Conditioned avoidance acquisition and extinction following repeated electroconvulsive shock: strain effect and response to vasopressin.
Male albino rats (Sabra strain) were exposed to electroconvulsive shock (ECS) once daily for periods ranging from 1 to 13 days, and proactive effects on conditioned avoidance response (CAR) acquisition and extinction were studied. CAR acquisition was intact following both single and repeated ECS, but extinction was accelerated by multiple ECS administration. These findings resembled the effect of repeated ECS on anterograde memory function in humans and confirmed previous observations based on a passive avoidance paradigm. However, extinction was not accelerated in a different rat strain (LC2). Parallel open field activity measures suggested that these findings were not related to ECS-induced alterations in locomotor activity. Administration of arginine vasopressin prior to each ECS, or following acquisition sessions, as well as 1-desamino-8-D-arginine vasopressin administration following acquisition sessions, did not ameliorate ECS-induced deficits in the Sabra rats. Differences between the present paradigm of ECS administration and those in which positive effects of vasopressin and other neuropeptides have been reported are discussed. The potential research applications of a rodent model of ECS-induced memory impairment that parallels deficits encountered in the clinical context are considered.


Stem cell plasticity in the hematopoietic system.
Bone marrow (BM) contains hematopoietic stem cells, which differentiate into all mature blood cells, and marrow stromal cells that provide the microenvironment for hematopoietic stem/progenitor cells along with the capability to differentiate into mature cells of multiple mesenchymal tissues including fat, bone, and cartilage. Recent studies indicate that adult BM also contains cells that can differentiate into nonhematopoietic cells of ectodermal, mesodermal, and endodermal tissues other than hematopoietic tissues, including liver, pancreas, kidney, lung, skin, gastrointestinal tract, heart, skeletal muscles, and neural tissues. Studies reporting the multipotentiality of BM cells have become a focus of interest because they suggest that clinical applications could be at hand using easily obtainable cells in the treatment of tissue damage or degenerative diseases. Presently, however, definitive evidence explaining the mechanism of this multipotentiality of BM stem cells is lacking. In this review, we summarize recent progress and controversies in investigation of the multipotentiality of adult BM-derived stem cells to differentiate into nonhematopoietic tissues.


Nucleotide sequence at the 5' extremity of tobacco-mosaic-virus RNA. 2. The coding region (nucleotides 69-236).
In the preceding paper it was shown that the first A-U-G codon in tobacco mosaic virus RNA is separated from the 5' terminus by a sequence of 68 nucleotides devoid of internal guanosine residues. In this paper we present the sequence of 165 residues immediately following the first potential initiation codon. The characterized sequence contains four nonsense codons but none are in phase with the prospective initiation codon. Several lines of evidence, including direct characterization of the portion of the RNA molecule which binds to and is protected by the ribosome in the course of initiation, all support the idea that the A-U-G at position 69-71 is a functional initiation signal for viral protein synthesis.


The independence of premovement H reflex gain and kinesthetic requirements for task performance.
The gain of the H reflex pathway is extensively altered prior to a voluntary contraction. We hypothesized that this gain change is modulated for the kinesthetic requirements of the ensuing task. The experiment involved a simple reaction time task, in which soleus H reflexes were evoked during the final 100 msec before the electromyographic activity for simple ankle movements of low, medium and high requirement for accurate positioning of the foot. The latter two conditions involved tracking and perturbed tracking, respectively. Subjects were required to respond with a non-ballistic movement. Over the 6 subjects and tasks, before plantar flexion, mean reflex magnitudes significantly increased (P < 0.05; to 160% of control, S.D. 60%). Before dorsiflexion they decreased (to 87% of control, S.D. 10%). However, the two accuracy requirements did not significantly alter the soleus H reflex changes, before either plantar flexion or dorsiflexion (P > 0.05). We conclude that the premovement gating of the spinal route from Ia afferents to the autogenic soleus muscle is independent of the changes in the presently tested types of kinesthetic requirements for movement.


Strategies for implementing pet robots in care homes and nursing homes for residents with dementia: protocol for a modified Delphi study.
Pet robots are a type of technology-based innovation that have shown positive psychosocial benefits for people with dementia in residential facilities, such as improving mood and social interaction and reducing agitation. Nevertheless, little is known about how pet robots can be implemented in care homes and nursing homes for dementia care in real-world practice. The objectives of this study are to (1) identify contextualised implementation strategies for implementing pet robots into care homes and nursing homes for dementia care and (2) achieve consensus on the most relevant strategies. This study is informed by a preceding scoping review and qualitative study, which used the Consolidated Framework of Implementation Research (CFIR) to identify multi-level determinants of implementation (i.e. barriers and facilitators). We will use the CFIR-ERIC matching tool to identify relevant implementation strategies from the Expert Recommendations for Implementing Change (ERIC) taxonomy to address these determinants. Data from the scoping review and qualitative study will be used to contextualise the generic ERIC strategies for our setting. After that, a group of key stakeholders will be consulted to further contextualise and refine these strategies. Next, a two-round modified Delphi process will be conducted. Fifty-four international expert participants including healthcare professionals and organisational leaders from care homes and nursing homes and academic researchers will be recruited through purposive sampling. During the first Delphi round, participants will be invited to rate the relevance of each implementation strategy on a 9-point Likert scale and provide comments or suggestions. Descriptive statistics will be used to identify whether consensus has been obtained. Inductive qualitative content analysis will be used to analyse and summarise textual responses for any new statements suggested by participants. Statements that do not reach consensus and new statements suggested in round 1 will be taken to the next round, which will follow the same rating process. This study will identify strategies for implementing pet robots in care homes and nursing homes for residents with dementia, which will have practical utility for clinicians, organisations and researchers. It will also demonstrate the practical application (and adaptation) of the CFIR-ERIC tool to identify and contextualise ERIC strategies.


Fluorescence emission spectra of calcofluor stained yeast cell suspensions: heuristic assessment of basis spectra for their linear unmixing.
Fluorescence emission spectra of yeast cell suspensions stained with calcofluor have recently been identified as promising markers of variations in the quality of yeast cell wall. It is shown in this paper how the raw fluorescence spectra of calcofluor can be transformed to reliable spectral signatures of cell wall quality, which are independent of actual dye-to-cell concentrations of examined cell suspensions. Moreover, the presented approach makes it possible to assess basis fluorescence spectra that allows for the spectral unmixing of raw fluorescence spectra in terms of respective fluorescence contributions of calcofluor solvated in the suspension medium and bound to yeast cell walls.


Toward Rapid Sepsis Diagnosis and Patient Stratification: What's New From Microbiology and Omics Science.
Early etiological diagnosis and characterization of host response to infection are becoming central in sepsis recognition and management. Still, limitations in conventional diagnosis and patient stratification contribute to the high mortality rates among septic patients, despite new antimicrobials and resuscitation agents. Novel microbiological techniques and omics analyses have led to the development of several tests that are now commercially available or in the pipeline as rapid diagnostic tools. We first reviewed emerging assays for the etiological diagnosis of sepsis starting directly from whole blood, assays based on target-specific polymerase chain reaction or metagenomics. We then investigated results of different omics approaches for both bedside diagnosis of immune dysfunction and detection of patient "signatures" associated with different clinical outcomes or potential response to individualized therapies. Finally, we considered how these novel laboratory tools might be translated into clinical practice, noting that they perform best when integrated within antimicrobial stewardship programs.


Patient and provider factors related to comprehensive arthritis care in a community setting in Ontario, Canada.
To determine factors that correlate with recommendations for nonpharmacologic and pharmacologic interventions (comprehensive therapy) in community dwelling adults. Eligible participants were >/= 55 years of age with hip and knee arthritis symptoms and disability. Comprehensive therapy was classified as a recommendation for exercise and weight loss (if required) and any pharmacotherapy. Only one-half of participants received a recommendation for comprehensive therapy. Participants who had seen a specialist and a therapist were almost twice as likely to receive a recommendation for comprehensive therapy. In our setting, many people with hip or knee arthritis were not receiving even minimum recommended treatment. Changes in educational and organizational policies are needed to address this situation.


Amyloid in intervertebral discs of surgery and autopsy material. A new class of amyloid?
Intervertebral discs from 82 consecutive operations on herniation and 59 autopsies (one case with generalized amyloidosis) were studied. Amyloid deposits observed in surgical and autopsy specimens increased with age in both series. Degenerative changes were related to age and to amyloid deposits in autopsy, but not in surgical cases. Calcium pyrophosphate dihydrate deposits (often in proximity to amyloid deposits) were found in autopsy discs of six patients and in surgical specimens of three patients with previous operations on herniated discs. Antisera against amyloid fibril proteins of different types including AA-, A lambda-, A kappa, AF- and AB-types showed no reaction with disc amyloid. In one case with generalized A lambda-amyloidosis the disc amyloid was not of the A lambda-type. Based on our results, we suppose that disc amyloid is a form of localized senile amyloidosis - possibly representing a new class of amyloid limited to cartilage tissue.


Nextcast: A software suite to analyse and model toxicogenomics data.
The recent advancements in toxicogenomics have led to the availability of large omics data sets, representing the starting point for studying the exposure mechanism of action and identifying candidate biomarkers for toxicity prediction. The current lack of standard methods in data generation and analysis hampers the full exploitation of toxicogenomics-based evidence in regulatory risk assessment. Moreover, the pipelines for the preprocessing and downstream analyses of toxicogenomic data sets can be quite challenging to implement. During the years, we have developed a number of software packages to address specific questions related to multiple steps of toxicogenomics data analysis and modelling. In this review we present the Nextcast software collection and discuss how its individual tools can be combined into efficient pipelines to answer specific biological questions. Nextcast components are of great support to the scientific community for analysing and interpreting large data sets for the toxicity evaluation of compounds in an unbiased, straightforward, and reliable manner. The Nextcast software suite is available at: ( https://github.com/fhaive/nextcast).


Differential regulation of VEGF signaling by PKC-alpha and PKC-epsilon in endothelial cells.
Vascular endothelial growth factor (VEGF) stimulates proangiogenic signal transduction and cell function in part through activation of protein kinase C (PKC). Our aim was to examine how individual isoforms of PKC affect VEGF action. Transfection of bovine aortic endothelial cells with small interfering RNA (siRNA) targeting either PKC-alpha, delta, or epsilon caused a reduction in the cognate PKC protein by 76% to 89% without changing expression of nontargeted isoforms. Downregulation of PKC-epsilon abrogated VEGF-stimulated phosphorylation of Akt at Ser473 and eNOS at Ser1179 and decreased VEGF-stimulated NO synthase activity in intact cells. In contrast, PKC-alpha knockdown increased Akt and eNOS phosphorylation, whereas PKCdelta knockdown had no significant effect. PKC-epsilon knockdown also decreased VEGF-stimulated Erk1/2 phosphorylation and abolished VEGF-stimulated DNA synthesis. Consistent with an effect on several pathways of VEGF signaling, VEGF receptor-2 (VEGFR2) tyrosine phosphorylation and expression of VEGFR2 protein and mRNA was decreased by 81, 90, and 84%, respectively, during knockdown of PKC-epsilon, but increased during PKC-alpha knockdown. By regulating VEGFR2 expression and activation, PKC-epsilon expression is critical for activation of Akt and eNOS by VEGF and contributes to VEGF-stimulated Erk activation, whereas PKC-alpha has opposite effects.


