Flow injection spectrophotometric determination of the antibiotic ciprofloxacin in drug formulations.
A flow injection spectrophotometric method for the assay of ciprofloxacin was developed. The method was based on the chelation of iron(III) with the drug in 0.023 mol dm-3 sulfuric acid solution in a 72 cm long coil and the brown-red complex produced was monitored at 447 nm. The super modified simplex computer program was employed for the optimization of the system and chemical parameters with respect to throughput and sensitivity as a measure of system performance. A working range for ciprofloxacin determination of 50-500 ppm for a 110 mm3 sample size with an optimum of 250 samples per hour was achieved with a relative standard deviation of less than 0.92%. The method was successfully applied to the determination of ciprofloxacin in drug formulations.


Fibrillin-1 mutations causing Weill-Marchesani syndrome and acromicric and geleophysic dysplasias disrupt heparan sulfate interactions.
The extracellular glycoprotein fibrillin-1 forms microfibrils that act as the template for elastic fibers. Most mutations in fibrillin-1 cause Marfan syndrome with severe cardiovascular and ocular symptoms, and tall stature. This is in contrast to mutations within a heparin-binding TB domain (TB5), which is downstream of the arg-gly-asp cell adhesion domain, which can cause Weill-Marchesani syndrome (WMS) or Acromicric (AD) and Geleophysic Dysplasias (GD). WMS is characterized by short limbs, joint stiffness and ocular defects, whilst fibrillin-1 AD and GD have severe short stature, joint defects and thickened skin. We previously showed that TB5 binds heparin. Here, we show that the corresponding region of fibrillin-2 binds heparin very poorly, highlighting a novel functional difference between the two isoforms. This finding enabled us to map heparin/heparan sulfate binding to two sites on fibrillin-1 TB5 using a mutagenesis approach. Once these sites were mapped, we were able to investigate whether disease-causing mutations in this domain disrupt binding to HS. We show that a WMS deletion mutant, and five AD and GD point mutants all have disrupted heparin binding to TB5. These data provide insights into the biology of fibrillins and the pathologies of WMS, AD and GD.


Quantitative determination of the infectivity of the proviral DNA of a retrovirus in vitro: Evaluation of methods for DNA inactivation.
All viral vaccines contain contaminating residual DNA derived from the production cell substrate. The potential risk of this DNA, particularly when derived from tumorigenic cells, has been debated for over 40 years. While the major risk has been considered to be the oncogenicity of the DNA, another potential risk is that a genome of an infectious virus is present in this DNA. Such a genome might generate an infectious agent that could establish an infection in vaccine recipients. To determine the quantity of a retroviral provirus in cellular DNA that can establish a productive infection in vitro, we developed a transfection/co-culture system capable of recovering infectious virus from 1 pg of cloned HIV DNA and from 2 microg of cellular DNA from HIV-infected cells. We demonstrate that infectivity can be reduced to below detectable levels either by lowering the median size of the DNA to 350 base pairs or by treatment with beta-propiolactone. From the amount of reduction of infectivity, we calculate that clearance values in excess of 10(7) are attainable with respect to the infectivity associated with residual cell-substrate DNA. Thus, the potential risk associated with DNA can be substantially reduced by degradation or by chemical inactivation.


Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia.
Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14-18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 ± 2 mmHg compared with 102 ± 3 mmHg in NP and decreased to 113 ± 3 mmHg with VD2 and 115 ± 3 mmHg with VD3 in RUPP rats. Circulating CD4+ T cells increased in RUPP to 7.90 ± 1.36% lymphocytes compared with 2.04 ± 0.67% in NP but was lowered to 0.90 ± 0.19% with VD2 and 4.26 ± 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 ± 0.4 bpm in RUPPs to 8.3 ± 0.5 bpm with VD2 and to 15.4 ± 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 ± 2.1-fold change from NP) and decreased with both VD2 (3.3 ± 1.1-fold) and VD3 (3.1 ± 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 ± 6.6 pg/ml in VD2-treated and 91.0 ± 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 ± 19.9 pg/ml in RUPP rats. VD treatment reduced CD4+ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia.


Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells.
Precise regulation of neuroprogenitor cell proliferation and differentiation is required for successful brain development, but the factors that contribute to this are only incompletely understood. The transcription factor ATF5 promotes proliferation of cerebral cortical neuroprogenitor cells and its down regulation permits their differentiation. Here, we examine the expression and regulation of ATF5 in cerebellar granule neuron progenitor cells (CGNPs) as well as the role of ATF5 in the transition of CGNPs to postmitotic cerebellar granule neurons (GCNs). We find that ATF5 is expressed by proliferating CGNPs in both the embryonic and postnatal cerebellar external granule layer (EGL) and in the rhombic lip, the embryonic structure from which the EGL arises. In contrast, ATF5 is undetectable in postmitotic GCNs. In highly enriched dissociated cultures of CGNPs and CGNs, ATF5 is expressed only in CGNPs. Constitutive ATF5 expression in CGNPs does not affect their proliferation or exit from the cell cycle. In contrast, in presence of sonic hedgehog (Shh), a mitogen for CGNPs, constitutively expressed ATF5 promotes CGNP proliferation and delays their cell cycle exit and differentiation. Conversely, ATF5 loss-of-function conferred by a dominant-negative form of ATF5 significantly diminishes Shh-stimulated CGNP proliferation and promotes differentiation. In parallel with its stimulation of CGNP proliferation, Shh enhances ATF5 expression by what appeared to be a posttranscriptional mechanism involving protein stabilization. These findings indicate a reciprocal interaction between ATF5 and Shh in which Shh stimulates ATF5 expression and in which ATF5 contributes to Shh-stimulated CGNP expansion.


Measuring community norms around women's empowerment in the West Bank: Opportunities and challenges of a novel approach using cultural consensus.
Understanding cultural norms is essential to achieving results in development interventions and preventing interventions from causing unintended negative consequences. However, capturing norms within everyday contexts in ways that can be monitored and evaluated can be expensive and time consuming and is not always feasible. We tested a novel method, the cultural consensus analysis (CCA), in the context of monitoring and evaluating a United States Agency for International Development (USAID) justice project in the West Bank, Palestine. We conducted 392 survey interviews with men and women, using 60 true or false questions in the knowledge domains of women's empowerment and gender-based violence (GBV), and tested three gender propositions using CCA. We found no singular cultural understanding of women's empowerment and GBV across West Bank Palestinians (proposition 1). Distinctive cultural models for women and other subgroups (e.g., those living in villages, women who identified as discriminated against within Palestinian society) exist, although there were no shared cultural models among men of any subgroup (proposition 2). Program assumptions regarding structural barriers to women's empowerment conformed to the women's cultural models (proposition 3). To our knowledge, this is the first application of CCA as an approach for describing gender norms in international development programming. CCA was able to distinguish subtle cultural patterns, including between population subgroups, and to identify how those are associated with specific risks, such as GBV. We conclude that CCA is a potentially useful approach for development practice, to ground-truth program assumptions and, potentially, to track program impacts.


Light-Enhanced Spin Fluctuations and d-Wave Superconductivity at a Phase Boundary.
Time-domain techniques have shown the potential of photomanipulating existing orders and inducing new states of matter in strongly correlated materials. Using time-resolved exact diagonalization, we perform numerical studies of pump dynamics in a Mott-Peierls system with competing charge and spin density waves. A light-enhanced d-wave superconductivity is observed when the system resides near a quantum phase boundary. By examining the evolution of spin, charge, and superconducting susceptibilities, we show that a subdominant state in equilibrium can be stabilized by photomanipulating the charge order to allow superconductivity to appear and dominate. This work provides an interpretation of light-induced superconductivity from the perspective of order competition and offers a promising approach for designing novel emergent states out of equilibrium.


Green tea reduces body fat accretion caused by high-fat diet in rats through beta-adrenoceptor activation of thermogenesis in brown adipose tissue.
The aim of the present study was to investigate body fat-suppressive effects of green tea in rats fed on a high-fat diet and to determine whether the effect is associated with beta-adrenoceptor activation of thermogenesis in brown adipose tissue. Feeding a high-fat diet containing water extract of green tea at the concentration of 20g/kg diet prevented the increase in body fat gain caused by high-fat diet without affecting energy intake. Energy expenditure was increased by green tea extract which was associated with an increase in protein content of interscapular brown adipose tissue. The simultaneous administration of the beta-adrenoceptor antagonist propranolol(500 mg/kg diet) inhibited the body fat-suppressive effect of green tea extract. Propranolol also prevented the increase in protein content of interscapular brown adipose tissue caused by green tea extract. Digestibility was slightly reduced by green tea extract and this effect was not affected by propranolol. Therefore it appeared that green tea exerts potent body fat-suppressive effects in rats fed on a high-fat diet and the effect was resulted in part from reduction in digestibility and to much greater extent from increase in brown adipose tissue thermogenesis through beta-adrenoceptor activation.


Modeling nonlinearity in coherent transmissions with dominant intrachannel-four-wave-mixing.
By extending a well-established time-domain perturbation approach to dual-polarization propagation, we provide an analytical framework to predict the nonlinear interference (NLI) variance, i.e., the variance induced by nonlinearity on the sampled field, and the nonlinear threshold (NLT) in coherent transmissions with dominant intrachannel-four-wave-mixing (IFWM). Such a framework applies to non dispersion managed (NDM) very long-haul coherent optical systems at nowadays typical baudrates of tens of Gigabaud, as well as to dispersion-managed (DM) systems at even higher baudrates, whenever IFWM is not removed by nonlinear equalization and is thus the dominant nonlinearity. The NLI variance formula has two fitting parameters which can be calibrated from simulations. From the NLI variance formula, analytical expressions of the NLT for both DM and NDM systems are derived and checked against recent NLT Monte-Carlo simulations.


