Parathyroid hormone and transforming growth factor-beta1 coregulate chondrocyte differentiation in vitro.
Parathyroid hormone (1-34) (PTH(1-34) and transforming growth factor-beta1 (TGF-beta1) regulate chondrocyte proliferation, differentiation, and matrix synthesis. Both proteins mediate their effects in a dose- and time-dependent manner, and the effects are cell maturation specific. Moreover, similar signaling pathways are used, suggesting that there may be cross talk leading to coregulated cell response. To test this hypothesis, confluent cultures of rat costochondral resting zone and growth zone chondrocytes were treated with 0.22, 0.44, or 0.88 ng/mL of rhTGF-beta1 for 24 h, followed by treatment with 10(-11) to 10(-8) M PTH(1-34) for 10 min or 24 h. [3H]-Thymidine incorporation, specific activity of alkaline phosphatase (AP), and [35S]-sulfate incorporation were measured. PTH(1-34) had no effect on [3H]-thymidine incorporation by growth zone cells pretreated with 0.22 or 0.44 ng/mL of TGF-beta1, but in cultures treated with 0.88 ng/mL, PTH(1-34) caused a dose-dependent decrease that was maximal at the lowest concentration tested. By contrast, PTH(1-34) stimulated [3H]-thymidine incorporation by resting zone cells, and this effect was additive with the stimulation caused by 0.22 ng/mL of TGF-beta1. PTH(1-34) caused a synergistic increase in AP in growth zone cells treated with 0.44 or 0.88 ng/mL of TGF-beta1, but not in cells treated with 0.22 ng/mL of TGF-beta1. It had no effect on AP in resting zone cells pretreated with any concentration of TGF-beta1. PTH(1-34) increased [35S]-sulfate incorporation in growth zone and resting zone cell cultures treated with 0.22 ng/mL of TGF-beta1 to levels seen in cultures treated with 0.88 ng/mL of TGF-beta1 alone. These results support the hypothesis that PTH(1-34) and TGF-beta1 coregulate growth plate chondrocytes and that the effects are cell maturation dependent.


Regional muscle and whole-body composition factors related to mobility in older individuals: a review.
To describe previously reported locomotor muscle and whole-body composition factors related to mobility in older individuals. A narrative review of the literature, including a combination of search terms related to muscle and whole-body composition factors and to mobility in older individuals, was carried out. Statistical measures of association and risk were consolidated to summarize the common effects between studies. Fifty-three studies were reviewed. Muscle and whole-body factors accounted for a substantial amount of the variability in walking speed, with coefficients of determination ranging from 0.30 to 0.47. Muscle power consistently accounted for a greater percentage of the variance in mobility than did strength. Risks associated with high fat mass presented a minimum odds ratio (OR) of 0.70 and a maximum OR of 4.07, while the minimum and maximum ORs associated with low lean mass were 0.87 and 2.30 respectively. Whole-body and regional fat deposits accounted for significant amounts of the variance in mobility. Muscle power accounts for a greater amount of the variance in the level of mobility in older individuals than does muscle strength. Whole-body fat accounts for a greater amount of the variance in level of mobility than does whole-body lean tissue. Fat stored within muscle also appears to increase the risk of a mobility limitation in older individuals.


The Clinical Value of PET with Amino Acid Tracers for Gliomas WHO Grade II.
The clinical management of adults with low-grade gliomas (LGGs) remains a challenge. There is no curative treatment, and management of individual patients is a matter of deciding optimal timing as well as right treatment modality. In addition to conventional imaging techniques, positron emission tomography (PET) with amino acid tracers can facilitate diagnostic and therapeutic procedures. In this paper, the clinical applications of PET with amino acid tracers (11)C-methyl-L-methionine (MET) and (18)F-fluoro-ethyl-L-tyrosine (FET) for patients with LGG are summarized. We also discuss the value of PET for the long-term followup of this patient group. Monitoring metabolic activity by PET in individual patients during course of disease will provide insight in the biological behavior and evolution of these tumors. As such, spatial changes in tumor activity over time, including shifts of hot-spot regions within the tumor, may reflect intratumoral heterogeneity and correlate to clinical parameters.