Evidence of an autologous immune complex pathogenic mechanism in acute poststreptococcal glomerulonephritis.
Clinical and experimental studies have suggested a role for antiimmunoglobulins in the pathogenesis of glomerulonephritis associated with streptococcal infection. We attempted to localize anti-IgG in the kidneys of 22 patients who had renal biopsies performed 7 to 66 days after the onset of acute poststreptococcal glomerulonephritis (APSGN). In addition to routine localization of immunoglobulins and C3, specimens were stained with neuraminidase-treated, heat-aggregated, and unmodified IgG. Twelve biopsies showed staining with fluorescein-labeled human neuraminidase-treated IgG. A lesser number gave positive staining with the other IgG preparations. Following treatment of slides with 0.01 M citrate buffer, seven previously negative biopsies showed positive staining with neuraminidase-treated IgG. The demonstration of anti-IgG by these methods was possible in 19 out of 22 biopsies. It correlated best with the presence of C3 and IgG, and to a lesser extent with IgM, in the renal glomerulus. These results and our previous finding of elevated levels of serum anti-IgG early in the course of APSGN, and as early as 8 days following the antecedent streptococcal infection, support a role for anti-IgG in the immune pathogenesis of APSGN. Although our series of studies support the hypothesis that anti-IgG is formed to an IgG modified enzymatically by streptococcal product, the formation of this autoantibody to IgG incorporated in an exogenous (streptococcal antigen-antibody) complex can not be ruled out.


Identification of the novel HLA-DPA1*01:03:43 allele resulting from an intralocus recombination involving the DPA1*04:01:01:03 and DPA1*01:03:01:27 alleles sequenced by Next Generation Sequencing (NGS).
HLA-DPA1 intralocus recombination between DPA1*04:01:01:03 and DPA1*01:03:01:27, or closely related other alleles, results in a novel allele HLA-DPA1*01:03:43.


Autoinactivation of xanthine oxidase: the role of superoxide radical and hydrogen peroxide.
Xanthine oxidase suffers autoinactivation in the course of catalyzing the oxidation of acetaldehyde. When no special efforts were made to maintain a high pO2 in these reaction mixtures catalase protected the xanthine oxidase, but superoxide dismutase did not. However, when oxygen depletion was slowed or prevented by working at lower concentrations of xanthine oxidase, at lower temperatures or by vigorous agitation under an atmosphere of 100% oxygen, superoxide dismutase or catalase protected markedly when added separately and protected almost completely when added together. This result correlates with the greater production of O2-, relative to H2O2, by xanthine oxidase, at elevated pO2. Since histidine also provided some protection and the high levels of acetaldehyde used would have precluded any significant effect of OH., we conclude that singlet oxygen, or something with similar reactivity, was generated from O2- plus H2O2 and contributed significantly to the observed autoinactivation.


Adhesion of suspension-cultured Catharanthus roseus cells to surfaces: effect of pH, ionic strength, and cation valency.
The correlation between the effects of pH, ionic strength and cation valency on the electrophoretic mobility and the extent of adhesion of suspension-cultured Catharanthus roseus cells to various polymer substrates is presented. The electrophoretic mobility of cells was unaltered in the pH range of 6-8, but decreased from approximately -2.2 x 10(-8) m V-1 s-1 and approached zero as the pH of the suspending liquid was decreased from 6 to 2. Similarly, the value of electrophoretic mobility decreased continuously as the ionic strength was increased from 0 to 1.0 M when cells were suspended in salt solutions of sodium chloride, calcium chloride, and aluminum chloride. However, using equimolar concentrations, the slope of the decrease in electrophoretic mobility increased following the sequence sodium chloride less than calcium chloride less than aluminium chloride. The electrophoretic mobility was near zero for suspensions containing 1.0 M calcium chloride or 0.1 M aluminium chloride. The extent of adhesion of the cells to the polymers sulphonated polystyrene less than polyethylene terephthalate less than polystyrene less than fluorinated ethylene-propylene followed this sequence. These results agree with a thermodynamic model of plant cell adhesion that implicates the importance of interfacial tensions in the adhesion process. However, higher levels of adhesion were generally observed when the electrophoretic mobility for the cells in the corresponding test liquid was at a minimum absolute value. These results can be explained by considering the effects of the electrolytic properties of the suspending liquid on the electrostatic repulsive interactions between the cells and the polymer surface in terms of a double-layer phenomenon and the DLVO theory.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation and management of upper extremity neuropathies in Charcot-Marie-Tooth disease.
The evaluation and treatment of five patients with upper extremity neuropathies secondary to Charcot-Marie-Tooth disease were reviewed with emphasis on age at onset of Charcot-Marie-Tooth disease and upper extremity deformities, clinical findings, signs of associated nerve compression, and outcome of surgical treatment. The onset of the disease generally occurred in the first or second decade of life. The onset of upper extremity symptoms lagged behind by an average of 8 years. All patients had intrinsic minus hands with decreased sensibility. Three of five patients had clinical or electrophysiologic evidence of associated nerve compression syndromes. Treatment with standard tendon transfers, nerve compression releases, soft tissue releases, and joint fusions resulted in subjectively improved function in three of four patients undergoing reconstruction. Release of six compression neuropathies in one patient provided excellent pain relief, but the underlying neuropathy progressed. Pessimism regarding reconstructive surgery in the patient with upper extremity neuropathies secondary to Charcot-Marie-Tooth disease is unwarranted.


The PP1 regulator PPP1R2 coordinately regulates AURKA and PP1 to control centrosome phosphorylation and maintain central spindle architecture.
Maintenance of centrosome number in cells is essential for accurate distribution of chromosomes at mitosis and is dependent on both proper centrosome duplication during interphase and their accurate distribution to daughter cells at cytokinesis. Two essential regulators of cell cycle progression are protein phosphatase 1 (PP1) and Aurora A kinase (AURKA), and their activities are each regulated by the PP1 regulatory subunit, protein phosphatase 1 regulatory subunit 2 (PPP1R2). We observed an increase in centrosome number after overexpression of these proteins in cells. Each of these proteins is found on the midbody in telophase and overexpression of PPP1R2 and its mutants increased cell ploidy and disrupted cytokinesis. This suggests that the increase in centrosome number we observed in PPP1R2 overexpressing cells was a consequence of errors in cell division. Furthermore, overexpression of PPP1R2 and its mutants increased midbody length and disrupted midbody architecture. Additionally, we show that overexpression of PPP1R2 alters activity of AURKA and PP1 and their phosphorylation state at the centrosome. Overexpression of PPP1R2 caused an increase in the frequency of supernumerary centrosomes in cells corresponding to aberrant cytokinesis reflected by increased nuclear content and cellular ploidy. Furthermore, AURKA, PP1, phospho PPP1R2, and PPP1R2 were all localized to the midbody at telophase, and PP1 localization there was dependent on binding of PPP1R2 with PP1 and AURKA as well as its phosphorylation state. Additionally, overexpression of both PPP1R2 and its C-terminal AURKA binding site altered enzymatic activity of AURKA and PP1 at the centrosome and disrupted central spindle structure. Results from our study reveal the involvement of PPP1R2 in coordinating PP1 and AURKA activity during cytokinesis. Overexpression of PPP1R2 or its mutants disrupted the midbody at cytokinesis causing accumulation of centrosomes in cells. PPP1R2 recruited PP1 to the midbody and interference with its targeting resulted in elongated and severely disrupted central spindles supporting an important role for PPP1R2 in cytokinesis.


Temperature effect on perfluorooctane sulfonate toxicokinetics in rainbow trout (Oncorhynchus mykiss): Exploration via a physiologically based toxicokinetic model.
Salmonids are poikilotherms, which means that their internal temperature varies with that of water. Water temperature thus controls many of their lifecycle processes and physiological functions, which could influence the mechanisms of absorption, distribution, metabolism and excretion (ADME) of many substances, including perfluorinated alkyl acids (PFAAs). However, the processes governing the fate of PFAAs are still poorly understood in fish. Here we developed a physiologically-based toxicokinetic (PBTK) model for rainbow trout (Oncorhynchus mykiss) to study changes in physiological functions and PFAA ADME at different temperatures. The model was calibrated using experimental data from dietary exposure to perfluorooctane sulfonate at 7 °C and 19 °C. Predictions of PFOS concentrations were globally satisfactory at both temperatures, when accounting for the influence of temperature on growth, ventilation rate, cardiac output, clearances, and absorption rates. Accounting for the influence of temperature on tissue-plasma partition coefficients significantly improved predicted in-organ PFOS concentrations.


[Danger of air embolism in the use of a new volumetric infusion pump].
This is a test report on the infusion pump IVAC Starflow model 581, which shows a serious risk of air embolism if the infusion bottle is accidentally brought into an upright position.


Impact of aging on the dynamics of memory retrieval: A time-course analysis.
The response-signal speed-accuracy trade-off (SAT) procedure was used to provide an in-depth investigation of the impact of aging on the dynamics of short-term memory retrieval. Young and older adults studied sequentially presented 3-item lists, immediately followed by a recognition probe. Analyses of composite list and serial position SAT functions found no differences in overall accuracy, but indicated slower retrieval speed for older adults. Analysis of false alarms to recent negatives (lures from the previous study list) revealed no differences in the timing or magnitude of early false alarms that are thought to reflect familiarity-based judgments. However, onset and accrual of recollective processing required for resolving interference was slower for older adults. These findings suggest that older adults have a selective impairment on controlled and recollective retrieval operations, and further specify this impairment to arise primarily from delayed onset of cognitive control potentially coupled with reduced availability of recollective information.