A balancing act: how plants integrate nitrogen and water signals.
Nitrogen (N) and water (W) are crucial inputs for plant survival as well as costly resources for agriculture. Given their importance, the molecular mechanisms that plants rely on to signal changes in either N or W status have been under intense scrutiny. However, how plants sense and respond to the combination of N and W signals at the molecular level has received scant attention. The purpose of this review is to shed light on what is currently known about how plant responses to N are impacted by W status. We review classic studies which detail how N and W combinations have both synergistic and antagonistic effects on key plant traits, such as root architecture and stomatal aperture. Recent molecular studies of N and W interactions show that mutations in genes involved in N metabolism affect drought responses, and vice versa. Specifically, perturbing key N signaling genes may lead to changes in drought-responsive gene expression programs, which is supported by a meta-analysis we conduct on available transcriptomic data. Additionally, we cite studies that show how combinatorial transcriptional responses to N and W status might drive crop phenotypes. Through these insights, we suggest research strategies that could help to develop crops adapted to marginal soils depleted in both N and W, an important task in the face of climate change.


Moderators, mediators, and other predictors of risperidone response in children with autistic disorder and irritability.
The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritability in autistic disorder. This paper explores moderators and mediators of this effect. Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results. Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo. The benefit-risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems nonspecifically predict better outcome. Mineral interactions with risperidone deserve further study.


Topical dual-stain difference imaging for rapid intra-operative tumor identification in fresh specimens.
Assessing tumor margin status during surgery is critical to ensure complete resection of cancer tissue; however, current approaches are ineffective and often result in repeat surgery. We present an optical imaging approach for margin assessment using topical application of two fluorescent stains, one targeted to a tumor biomarker and the other a nontargeted reference, to freshly excised specimens. Computing a normalized difference image from fluorescence images of the targeted and untargeted stains suppresses the confounding effects of nonspecific uptake. Applying this approach in excised breast tumor models produced promising tumor-to-normal tissue contrasts that were significantly higher than single-targeted-stain imaging.


Longitudinal relations between beliefs supporting aggression and externalizing outcomes: Indirect effects of anger dysregulation and callous-unemotional traits.
Aggression is prevalent in early- to mid-adolescence and is associated with physical health and psychosocial adjustment difficulties. This underscores the need to identify risk processes that lead to externalizing outcomes. This study examined the extent to which the effects of three dimensions of beliefs supporting aggression on physical aggression and externalizing behavior are mediated by anger dysregulation and callous-unemotional (CU) traits. Three waves of data were collected from a primarily African American (77%) sample of 265 middle school students between the ages of 11 and 15 (52% were female). We found evidence supporting mediation such that the effects of beliefs supporting instrumental aggression and beliefs that fighting is sometimes necessary at Wave 1 on student-reported physical aggression at Wave 3 were mediated by CU traits at Wave 2, and relations between beliefs supporting reactive aggression at Wave 1 and teacher-report of student frequencies of physical aggression and externalizing behavior at Wave 3 were mediated by anger dysregulation at Wave 2. Our findings demonstrated the importance of distinguishing between dimensions of beliefs supporting aggression, as differential paths emerged between specific beliefs, CU traits and anger dysregulation, and externalizing outcomes. These findings have important clinical implications, as they suggest that specific dimensions of beliefs supporting aggression could be targeted based on whether an individual is at risk for behavior patterns characterizing CU traits or anger dysregulation.


Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor.
Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na+, K+, and Cl- transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C(-/-) null). In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest approximately 40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C(-/-) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C(-/-) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na+/K+ ATPase gamma-subunit and the Cl- channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C-independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na+/K+ ATPase and ClC-K2.


Explaining the Paradoxical Age-based Racial Disparities in Survival After Trauma: The Role of the Treating Facility.
The objective of our study was to determine if differences in outcomes at treating facilities can help explain these age-based racial disparities in survival after trauma. It has been previously demonstrated that racial disparities in survival after trauma are dependent on age. For patients younger than 65 years, blacks had an increased odds of mortality compared with whites, but among patients 65 years or older the opposite association was found. Data on white and black trauma patients were extracted from the Nationwide Inpatient Sample (2003-2009) using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Standardized observed-to-expected mortality ratios were calculated for individual treating facilities, adjusting for age, sex, insurance status, mechanism of injury, overall injury severity, head injury severity, and comorbid conditions. Observed-to-expected ratios were used to benchmark facilities as high-, average-, or low-performing facilities. Proportions and survival outcomes of younger (range, 16-64 years) and older (≥65 years) patients admitted within each performance stratum were compared. A total of 934,476 patients from 1137 facilities (8.3% high-performing, 85% average-performing, and 6.7% low-performing) were analyzed. Younger black patients had a higher adjusted odds of mortality compared with younger white patients [odds ratio, 1.19; 95% confidence interval, 1.11-1.27], whereas older black patients had a lower odds of mortality compared with older white patients [odds ratio, 0.81; 95% confidence interval, 0.74-88]. A significantly greater proportion of younger black patients were treated at low-performing facilities compared with both younger white patients and older black patients (49.6% vs 42.2% and 38.7%, respectively; P < 0.05). Nearly half of all young black trauma patients are treated at low-performing facilities. However, facility-based differences do not seem to explain the paradoxical age-based racial disparities after trauma observed in the older population.


CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors.
Stressful life events during childhood and adolescence are important risk factors for the development of psychopathologies later in life. The corticotropin releasing hormone (CRH) and the CRH receptor 1 (CRHR1) have been implicated in the link between early life adversity and adult anxiety and depression, with rodent studies identifying the very early postnatal period as highly susceptible to this programming. Here, we investigated whether stress exposure during the peripubertal period - comprising juvenility and puberty - is effective in inducing long-lasting changes in the expression of CRHR1 and CRHR2 in the hippocampus and amygdala, and whether treating animals with a CRHR1 antagonist following stress exposure could reverse behavioral alterations induced by peripuberty stress. We show that peripuberty stress leads to enhanced expression of the Crhr1, but not Crhr2, gene in the hippocampal CA1 and the central nucleus of the amygdala, in association with social deficits in the social exploration test and increased stress-coping behaviors in the forced swim test. Treatment with the CRHR1 antagonist NBI30775 (10 mg/kg) daily for 1 week (from P43 to P49), immediately following peripuberty stress exposure, prevented the occurrence of those psychopathological behaviors at adulthood. These findings highlight peripuberty as a period of plasticity for the enduring modulation of the CRHR1 system and support a growing body of data implicating the CRHR1 system in the programming effects of early life stress on eventual psychopathology. They also support recent evidence indicating that temporarily tackling CRHR1 during development might represent a therapeutic opportunity to correct behavioral trajectories linking early stress to adult psychopathology.


Assessing equity: a way to improve sanitation service delivery in South African informal settlements.
This paper discusses the need to incorporate equity assessment into the planning and monitoring of sanitation service delivery to South African informal settlements. Equity assessment criteria were drawn from literature and a study of sanitation service delivery to informal settlements in three South African municipalities (Cape Town, Johannesburg and eThekwini) over the period 2012-2015. Three key dimensions of equity - resource allocation, access and stakeholder perceptions - were identified. These had eight associated criteria: (1) funds allocated for basic sanitation, (2) number of staff allocated to informal settlements, (3) disparities in access, (4) proportion of functioning sanitation facilities, (5) menstrual hygiene management (MHM) inclusion, (6) access to information, (7) meets users' notions of dignity, and (8) integration of the perspectives of key stakeholders. Key findings of the study indicate that the current focus on reducing service backlogs largely ignores equity and there is a need to better address this through the incorporation of: equity assessments, improving access to information, and the inclusion of marginalised communities in the planning of sanitation services.


The effects of preferential deposition of histamine in the human airway.
Two inhalation techniques were performed to obtain airway and diffuse airway deposition of histamine aerosol. A radiotracer method was used to confirm the patterns of aerosol deposition and to measure the dose of histamine aerosol in the airways. In 5 subjects the effect of cumulative doses of histamine aerosol given either centrally or diffusely to the airways was measured. Histamine aerosol deposited predominantly in the large airways was more effective in increasing airway obstruction that was diffusely deposited histamine aerosol, suggesting that the receptors mediating the action of histamine reside mainly in the large airways.


The cyclin-like protein Spy1/RINGO promotes mammary transformation and is elevated in human breast cancer.
Spy1 is a novel 'cyclin-like' activator of the G1/S transition capable of enhancing cell proliferation as well as inhibiting apoptosis. Spy1 protein levels are tightly regulated during normal mammary development and forced overexpression in mammary mouse models accelerates mammary tumorigenesis. Using human tissue samples, cell culture models and in vivo analysis we study the implications of Spy1 as a mediator of mammary transformation and breast cancer proliferation. We demonstrate that this protein can facilitate transformation in a manner dependent upon the activation of the G2/M Cdk, Cdk1, and the subsequent inhibition of the anti-apoptotic regulator FOXO1. Importantly, we show for the first time that enhanced levels of Spy1 protein are found in a large number of human breast cancers and that knockdown of Spy1 impairs breast cancer cell proliferation. Collectively, this work supports that Spy1 is a unique activator of Cdk1 in breast cancer cells and may represent a valuable drug target and/or a prognostic marker for subsets of breast cancers.