Bradykinin-induced bronchospasm in the rat in vivo: a role for nitric oxide modulation.
Bradykinin has an important role in asthma pathogenesis, but its site of action is unclear. It was previously reported by the authors that bradykinin causes a dose-dependent reduction in dynamic compliance but little change in total lung resistance. This suggested that bradykinin may have a preferential effect in the distant lung. The purpose of the current investigation was to better characterize the effects of bradykinin on pulmonary resistance in rodents and explore the role of nitric oxide release in modulating the effect of bradykinin. Airway constriction was induced in the rats by aerosol administration of bradykinin with or without treatments with the inhaled bradykinin-2 receptor antagonist, Hoe 140 or the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methylester or N(G)-monomethyl-L-arginine. Total lung resistance was partitioned into tissue and airway resistance by using the alveolar capsule method. Bradykinin induced a significant increase in both resistances. Hoe 140 abolished the response to bradykinin. The nitric oxide synthase inhibitors enhanced the bronchoconstricting response. In conclusion, the bradykinin response in the rats was not only localized to conducting airways but also involved a relatively selective tissue reaction. Bradykinin-induced bronchospasm in the rat is solely due to activation of bradykinin-2 receptor. Further, it was shown that nitric oxide significantly modulates the bronchospasm caused by bradykinin, suggesting that nitric oxide is an important modulator of airways responsiveness to bradykinin.


Prevalence of oral candidiasis in HIV/AIDS children in highly active antiretroviral therapy era. A literature analysis.
SummaryHighly active antiretroviral therapy has decreased the morbidity and mortality related to HIV infection, including oral opportunistic infections. This paper offers an analysis of the scientific literature on the epidemiological aspects of oral candidiasis in HIV-positive children in the combination antiretroviral therapy era. An electronic databases search was made covering the highly active antiretroviral therapy era (1998 onwards). The terms used were oral lesions, oral candidiasis and their combination with highly active antiretroviral therapy and HIV/AIDS children. The following data were collected from each paper: year and country in which the investigation was conducted, antiretroviral treatment, oral candidiasis prevalence and diagnostic parameters (clinical or microbiological). Prevalence of oral candidiasis varied from 2.9% in American HIV-positive children undergoing highly active antiretroviral therapy to 88% in Chilean HIV-positive children without antiretroviral therapy. With respect to geographical location and antiretroviral treatment, higher oral candidiasis prevalence in HIV-positive children on combination antiretroviral therapy/antiretroviral therapy was reported in African children (79.1%) followed by 45.9% reported in Hindu children. In HIV-positive Chilean children on no antiretroviral therapy, high oral candidiasis prevalence was reported (88%) followed by Nigerian children (80%). Oral candidiasis is still frequent in HIV-positive children in the highly active antiretroviral therapy era irrespective of geographical location, race and use of antiretroviral therapy.


The RAV transcription factor TEMPRANILLO1 involved in ethylene-mediated delay of chrysanthemum flowering.
TEMPRANILLO1 (TEM1) is a transcription factor belonging to related to ABI3 and VP1 family, which is also known as ethylene response DNA-binding factor 1 and functions as a repressor of flowering in Arabidopsis. Here, a putative homolog of AtTEM1 was isolated and characterized from chrysanthemum, designated as CmTEM1. Exogenous application of ethephon leads to an upregulation in the expression of CmTEM1. Knockdown of CmTEM1 promotes floral initiation, while overexpression of CmTEM1 retards floral transition. Further phenotypic observations suggested that CmTEM1 involves in the ethylene-mediated inhibition of flowering. Transcriptomic analysis established that expression of the flowering integrator CmAFL1, a member of the APETALA1/FRUITFULL subfamily, was downregulated significantly in CmTEM1-overexpressing transgenic plants compared with wild-type plants but was verified to be upregulated in amiR-CmTEM1 lines by quantitative RT-PCR. In addition, CmTEM1 is capable of binding to the promoter of the CmAFL1 gene to inhibit its transcription. Moreover, the genetic evidence supported the notion that CmTEM1 partially inhibits floral transition by targeting CmAFL1. In conclusion, these findings demonstrate that CmTEM1 acts as a regulator of ethylene-mediated delayed flowering in chrysanthemum, partly through its interaction with CmAFL1.