Incidence rates and temporal trends of cervical cancer relating to opportunistic screening in two developed metropolitan regions of Brazil: a population-based cohort study.
Brazilian opportunistic screening programs for cervical cancer have limited impact. In the regions of two cities (Campinas and Curitiba) with high human development indices, consistent information from 96-97% of all cervical cancer cases managed within the public healthcare system is available. To estimate the incidence rate (IR) and temporal trends in these regions, covering 2001-2012. A population-based cohort study was conducted under the assumption that all cervical cancer cases were managed in cancer referral center hospitals. 3,364 records (1,646 from Campinas; 1,718 from Curitiba) were analyzed to provide estimates of IR, age-standardized IR (ASR) and cervical cancer trends (shown per 100,000 women/year). Longitudinal patterns were analyzed using linear regression and shown as annual percentage change (APC); P < 0.05 for significance. Annual IR and ASR estimates for cervical cancer ranged from 3.8 to 8.0 over 2001-2012, decreasing over more recent years, and were similar for the two regions. The age-specific IR was about 50% lower among women aged 45 years or older (IR-2001/IR-2012: Campinas = 14.8/8.0; Curitiba = 18.7/8.3; P < 0.001). There was an increasing APC trend in Campinas among women aged 15-24 years, and a decreasing IR trend for squamous-cell histology in both regions (P < 0.05). Cervical cancer incidence estimates showed slowly decreasing trends in both regions, most evidently for women aged 45 years or older and for squamous-cell histology. These findings reflect the opportunistic nature of the population screening program, despite the comparatively high economic development level in the two regions.


Impact of Timing of Smoking Cessation on 30-Day Outcomes in Veterans Undergoing Lobectomy for Cancer.
The adverse effects of tobacco use on postoperative outcomes are well documented. While smoking cessation is associated with overall improvement in long-term survival for lung cancer patients, the effects of cessation shortly before lung surgery are unclear. This study compares 30-day outcomes after lobectomy between active smokers, recent quitters, and nonsmokers. Patients who underwent lobectomy for cancer at national Veterans Affairs medical centers from 2012 to 2018 were retrospectively identified in the Veterans Affairs Surgical Quality Improvement Program database. The sample was stratified into 3 groups: smokers within 2 weeks of surgery ("active smokers"), those who quit between 2 weeks and 3 months prior to surgery ("recent quitters"), and "nonsmokers." Propensity score matching was performed to compare groups. Of 5715 patients who met inclusion criteria, 2696 were nonsmokers, 774 were recent quitters, and 2245 were active smokers. After propensity matching, 572 patients comprised each group. Compared to recent quitters, active smokers had 48% higher odds of suffering a pulmonary complication (95% confidence interval [CI]: 1.03-2.14; P = 0.035) and 72% higher odds of suffering multiple complications (CI: 1.07-2.76; P = 0.026). Relative to nonsmokers, active smokers had 81% higher odds of pulmonary complications (CI: 1.34-2.65; P = 0.003). No differences were detected in outcomes comparing recent quitters to nonsmokers. Veterans undergoing lobectomy for cancer who quit 2 weeks before surgery had less pulmonary complications than active smokers. Recent quitters have similar outcomes to nonsmokers. Surgeons should therefore encourage patients to quit smoking, including just prior to lung surgery.


Prevalence and determinants of the metabolic syndrome among subjects with advanced nondiabetes-related chronic kidney disease in Gran Canaria, Spain.
The relationship between the metabolic syndrome and mild chronic kidney disease (CKD) has been extensively studied. This study was aimed to estimate the prevalence and factors associated with the metabolic syndrome among subjects with advanced stages of nondiabetes-related CKD. Study population was composed of incident patients with advanced CKD not related to diabetes in a tertiary hospital from Gran Canaria (Spain) since February 2011 to December 2014. Participants fulfilled a survey questionnaire and underwent physical examination and biochemical evaluation. The sample was composed of 167 subjects (mean age 63.9 ± 13.7 years; estimated glomerular filtration rate 21.9 ± 6.6 mL/min/1.73 m(2)). The prevalence of the metabolic syndrome was 68.9% (65.2% in men and 73.3% in women). Highest rates were observed in groups with chronic interstitial nephropathy (80%), CKD of uncertain etiology (76.7%) and CKD related to vascular causes (76.2%). Subjects with metabolic syndrome were older, had higher values of C-reactive protein and more often reported to have first-degree relatives with diabetes and to be physically inactive. In multivariate analyses, age (OR: 1.034 [CI 95%: 1.004-1.065]; p = 0.024) and family history of diabetes (OR: 2.550 [1.159-5.608]; p = 0.020) were independently associated with the metabolic syndrome. The prevalence of the metabolic syndrome among subjects with advanced nondiabetes-related CKD is high, and greater than that observed in general Canarian population of similar age groups. Age and family history of diabetes are the two factors more strongly associated with the metabolic syndrome in this population.


Prevalence of toxoplasma infection in Mexican newborns and children: a systematic review from 1954 to 2009.
Introduction. Recent studies in Mexico have shown that from 20/10,000 to 58/10,000 newborns with Toxoplasma infection could be undetected. The aim of this study was to determine the weighed prevalence of T. gondii infection and describe the epidemiological transition of infection in newborns. Methods. Research literature reporting Toxoplasma infection prevalence in Mexican newborns and children were searched in five international databases. Weighted prevalence was calculated by inverse variance-weighted method in asymptomatic and symptomatic study groups, and the epidemiological transition was estimated by a lineal regression analysis. Results. The weighed prevalence in 4833 asymptomatic newborns was 0.616%, CI95% (0.396%-0.835%) (P < 0.001), whereas, among 895 symptomatic newborns, the weighed prevalence was 3.02%, CI 95% (1.91%-4.1%) (P < 0.001). A downward trend of 0.25%/year represented an accumulated decrease of -13,75% in the prevalence in the symptomatic newborns throughout 55 years, whereas, in the asymptomatic children, the prevalence was similar over the course of the years. Conclusion. The high-weighted prevalence of congenital Toxoplasma infection in newborns justifies that Toxoplasma gondii testing be included in the screening programs for women during pregnancy and newborns in Mexico. A rapid diagnosis and treatment strategy could aid in limiting a potential damage to the newborns.


Effects of chronic lithium treatments on central dopaminergic receptor systems: G proteins as possible targets.
Numerous biochemical and electrophysiological studies have proposed a role for dopamine (DA) in the therapeutic efficacy of lithium (Li+) salts. The effects of ex vivo chronic Li+ treatments on neostriatal DA receptors, as well as on the G protein adenylyl cyclase complex and on tissue cAMP levels were investigated in adult rats. The animals were administered LiCl in their drinking water (1 g/l) for varying periods of time, i.e. 1, 15 and 28 days. After sacrifice by decapitation, their brains were removed and the neostriatum dissected out to assay DA receptors and adenylyl cyclase activity. The antagonists [3H]SCH23390 and [3H]raclopride were employed to label D1 and D2 receptors, respectively. Chronic Li+ treatments did not modify the saturation binding of either ligand. However, competition studies of the same antagonists by DA revealed biphasic curves, and the inhibition constant of the high-affinity site was significatively increased after chronic Li+. The data suggest an alteration in the coupling efficacy between G proteins and DA receptors. Moreover, chronic (28 day) Li+ treatment, but not a 1 day Li+ administration, lead to a reduction of the GTP-induced and DA-sensitive adenylyl cyclase activity, without changes in the basal activity or in forskolin-induced cAMP production. The results demonstrate that chronic Li+ treatments diminish neostriatal dopaminergic activity, probably through a direct action on the G protein itself. The underlying mechanisms do not appear to involve modifications in either the D1 or the D2 receptor primary ligand recognition sites, but may represent alterations in both the coupling process and the capacity of the G proteins, once activated, to stimulate adenylyl cyclase.


Effect of Hyperacute Administration (Within 6 Hours) of Transdermal Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome After Stroke: Subgroup Analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial.
Nitric oxide donors are candidate treatments for acute stroke, potentially through hemodynamic, reperfusion, and neuroprotectant effects, especially if given early. Although the large Efficacy of Nitric Oxide in Stroke (ENOS) trial of transdermal glyceryl trinitrate (GTN) was neutral, a prespecified subgroup suggested that GTN improved functional outcome if administered early after stroke onset. Prospective analysis of subgroup of patients randomized into the ENOS trial within 6 hours of stroke onset. Safety and efficacy of GTN versus no GTN were assessed using data on early and late outcomes. Two hundred seventy-three patients were randomized within 6 hours of ictus: mean (SD) age, 69.9 (12.7) years; men, 154 (56.4%); ischemic stroke, 208 (76.2%); Scandinavian Stroke Scale, 32.1 (11.9); and total anterior circulation syndrome, 86 (31.5%). When compared with no GTN, the first dose of GTN lowered blood pressure by 9.4/3.3 mm Hg (P<0.01, P=0.064) and shifted the modified Rankin Scale to a better outcome by day 90, adjusted common odds ratio, 0.51 (95% confidence interval, 0.32-0.80). Significant beneficial effects were also seen with GTN for disability (Barthel Index), quality of life (EuroQol-Visual Analogue Scale), cognition (telephone Mini-Mental State Examination), and mood (Zung Depression Scale). GTN was safe to administer with less serious adverse events by day 90 (GTN 18.8% versus no GTN 34.1%) and death (hazard ratio, 0.44; 95% confidence interval, 0.20-0.99; P=0.047). In a subgroup analysis of the large ENOS trial, transdermal GTN was safe to administer and associated with improved functional outcome and fewer deaths when administered within 6 hours of stroke onset. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00989716.


Genomic insight into domestication of rubber tree.
Understanding the genetic basis of rubber tree (Hevea brasiliensis) domestication is crucial for further improving natural rubber production to meet its increasing demand worldwide. Here we provide a high-quality H. brasiliensis genome assembly (1.58 Gb, contig N50 of 11.21 megabases), present a map of genome variations by resequencing 335 accessions and reveal domestication-related molecular signals and a major domestication trait, the higher number of laticifer rings. We further show that HbPSK5, encoding the small-peptide hormone phytosulfokine (PSK), is a key domestication gene and closely correlated with the major domestication trait. The transcriptional activation of HbPSK5 by myelocytomatosis (MYC) members links PSK signaling to jasmonates in regulating the laticifer differentiation in rubber tree. Heterologous overexpression of HbPSK5 in Russian dandelion (Taraxacum kok-saghyz) can increase rubber content by promoting laticifer formation. Our results provide an insight into target genes for improving rubber tree and accelerating the domestication of other rubber-producing plants.