The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues.
We have previously reported the origin of a class of skeletal myogenic cells from explants of dorsal aorta. This finding disagrees with the known origin of all skeletal muscle from somites and has therefore led us to investigate the in vivo origin of these cells and, moreover, whether their fate is restricted to skeletal muscle, as observed in vitro under the experimental conditions used. To address these issues, we grafted quail or mouse embryonic aorta into host chick embryos. Donor cells, initially incorporated into the host vessels, were later integrated into mesodermal tissues, including blood, cartilage, bone, smooth, skeletal and cardiac muscle. When expanded on a feeder layer of embryonic fibroblasts, the clonal progeny of a single cell from the mouse dorsal aorta acquired unlimited lifespan, expressed hemo-angioblastic markers (CD34, Flk1 and Kit) at both early and late passages, and maintained multipotency in culture or when transplanted into a chick embryo. We conclude that these newly identified vessel-associated stem cells, the meso-angioblasts, participate in postembryonic development of the mesoderm, and we speculate that postnatal mesodermal stem cells may be derived from a vascular developmental origin.


Multiscale image segmentation using wavelet-domain hidden Markov models.
We introduce a new image texture segmentation algorithm, HMTseg, based on wavelets and the hidden Markov tree (HMT) model. The HMT is a tree-structured probabilistic graph that captures the statistical properties of the coefficients of the wavelet transform. Since the HMT is particularly well suited to images containing singularities (edges and ridges), it provides a good classifier for distinguishing between textures. Utilizing the inherent tree structure of the wavelet HMT and its fast training and likelihood computation algorithms, we perform texture classification at a range of different scales. We then fuse these multiscale classifications using a Bayesian probabilistic graph to obtain reliable final segmentations. Since HMTseg works on the wavelet transform of the image, it can directly segment wavelet-compressed images without the need for decompression into the space domain. We demonstrate the performance of HMTseg with synthetic, aerial photo, and document image segmentations.


Comparative pathology of Lassa virus infection in monkeys, guinea-pigs, and Mastomys natalensis.
Experimental Lassa virus infections of squirrel monkeys, guinea-pigs, and the African multimammate rat, Mastomys natalensis, were studied virologically and pathologically. In the monkeys, early viral lymphoreticulotropism, hepatotropism, nephrotropism, and viraemia were noted. At the time of death, viral titres in nearly all target organs were associated with necrotic changes: splenic lymphoid necrosis, renal tubular necrosis, myocarditis, arteritis, and hepatocytic regeneration. In convalescent monkeys, organ titres diminished slowly, and viraemia persisted at 28 days. At this time, renal and splenic regeneration was occurring and a new lesion, choriomeningitis, was present.Guinea-pigs infected with Lassa virus developed respiratory insufficiency with pulmonary oedema, alveolar hyaline membranes, myocarditis, and focal calcification of myocardial fibres and hepatocytes. Dying animals contained Lassa virus in virtually every organ tested, whereas survivors at 56 days were free of virus and had high complement-fixing antibody titres.Infection of neonatal Mastomys did not cause any clinical disease or pathological lesions despite the presence of virus in the blood, lymph nodes, liver, spleen, lung, brain, urine, and throat secretions throughout the 74-day study. Infected adult Mastomys also remained normal but had virus in many organs. In one animal, virus persisted until the termination of the study at 103 days. Several animals developed a mild meningoencephalitis. The pattern of infection and virus shedding in M. natalensis is ideal for maintenance of the virus in nature; together with the epidemiological field data this emphasizes the incidental nature of the exposure and infection of man.


The IGF2-intron3-G3072A substitution explains a major imprinted QTL effect on backfat thickness in a Meishan x European white pig intercross.
A paternally expressed QTL for muscle growth and backfat thickness (BFT) has previously been identified near the IGF2 locus on the distal tip of pig chromosome 2 (SSC2p) in three experimental F2 populations. Recently, a mutation in a regulatory element of the IGF2 gene was identified as the quantitative trait nucleotide (QTN) underlying the major QTL effect on muscle growth and BFT in crosses between Large White and Wild Boar or Pietrain. This study demonstrates that the IGF2 mutation also controls the paternally expressed QTL for backfat thickness in a cross between Meishan and European Whites. In addition, a comparison of QTL of backfat thickness measured by Hennessy grading probe (HGP) and by ultrasound measurement (USM) was made. In the USM analyses, the IFG2 mutation explains the entire QTL effect on SSC2p, whereas in the HGP analysis the presence of a second minor QTL can not be excluded. Finally, this study shows that this particular IGF2 mutation does not cause the paternally expressed QTL for teat number mapping to the same region of SSC2p as the BFT QTL.


Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity.
Natural killer T (NKT) cells are important regulators of the immune system, but their trafficking machinery, including expression of chemokine receptors, has been poorly defined. Unlike other conventional T-cell populations, we show that most NKT cells express receptors for extralymphoid tissue or inflammation-related chemokines (CCR2, CCR5, and CXCR3), while few NKT cells express lymphoid tissue-homing chemokine receptors (CCR7 and CXCR5). A population with homing potential for lymph nodes (L selectin(+) CCR7(+)) exists only within a small subset of CD4 NKT cells. We show differential expression of chemokine receptors among NKT cell subsets: CCR4 is mainly expressed by a high cytokine (interleukin-4/interleukin-2)-producing (CD4) NKT subset, while CCR1, CCR6, and CXCR6 are preferentially expressed by the low cytokine-producing CD8 and CD4(-)CD8(-) subsets. In line with this, TARC/CCL17 (a CCR4 ligand) induces preferential chemotaxis of the CD4 NKT subset, while chemotactic activities of LARC/CCL20 (a CCR6 ligand) and MIP-1 alpha/CCL3 (a CCR1 ligand) are focused on the CD8 and CD4(-)CD8(-) NKT cells. We conclude that, unlike conventional naive, memory, or effector T cells, the entire NKT cell population expresses nonlymphoid tissue homing chemokine receptors, yet NKT cell subsets differ considerably from each other by displaying distinct and reciprocal expression patterns of some chemokine receptors. Our results identify chemokine receptors that are potentially important for trafficking of human blood NKT cell subsets and reveal their function (cytokine production capacity)-dependent differential trafficking potentials.


Aging and uremia: Is there cellular and molecular crossover?
Many observers have noted that the morphological changes that occur in chronic kidney disease (CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and rates of frailty in the two groups, and shared characteristics at a pathophysiological level especially in respect to the changes seen in their vascular and immune systems. However, whilst much has been documented about the shared physical characteristics of aging and uremia, the molecular and cellular similarities between the two have received less attention. In order to bridge this perceived gap we have reviewed published research concerning the common molecular processes seen in aging subjects and CKD patients, with specific attention to altered proteostasis, mitochondrial dysfunction, post-translational protein modification, and senescence and telomere attrition. We have also sought to illustrate how the cell death and survival pathways apoptosis, necroptosis and autophagy are closely interrelated, and how an understanding of these overlapping pathways is helpful in order to appreciate the shared molecular basis behind the pathophysiology of aging and uremia. This analysis revealed many common molecular characteristics and showed similar patterns of cellular dysfunction. We conclude that the accelerated aging seen in patients with CKD is underpinned at the molecular level, and that a greater understanding of these molecular processes might eventually lead to new much needed therapeutic strategies of benefit to patients with renal disease.


Study on the ethical concepts of the Japanese writer Yukio Mishima, ultra-nationalist.
After WWII, ultra-nationalism, which was the leading ideology of wartime Japan, seemed to have lost its power to inspire the Japanese. In the 1960s, when the Japanese began to enjoy economic prosperity, Yukio Mishima, deploring that the Japanese were losing the traditional spirit and morality of the nation, was one of those citizens who felt a strong nostalgia for wartime Japan. In an attempt to revive the spiritual exaltation of wartime Japan, Mishima took radical action as an ultra-nationalist, and killed himself by Hara-kiri. Mishima's ethical concepts, which center on the ethos of warriors who dedicate themselves to the defense of their commune, have structural similarities to the ethical structure of the Kanun, which may be called the ethics of "blood". Mishima's theory of ultra-nationalism has a paradoxical logic, which seems to be related to the ethical concepts of a society without state power.


Food and health in Europe: a new basis for action.
Poor nutrition, foodborne disease and lack of secure access to good food make an important contribution to the burden of disease and death in the WHO European Region. Better diets, food safety and food security will not only reduce or prevent suffering to individuals and societies but also help cut costs to health care systems and bring social and economic benefits to countries. People's chances for a healthy diet depend less on individual choices than on what food is available and whether it is affordable. Policies to benefit health through good food and nutrition must extend beyond the health sector to include sectors ranging from agriculture and food processing, manufacturing and trade to transport, retailing, catering and advertising. Food and nutrition policies should be coordinated so that public health is given due priority in the making of food policies by non-health sectors. This publication discusses in depth the components of food and nutrition policies and the evidence supporting them. It describes food- and nutrition-related ill health and its costs, shows the need for action and describes the steps for decision-makers to take. This book highlights the urgent need for integrated, multisectoral food and nutrition policies to encourage the sustainable production of food, its safety and the provision of food of high nutritional quality for all.