Impact of a nurses' protocol-directed weaning procedure on outcomes in patients undergoing mechanical ventilation for longer than 48 hours: a prospective cohort study with a matched historical control group.
The aim of the study was to determine whether the use of a nurses' protocol-directed weaning procedure, based on the French intensive care society (SRLF) consensus recommendations, was associated with reductions in the duration of mechanical ventilation and intensive care unit (ICU) length of stay in patients requiring more than 48 hours of mechanical ventilation. This prospective study was conducted in a university hospital ICU from January 2002 through to February 2003. A total of 104 patients who had been ventilated for more than 48 hours and were weaned from mechanical ventilation using a nurses' protocol-directed procedure (cases) were compared with a 1:1 matched historical control group who underwent conventional physician-directed weaning (between 1999 and 2001). Duration of ventilation and length of ICU stay, rate of unsuccessful extubation and rate of ventilator-associated pneumonia were compared between cases and controls. The duration of mechanical ventilation (16.6 +/- 13 days versus 22.5 +/- 21 days; P = 0.02) and ICU length of stay (21.6 +/- 14.3 days versus 27.6 +/- 21.7 days; P = 0.02) were lower among patients who underwent the nurses' protocol-directed weaning than among control individuals. Ventilator-associated pneumonia, ventilator discontinuation failure rates and ICU mortality were similar between the two groups. Application of the nurses' protocol-directed weaning procedure described here is safe and promotes significant outcome benefits in patients who require more than 48 hours of mechanical ventilation.


Dermatological and cosmeceutical benefits of Glycine max (soybean) and its active components.
Glycine max, known as the soybean or soya bean, is a species of legume native to East Asia. Soya beans contain many functional components including phenolic acids, flavonoids, isoflavonoids (quercetin, genistein, and daidzein), small proteins (Bowman-Birk inhibitor, soybean trypsin inhibitor) tannins, and proanthocyanidins. Soybean seeds extract and fresh soymilk fractions have been reported to possess the cosmeceutical and dermatological benefits such as anti-inflammatory, collagen stimulating effect, potent anti-oxidant scavenging peroxyl radicals, skin lightening effect and protection against UV radiation. Thus, present review attempts to give a short overview on dermatological and cosmeceutical studies of soybean and its bioactive compounds.


Erosive osteoarthritis: a current review of a clinical challenge.
Erosive osteoarthritis, a less common subtype of osteoarthritis, is often described as a more severe form. This combination of cartilage degeneration with pathologic features suggestive of inflammatory synovial changes generally manifests in women around the time of menopause and hormonal levels as well as genetics are thought to play a role in its onset. The hands are most often involved with the sudden onset of palpable pain and swelling of the distal interphalangeal joints and proximal interphalangeal joints most frequently, but other joints have been reported. Phalangeal deformities appearing as wavy or subluxed as well as Heberden and Bouchard nodes can be seen clinically. Laboratory tests for systemic inflammation are usually normal but small studies looking at markers of bone resorption have shown increased levels in these patients. Radiographs reveal central joint erosions implying an inflammatory process which has been described in synovial specimens. Treatment options that have been tried include those utilized for general osteoarthritis as well as those for rheumatoid arthritis. Since prolonged disability in hand function can occur, further studies looking at its pathogenesis and targeted treatment options are needed.


An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.
To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers.


A novel thrombopoietin signaling defect in polycythemia vera platelets.
The pathogenesis of polycythemia vera (PV), a disease involving a multipotent hematopoietic progenitor cell, is unknown. Thrombopoietin (TPO) is a newly characterized hematopoietic growth factor which regulates the production of multipotent hematopoietic progenitor cells as well as platelets. To evaluate the possibility that an abnormality in TPO-mediated signal transduction might be involved in the pathogenesis of PV, we examined TPO-induced protein tyrosine phosphorylation using platelets as a surrogate model system. Platelets were isolated from the blood of patients with PV as well as from patients with other chronic myeloproliferative disorders and control subjects. Impaired TPO-mediated platelet protein tyrosine phosphorylation was a consistent observation in patients with PV as well as those with idiopathic myelofibrosis (IMF), in contrast to patients with essential thrombocytosis, chronic myelogenous leukemia, secondary erythrocytosis, iron deficiency anemia, hemochromatosis, or normal volunteers. Thrombin-mediated platelet protein tyrosine phosphorylation was intact in PV platelets as was expression of the appropriate tyrosine kinases and their cognate substrates. However, expression of the platelet TPO receptor, Mpl, as determined by immunoblotting, chemical crosslinking or flow cytometry was markedly reduced or absent in 34 of 34 PV patients and also in 13 of 14 IMF patients. Impaired TPO-induced protein tyrosine phosphorylation in PV and IMF platelets was uniformly associated with markedly reduced or absent expression of Mpl. We conclude that reduced expression of Mpl is a phenotypic characteristic of platelets from patients with PV and IMF. The abnormality appears to distinguish PV from other forms of erythrocytosis and may be involved in the platelet function defect associated with PV.