HER-2/neu overexpression and hormone dependency in endometrial cancer: analysis of cohort and review of literature.
Overexpression of HER-2/neu (HER) is associated with unfavorable prognoses in both endometrial and breast cancer. To determine whether an association exists between HER expression and markers of hormone dependency in endometrial cancers, we subjected hysterectomy specimens from 125 patients to immunohistochemical staining for HER. HER was visually interpreted as negative/weakly positive (HER-) versus strongly positive (HER+). Estrogen receptor (ER) and progesterone receptor (PR) levels were quantitated on fresh tissue using a dextran-coated charcoal assay. HER+ was observed in 12% of endometrioid tumors and 22% of nonendometrioid tumors (p = 0.07). Mean ER and PR levels were 255 fmol/mg and 457 fmol/mg in endometrioid tumors, compared with 74 and 104 in nonendometrioid tumors (p < 0.01). Hyperplasia associated with the tumor was related to high levels of both ER and PR (p < 0.05), but not with HER expression. Age was significantly related to high levels of ER (p = 0.007). Both recurrence and death rates were significantly associated with low levels of ER and PR (p < 0.01). Mean ER and PR levels were 270 and 466 fmol/mg, respectively, in HER-tumors, compared with 95 (p = 0.14) and 138 fmol/mg (p = 0.02) in HER+ tumors. HER overexpression may be an important step in hormone-independent growth and proliferation in a subgroup of endometrial cancers.


Low-dose cyclosporin A in severe psoriasis. A double-blind study.
Twenty patients with severe plaque psoriasis were selected to receive either low-dose cyclosporin A (CyA) or placebo (CyA vehicle) in a double-blind randomized trial at two centres. Within 4 weeks the mean reduction in the Psoriasis Area and Severity Index (PASI) in 10 patients receiving CyA (mean dose 5.5 mg/kg/day) differed significantly from the mean reduction in 10 patients receiving placebo. In eight patients given placebo a switch to CyA therapy resulted within 4 weeks in a mean reduction in PASI of 90%. In a total 15 out of 18 patients given CyA (83%) (mean dose 5.6 mg/kg/day) there was an improvement of greater than or equal to 75% in PASI within 4 weeks. In a 2-month tapering off phase a lower mean CyA dose (3 mg/kg/day) was effective in maintaining the reduced PASI scores in seven of nine patients. Four out of five CyA treated patients who entered a post-treatment observation phase had a relapse (PASI score greater than or equal to 50% of score at baseline) after a mean interval of 6.5 weeks. The most important side-effects were mild reversible hypertension in 5 of 18 patients (28%), and reversible elevated serum creatinine levels in 7 of 18 patients (39%). We consider that further studies are justified in severe chronic psoriasis to establish suitable regimens for maintenance of remission in psoriasis with low-doses of CyA or a combination of CyA with other anti-psoriatic agents.


Introduction to Equine Biologic and Regenerative Therapies.
Regenerative medicine is defined as the process of replacing or regenerating cells, tissues, or organs to restore or establish normal function. The use of regenerative medicine in equine practice to treat injured musculoskeletal tissues with limited capacity for intrinsic healing is growing. This article provides the practitioner with a brief and basic overview of the regenerative products currently used in equine practice.


Cisplatin-induced changes in cytochrome P-450, lipid peroxidation and drug-metabolizing enzyme activities in rat kidney cortex.
This study investigates the effects of 3 successive cisplatin administrations on rat kidney cytochrome P-450 and drug-metabolizing enzyme activities. Furthermore, because glutathione (GSH) and its related enzymatic system are involved in cellular detoxification processes, we examined the effects of cisplatin on lipid peroxidation, GSH levels, and GSH reductase and peroxidase activities. Cisplatin induced a decrease in cytochrome P-450, GSH, GSH S-transferase, GSH reductase and GSH peroxidase activities, and an increase in N-glucuronyl transferase, lipid peroxidation and oxidized glutathione (GSSG) in kidney cortical microsomes and cytosolic fractions. It is suggested that cisplatin nephrotoxicity could be explained by its affinity for SH-groups of several enzymes and SH-containing compounds. Among these, GSH and its related enzymatic system play a primary role. Moreover, cisplatin increases lipid peroxidation, which might participate in cisplatin nephrotoxicity.


Skin diseases associated with atopic dermatitis.
Atopic dermatitis is a common chronic pruritic inflammatory skin disorder, characterized by an abnormal skin barrier, immune dysfunction, and an altered skin microbiome. Atopic dermatitis may be seen in conjunction with a variety of other skin disorders due to the complex pathogenesis of atopic dermatitis, involving genetic and environmental factors that are associated with immune dysfunction, barrier defects, and altered skin microbiomes. Skin disorders associated with atopic dermatitis include diseases sharing similar genetic origins like ichthyosis vulgaris, infectious diseases such as impetigo, and eczema herpeticum, in addition to the cutaneous autoimmune diseases, alopecia areata, and vitiligo. Atopic dermatitis is also often linked to such benign conditions as pityriasis alba and keratosis pilaris. This review discusses the cutaneous comorbidities of atopic dermatitis and their relationship via their occurrence in conjunction with atopic dermatitis.


Exploring small cationic peptides of different origin as potential antimicrobial agents in aquaculture.
Antimicrobial peptides (AMPs) form part of the innate immune response, which is of vital importance in fish, especially in eggs and early larval stages. Compared to antibiotics, AMPs show action against a wider spectrum of pathogens, including viruses, fungi and parasites, are more friendly to the environment, and do not seem to generate resistance in bacteria. Thus, we have tested in vitro the potential use of several synthetic peptides as antimicrobial agents in aquaculture: frog Caerin1.1, European sea bass Dicentracin (Dic) and NK-lysin peptides (NKLPs) and sole NKLP27. Our results demonstrate that the highest bactericidal activity against both human and fish pathogens was obtained with Caerin1.1 followed by sea bass Dic and NKLPs, having the sea bass NKLP20.2 none to negligible activity. Interestingly, Aeromonas salmonicida was refractory to all the fish peptides tested. Regarding the antiviral activity, synthetic peptides were able to inhibit the viral infection of nodavirus (NNV), viral septicaemia haemorrhagic virus (VHSV), infectious pancreatic necrosis virus (IPNV) and spring viremia carp virus (SVCV), which are some of the most devastating virus for aquaculture. However, their effectiveness was highly dependent on the type of virus. Strikingly, IPNV resulted the most resistant virus since Caeerin1.1 and sea bass NKLP20.2 were unable to reduce its titre and the other peptides tested only reduced it to values in the 43-78% range. These data demonstrate that synthetic peptides have great antibacterial and antiviral in vitro activity against important fish pathogens and point to their use as potential therapeutic agents in aquaculture.


Characterization of plant-derived carbon and phosphorus in lakes by sequential fractionation and NMR spectroscopy.
Although debris from aquatic macrophytes is one of the most important endogenous sources of organic matter (OM) and nutrients in lakes, its biogeochemical cycling and contribution to internal load of nutrients in eutrophic lakes are still poorly understood. In this study, sequential fractionation by H2O, 0.1M NaOH and 1.0M HCl, combined with (13)C and (31)P NMR spectroscopy, was developed and used to characterize organic carbon (C) and phosphorus (P) in six aquatic plants collected from Tai Lake (Ch: Taihu), China. Organic matter, determined by total organic carbon (TOC), was unequally distributed in H2O (21.2%), NaOH (29.9%), HCl (3.5%) and residual (45.3%) fractions. For P in debris of aquatic plants, 53.3% was extracted by H2O, 31.9% by NaOH, and 11% by HCl, with 3.8% in residual fractions. Predominant OM components extracted by H2O and NaOH were carbohydrates, proteins and aliphatic acids. Inorganic P (Pi) was the primary form of P in H2O fractions, whereas organic P (Po) was the primary form of P in NaOH fractions. The subsequent HCl fractions extracted fewer species of C and P. Some non-extractable carbohydrates, aromatics and metal phytate compounds remained in residual fractions. Based on sequential extraction and NMR analysis, it was proposed that those forms of C (54.7% of TOC) and P (96.2% of TP) in H2O, NaOH and HCl fractions are potentially released to overlying water as labile components, while those in residues are stable and likely preserved in sediments of lakes. These results will be helpful in understanding internal loading of nutrients from debris of aquatic macrophytes and their recycling in lakes.


Analytical investigation of an incompressible viscous laminar Casson fluid flow past a stretching/shrinking sheet.
This paper presents an analytical approach on capturing the effect of incompressible, non-Newtonian, viscous, Casson nanofluid flow past a stretching/shrinking surface, under the influence of heat radiation and mass transfer parameter. The governing nonlinear partial differential equations are first transformed into a series of associated nonlinear ordinary differential equations with aid of predictable transformation, while numerical computations follow. The implied nanofluid here is aluminum oxide ([Formula: see text]). The analytical solution is exploited to reveal the accompanying non-dimensional boundary value problem and output results are employed to verify the method's reliability, where it is shown that they agree with current findings in the field. An incomplete gamma function is used to solve temperature equation analytically. We present various instances of the solution, depicting effects of the essential flow factor, the stretching/shrinking parameter, the mass transfer parameter, radiation parameter, and Prandtl number.


Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the β1 integrin-RACK1 axis.
Trop-2 is a transmembrane glycoprotein upregulated in several human carcinomas, including prostate cancer (PrCa). Trop-2 has been suggested to regulate cell-cell adhesion, given its high homology with the other member of the Trop family, Trop-1/EpCAM, and its ability to bind the tight junction proteins claudin-1 and claudin-7. However, a role for Trop-2 in cell adhesion to the extracellular matrix has never been postulated. Here, we show for the first time that Trop-2 expression in PrCa cells correlates with their aggressiveness. Using either shRNA-mediated silencing of Trop-2 in cells that endogenously express it, or ectopic expression of Trop-2 in cells that do not express it, we show that Trop-2 inhibits PrCa cell adhesion to fibronectin (FN). In contrast, expression of another transmembrane receptor, α(v) β(5) integrin, does not affect cell adhesion to this ligand. We find that Trop-2 does not modulate either protein or activation levels of the prominent FN receptors, β(1) integrins, but acts through increasing β(1) association with the adaptor molecule RACK1 and redistribution of RACK1 to the cell membrane. As a result of Trop-2 expression, we also observe activation of Src and FAK, known to occur upon β(1) -RACK1 interaction. These enhanced Src and FAK activities are not mediated by changes in either the activity of IGF-IR, which is known to bind RACK1, or IGF-IR's ability to associate with β(1) integrins. In summary, our data demonstrate that the transmembrane receptor Trop-2 is a regulator of PrCa cell adhesion to FN through activation of the β(1) integrin-RACK1-FAK-Src signaling axis.