Gene deletion of 7,8-linoleate diol synthase of the rice blast fungus: studies on pathogenicity, stereochemistry, and oxygenation mechanisms.
Linoleate diol synthases (LDS) are heme enzymes, which oxygenate 18:2n-6 sequentially to (8R)-hydroperoxylinoleic acid ((8R)-HPODE) and to (5S,8R)-dihydroxy-, (7S,8S)-dihydroxy-, or (8R,11S)-dihydroxylinoleic acids (DiHODE). The genome of the rice blast fungus, Magnaporthe oryzae, contains two genes with homology to LDS. M. oryzae oxidized 18:2n-6 to (8R)-HPODE and to (7S,8S)-DiHODE, (6S,8R)-DiHODE, and (8R,11S)-HODE. Small amounts of 10-hydroxy-(8E,12Z)-octadecadienoic acid and traces of 5,8-DiHODE were also detected by liquid chromatography-mass spectrometry. The contribution of the 7,8-LDS gene to M. oryzae pathogenicity was evaluated by replacement of the catalytic domain with hygromycin and green fluorescent protein variant (SGFP) cassettes. This genetically modified strain Delta7,8-LDS infected rice leaves and roots and formed appressoria and conidia as the native fungus. The Delta7,8-LDS mutant had lost the capacity to biosynthesize all the metabolites except small amounts of 8-hydroxylinoleic acid. Studies with stereospecifically deuterated linoleic acids showed that (8R)-HPODE was formed by abstraction of the pro-S hydrogen at C-8 and antarafacial oxygenation, whereas (7S,8S)-DiHODE and (8R,11S)-DiHODE were formed from (8R)-HPODE by suprafacial hydrogen abstraction and oxygenation at C-7 and C-11, respectively. A mac1 suppressor mutant (Delta mac1 sum1-99) of M. oryzae, which shows cAMP-independent protein kinase A activity, oxygenated 18:2n-6 to increased amounts of (10R)-HPODE and (5S,8R)-DiHODE. Expression of the 7,8-LDS gene but not of the second homologue was detected in the suppressor mutant. This suggests that PKA-mediated signaling pathway regulates the dioxygenase and hydroperoxide isomerase activities of M. oryzae.


Carbon and nitrogen stoichiometry and nitrogen cycling rates in streams.
Stoichiometric analyses can be used to investigate the linkages between N and C cycles and how these linkages influence biogeochemistry at many scales, from components of individual ecosystems up to the biosphere. N-specific NH4+ uptake rates were measured in eight streams using short-term 15N tracer additions, and C to N ratios (C:N) were determined from living and non-living organic matter collected from ten streams. These data were also compared to previously published data compiled from studies of lakes, ponds, wetlands, forests, and tundra. There was a significant negative relationship between C:N and N-specific uptake rate; C:N could account for 41% of the variance in N-specific uptake rate across all streams, and the relationship held in five of eight streams. Most of the variation in N-specific uptake rate was contributed by detrital and primary producer compartments with large values of C:N and small values for N-specific uptake rate. In streams, particulate materials are not as likely to move downstream as dissolved N, so if N is cycling in a particulate compartment, N retention is likely to be greater. Together, these data suggest that N retention may depend in part on C:N of living and non-living organic matter in streams. Factors that alter C:N of stream ecosystem compartments, such as removal of riparian vegetation or N fertilization, may influence the amount of retention attributed to these ecosystem compartments by causing shifts in stoichiometry. Our analysis suggests that C:N of ecosystem compartments can be used to link N-cycling models across streams.


MuLoG, or How to Apply Gaussian Denoisers to Multi-Channel SAR Speckle Reduction?
Speckle reduction is a longstanding topic in synthetic aperture radar (SAR) imaging. Since most current and planned SAR imaging satellites operate in polarimetric, interferometric, or tomographic modes, SAR images are multi-channel and speckle reduction techniques must jointly process all channels to recover polarimetric and interferometric information. The distinctive nature of SAR signal (complex-valued, corrupted by multiplicative fluctuations) calls for the development of specialized methods for speckle reduction. Image denoising is a very active topic in image processing with a wide variety of approaches and many denoising algorithms available, almost always designed for additive Gaussian noise suppression. This paper proposes a general scheme, called MuLoG (MUlti-channel LOgarithm with Gaussian denoising), to include such Gaussian denoisers within a multi-channel SAR speckle reduction technique. A new family of speckle reduction algorithms can thus be obtained, benefiting from the ongoing progress in Gaussian denoising, and offering several speckle reduction results often displaying method-specific artifacts that can be dismissed by comparison between results.


Relationship of Height to Site-Specific Fracture Risk in Postmenopausal Women.
Height has been associated with increased risk of fracture of the neck of femur. However, information on the association of height with fractures at other sites is limited and conflicting. A total of 796,081 postmenopausal women, who reported on health and lifestyle factors including a history of previous fractures and osteoporosis, were followed for 8 years for incident fracture at various sites by record linkage to National Health Service hospital admission data. Adjusted relative risks of fracture at different sites per 10-cm increase in height were estimated using Cox regression. Numbers with site-specific fractures were: humerus (3036 cases), radius and/or ulna (1775), wrist (9684), neck of femur (5734), femur (not neck) (713), patella (649), tibia and/or fibula (1811), ankle (5523), and clavicle/spine/rib (2174). The risk of fracture of the neck of femur increased with increasing height (relative risk [RR] = 1.48 per 10-cm increase, 99% confidence interval [CI] 1.39-1.57) and the proportional increase in risk was significantly greater than for all other fracture sites (pheterogeneity < 0.001). For the other sites, fracture risk also increased with height (RR = 1.15 per 10 cm, CI 1.12-1.18), but there was only very weak evidence of a possible difference in risk between the sites (pheterogeneity = 0.03). In conclusion, taller women are at increased risk of fracture, especially of the neck of femur.


From bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.


Probing the role of stochasticity in a model of the embryonic stem cell: heterogeneous gene expression and reprogramming efficiency.
Embryonic stem cells (ESC) have the capacity to self-renew and remain pluripotent, while continuously providing a source of a variety of differentiated cell types. Understanding what governs these properties at the molecular level is crucial for stem cell biology and its application to regenerative medicine. Of particular relevance is to elucidate those molecular interactions which govern the reprogramming of somatic cells into ESC. A computational approach can be used as a framework to explore the dynamics of a simplified network of the ESC with the aim to understand how stem cells differentiate and also how they can be reprogrammed from somatic cells. We propose a computational model of the embryonic stem cell network, in which a core set of transcription factors (TFs) interact with each other and are induced by external factors. A stochastic treatment of the network dynamics suggests that NANOG heterogeneity is the deciding factor for the stem cell fate. In particular, our results show that the decision of staying in the ground state or commitment to a differentiated state is fundamentally stochastic, and can be modulated by the addition of external factors (2i/3i media), which have the effect of reducing fluctuations in NANOG expression. Our model also hosts reprogramming of a committed cell into an ESC by over-expressing OCT4. In this context, we recapitulate the important experimental result that reprogramming efficiency peaks when OCT4 is over-expressed within a specific range of values. We have demonstrated how a stochastic computational model based upon a simplified network of TFs in ESCs can elucidate several key observed dynamical features. It accounts for (i) the observed heterogeneity of key regulators, (ii) characterizes the ESC under certain external stimuli conditions and (iii) describes the occurrence of transitions from the ESC to the differentiated state. Furthermore, the model (iv) provides a framework for reprogramming from somatic cells and conveys an understanding of reprogramming efficiency as a function of OCT4 over-expression.


[The assessment of nursing workload].
The measurement of nursing workload first began in the 1970s, because of the need for determining severity of illness and cost-effectiveness in the intensive care unit. In the following decades, the need for more specific tools for assessing nursing workload brought to the development of scoring systems more focused on nursing activities. We will briefly review the scoring systems validated since 1974. TISS-Therapeutic Intervention Scoring System elaborated by Cullen in 1974 is based on 57 therapeutic procedures and was designed to assess the severity of illness in the ICU. Each intervention scores 1 to 4. Patients are grouped in 5 classes. It was not sufficiently validated and was abandoned. However it first introduced the idea of "patient point managed per nurse". TISS update was elaborated by Keene in 1983. The therapeutic procedures were increased to 76. It was assumed that a single nurse can manage 40/50 points per day. Though not validated, it became the most used tool to assess complexity of treatment and nurse/patient ratio. However many of these items are obsolete and frequently related to the severity of illness rather than to specific nursing interventions. PRN-Project Research of Nursing was elaborated by EROS during 1980-1987. Points are assigned to each nursing activity according to their frequency, duration, need for more than one nurse, etc. It results quite time consuming, thus unsuitable for routine use. OMEGA elaborated in 1986 describes 86 therapeutic interventions, grouped in 3 categories, measured at the end of ICU stay, thus representing a measure of global workload and use of resources. TOSS-Time Oriented Score System was elaborated by GIRTI in 1991. This score was studied and tested in Italy. It represents a direct temporal evaluation of nursing workload. The score is expressed in minutes. It is reliable and relatively simple, and has been validated on over 2 700 ICU patients. TISS 28 was elaborated by Miranda in 1996. It represents a simplified and updated version of the original TISS, proposed to assess the nursing workload. The authors stated that a nurse can deal with 46 points over the 24 hours. NEMS-Nine Equivalents of nursing Manpower use Score was elaborated by Miranda in 1997. It was derived from TISS and TISS28. Only 9 items, related to specific organ support, nursing and diagnostic/therapeutic interventions inside or outside the ICU, are considered. These items were weighted by multivariate analysis, obtaining a score comparable to the TISS28 score. Each nurse can deal with 45/50 points per day. NAS-Nursing Activity Score was elaborated by Miranda in 2003. It was derived from TISS28, aiming at the description of nursing activities not necessarily correlated to the severity of illness. It describes 81% of the nursing time, compared to 43% of TISS 28. In conclusion, many scoring systems have been proposed to describe nursing workload, both directly (as with TOSS and PRN) or through severity and complexity of treatment (TISS, TISS 28, NAS and NEMS). These scores represent the instruments to assess the correct use of ICU resources.


Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding.
Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for the justification of alternative pain therapies. This study systematically examined the antihyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen. Von Frey and Hargreaves tests were used to examine the antihyperalgesic effects of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays. 2-BFI (3.2-17.8 mg/kg, i.p.), phenyzoline (17.8-100 mg/kg, i.p.), and acetaminophen (56-178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner. Quantitative analysis of the antihyperalgesic and response rate-suppressing effects suggests that I2 receptor ligands are not well suited to combination therapy with acetaminophen.


Pseudomonas syringae pv. syringae B728a hydrolyses indole-3-acetonitrile to the plant hormone indole-3-acetic acid.
Nitrilase enzymes catalyse the hydrolysis of nitrile compounds to the corresponding carboxylic acid and ammonia, and have been identified in plants, bacteria and fungi. There is mounting evidence to support a role for nitrilases in plant-microbe interactions, but the activity of these enzymes in plant pathogenic bacteria remains unexplored. The genomes of the plant pathogenic bacteria Pseudomonas syringae pv. syringae B728a and Pseudomonas syringae pv. tomato DC3000 contain nitrilase genes with high similarity to characterized bacterial arylacetonitrilases. In this study, we show that the nitrilase of P. syringae pv. syringae B728a is an arylacetonitrilase, which is capable of hydrolysing indole-3-acetonitrile to the plant hormone indole-3-acetic acid, and allows P. syringae pv. syringae B728a to use indole-3-acetonitrile as a nitrogen source. This enzyme may represent an additional mechanism for indole-3-acetic acid biosynthesis by P. syringae pv. syringae B728a, or may be used to degrade and assimilate aldoximes and nitriles produced during plant secondary metabolism. Nitrilase activity was not detected in P. syringae pv. tomato DC3000, despite the presence of a homologous nitrilase gene. This raises the interesting question of why nitrilase activity has been retained in P. syringae pv. syringae B728a and not in P. syringae pv. tomato DC3000.


Characterization of strand displacement synthesis catalyzed by bacteriophage T7 DNA polymerase.
The DNA polymerase induced after infection of Escherichia coli by bacteriophage T7 can exist in two forms. One distinguishing property of Form I, the elimination of nicks in double-stranded DNA templates, strongly suggests that this form of the polymerase catalyzes limited DNA synthesis at nicks, resulting in displacement of the downstream strand. In this paper, we document this reaction by a detailed characterization of the DNA product. DNA synthesis on circular, duplex DNA templates containing a single site-specific nick results in circular molecules bearing duplex branches. Analysis of newly synthesized DNA excised from the product shows that the majority of the branches are less than 500 base pairs in length and that they arise from a limited number of sites. The branches have fully base-paired termini but are attached by two noncomplementary DNA strands that have a combined length of less than 30 nucleotides. The product molecules are topologically constrained as a result of the duplex branch. DNA sequence analysis has provided an unequivocal structure of one such product molecule. We conclude that strand displacement synthesis catalyzed by Form I of T7 DNA polymerase is terminated by a template-switching reaction. We propose two distinct models for template-switching that we call primer relocation and rotational strand exchange. Strand displacement synthesis catalyzed by Form I of T7 DNA polymerase effectively converts T7 DNA circles that are held together by hydrogen bonds in their 160-nucleotide-long terminal redundancy to T7-length linear molecules. We suggest that strand displacement synthesis catalyzed by T7 DNA polymerase is essential in vivo to the processing of a T7 DNA concatemer to mature T7 genomes.


Complex dysrhythmias in infants and children.
Dysrhythmias in infants and children are, in many ways, similar to those in adults, yet several important differences exist in their presentation and management. Complex dysrhythmias most frequently encountered in pediatrics include sinus node dysfunction, chaotic atrial rhythm, atrial flutter, supraventricular tachycardia (including Wolff-Parkinson-White syndrome and junctional ectopic tachycardia), complete atrioventricular block (congenital and acquired), and ventricular dysrhythmias (premature ventricular contractions and ventricular tachycardia). Newer approaches to the diagnosis and management of these dysrhythmias are addressed in this paper.


Hospital-wide survey of the adequacy in the number of vascular catheters and catheter lumens.
Removal of unnecessary catheters has been proposed as an important measure to reduce catheter-related morbidity. Nevertheless, there is scarce information about the potential magnitude of such intervention. The present study was aimed at analyzing the appropriateness of use of vascular catheters and catheter lumens in the inpatient setting. Cross-sectional survey. The entire population of adult inpatients admitted to a 1368-bed tertiary-care hospital in a single day. We used a set of preestablished criteria to evaluate the appropriateness of use of vascular catheters and catheter lumens according to the number and administration regimen of intravenous drugs. Out of 834 patients, 575 (68.9%) had ≥1 vascular catheters in place on the day of the survey. The type and distribution of the 703 surveyed catheters were peripheral venous catheter, 80.6%; central venous catheter, 15.8%; and arterial catheter, 3.6%. We found an overall mean of 2.06 ± 0.82 lumens per catheter, with significant differences between intensive care units and conventional wards (P < 0.0001). Based on our criteria, 126 out of 575 patients (21.9%) had an inappropriate number of catheters (medical wards, 20.0%; surgical wards, 23.9%; intensive care units, 26.3%), and 631 out of 14248 nonarterial catheter lumens (43.6%) were considered unnecessary. Significant room exists for improving the adequacy of the number of vascular catheters and catheter lumens as a potentially useful tool for decreasing the incidence of catheter-related bloodstream infection.


Lysosomal recycling of amino acids affects ER quality control.
Recent work has highlighted the fact that lysosomes are a critical signaling hub of metabolic processes, providing fundamental building blocks crucial for anabolic functions. How lysosomal functions affect other cellular compartments is not fully understood. Here, we find that lysosomal recycling of the amino acids lysine and arginine is essential for proper ER quality control through the UPRER. Specifically, loss of the lysine and arginine amino acid transporter LAAT-1 results in increased sensitivity to proteotoxic stress in the ER and decreased animal physiology. We find that these LAAT-1-dependent effects are linked to glycine metabolism and transport and that the loss of function of the glycine transporter SKAT-1 also increases sensitivity to ER stress. Direct lysine and arginine supplementation, or glycine supplementation alone, can ameliorate increased ER stress sensitivity found in laat-1 mutants. These data implicate a crucial role in recycling lysine, arginine, and glycine in communication between the lysosome and ER.


X-CAL: Explicit Calibration for Survival Analysis.
Survival analysis models the distribution of time until an event of interest, such as discharge from the hospital or admission to the ICU. When a model's predicted number of events within any time interval is similar to the observed number, it is called well-calibrated. A survival model's calibration can be measured using, for instance, distributional calibration (D-CALIBRATION) [Haider et al., 2020] which computes the squared difference between the observed and predicted number of events within different time intervals. Classically, calibration is addressed in post-training analysis. We develop explicit calibration (X-CAL), which turns D-CALIBRATION into a differentiable objective that can be used in survival modeling alongside maximum likelihood estimation and other objectives. X-CAL allows practitioners to directly optimize calibration and strike a desired balance between predictive power and calibration. In our experiments, we fit a variety of shallow and deep models on simulated data, a survival dataset based on MNIST, on length-of-stay prediction using MIMIC-III data, and on brain cancer data from The Cancer Genome Atlas. We show that the models we study can be miscalibrated. We give experimental evidence on these datasets that X-CAL improves D-CALIBRATION without a large decrease in concordance or likelihood.


Prescribing pattern of antidiabetic drugs in indore city hospital.
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, glycosuria, and sometimes ketonemia. The present study was carried out to assess prescribing practice and general trend of diabetes among patients at the Bombay Hospital, Indore. Prescriptions and complete records of diabetic patients were monitored and data was filed as per WHO prescription proforma. The study revealed that prescription of metformin (27%) and glimepiride (22.60%) were found to be maximum among various available antidiabetic drugs. Category wise the maximum prescribed drugs are glimepride (22.60%, sulfonylurea category), metformin (27%, biguanide category) and pioglitazones (13.90%, glitazone category). Insulin prescription was found to be very less (4.5%). Combination of metformin and glimepiride (20.86%) was prescribed most commonly. Most common disease associated with diabetes mellitus was found to be hypertension (35%). Highest prevalence of disease was found to be in the age group of 51 to 60 followed by age group of 41 to 50. Men patients (66.36%) were found to be predominated over women patients (33.64%).


