangements were symmetrical chromosome exchanges. Abnormal cell clones in peripheral blood lymphocytes of monkeys irradiated at low doses had no selective advantages during the periods of investigation.


Association of diabetes susceptibility gene calpain-10 with pancreatic cancer among smokers.
The objective of this study was to test the association between calpain-10 (CAPN10), a diabetes susceptibility gene, with risk of pancreatic cancer (PC). DNA samples from 83 incident exocrine PC cases and 166 controls, all of whom were smokers, were genotyped for four markers of CAPN10 in a nested case-control study based on the Beta-Carotene and Retinol Efficacy Trial (CARET), a randomized chemoprevention trial of subjects at high risk of lung cancer. Controls were matched on sex, race, age, CARET intervention arm, duration of exposure to asbestos, and smoking history. Conditional logistic regression was used for statistical analyses. The minor allele of SNP-43 (rs3792267) in intron 3 was associated with increased risk of PC with an odds ratio of 1.57 (95%CI 1.03-2.38, p = 0.035) per allele. The three markers of the highest risk haplotype had an odds ratio of 1.98 (95%CI 1.12-3.49, p = 0.019) for risk of PC compared to the most common haplotype. There was no evidence of interaction between either of these associations by diabetes status. These results suggest that variation in CAPN10 may be associated with increased risk of PC among smokers. Thus, studies of genes associated with diabetes risk in PC are warranted in a larger population.


[Nipecotic acid, a competitive inhibitor of the net uptake of 3H-GABA by rat brain synaptosomes].
The kinetics of inhibitory effect of nipecotic acid on two different types of 3H-GABA uptake (apparent uptake by intake and net-uptake by predepolarized synaptosomes) was studied. Nipecotic acid was shown to inhibit the net-uptake of 3H-GABA by competitive route. It is concluded that analysis of inhibitory, action of a substance and of its kinetics should by performed with due regard for at least two components; homoexchange of GABA which might reach 50-60% of total radioactivity taken up and the net-uptake of the neurotransmitter.


Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation.
To understand cell cycle control mechanisms in early development and how they change during differentiation, we used embryonic stem cells to model embryonic events. Our results demonstrate that as pluripotent cells differentiate, the length of G(1) phase increases substantially. At the molecular level, this is associated with a significant change in the size of active cyclin-dependent kinase (Cdk) complexes, the establishment of cell cycle-regulated Cdk2 activity and the activation of a functional Rb-E2F pathway. The switch from constitutive to cell cycle-dependent Cdk2 activity coincides with temporal changes in cyclin A2 and E1 protein levels during the cell cycle. Transcriptional mechanisms underpin the down-regulation of cyclin levels and the establishment of their periodicity during differentiation. As pluripotent cells differentiate and pRb/p107 kinase activities become cell cycle dependent, the E2F-pRb pathway is activated and imposes cell cycle-regulated transcriptional control on E2F target genes, such as cyclin E1. These results suggest the existence of a feedback loop where Cdk2 controls its own activity through regulation of cyclin E1 transcription. Changes in rates of cell division, cell cycle structure and the establishment of cell cycle-regulated Cdk2 activity can therefore be explained by activation of the E2F-pRb pathway.


Effects of Tibial Rotational-guided Growth on the Geometries of Tibial Plateaus and Menisci in Rabbits.
There are studies on the use of oblique plate over epiphyses for rotational deformities but the effects of this method on bone are not yet known. The purpose of this study was to determine the effect and rebound effect of rotational-guided growth on the geometries of the tibial plateaus and menisci in a rabbit model of tibial axial rotation. Thirty male rabbits were 6 weeks old when medial and lateral plates were applied to the proximal tibias of the left side. After 4 weeks, 15 rabbits were euthanized (group 1), and the plates from the tibias of the remaining 15 rabbits (group 2) were removed. The rabbits in group 2 were euthanized 4 weeks later. In the rabbits of group 1, the most striking differences were a decrease in the lateral tibial slope (from 28.3 to 10.8 degrees) and decrease in the ratio of the lateral plateau covered by the meniscus (from 71.9% to 61.3%). After removing the plates (group 2), the observed values of the rebound effects were 25.9 and 29.8 degrees for the lateral tibial slope, and 76.5% and 77.2% for the ratio of the lateral plateau covered by the meniscus. However, the meniscal geometries continued to change. The rotational-guided growth provided by using plates caused a change in the tibial plateau geometry, and the rebound effect, except in the meniscal geometry, was observed after removing the plates in the growing period of the rabbits. Rotational-guided growth for the restoration of tibial axial rotation deformities may be suggested after determining the clinical effects of the increasing meniscal variables. Clinical relevance: the rotational-guided growth needs close follow-up because of possible changes in anatomy of the bone.


Effectiveness and tolerability of antifibrotics in rheumatoid arthritis-associated interstitial lung disease.
Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD). In this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014-2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality. We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (-0.3 % per year after initiation compared to -6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68). In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety.


Tuning the size and the optical properties of ZnO mesocrystals synthesized under solvothermal conditions.
Mesocrystals are a promising class of nanomaterials enabling new optical and mechanical properties due to their three dimensional organization of primary crystallites sharing a common crystallographic orientation. In the present article, the influence of process parameters such as temperature profile and stirring on the primary and secondary size of ZnO mesocrystals synthesized under solvothermal conditions has been investigated. In general, small but noticeable lattice strain is introduced to the particles during the synthesis process. Additionally, with increasing mass transport the fusion of primary crystallites due to coarsening is enhanced. A closer analysis revealed an influence of the polymer chain length on the final particle structure throughout different hierarchical levels. Based on our findings a reaction mechanism with nucleation and growth taking place embedded in poly-N-vinylpyrrolidone (PVP), followed by a polymer-mediated step of oriented aggregation and subsequent coarsening is proposed. In consequence, the careful control throughout all hierarchical levels of particle synthesis allows fine-tuning of the optical properties of ZnO mesocrystals which show a high UV absorption and minimal scattering in the visible region.


Using the incidence and impact of behavioural conditions in guide dogs to investigate patterns in undesirable behaviour in dogs.
The domestic dog is one of our most popular companions and longest relationships, occupying different roles, from pet to working guide dog for the blind. As dogs age different behavioural issues occur and in some cases dogs may be relinquished or removed from their working service. Here we analyse a dataset on working guide dogs that were removed from their service between 1994 and 2013. We use the withdrawal reasons as a proxy for the manifestation of undesirable behaviour. More than 7,500 dogs were in the dataset used, 83% of which were retired (due to old age) and 17% were withdrawn for behavioural issues. We found that the main reasons for behaviour withdrawal were environmental anxiety, training, and fear/aggression. Breed and sex had an effect on the odds of dogs being withdrawn under the different reasons. The age at withdrawal for the different withdrawal reasons suggested that dogs were more likely to develop fear/aggression related issues early on, whilst issues related to training could develop at almost any age. We found no evidence for heterosis effecting behaviour. We believe that this work is relevant to the pet dog population and had implications for understanding ageing and genetic influences on behaviour.