Upper airway inflammatory diseases and bronchial hyperresponsiveness.
Inflammatory processes of the upper airway may alter the responsiveness of the lower airway. For example, bronchial hyperresponsiveness may be seen in patients with allergic rhinitis. This could represent coexistent but unrecognized asthma, but also suggests that IgE-dependent inflammation may occur in the lower airway that can increase bronchial hyperresponsiveness without at the same time precipitating obvious obstruction. Clearly, allergic rhinitis is a risk factor for asthma. A second example of the interaction of upper airway inflammation and bronchial hyperreactivity are reports that viral upper respiratory tract infections may cause otherwise healthy persons to respond abnormally to inhaled histamine or irritants for several months after the infections. These same viruses usually precipitate attacks in patients with asthma, who already have hyperresponsive airways. Both of these examples suggest that inflammatory processes occurring totally or primarily in the upper airway may participate in the pathogenesis of lower respiratory tract hyperresponsiveness and asthma.


Evaluation of an inhibitor assay to determine serum isoamylase distribution.
We tested a technique to distinguish salivary from pancreatic isoamylase using a wheat protein which inhibits salivary isoamylase. The inhibitor technique accurately reflected the preponderance of pancreatic or salivary isoamylase in sera which had been "spiked" with human pancreatic or salivary isoamylase. Comparison of the results of either cellulose acetate electrophoresis or isoelectric focusing showed an excellent correlation (r = 0.99) in 43 hyperamylasemic sera which did not contain macroamylase. Normal values obtained in 160 healthy subjects indicated that pancreatic isoamylase comprised 41 +/- 21% (1 SD) of total serum amylase activity and the upper limit of normal for serum pancreatic isoamylase was 166 IU/liter. The inhibitor assay provides a simple and accurate means of differentiating salivary from pancreatic hyperamylasemia.


Computer-automated method to study cardiac conditioning to a chemical cue in young salmon.
An apparatus was designed in which young Atlantic salmon (Salmo salar) are rapidly conditioned to reduce heart rate using a chemical-electric shock conditioning procedure. A chemical calibration system permitting efficient stimulus control is described as well as the electronic systems and computer software used to control all events of an experimental session and to quantify cardiac and chemical data. Efficient stimulus control and computer-automated recording techniques minimize inter-trial intervals and the time required for the measurement and analysis of cardiac responses. Data are presented showing that 15-month-old Atlantic salmon can be trained to reduce by 20% their heart rate to the synthetic chemical morpholine within 5 training trials whereas 10-month-old fish did not do so until 15 training trials.


Intracellular trafficking of nonviral vectors.
Nonviral vectors continue to be attractive alternatives to viruses due to their low toxicity and immunogenicity, lack of pathogenicity, and ease of pharmacologic production. However, nonviral vectors also continue to suffer from relatively low levels of gene transfer compared to viruses, thus the drive to improve these vectors continues. Many studies on vector-cell interactions have reported that nonviral vectors bind and enter cells efficiently, but yield low gene expression, thus directing our attention to the intracellular trafficking of these vectors to understand where the obstacles occur. Here, we will review nonviral vector trafficking pathways, which will be considered here as the steps from cell binding to nuclear delivery. Studies on the intracellular trafficking of nonviral vectors has given us valuable insights into the barriers these vectors must overcome to mediate efficient gene transfer. Importantly, we will highlight the different approaches used by researchers to overcome certain trafficking barriers to gene transfer, many of which incorporate components from biological systems that have naturally evolved the capacity to overcome such obstacles. The tools used to study trafficking pathways will also be discussed.


A prospective pathologic study to define the clinical target volume for partial breast radiation therapy in women with early breast cancer.
To determine an appropriate clinical target volume for partial breast radiation therapy (PBRT) based on the spatial distribution of residual invasive and in situ carcinoma after wide local excision (WLE) for early breast cancer or ductal carcinoma in situ (DCIS). We performed a prospective pathologic study of women potentially eligible for PBRT who had re-excision and/or completion mastectomy after WLE for early breast cancer or DCIS. A pathologic assessment protocol was used to determine the maximum radial extension (MRE) of residual carcinoma from the margin of the initial surgical cavity. Women were stratified by the closest initial radial margin width: negative (>1 mm), close (>0 mm and ≤ 1 mm), or involved. The study population was composed of 133 women with a median age of 59 years (range, 27-82 years) and the following stage groups: 0 (13.5%), I (40.6%), II (38.3%), and III (7.5%). The histologic subtypes of the primary tumor were invasive ductal carcinoma (74.4%), invasive lobular carcinoma (12.0%), and DCIS alone (13.5%). Residual carcinoma was present in the re-excision and completion mastectomy specimens in 55.4%, 14.3%, and 7.2% of women with an involved, close, and negative margin, respectively. In the 77 women with a noninvolved radial margin, the MRE of residual disease, if present, was ≤ 10 mm in 97.4% (95% confidence interval 91.6-99.5) of cases. Larger MRE measurements were significantly associated with an involved margin (P<.001), tumor size >30 mm (P=.03), premenopausal status (P=.03), and negative progesterone receptor status (P=.05). A clinical target volume margin of 10 mm would encompass microscopic residual disease in >90% of women potentially eligible for PBRT after WLE with noninvolved resection margins.


Chronic disease concordance within Indian households: A cross-sectional study.
The household is a potentially important but understudied unit of analysis and intervention in chronic disease research. We sought to estimate the association between living with someone with a chronic condition and one's own chronic condition status. We conducted a cross-sectional analysis of population-based household- and individual-level data collected in 4 socioculturally and geographically diverse settings across rural and urban India in 2013 and 2014. Of 10,703 adults ages 18 years and older with coresiding household members surveyed, data from 7,522 adults (mean age 39 years) in 2,574 households with complete covariate information were analyzed. The main outcome measures were diabetes (fasting plasma glucose ≥ 126 mg/dL or taking medication), common mental disorder (General Health Questionnaire score ≥ 12), hypertension (blood pressure ≥ 140/90 mmHg or taking medication), obesity (body mass index ≥ 30 kg/m2), and high cholesterol (total blood cholesterol ≥ 240 mg/dL or taking medication). Logistic regression with generalized estimating equations was used to model associations with adjustment for a participant's age, sex, education, marital status, religion, and study site. Inverse probability weighting was applied to account for missing data. We found that 44% of adults had 1 or more of the chronic conditions examined. Irrespective of familial relationship, adults who resided with another adult with any chronic condition had 29% higher adjusted relative odds of having 1 or more chronic conditions themselves (adjusted odds ratio [aOR] = 1.29; 95% confidence interval [95% CI] 1.10-1.50). We also observed positive statistically significant associations of diabetes, common mental disorder, and hypertension with any chronic condition (aORs ranging from 1.19 to 1.61) in the analysis of all coresiding household members. Associations, however, were stronger for concordance of certain chronic conditions among coresiding household members. Specifically, we observed positive statistically significant associations between living with another adult with diabetes (aOR = 1.60; 95% CI 1.23-2.07), common mental disorder (aOR = 2.69; 95% CI 2.12-3.42), or obesity (aOR = 1.82; 95% CI 1.33-2.50) and having the same condition. Among separate analyses of dyads of parents and their adult children and dyads of spouses, the concordance between the chronic disease status was striking. The associations between common mental disorder, hypertension, obesity, and high cholesterol in parents and those same conditions in their adult children were aOR = 2.20 (95% CI 1.28-3.77), 1.58 (95% CI 1.15-2.16), 4.99 (95% CI 2.71-9.20), and 2.57 (95% CI 1.15-5.73), respectively. The associations between diabetes and common mental disorder in husbands and those same conditions in their wives were aORs = 2.28 (95% CI 1.52-3.42) and 3.01 (95% CI 2.01-4.52), respectively. Relative odds were raised even across different chronic condition phenotypes; specifically, we observed positive statistically significant associations between hypertension and obesity in the total sample of all coresiding adults (aOR = 1.24; 95% CI 1.02-1.52), high cholesterol and diabetes in the adult-parent sample (aOR = 2.02; 95% CI 1.08-3.78), and hypertension and diabetes in the spousal sample (aOR = 1.51; 95% CI 1.05-2.17). Of all associations examined, only the relationship between hypertension and diabetes in the adult-parent dyads was statistically significantly negative (aOR = 0.62; 95% CI 0.40-0.94). Relatively small samples in the dyadic analysis and site-specific analysis call for caution in interpreting qualitative differences between associations among different dyad types and geographical locations. Because of the cross-sectional nature of the analysis, the findings do not provide information on the etiology of incident chronic conditions among household members. We observed strong concordance of chronic conditions within coresiding adults across diverse settings in India. These data provide early evidence that a household-based approach to chronic disease research may advance public health strategies to prevent and control chronic conditions. Clinical Trials Registry India CTRI/2013/10/004049; http://ctri.nic.in/Clinicaltrials/login.php.


Differential effects of copper and zinc on human peripheral blood monocyte cytokine secretion.
The addition of copper and zinc salts to human peripheral blood leukocytes cultured in complete medium containing endotoxin and fetal calf serum stimulated tumor necrosis factor (TNF) secretion in a concentration-dependent manner. The secretion of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) was inhibited by copper under the same culture conditions, while zinc stimulated IL-1 beta secretion in a concentration-dependent manner and had no effect on leukocyte IL-6 release. Both copper and zinc induced increases in TNF mRNA (54 and 14%, respectively) when compared to cells cultured in complete medium alone. In serum-free, low endotoxin medium (less than 6 pg/ml), both copper and zinc failed to stimulate either TNF or IL-1 beta secretion. Under the same conditions the addition of lipopolysaccharide (LPS), at concentrations above 0.01 micrograms/ml, induced a concentration-dependent release of both cytokines. When either copper or zinc were combined with 0.01 micrograms/ml LPS, a synergistic stimulation of TNF secretion resulted. IL-1 beta secretion, unlike TNF, was not synergistically stimulated by combining metals and LPS in serum-free medium. Combining copper and zinc with inhibitors of TNF secretion, transforming growth factor beta, prostaglandin E2, and plasma alpha-globulins, resulted in a reduction of the suppressive effects of each of these agents. This study suggests that the trace metals copper and zinc may play important and possibly distinct roles in regulating leukocyte secretion of TNF, IL-1 beta, and IL-6.


Antibodies to a CA 19-9 Related Antigen Complex Identify SOX9 Expressing Progenitor Cells In Human Foetal Pancreas and Pancreatic Adenocarcinoma.
The Sialyl Lewis A antigen, or CA 19-9, is the prototype serum biomarker for adenocarcinoma of the pancreas. Despite extensive clinical study of CA 19-9 in gastrointestinal malignancies, surprisingly little is known concerning the specific cell types that express this marker during development, tissue regeneration and neoplasia. SOX9 is a transcription factor that plays a key role in these processes in foregut tissues. We report the biochemistry and tissue expression of the GCTM-5 antigen, a pancreatic cancer marker related to, but distinct from, CA19-9. This antigen, defined by two monoclonal antibodies recognising separate epitopes on a large glycoconjugate protein complex, is co-expressed with SOX9 by foregut ductal progenitors in the developing human liver and pancreas, and in pancreatic adenocarcinoma. These progenitors are distinct from cell populations identified by DCLK1, LGR5, or canonical markers of liver and pancreatic progenitor cells. Co-expression of this antigen complex and SOX9 also characterises the ductal metaplasia of submucosal glands that occurs during the development of Barrett's oesophagus. The GCTM-5 antigen complex can be detected in the sera of patients with pancreatic adenocarcinoma. The GCTM-5 epitope shows a much more restricted pattern of expression in the normal adult pancreas relative to CA19-9. Our findings will aid in the identification, characterisation, and monitoring of ductal progenitor cells during development and progression of pancreatic adenocarcinoma in man.