The impact of acute exercise on implicit cognitive reappraisal in association with left dorsolateral prefronta activation: A fNIRS study.
Despite findings showing that acute exercise may help enhance emotion regulation, the neurophysiological mechanisms of these effects remain poorly understood. In this study, we examined whether acute exercise influences cognitive emotion regulation, and, in particular, an implicit cognitive reappraisal. Twenty sedentary young women were randomly assigned to either a control group (n = 10) or an exercise group (n = 10). Participants underwent an implicit cognitive reappraisal task twice, before and after the 30-min acute exercise or control, alongside functional near-infrared spectroscopy recordings (NIRS). The left dorsolateral prefrontal cortex (dlPFC) and left orbital frontal cortex (OFC) were activated during implicit cognitive reappraisal at baseline, but only the left dlPFC activation was linked with behavioral performance. Acute exercise enhanced the activation of these regions, reflective of the partial neural bases of implicit cognitive reappraisal, in the left dlPFC and left OFC, but did not alter the behavioral performance. Results also showed that acute exercise moderated the positive effect of left dlPFC activation on implicit cognitive reappraisal performance; specifically, this effect was stronger in the exercise group. In conclusion, the enhanced activation of the left dlPFC by acute exercise and the increased link between behavioral performance and its neural indices may point to acute exercise as a promoter of implicit cognitive reappraisal.


Role of the thymus in directing the development of a subset of B lymphocytes.
In an effort to evaluate the role of the thymus in influencing the development of Lyb-5- B lymphocytes, mice expressing both the xid and nu gene defects were studied. Mice expressing either of these defects respond to both trinitrophenylated Brucellus abortus and lipopolysaccharide; whereas mice with the combined defect show markedly suppressed responses. The other abnormalities included: (a) greater than 80 percent diminution of serum Ig levels; (b) significant increase in the number of sIgM+ sIgD- B lymphocytes; (c) reduced expression of IgD on sIgD+ cells; and (d) a strikingly abnormal histology of their lymphoid tissue. Because nu/nu mice that do not express the xid defect appear relatively normal, it would suggest that the development of Lyb-5- B lymphocytes require a thymic influence for normal maturation, whereas, Lyb-5+ B lymphocytes are relatively independent of such influences.


The mutational decay of male-male and hermaphrodite-hermaphrodite competitive fitness in the androdioecious nematode C. elegans.
Androdioecious Caenorhabditis have a high frequency of self-compatible hermaphrodites and a low frequency of males. The effects of mutations on male fitness are of interest for two reasons. First, when males are rare, selection on male-specific mutations is less efficient than in hermaphrodites. Second, males may present a larger mutational target than hermaphrodites because of the different ways in which fitness accrues in the two sexes. We report the first estimates of male-specific mutational effects in an androdioecious organism. The rate of male-specific inviable or sterile mutations is ⩽5 × 10-4/generation, below the rate at which males would be lost solely due to those kinds of mutations. The rate of mutational decay of male competitive fitness is ~ 0.17%/generation; that of hermaphrodite competitive fitness is ~ 0.11%/generation. The point estimate of ~ 1.5X faster rate of mutational decay of male fitness is nearly identical to the same ratio in Drosophila. Estimates of mutational variance (VM) for male mating success and competitive fitness are not significantly different from zero, whereas VM for hermaphrodite competitive fitness is similar to that of non-competitive fitness. Two independent estimates of the average selection coefficient against mutations affecting hermaphrodite competitive fitness agree to within two-fold, 0.33-0.5%.


GENETIC VARIATION IN THE BETA-3-ADRENORECEPTOR GENE (TRP64ARG POLYMORPHISM) AND THEIR INFLUENCE ON ANTHROPOMETRIC PARAMETERS AND INSULIN RESISTANCE AFTER A HIGH PROTEIN/LOW CARBOHYDRATE VERSUS A STANDARD HYPOCALORIC DIET.
the Trp64Arg variant in Beta receptor has been reported to be associated with increased body weight and insulin resistance Objective: the aim of our study was to investigate the influence of polymorphism (rs 4994) in Beta-3-adrenergic receptor gene on metabolic response and weight loss in a medium-term intervention study secondary's to a high protein/low carbohydrate vs. a standard hypocaloric diets (1000 kcal/day). a population of 284 obese subjects was analyzed in a randomized trial. A nutritional evaluation was performed at the beginning and at the end of a 9-month period in which subjects received 1 of 2 diets (diet HP: high protein/low carbohydrate vs diet S: standard diet). there were no significant differences between the positive effects (on weight, BMI, waist circumference, fat mass, systolic blood pressure and leptin levels) in either genotype group with both diets. With both diets and only in wild genotype (diet HP vs diet S), total cholesterol (-10.1 ± 3.9 mg/dl vs -10.1 ± 2.2 mg/dl;p>0.05), LDL cholesterol (-9.5 ± 2.1 mg/dl vs -8.5 ± 2.3 mg/dl;p>0.05) and triglycerides (-19.1 ± 2.1 mg/dl vs -14.3 ± 2.1 mg/dl;p>0.05) decreased. The improvement in these parameters was similar in subjects with diet HP than HS. With diet HP and only in wild genotype, insulin levels (-3.7 ± 1.9 UI/L;p<0.05) and HOMA-R (-0.7 ± 0.1 units;p<0.05) decreased. metabolic effect of weight reduction by two hypocaloric diets is the greatest in subjects with normal homozygous beta 3-AR gene. Improvement in total cholesterol, LDL-cholesterol, triglyceride, glucose, insulin and HOMA-R levels is better than in the heterozygous group.


Systemic immune responses in Cytauxzoon felis-infected domestic cats.
To characterize systemic immune responses in Cytauxzoon felis-infected cats. Blood and lung samples obtained from 27 cats. Cats were allocated into 4 groups: cats that died of cytauxzoonosis, acutely ill C felis-infected cats, healthy survivors of C felis infection, and healthy uninfected cats. Serum concentrations of tumor necrosis factor-α and interleukin-1 β were measured and serum proteins characterized. Blood smears were stained immunocytochemically and used to assess immunoglobulin deposition. Immunohistochemical expression of CD18 and tumor necrosis factor-α were compared in lung tissues obtained from cats that died and healthy uninfected cats. A real-time reverse-transcription PCR assay for CD18 expression was performed on selected blood samples from all groups. Concentrations of both cytokines were greater and serum albumin concentrations were significantly lower in cats that died of cytauxzoonosis, compared with results for all other groups. Erythrocytes from acutely ill cats and survivors of C felis infection had staining for plasmalemmal IgM, whereas erythrocytes from the other groups did not. Increased staining of C felis-infected monocytes and interstitial neutrophils for CD18 was detected. The real-time reverse-transcription PCR assay confirmed a relative increase in CD18 expression in cats that died of cytauxzoonosis and acutely ill cats, compared with expression in other groups. Immunostaining for TNF-α in lung samples confirmed a local proinflammatory response. Results indicated immunopathologic responses were greater in cats that died of C felis infection than in cats that survived C felis infection.


Homozygous inactivating mutations in the NKX3-2 gene result in spondylo-megaepiphyseal-metaphyseal dysplasia.
Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is a rare skeletal dysplasia with only a few cases reported in the literature. Affected individuals have a disproportionate short stature with a short and stiff neck and trunk. The limbs appear relatively long and may show flexion contractures of the distal joints. The most remarkable radiographic features are the delayed and impaired ossification of the vertebral bodies as well as the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones. Numerous pseudoepiphyses of the short tubular bones in hands and feet are another remarkable feature of the disorder. Genome wide homozygosity mapping followed by a candidate gene approach resulted in the elucidation of the genetic cause in three new consanguineous families with SMMD. Each proband was homozygous for a different inactivating mutation in NKX3-2, a homeobox-containing gene located on chromosome 4p15.33. Striking similarities were found when comparing the vertebral ossification defects in SMMD patients with those observed in the Nkx3-2 null mice. Distinguishing features were the asplenia found in the mutant mice and the radiographic abnormalities in the limbs only observed in SMMD patients. The absence of the latter anomalies in the murine model may be due to the perinatal death of the affected animals. This study illustrates that NKX3-2 plays an important role in endochondral ossification of both the axial and appendicular skeleton in humans. In addition, it defines SMMD as yet another skeletal dysplasia with autosomal-recessive inheritance and a distinct phenotype.


Sex-specific genetic effects influence variation in body composition.
Despite well-known sex differences in body composition it is not known whether sex-specific genetic or environmental effects contribute to these differences. We assessed body composition in 2,506 individuals, from a young Dutch genetic isolate participating in the Erasmus Rucphen Family study, by dual-energy X-ray absorptiometry and anthropometry. We used variance decomposition procedures to partition variation of body composition into genetic and environmental components common to both sexes and to men and women separately and calculated the correlation between genetic components in men and women. After accounting for age, sex and inbreeding, heritability ranged from 0.39 for fat mass index to 0.84 for height. We found sex-specific genetic effects for fat percentage (fat%), lean mass, lean mass index (LMI) and fat distribution, but not for BMI and height. Genetic correlations between sexes were significantly different from 1 for fat%, lean mass, LMI, android fat, android:gynoid fat ratio and WHR, indicating that there are sex-specific genes contributing to variation of these traits. Genetic variance was significantly higher in women for the waist, hip and thigh circumference and WHR, implying that genes account for more variance of fat distribution in women than in men. Environmental variance was significantly higher in men for the android:gynoid fat ratio. Sex-specific genetic effects underlie sexual dimorphism in several body composition traits. The findings are relevant for studies on the relationship of body composition with common diseases like cardiovascular disease and type 2 diabetes and for genetic association studies.