Risks of psychiatric disorders and suicide attempts in children and adolescents with type 1 diabetes: a population-based cohort study.
To assess the risk of psychiatric disorders and suicide attempts in children with type 1 diabetes and their healthy siblings. We performed a population-based case-cohort study of individuals born in Sweden between 1973 and 2009. Children with type 1 diabetes (n = 17,122) and their healthy siblings (n = 18,847) were identified and followed until their 18th birthday. Their risk of psychiatric disorders was compared with that of matched control subjects. The risk of psychiatric morbidity in children with type 1 diabetes compared with the general population was tripled within 6 months after the onset of diabetes (hazard ratio [HR] 3.0 [95% CI 2.7-3.4]) and doubled within the total observation period (HR 2.1 [95% CI 2.0-2.2]). An increased risk was noted in suicide attempts (HR 1.7 [95% CI 1.4-2.0]) and in most categories of psychiatric disorders. The risk of psychiatric disorders in probands declined from HR 2.7 (95% CI 2.2-3.3) for those in the cohort born 1973-1986 to 1.9 (95% CI 1.8-2.0) in those born 1997-2009. The risk for any psychiatric disorders among siblings of patients with type 1 diabetes was estimated to be HR 1.1 (95% CI 1.0-1.1), and there was no increased risk in any of the specific category of disorders. Children with type 1 diabetes are at high risk of psychiatric disorders, which seems to be a consequence of the disease rather than due to a common familial etiology. The results support recommendations on comprehensive mental health surveillance in children with type 1 diabetes, especially in recently diagnosed children.


Current-induced forces in mesoscopic systems: A scattering-matrix approach.
Nanoelectromechanical systems are characterized by an intimate connection between electronic and mechanical degrees of freedom. Due to the nanoscopic scale, current flowing through the system noticeably impacts upons the vibrational dynamics of the device, complementing the effect of the vibrational modes on the electronic dynamics. We employ the scattering-matrix approach to quantum transport in order to develop a unified theory of nanoelectromechanical systems out of equilibrium. For a slow mechanical mode the current can be obtained from the Landauer-Büttiker formula in the strictly adiabatic limit. The leading correction to the adiabatic limit reduces to Brouwer's formula for the current of a quantum pump in the absence of a bias voltage. The principal results of the present paper are the scattering-matrix expressions for the current-induced forces acting on the mechanical degrees of freedom. These forces control the Langevin dynamics of the mechanical modes. Specifically, we derive expressions for the (typically nonconservative) mean force, for the (possibly negative) damping force, an effective "Lorentz" force that exists even for time-reversal-invariant systems, and the fluctuating Langevin force originating from Nyquist and shot noise of the current flow. We apply our general formalism to several simple models that illustrate the peculiar nature of the current-induced forces. Specifically, we find that in out-of-equilibrium situations the current-induced forces can destabilize the mechanical vibrations and cause limit-cycle dynamics.


Profile of the oral healthcare team in countries with emerging economies.
Health is a critical dimension of human well-being and flourishing, and oral health is an integral component of health: one is not healthy without oral health. Significant barriers exist to ensuring the world's people receive basic healthcare, including oral healthcare. Amongst these are poverty, ignorance, inadequate financial resources and lack of adequate numbers of educated and trained (oral) healthcare workers. Emerging economies are encouraged to develop a national strategic plan for oral health. International organizations have developed goals for oral health that can be referenced and adapted by emerging economies as they seek to formulate specific objectives for their countries. Demographic data that assess the nature and extent of oral diseases in a country are essential to sound planning and the development of an oral healthcare system that is relevant, effective and economically viable. Prevention should be emphasized and priority consideration be given to oral healthcare for children. The types and numbers of members of the oral healthcare team (workforce) will vary from country to country depending on the system developed. Potential members of the workforce include: generalist dentists, specialist dentists, dental therapists, dental hygienists, denturists, expanded function dental assistants (dental nurses) and community oral health workers/aides. Competences for dentists, and other members of the team, should be developed to ensure quality care and developed economies should cooperate with emerging economies. The development, by more advanced economies, of digital, virtual curricula, which could be used by emerging economies for educating and training members of the oral healthcare team, should be an important initiative. The International Federation of Dental Educators and Associations (IFDEA) should lead in such an effort.