High levels of antibodies against PtpA and PknG secreted by Mycobacterium avium ssp. paratuberculosis are present in neuromyelitis optica spectrum disorder and multiple sclerosis patients.
Mycobacterium avium ssp. paratuberculosis (Map) is the etiological agent of Paratuberculosis in ruminants. Protein tyrosine phosphatase A (PtpA) and protein kinase G (PknG) are secreted proteins necessary for the survival of the pathogen within macrophages. In this study we analyzed if Map was able to grow within astrocytes and investigated on the presence of antibodies against PtpA and PknG proteins in MS and NMOSD patients by ELISA. Map was unable to proliferate in astrocytes after of 72 h post-infection, but we observed a high level of antibodies against both virulence factors, suggesting that these patients have been exposed/infected with Map.


Dysregulation of organelle membrane contact sites in neurological diseases.
The defining evolutionary feature of eukaryotic cells is the emergence of membrane-bound organelles. Compartmentalization allows each organelle to maintain a spatially, physically, and chemically distinct environment, which greatly bolsters individual organelle function. However, the activities of each organelle must be balanced and are interdependent for cellular homeostasis. Therefore, properly regulated interactions between organelles, either physically or functionally, remain critical for overall cellular health and behavior. In particular, neuronal homeostasis depends heavily on the proper regulation of organelle function and cross talk, and deficits in these functions are frequently associated with diseases. In this review, we examine the emerging role of organelle contacts in neurological diseases and discuss how the disruption of contacts contributes to disease pathogenesis. Understanding the molecular mechanisms underlying the formation and regulation of organelle contacts will broaden our knowledge of their role in health and disease, laying the groundwork for the development of new therapies targeting interorganelle cross talk and function.


External validation of an online nomogram in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma.
The objective was to validate an online nomogram developed based on the French collaborative national database on upper urinary tract urothelial carcinoma (UUT-UC) using a different cohort. The study comprised 328 patients with UUT-UC who underwent radical nephroureterectomy. The discrimination of models was quantified using Harrell's concordance index. The relationship between the model-derived and actuarial cancer-specific mortality was graphically explored within calibration plots. Calibration was also assessed using the quartiles of the predicted survival at 3 and 5 years and calculation of the corresponding observed Kaplan-Meier estimates. Clinical net benefit was evaluated constructing decision curve analysis. The discrimination accuracy of the nomograms at 3 and 5 years was 71.6% and 71.8%, respectively. Although nomograms discriminated well by Kaplan-Meier curves, and log-rank tests were all highly significant, the calibration plots tended to exaggerate the overestimation of mortality between predicted and observed probabilities at 3 and 5 years for survival. When compared with the AJCC/UICC staging system, the nomograms performed well across a wide range of threshold probabilities using decision curve analysis. The online nomogram is a highly accurate prognostic tool for patients with UUT-UC treated with radical nephroureterectomy. The model can provide an accurate estimate of the individual risk of cancer-specific mortality. Further improvement and implementation of novel molecular marker is needed.


Effects of hormonal treatments which alter ovum transport on beta-adrenoceptors of the rabbit oviduct.
Beta-Adrenoceptor activity of rabbit oviductal isthmus has been determined quantitatively in vitro in tissues isolated 24 and 72 hours after human chorionic gonadotropin injection and after two hormonal treatments known to accelerate (progesterone) and retard (estrogen) ovum transport. Under conditions in which ova are located at the ampullary-isthmic junction and distal isthmus, the isthmus demonstrates a low incidence of spontaneous activity in vitro, poor response to acetylcholine, low affinity of beta-adrenoceptors for isoproterenol, and low efficacy of isoproterenol to inhibit acetylcholine-induced contractions. Under conditions in which ova are passing into the uterus, the isthmus shows the converse of these parameters. These data support the hypotheses that the oviductal isthmus functions as an adrenergic sphincter and that the actions of progesterone and estrogen in altering ovum transport rates are at least partially mediated through changes in adrenoceptors.


Antitumor effects of GBS toxin: a polysaccharide exotoxin from group B beta-hemolytic streptococcus.
A group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress ("early-onset disease") produces a polysaccharide exotoxin (GBS toxin) that, when infused in sheep, causes lung pathophysiology similar to that seen in humans. Histological studies have demonstrated that GBS toxin induces a strong inflammatory response in the lung, with pulmonary sequestration of granulocytes and extensive capillary endothelial damage. The susceptibility of humans to GBS toxin is age-dependent and limited to about 4 days after birth. It is rarely evident thereafter. This suggests that the binding of GBS toxin to the target endothelium occurs via specific components in the developing lung endothelial cells of the newborn that are later lost. We report here that GBS toxin can also bind to developing endothelium associated with neoplasia and induce an inflammatory response. GBS toxin was shown by immunohistochemistry to bind to capillary endothelium of human large-cell carcinomas. In nude mice bearing human tumor xenografts, intravenously administered GBS toxin caused tumor necrosis and hemorrhagic lesions, and substantially inhibited the rate of growth of the tumors. In BALB/c mice bearing Madison lung tumors, GBS toxin induced an inflammatory response resulting in marked changes in tumor morphology, including vasodilation, endothelial and tumor cell necrosis, invasion of lymphocytes and macrophages, and capillary thrombosis. In these tumor models, no evidence of toxicity to the vasculature of other tissues was observed. The reported pathophysiology of GBS in human neonates, the lack of disease in non-neonates colonized with GBS, and these results suggest that GBS toxin may have potential as a well tolerated agent in cancer therapy of some human tumors.


Structural Motifs for CTD Kinase Specificity on RNA Polymerase II during Eukaryotic Transcription.
The phosphorylation states of RNA polymerase II coordinate the process of eukaryotic transcription by recruitment of transcription regulators. The individual residues of the repetitive heptad of the C-terminal domain (CTD) of the biggest subunit of RNA polymerase II are phosphorylated temporally at different stages of transcription. Intriguingly, despite similar flanking residues, phosphorylation of Ser2 and Ser5 in CTD heptads play dramatically different roles. The mechanism of how the kinases place phosphorylation on the correct serine is not well understood. In this paper, we use biochemical assays, mass spectrometry, molecular modeling, and structural analysis to understand the structural elements determining which serine of the CTD heptad is subject to phosphorylation. We identified three motifs in the activation/P+1 loops differentiating the intrinsic specificity of CTD in various CTD kinases. We characterized the enzyme specificity of the CTD kinases-CDK7 as Ser5-specific, Erk2 with dual specificity for Ser2 and Ser5, and Dyrk1a as a Ser2-specific kinase. We also show that the specificities of kinases are malleable and can be modified by incorporating mutations in their activation/P+1 loops that alter the interactions of the three motifs. Our results provide an important clue to the understanding of post-translational modification of RNA polymerase II temporally during active transcription.


Inference of causality in epidemics on temporal contact networks.
Investigating into the past history of an epidemic outbreak is a paramount problem in epidemiology. Based on observations about the state of individuals, on the knowledge of the network of contacts and on a mathematical model for the epidemic process, the problem consists in describing some features of the posterior distribution of unobserved past events, such as the source, potential transmissions, and undetected positive cases. Several methods have been proposed for the study of these inference problems on discrete-time, synchronous epidemic models on networks, including naive Bayes, centrality measures, accelerated Monte-Carlo approaches and Belief Propagation. However, most traced real networks consist of short-time contacts on continuous time. A possibility that has been adopted is to discretize time line into identical intervals, a method that becomes more and more precise as the length of the intervals vanishes. Unfortunately, the computational time of the inference methods increase with the number of intervals, turning a sufficiently precise inference procedure often impractical. We show here an extension of the Belief Propagation method that is able to deal with a model of continuous-time events, without resorting to time discretization. We also investigate the effect of time discretization on the quality of the inference.


Behavioral Neurology of Multiple Sclerosis and Autoimmune Encephalopathies.
Multiple sclerosis (MS) is the most common nontraumatic cause of physical disability in young adults. Cognitive and neuropsychiatric problems are common in this disease independent of motor disability. Such problems especially in mild cases are ignored by physicians, although they may have a major impact on quality of life. Neurobehavioral changes may affect the adherence to treatment and worsen the ultimate prognosis. Although many studies have been performed in this regard, it seems that combining cognitive evaluations with other outcome measures in MS will enhance the understanding of neurobehavioral changes in MS.


Fixation techniques in lower extremity correction osteotomies and fractures in mild-to-severe osteogenesis imperfecta patients: evaluation of the results and complications.
Osteogenesis imperfecta is a genetic disorder leading to multiple fractures and deformities. Intramedullary rods have been used in the surgical treatment of osteogenesis imperfecta for decades. Complication rates reported by current techniques have been high. This study aimed to examine the results of intramedullary fixation combined with plate and screw technique in patients with osteogenesis imperfecta compared to isolated intramedullary fixation. Between 2006 and 2020, forty patients who had surgical treatment for deformities or fractures of the femur, tibia or both with at least two years of follow-up after surgery were included in the study. Patients were divided into groups according to fixation methods. Group 1 was intramedullary fixation only (Titanium Elastic Nail [TEN], Rush Pin, and Fassier-Duval Rod), and Group 2 was intramedullary fixation combined with plate and screws. Medical records and follow-up radiographs were reviewed to evaluate healing and callus formation, types of complications and infection rates. The total number of operated lower extremities of these forty patients was 61 (45 femur and 16 tibia). The mean age of the patients was 9.3 ± 4.6 years. Mean follow-up duration of the patients was 4.4 ± 1.7 years. Thirty-seven (61%) were in Group 1, and 24 (39%) were in Group 2. There was no statistically significant difference in callus formation time between Group 1 and Group 2 (p = 0.67). Complications occurred in 21 of 61 surgeries. While 17 of these complications were in Group 1, 4 were in Group 2 (p = 0.01). Intramedullary fixation combined with the plate and screw technique in children with osteogenesis imperfecta is successful considering the complications and revision requirements.