Prolonged adherence of human immunodeficiency virus-derived vector particles to hematopoietic target cells leads to secondary transduction in vitro and in vivo.
Human immunodeficiency virus type 1-derived lentivirus vectors bearing the vesicular stomatitis virus G (VSV-G) envelope glycoprotein demonstrate a wide host range and can stably transduce quiescent hematopoietic stem cells. In light of concerns about biosafety and potential germ line transmission, they have been used predominantly for ex vivo strategies, thought to ensure the removal of excess surface-bound particles and prevent in vivo dissemination. Studies presented here instead reveal prolonged particle adherence after ex vivo exposure, despite serial wash procedures, with subsequent transduction of secondary target cells in direct and transwell cocultures. We explored the critical parameters affecting particle retention and transfer and show that attachment to the cell surface selectively protects virus particles from serum complement-mediated inactivation. Moreover, studies with nonmyeloablated murine recipients show that transplantation of vector-exposed, washed hematopoietic cells results in systemic dissemination of functional VSV-G/lentivector particles. We demonstrate genetic marking by inadvertent transfer of vector particles and prolonged expression of transgene product in recipient tissues. Our findings have implications for biosafety, vector design, and cell biology research.


Treatment of relapsed aggressive lymphomas: regimens with and without high-dose therapy and stem cell rescue.
Treatment of aggressive lymphoma in relapse is difficult. Patients who initially present with these diseases often know they have a malignancy considered curable in many cases, and diagnosis of relapse can be devastating. For this reason, it is useful to know the individual patient's risk of relapse prior to starting initial therapy, since it may be appropriate to treat patients with poor prognoses with intensive programs or investigational studies. In the private practice setting, most patients with these diseases receive CHOP or similar cyclophosphamide and doxorubicin-containing regimens at the time of initial diagnosis. However, there are certain disease-related features which determine whether these patients have a high or low risk of relapse, and investigators are now using combinations of these features to determine which patients may be safely treated with CHOP and which may benefit from more intensive chemotherapy management. For example, the International Prognostic Factor Index system, now in common usage, delineates four different groups of patients with differing complete remission, freedom from progression, and overall survival rates. The Tumor Score System, developed at MDACC, delineates only two groups with very different survival rates, and may be a better scoring system for patients with diffuse large cell lymphomas, primarily because of its inclusion of the serum beta(2)-microglobulin level prior to treatment, an important predictor of relapse. In addition to pretreatment features, certain treatment-related factors are also important in determining the risk of relapse, including the dose of chemotherapy administered and the rapidity of response. Results of a gallium scan with SPECT imaging may be an important method of confirming complete response, and should be incorporated into treatment programs, whether the treatment is standard CHOP or an investigational program. For the patient with relapse or progressive disease following induction with CHOP or a similar regimen, the type of response to initial therapy plays an important role in determining potential response to salvage therapy, including high-dose therapy followed by stem cell rescue. Patients for whom initial treatment fails to achieve any response have a very poor chance of responding to any currently used standard-dose program for relapse. Those with partial responses have a better chance of responding to relapse therapy, but a high risk of disease progression or early relapse, and those with a prior complete response to initial therapy have a good chance of responding to relapse therapy, especially those in whom the complete response lasted more than a year. For these reasons, stem cell transplant (SCT) protocols routinely require complete response with initial therapy as a requirement for entry, although "good partial remission" may be acceptable at certain centers. Other limitations for SCT protocols include age greater than 60 or 65 years, significant chronic obstructive pulmonary, renal, or cardiac disease, a poor performance status, and central nervous system or marrow involvement. For these reasons, there is a continued need for newer treatment programs which offer the potential for higher response rates and better survival rates, not only for those for whom SCT is not an option, but also for those who must have an adequate response to "standard dose therapy" prior to selecting SCT as a treatment option. Three broad groups of relapse therapy for aggressive lymphoma have been described, based upon the drugs contained within these regimens. These include platinum-based, mitoxantrone-based, and ifosfamide-based chemotherapy regimens. Results with these programs vary widely and are likely different because of tumor-related features prior to relapse therapy, including size of mass, beta(2)-microglobulin level, LDH level, and type of response to initial therapy. Other features, such as dose of therapy, specific drugs utilized, and number of prior treatments also play important roles in determining results with relapse therapy. In a study of DHAP followed by transplant or more DHAP, DHAP induced a response in 56% of patients, and at 5 years, significantly more of the responders to DHAP who were subsequently treated with high-dose therapy and bone marrow transplant were free of disease compared to those who continued to receive DHAP after response to this regimen. Therefore, high-dose therapy is clearly better for DHAP responders than is continued DHAP. However, results for the overall population are still not good when non-responders are included in the analysis, and DHAP, a first-generation platinum regimen, may not be the optimal regimen to use prior to high-dose therapy followed by peripheral stem cell rescue. At MDACC, we have extensively investigated various combinations containing ifosfamide and etoposide. The most recently reported regimen, MINE-ESHAP, contains mesna, ifosfamide, mitoxantrone, and etoposide, followed after adequate response with etoposide, methylprednisolone, high-dose cytarabine, and continuous infusion as cis-platinum, a second-generation platinum regimen. This strategy resulted in a complete response in 47% of the patients treated, with a 44% complete response in patients with intermediate-grade lymphoma, 56% in those with low-grade lymphoma and 36% in those with transformed lymphoma. Results varied according to type of response achieved with initial therapy, and serum LDH and beta(2)-microglobulin levels prior to treatment with MINE-ESHAP. Using more intensive doses of ifosfamide and etoposide, we have described therapy for 36 patients with relapsed aggressive lymphomas, prior to pheresis and SCT. Results of this study are encouraging: 42% entered complete response with ifosfamide-etoposide and the overall survival was 52%, with a progression-free survival of 32%. Therapy with a similar regimen, combining ifosfamide, carboplatin, and etoposide in standard doses (ICE) has also been described. This regimen has been extensively studied in patients with relapsed aggressive lymphomas and Hodgkin's disease, followed by SCT. In patients with relapsed lymphomas, ICE has achieved a 66% complete response rate, with 89% undergoing transplant. Overall survival in these studies is affected by the quality of the response to ICE. The same program was used to treat 65 patients with Hodgkin's disease. The response rate to ICE was 88%, and the 5-year event-free survival for those transplanted was 68%. These factors predicted outcome: B symptoms, extranodal disease, and complete response less than 1 year. Finally, we have recently studied paclitaxel in combination with topotecan for relapsed and refractory aggressive lymphomas. These and newer combinations should be further developed to treat patients in relapse of aggressive lymphomas.


Positive and negative regulation of APP amyloidogenesis by sumoylation.
Amyloid beta peptide (Abeta) generated from amyloid precursor protein (APP) is central to Alzheimer's disease (AD). Signaling pathways affecting APP amyloidogenesis play critical roles in AD pathogenesis and can be exploited for therapeutic intervention. Here, we show that sumoylation, covalent modification of cellular proteins by small ubiquitin-like modifier (SUMO) proteins, regulates Abeta generation. Increased protein sumoylation resulting from overexpression of SUMO-3 dramatically reduces Abeta production. Conversely, reducing endogenous protein sumoylation with dominant-negative SUMO-3 mutants significantly increases Abeta production. We also show that mutant SUMO-3, K11R, which can only be monomerically conjugated to target proteins, has an opposite effect on Abeta generation to that by SUMO-3, which can form polymeric chains on target proteins. In addition, SUMO-3 immunoreactivity is predominantly detected in neurons in brains from AD, Down's syndrome, and nondemented humans. Therefore, polysumoylation reduces whereas monosumoylation or undersumoylation enhances Abeta generation. These findings provide a regulatory mechanism in APP amyloidogenesis and suggest that components in the sumoylation pathway may be critical in AD onset or progression.


Reduced intracellular drug accumulation in the absence of P-glycoprotein (mdr1) overexpression in mitoxantrone-resistant human MCF-7 breast cancer cells.
A mitoxantrone-resistant human MCF-7 breast cancer subline (MCF/MX) which is approximately 4000-fold resistant to mitoxantrone was isolated by serial passage of the parental wild-type MCF-7 cells (MCF/WT) in stepwise increasing concentrations of drug. MCF/MX cells were also approximately 10-fold cross-resistant to doxorubicin and etoposide but were not cross-resistant to vinblastine. Intracellular accumulation of radiolabeled mitoxantrone was markedly reduced in MCF/MX cells relative to that in the drug-sensitive MCF/WT cells. This decrease in intracellular drug accumulation into MCF/MX cells was associated with enhanced drug efflux, which was reversed when cells were incubated in the presence of sodium azide and 2, 4-dinitrophenol, suggesting an energy-dependent process. Incubation of MCF/MX cells with verapamil did not affect either the accumulation of mitoxantrone or the level of resistance in these cells. Furthermore, RNase protection and Western blot analyses failed to detect the expression of the mdr1 RNA or P-glycoprotein, a drug efflux pump known to be associated with the development of multidrug resistance in vitro. However, a polyclonal antibody directed against a synthetic peptide corresponding to the putative ATP binding domain of P-glycoprotein reacted with two (M(r) 42,000 and 85,000) membrane proteins from MCF/MX cells which were not found in MCF/WT. Functional assays and Western blot analysis for topoisomerase II revealed no differences in topoisomerase II activity or protein levels in MCF/MX cells. Thus, resistance in this cell line is apparently associated with enhanced drug efflux involving a pathway distinct from the mdr1-encoded multidrug transporter P-glycoprotein.