Clip-on eyeglass loupe as a writing aid for low-vision patients.
To aid the partially sighted in writing on small areas, such as bank drafts, a clip-on eyeglass loupe (11 diopters, 3.5 inches, Bausch and Lomb) attached to a finepoint felt pen provides adequate vision.


Engineering ROS-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Postablative Immunotherapy.
The existence of inadequate ablation remains an important cause of treatment failure for loco-regional ablation therapies. Here, using a preclinical model, it is reported that inadequate microwave ablation (iMWA) induces immunosuppressive niche predominated by myeloid cells. The gene signature of ablated tumor presented by transcriptome analyses is highly correlated with immune checkpoint blocking (ICB) resistance. Thus, an in situ scaffold with synergistic delivery of IPI549 and anti-programmed death-ligand 1 blocking antibody (aPDL1) for postablative cancer immunotherapy is designed and engineered, in which IPI549 capable of targeting myeloid cells could disrupt the immunosuppressive niche and subsequently improve ICB-mediated antitumor immune response. Based on five mouse cancer models, it is demonstrated that this biomaterial system (aPDL1&IPI549@Gel) could mimic a "hot" tumor-immunity niche to inhibit tumor progression and metastasis, and protect cured mice against tumor rechallenge. This work enables a new standard-of-care paradigm for the immunotherapy of myeloid cells-mediated "cold" tumors after loco-regional inadequate practices.


Cannabinoid receptors and cholecystokinin in feeding inhibition.
The endocannabinoid system functions as a potent regulator of feeding behavior and energy balance through complex central and peripheral mechanisms. Recent findings have demonstrated the existence of cooperation between peripheral cannabinoid CB1 receptors and the satiety hormone cholecystokinin (CCK). The two systems have opposing actions in the modulation of feeding: while endocannabinoids such as anandamide promote feeding, CCK controls gastrointestinal motility and appetite suppression. In this review, we examine the individual contribution of endocannabinoids and CCK in the modulation of appetite and explore the interaction between the two systems. We also highlight the potential benefits of simultaneously targeting peripheral CB1 and CCK1 receptors to design new therapies to fight obesity.


Bio-analytical methods for investigating the effect of age, body mass index and gender on the PK/PD ratio of antibiotics.
The effectiveness of antibiotics (ABs) is governed by achieving the adequate pharmacokinetic (PK)/pharmacodynamics (PD) ratio. In this study, fast LC-MS/MS methods were developed and validated for the bioanalysis of cefaclor (CFC), ciprofloxacin (CFC), roxithomycin (RXM) and clindamycin (CLD). Chromatographic separation was performed on a C18 Zorbax-Eclipse Plus (3.5 μm, 100 × 4.6 mm) using isocratic elution. Detection was performed by positive electrospray ionization. The methods were applied for the assessment of PK parameters in volunteers (n = 101, 64 male and 37 female) and the effects of age, body mass index (BMI) and gender were investigated. Good linearity (r2 ≥ 0.99), accuracy (>86%), precision (CV% ≤ 11) and extraction recovery (>83%) were observed for CFC, CFX, RXM and CLD. Application to PK studies revealed that age and BMI affected the Thalf and the AUC of RXM and CLD (p < 0.023). Gender difference affected the critical PK parameters of the four ABs (Thalf (U = 18; P = 0.036) of CFC, the Cmax of CFX (U = 30; P = 0.017), the Thalf (U = 23; P = 0.009) and AUC (U = 26; P = 0.008) of RXM and CLD), respectively. These results highlight the significance of age and BMI variations for RXM and CLD dosing. Furthermore, it indicates that the gender difference may be considered when adjusting the AB dose.


Resection of an Isolated Pituitary Stalk Epidermoid Cyst Through a Pretemporal Approach: Case Report and Review of the Literature.
Intracranial epidermoid cysts are congenital epidermal inclusion cysts derived from ectodermal origin with desquamated skin. The majority of these cysts occur in the cerebellopontine angle cistern. Epidermoid cyst of the pituitary stalk, however, is a rare location. To date, only 4 previous cases have been reported. A 63-year-old male presented to our clinic with migraine headaches, dizziness, increased thirst, increased urinary frequency, and impotence. Magnetic resonance imaging of the brain demonstrated a rim-enhancing cystic mass with diffusion restriction on diffusion-weighted imaging located within the pituitary stalk. The patient underwent a pretemporal approach with gross total resection of the cyst. The patient's postoperative course was uneventful with no new deficits and/or endocrinopathies. Epidermoid cyst of the pituitary stalk is an unusual and rare presentation. Four other cases treated via endoscopic approaches have been previously reported in the neurosurgical literature. To our knowledge this is the first case description of an infundibular epidermoid cyst pressing with isolated diabetes insipidus surgically treated via a transcranial pretemporal approach with gross total resection. The patient had a smooth and uneventful postoperative course with persistent diabetes insipidus.


Increases in spontaneous neural activity in the hamster dorsal cochlear nucleus following cisplatin treatment: a possible basis for cisplatin-induced tinnitus.
Recent investigations in the hamster have implicated increased spontaneous activity (SA) in the dorsal cochlear nucleus (DCN) as a contributing factor in the etiology of tinnitus induced by intense sound exposure. It might therefore be expected that increased SA would also develop in the DCN of hamsters treated with cisplatin, another cause of tinnitus. We tested this hypothesis by measuring the effects of cisplatin on SA in the DCN. Adult hamsters were divided into three groups, each receiving five injections of cisplatin at one of the following doses: 3 mg/kg, 2.25 mg/kg, or 1.5 mg/kg. Each group had corresponding controls receiving injections of isotonic saline. The effects of cisplatin were studied electrophysiologically 1 month after treatment by recording multiunit SA on the surface of the DCN. Measurements of SA were obtained in three rows of 13-15 locations spaced roughly 100 microm apart and spanning the length of the DCN along the tonotopic axis. Effects of cisplatin were evaluated by comparing plots of mean SA vs. tonotopic locus for cisplatin-treated groups with those of their corresponding untreated control groups. The results demonstrated a consistently higher level of SA in cisplatin-treated groups than in untreated controls. Whereas the highest rates of mean SA in control groups were between 10 and 15 events/s, the highest mean spontaneous rates in cisplatin-treated groups were between 25 and 38 events/s. The cisplatin-induced hyperactivity was greatest in the medial half of the DCN corresponding to the high frequency portion of the tonotopic range. These results suggest that cisplatin treatment is an effective inducer of hyperactivity in the DCN. This hyperactivity may be an important neural correlate of cisplatin-induced tinnitus.


What an acute care nurse practitioner should know about reimbursement.
How to apply for reimbursement for ACNP services should be a carefully considered decision.It can be a complicated process and should be well understood before embarking on the"billing experience." The ACNP can expect that this course of action may be challenging,but if successful, the NP can further pursue the quantification of patient outcomes that can enhance the NP role in the acute and critical care environment.


Toxoplasma gondii is capable of exogenous folate transport. A likely expansion of the BT1 family of transmembrane proteins.
Folates are key elements in eukaryotic biosynthetic processes. The protozoan parasite Toxoplasma gondii possesses the enzymes necessary for de novo folate synthesis and has been suggested to lack alternative mechanisms for folate acquisition. In this paper, we present a different view by providing evidence that Toxoplasma is capable of salvaging exogenous folates. By monitoring uptake of radiolabeled folates by parasites in axenic conditions, our studies revealed a common folate transporter that has a high affinity for folic acid. Transport of this compound across the parasite plasma membrane is rapid, biphasic, temperature dependent, bi-directional, concentration dependent and specific. In addition, morphological evidence demonstrates that fluorescent methotrexate, a folate analog, is internalized by Toxoplasma and shows localization reminiscent to the mitochondrion. The presence of putative folate transporter genes in the Toxoplasma genome, which are homologous to the BT1 family of proteins, suggests that Toxoplasma may encode proteins involved in folate transport. Interestingly, genome analysis suggests that the BT1 family of proteins exists not only in Toxoplasma, but in other Apicomplexan parasites as well. Altogether, our results not only have implications for current therapeutic regimens against T. gondii, but they also allude that the folate transport mechanism may represent a novel Apicomplexan target for the development of new drugs.


Oral tolerance: an updated review.
Oral tolerance (OT) has classically been defined as the specific suppression of cellular and/or humoral immune responses to an antigen by prior administration of the antigen through the oral route. Multiple mechanisms have been proposed to explain the induction of OT including T cell clonal depletion and anergy when high doses of antigens are fed, and regulatory T (Treg) cell generation following oral administration of low and repeated doses of antigens. Oral antigen administration suppresses the immune response in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis, uveitis, thyroiditis, myasthenia, arthritis and diabetes, but also non-autoimmune inflammatory conditions such as asthma, atherosclerosis, graft rejection, allergy and stroke. However, human trials have given mixed results and a great deal remains to be learned about the mechanisms of OT before it can be successfully applied to people. One of the possible mechanisms relates to the gut microbiota and in this review, we will explore the cellular components involved in the induction of OT and the role of the gut microbiota in contributing to OT development.


Bixa orellana L. (Achiote, Annatto) as an antimicrobial agent: A scoping review of its efficiency and technological prospecting.
Bixa orellana L. is reported to have numerous applications in traditional medicine and pharmacological properties such as wound healing, analgesic, hemostatic, and antioxidant activities. Recently, the literature has shown scientific interest of its antimicrobial properties aiming the development of cost-effective phytotherapeutic agents. However, no literature are available in witch the antimicrobial and technological prospecting are summarized. This study aimed to systematically review articles and patents related to the antimicrobial activity of B. orellana. The review followed the guidelines proposed by The Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Two reviewers performed a literature search up to November 2021 in eight databases: Medline (PubMed), Scopus, Scifinder, Web of Science, Cochrane, Embase, Scielo, and Biblioteca Virtual em Saúde. The following databases for the patent search were analyzed: United States Patent and Trademark Office (USPTO), Google Patents, National Institute of Industrial Property (INPI), World Intellectual Property Organization (WIPO), and Espacenet (European Patent Office, EPO). The grey literature was searched using the ProQuest Dissertations and Periódicos Capes Theses database. The methodological quality and risk of bias in the included studies were carried out using Review Manager (RevMan) 5.3.5. After analyzing the 47 studies and five patents fulfilled all the criteria and were included in the present investigation. The evidence suggests that this herbal medicine is effective against several fungi, Gram-positive and Gram-negative bacteria, being more effective to Gram-negative bacteria. Regarding the risk of bias and methodological quality analysis, most studies a high risk of bias related to random sequence generation and allocation concealment. Up to now, the evidence in the literature suggests that the use of B. orellana preparations for antimicrobial preparations has some effectiveness. However, further research is needed using standard B. orellana preparations to determine their effectiveness as antimicrobial agents and expanding their application at an industrial level, in addition in vivo studies are needed for this confirmation.