The risk of axillary relapse after sentinel lymph node biopsy for breast cancer is comparable with that of axillary lymph node dissection: a follow-up study of 4008 procedures.
We sought to identify the rate of axillary recurrence after sentinel lymph node (SLN) biopsy for breast cancer. SLN biopsy is a new standard of care for axillary lymph node staging in breast cancer. Nevertheless, most validated series of SLN biopsy confirm that the SLN is falsely negative in 5-10% of node-positive cases, and few studies report the rate of axillary local recurrence (LR) for that subset of patients staged by SLN biopsy alone. Through December of 2002, 4008 consecutive SLN biopsy procedures were performed at Memorial Sloan-Kettering Cancer Center for unilateral invasive breast cancer. Patients were categorized in 4 groups: SLN-negative with axillary lymph node dissection (ALND; n = 326), SLN-negative without ALND (n = 2340), SLN-positive with ALND (n = 1132), and SLN-positive without ALND (n = 210). Clinical and pathologic characteristics and follow-up data for each of the 4 cohorts were evaluated with emphasis on patterns of axillary LR. With a median follow-up of 31 months (range, 1-75), axillary LR occurred in 10/4008 (0.25%) patients overall. In 3 cases (0.07%) the axillary LR was the first site of treatment failure, in 4 (0.1%) it was coincident with breast LR, and in 3 (0.07%) it was coincident with distant metastases. Axillary LR was more frequent among the unconventionally treated SLN-positive/no ALND patients than in the other 3 conventionally treated cohorts (1.4% versus 0.18%, P = 0.013). Axillary LR after SLN biopsy, with or without ALND, is a rare event, and this low relapse rate supports wider use of SLN biopsy for breast cancer staging. There is a low-risk subset of SLN-positive patients in whom completion ALND may not be required.


Care needs of people with dementia in the peri-operative environment: A systematic review.
The care of people with dementia within the hospital setting is challenging for healthcare professionals. Hospital design and services are not optimized for people with dementia, owing to the lack of preparation of healthcare professionals and the busy environment of the acute hospital. The peri-operative environment may present particular difficulties but little is known about the experience and care of people with dementia in this setting. The aim of this review was to examine the care of surgical patients who have dementia and their family members in peri-operative environments and describe strategies adopted by healthcare professionals. A systematic search of the following databases was completed: BNI, CINAHL, PubMED and PsychINFO in accordance with PRISMA guidelines. Data were extracted and analysed within a thematic analysis framework as described by Braun and Clarke. Ten papers based on eight studies were included, five (n = 355,010 participants) containing quantitative data and five reporting qualitative data (n = 395 participants). People with dementia who go undergo surgery experienced higher adverse post-operative outcomes such as respiratory problems or urinary tract infections. The key elements in surgical care for people with dementia included: health assessment throughout the surgical trajectory (pre-, intra- and post-operative) and the resources used by healthcare professionals in the peri-operative care. Healthcare professionals reported difficulties in the completion of health assessments due to the cognitive status of people with dementia and a lack of skills in dementia management. The use of restraints was still a common practice and a source of conflict. Dementia-specific training and guidelines focused on the care of surgical patients who have dementia in peri-operative environments are required to improve care and post-operative outcomes. More research is required to develop effective interventions to improve care and decrease the risk of complications for people with dementia in the peri-operative care environment.


2013 Update in addiction medicine for the generalist.
Increasingly, patients with unhealthy alcohol and other drug use are being seen in primary care and other non-specialty addiction settings. Primary care providers are well positioned to screen, assess, and treat patients with alcohol and other drug use because this use, and substance use disorders, may contribute to a host of medical and mental health harms. We sought to identify and examine important recent advances in addiction medicine in the medical literature that have implications for the care of patients in primary care or other generalist settings. To accomplish this aim, we selected articles in the field of addiction medicine, critically appraised and summarized the manuscripts, and highlighted their implications for generalist practice. During an initial review, we identified articles through an electronic Medline search (limited to human studies and in English) using search terms for alcohol and other drugs of abuse published from January 2010 to January 2012. After this initial review, we searched for other literature in web-based or journal resources for potential articles of interest. From the list of articles identified in these initial reviews, each of the six authors independently selected articles for more intensive review and identified the ones they found to have a potential impact on generalist practice. The identified articles were then ranked by the number of authors who selected each article. Through a consensus process over 4 meetings, the authors reached agreement on the articles with implications for practice for generalist clinicians that warranted inclusion for discussion. The authors then grouped the articles into five categories: 1) screening and brief interventions in outpatient settings, 2) identification and management of substance use among inpatients, 3) medical complications of substance use, 4) use of pharmacotherapy for addiction treatment in primary care and its complications, and 5) integration of addiction treatment and medical care. The authors discuss each selected articles' merits, limitations, conclusions, and implication to advancing addiction screening, assessment, and treatment of addiction in generalist physician practice environments.


Histologically derived fiber response functions for diffusion MRI vary across white matter fibers-An ex vivo validation study in the squirrel monkey brain.
Understanding the relationship between the diffusion-weighted MRI signal and the arrangement of white matter fibers is fundamental for accurate voxel-wise reconstruction of the fiber orientation distribution (FOD) and subsequent fiber tractography. Spherical deconvolution reconstruction techniques model the diffusion signal as the convolution of the FOD with a response function that represents the signal profile of a single fiber orientation. Thus, given the signal and a fiber response function, the FOD can be estimated in every imaging voxel by deconvolution. However, the selection of the appropriate response function remains relatively under-studied, and requires further validation. In this work, using 3D histologically defined FODs and the corresponding diffusion signal from three ex vivo squirrel monkey brains, we derive the ground truth response functions. We find that the histologically derived response functions differ from those conventionally used. Next, we find that response functions statistically vary across brain regions, which suggests that the practice of using the same kernel throughout the brain is not optimal. We show that different kernels lead to different FOD reconstructions, which in turn can lead to different tractography results depending on algorithmic parameters, with large variations in the accuracy of resulting reconstructions. Together, these results suggest there is room for improvement in estimating and understanding the relationship between the diffusion signal and the underlying FOD.


Coanalysis of GWAS with eQTLs reveals disease-tissue associations.
Expression quantitative trait loci (eQTL), or genetic variants associated with changes in gene expression, have the potential to assist in interpreting results of genome-wide association studies (GWAS). eQTLs also have varying degrees of tissue specificity. By correlating the statistical significance of eQTLs mapped in various tissue types to their odds ratios reported in a large GWAS by the Wellcome Trust Case Control Consortium (WTCCC), we discovered that there is a significant association between diseases studied genetically and their relevant tissues. This suggests that eQTL data sets can be used to determine tissues that play a role in the pathogenesis of a disease, thereby highlighting these tissue types for further post-GWAS functional studies.


Variations in mental health problems, substance use, and delinquency between African American and Caucasian juvenile offenders: implications for reentry services.
The incarceration of young people is a growing national problem. Key correlates of incarceration among American youth include mental health problems, substance use, and delinquency. The present study uses a statewide sample of incarcerated youth to examine racial differences in African American and Caucasian juvenile offenders' outcomes related to mental health, substance use, and delinquency. The data indicate that relative to Caucasian offenders, African American offenders report lower levels of mental health problems and substance use but higher levels of delinquent behavior such as violence, weapon carrying, and gang fighting. The data further reveal that African American offenders are more likely than Caucasian offenders to be victims of violence and to experience traumatic events such as witnessing injury and death. Recognition of these patterns may help to improve postrelease services by tailoring or adapting preexisting programs to patterns of risk factors and their relative magnitudes of effect.


The influence of income on the experience of informal caregiving: policy implications.
Examining the need for an eldercare policy is relevant and timely because the population is aging, a focus of care has shifted from institutional to community based, and informal caregivers, primarily women, are increasingly pressured to be responsible for eldercare. The purpose of the study is to examine the differences in the experiences of low-income and those who are not low-income informal caregivers. Three hundred questionnaires were mailed to past and present home care clients and 58 questionnaires were returned (19% response rate). This research revealed that low-income caregivers have increased needs for support and education from those who can afford to pay for their support services. Low-income caregivers experience significantly greater caregiver distress than do caregivers who are not low income. The unique needs of low-income caregivers must be considered in the formation of Canadian eldercare policy as increased health care privatization promotes the growing inequality in health care provision.


Pathogen reduction in human plasma using an ultrashort pulsed laser.
Pathogen reduction is a viable approach to ensure the continued safety of the blood supply against emerging pathogens. However, the currently licensed pathogen reduction techniques are ineffective against non-enveloped viruses such as hepatitis A virus, and they introduce chemicals with concerns of side effects which prevent their widespread use. In this report, we demonstrate the inactivation of both enveloped and non-enveloped viruses in human plasma using a novel chemical-free method, a visible ultrashort pulsed laser. We found that laser treatment resulted in 2-log, 1-log, and 3-log reductions in human immunodeficiency virus, hepatitis A virus, and murine cytomegalovirus in human plasma, respectively. Laser-treated plasma showed ≥70% retention for most coagulation factors tested. Furthermore, laser treatment did not alter the structure of a model coagulation factor, fibrinogen. Ultrashort pulsed lasers are a promising new method for chemical-free, broad-spectrum pathogen reduction in human plasma.