Reliability of the Impulsive-Premeditated Aggression Scale (IPAS) in treated opiate-dependent individuals.
The purpose of the study was to evaluate the internal consistency and test-retest reliability of the Impulsive Aggression (IA) and Premeditated Aggression (PM) scales of the Impulsive-Premeditated Aggression Scale (IPAS) in male and female substance-dependent patients, and to compare the findings to those obtained on widely used, validated measures of aggression. Using a sample of 121 patients (61 women) in methadone maintenance treatment, 69 (35 women) of which were re-evaluated after a minimum of 2weeks, the IPAS scales showed acceptable internal consistency (alpha>.72) and test-retest reliability (ICC>.54). These results were comparable to the other aggression measures, and results among women were comparable to men. This was the first study to examine the IPAS scales in a substance use population, to contain a sufficient sample of women for sub-analyses, and to examine the stability of the measure. Findings support the internal consistency and test-retest reliability of the IPAS in male and female opiate-dependent individuals.


Alterations in phenylephrine-induced contractions and the vascular expression of Na+,K+-ATPase in ouabain-induced hypertension.
Hypertension development, phenylephrine-induced contraction and Na(+),K(+)-ATPase functional activity and protein expression in aorta (AO), tail (TA) and superior mesenteric (SMA) arteries from ouabain- (25 microg day(-1), s.c., 5 weeks) and vehicle-treated rats were evaluated. Ouabain treatment increased systolic blood pressure (127+/-1 vs 160+/-2 mmHg, n=24, 35; P<0.001) while the maximum response to phenylephrine was reduced (P<0.01) in AO (102.8+/-3.9 vs 67.1+/-10.1% of KCl response, n=12, 9) and SMA (82.5+/-7.5 vs 52.2+/-5.8%, n=12, 9). Endothelium removal potentiated the phenylephrine response to a greater extent in segments from ouabain-treated rats. Thus, differences of area under the concentration-response curves (dAUC) in endothelium-denuded and intact segments for control and ouabain-treated rats were, respectively: AO, 56.6+/-9.6 vs 198.3+/-18.3 (n=9, 7); SMA, 85.5+/-15.4 vs 165.4+/-24.8 (n=6, 6); TA, 13.0+/-6.1 vs 39.5+/-10.4% of the corresponding control AUC (n=6, 6); P<0.05. The relaxation to KCl (1 - 10 mM) was similar in segments from both groups. Compared to controls, the inhibition of 0.1 mM ouabain on KCl relaxation was greater in AO (dAUC: 64.8+/-4.6 vs 84.0+/-5.1%, n=11, 14; P<0.05), similar in SMA (dAUC: 39.1+/-3.9 vs 43.3+/-7.8%, n=6, 7; P>0.05) and smaller in TA (dAUC: 62.1+/-5.5 vs 41.4+/-8.2%, n=12, 13; P<0.05) in ouabain-treated rats. Protein expression of both alpha(1) and alpha(2) isoforms of Na(+),K(+)-ATPase was augmented in AO, unmodified in SMA and reduced in TA from ouabain-treated rats. These results suggest that chronic administration of ouabain induces hypertension and regional vascular alterations, the latter possibly as a consequence of the hypertension.


A pathological and immunohistological case report of fatal infectious mononucleosis, Epstein-Barr virus infection, demonstrated by in situ and Southern blot hybridization.
We present an autopsy case of 20-month-old boy who had a fulminant course of infectious mononucleosis, with severe hepatic failure. Autopsy revealed marked infiltration of immunoblasts in the lymph nodes, liver, spleen, thymus and kidneys. We identified a large number of Epstein-Barr virus (EBV) genomes in the immunoblasts of the lymph nodes, liver and spleen by in situ hybridization. EBV genomes were also detected in the liver and spleen by Southern blot hybridization. Histology of the liver revealed diffuse feathery degeneration of the hepatocytes. However, EBV genomes were not detected in the hepatocytes by in situ hybridization and monoclonal antibody studies. Immunostaining of the autopsy liver specimen revealed a large number of suppressor/cytotoxic T cells (Leu2a positive) in the portal areas and of natural killer (NK) cells (Leu7 positive) in the portal areas and sinusoids of the liver. We therefore suggest that the hepatocellular damage was not caused by the viral replication in the hepatocytes but was mainly caused by the abnormal killer cell activity of the suppressor/cytotoxic T cells and NK cells.


Cadmium induces a heterogeneous and caspase-dependent apoptotic response in Saccharomyces cerevisiae.
The toxic metal cadmium is linked to a series of degenerative disorders in humans, in which Cd-induced programmed cell death (apoptosis) may play a role. The yeast, Saccharomyces cerevisiae, provides a valuable model for elucidating apoptosis mechanisms, and this study extends that capability to Cd-induced apoptosis. We demonstrate that S. cerevisiae undergoes a glucose-dependent, programmed cell death in response to low cadmium concentrations, which is initiated within the first hour of Cd exposure. The response was associated with induction of the yeast caspase, Yca1p, and was abolished in a yca1Delta mutant. Cadmium-dependent apoptosis was also suppressed in a gsh1Delta mutant, indicating a requirement for glutathione. Other apoptotic markers, including sub-G(1) DNA fragmentation and hyper-polarization of mitochondrial membranes, were also evident among Cd-exposed cells. These responses were not distributed uniformly throughout the cell population, but were restricted to a subset of cells. This apoptotic subpopulation also exhibited markedly elevated levels of intracellular reactive oxygen species (ROS). The heightened ROS levels alone were not sufficient to induce apoptosis. These findings highlight several new perspectives to the mechanism of Cd-dependent apoptosis and its phenotypic heterogeneity, while opening up future analyses to the power of the yeast model system.


The polymorphism and haplotypes of XRCC1 and survival of non-small-cell lung cancer after radiotherapy.
The X-ray repair cross-complementing Group 1 (XRCC1) protein is involved mainly in the base excision repair of the DNA repair process. This study examined the association of 3 polymorphisms (codon 194, 280, and 399) of XRCC1 and lung cancer in terms of whether or not these polymorphisms have an effect on the survival of lung cancer patients who have received radiotherapy. Between January 2000 and April 2004, 229 lung cancer patients with non-small-cell lung cancer in Stages I-III were enrolled. Genotyping was performed by single base primer extension assay using the SNP-IT Kit with genomic DNA samples from all patients. The haplotype of the XRCC1 polymorphisms was estimated by PHASE version 2.1. The patients consisted of 191 (83.4%) males and 38 (16.6%) females with a median age of 62 (range, 26-88 years). Sixty percent of the patients were included in Stage I-IIIa. The median progression-free and overall survival was 13 months and 16 months, respectively. The XRCC1 codon 194, histology, and stage were shown to be significant predictors of the progression-free survival. The 6 haplotypes among the XRCC1 polymorphisms (194, 280, and 399) were estimated by PHASE v.2.1. The patients with haplotype pairs other than the homozygous TGG haplotype pairs survived significantly longer (p = 0.04). Polymorphisms of XRCC1 have an effect on the survival of lung cancer patients treated with radiotherapy, and this effect seems to be more significant after the haplotype pairs are considered.


Dental amalgam: the history and legacy you perhaps never knew?
Much has been written about dental amalgam. Over many years, it has served the profession well, yet on environmental grounds its use is being phased down. This article seeks to explore key milestones in the history and development of this versatile material, as well as highlighting how international standards have assisted in reducing environmental mercury contamination.


The effect of short-term immunotherapy with molecular standardized grass and rye allergens on eosinophil cationic protein and tryptase in nasal secretions.
Activation of mast cells and eosinophils under pollen exposure can be inhibited by specific immunotherapy. The effect of short-term immunotherapy with 7 preseasonal injections of molecular standardized allergens from grass and rye pollen on eosinophil cationic protein (ECP) and tryptase levels in nasal secretions has been compared with symptomatic drug treatment in an open, randomized study with 48 patients. Nasal reactivity and mediator levels in nasal secretions were measured at baseline, before season, in season, and after season. Symptom scores in the immunotherapy group were 134.5 (95% CI, 65 to 336) versus 386. 0 (95% CI, 185 to 563), significantly lower as in the drug-treated group. ECP and tryptase levels increased significantly during natural allergen exposition. The seasonal levels in the immunotherapy group were significantly lower than in the drug-treated group with 272.1 ng/mL (252.0 to 293.9 ng/mL; immunotherapy) versus 470.4 ng/mL (SEM, 435.6 to 508.0 ng/mL; drugs) for ECP and with 8.73 ng/mL (SEM, 8.20 to 9.29 ng/mL) versus 17.47 ng/mL (16.42 to 18.60 ng/mL) for tryptase (all, P <.001). The ECP level induced by nasal provocation was 105.6 ng/mL (99.0 to 112.6 ng/mL) versus 180.4 ng/mL (169.2 to 192.4 ng/mL), significantly lower (P <.001) in the immunotherapy group, as was the tryptase level with 12.12 ng/mL (11.53 to 12.75 ng/mL) versus 8.19 ng/mL (7. 79 to 8.62 ng/mL; P <.001) at the after-season visit. Short-term immunotherapy is able to reduce tryptase and ECP in nasal secretions more effectively than drug treatment in patients with allergic rhinitis.


Tumor suppressor gene BLU is frequently downregulated by promoter hypermethylation in myelodysplastic syndrome.
BLU methylation status was investigated in bone marrow mononuclear cells from newly diagnosed myelodysplastic syndrome (MDS) patients and patients who received 5-aza-2'-deoxycytidine (decitabine) treatment so as to determine the effect of BLU in the pathogenesis of MDS. Methylation-specific polymerase chain reaction and bisulfite sequencing were used to evaluate the methylation status of the promoter region of the BLU gene. BLU expression was investigated by using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot analysis. Hypermethylation in the promoter region of BLU was detected in 34 of 79 (43%) newly diagnosed MDS patient samples and was significantly correlated with the loss of BLU mRNA and protein expression. There was a statistically significant difference in methylation frequency between the refractory anemia/refractory anemia with ringed sideroblasts/5q-syndrome (RA/RARS/5q-) group and the refractory anemia with excess blasts-1/-2 (RAEB-1/RAEB-2) group. A higher frequency of hypermethylation was observed in the intermediate-2/high-risk group compared to the low-risk/intermediate-1-risk group. The demethylating agent decitabine could partly reverse hypermethylation and restore the expression of the BLU gene. BLU promoter hypermethylation frequently occurs in MDS cases, especially in higher risk MDS cases, and is significantly associated with the downregulated expression of BLU. BLU gene re-expression was induced in some MDS cases undergoing decitabine therapy. BLU may play a substantial role in the development and etiology of MDS.