Big Data: Why Should Canadian Nurse Leaders Care?
Big data using data science methods (data analytics) has the potential to effectively inform strategies to address complex healthcare challenges. However, this potential can only be realized if healthcare professionals have the requisite depth and breadth of knowledge (i.e., informatics competencies). With the emergence of electronic health records (EHRs - commonly known as clinical information systems [CISs]) in healthcare organizations, data analytics that can "interrogate" CIS big data are now possible. In its digitized form, CIS healthcare data meant to support real-time, evidence-based practice decisions and guide new health policy directions remain more of a conceptual promise than a practice reality. Further, the "data rich information poor" phenomenon existing with today's CISs is often the reality for nurses who document more patient information compared to other healthcare professionals and get negligible results in return. However, data science methods when applied to CIS big data are "uncovering" new evidence currently unavailable through traditional data analytic approaches. Big data science is predicted to provide immense opportunities for nurse leaders by offering robust, electronic tools, which support informed decision-making at corporate tables and "arm" all point-of-care/service clinicians with real-time evidence. In this article, we provide a perspective on how the field of data science can enable informatics-savvy nurse executives to lead clinical transformation in the development of the next generation of evidence-based practice, "practice-based evidence."


Effects of light and melatonin treatment on body temperature and melatonin secretion daily rhythms in a diurnal rodent, the fat sand rat.
Many mammals display predictable daily rhythmicity in both neuroendocrine function and behavior. The basic rest-activity cycles are usually consistent for a given species and vary from night-active (nocturnal), those mostly active at dawn and dusk (i.e., crepuscular), and to day-active (diurnal) species. A number of daily rhythms are oppositely phased with respect to the light/dark (LD) cycle in diurnal compared with nocturnal mammals, whereas others are equally phased with respect to the LD cycle, regardless of diurnality/nocturnality. Pineal produced melatonin (MLT) perfectly matches this phase-locked feature in that its production and secretion always occurs during the night in both diurnal and nocturnal mammals. As most rodents studied to date in the field of chronobiology are nocturnal, the aim in this study was to evaluate the effect of light manipulations and different photoperiods on a diurnal rodent, the fat sand rat, Psammomys obesus. The authors studied its daily rhythms of body temperature (T(b)) and 6-sulphatoxymelatonin (6-SMT) under various photoperiodic regimes and light manipulations (acute and chronic exposures) while maintaining a constant ambient temperature of 30 degrees C +/- 1 degrees C. The following protocols were used: (A) Control (CON) conditions 12L:12D; (A1) exposure to one light interference (LI) of CON-acclimated individuals for 30 min, 5 h after lights-off; (A2) short photoperiod (SP) acclimation (8L:16D) for 3 wks; (A3) 3 wks of SP acclimation with chronic LI of 15 min, three times a night at 4-h intervals; (A4) chronic exposure to constant dim blue light (470 nm, 30 lux) for 24 h for 3 wks (LL). (B) The response to exogenous MLT administration, provided in drinking water, was measured under the following protocols: (B1) After chronic exposure to SP with LI, MLT was provided once, starting 1 h before the end of photophase; (B2) after a continuous exposure to dim blue light, MLT was provided at 15:00 h for 2 h for 2 wks; (B3) to CON animals, MLT was given intraperitoneally (i.p.) at 14:00 h. The results demonstrate that under CON acclimation, Psammomys obesus has robust T(b) and 6-SMT daily rhythms in which the acrophase (peak time) of T(b) is during the photophase, whereas that of 6-SMT is during scotophase. LI resulted in an elevation of T(b) and a reduction of 6-SMT levels. A significant difference in the response was noted between acute and chronic exposure to LI, particularly in 6-SMT levels, which were lower than CON after LI and higher after chronic LI, implying an acclimation process. Constant exposure to blue light abolished T(b) and 6-SMT rhythms in all the animals. MLT administration resumed the T(b) daily rhythm in these animals, and had a recovery effect on the chronic LI-exposed animals, resulting in a T(b) decrease. Altogether, the authors show in this study the different modifications of T(b) rhythms and MLT levels in response to environmental light manipulations. These series of experiments may serve as a basis for establishing P. obesus as an animal model for further studies in chronobiology.


[Surgical removal of diaphragmatic metastasis of advanced ovarian cancer. Review of the literature].
Many studies have established the close relationship between the survival and the residual tumoral volume after a first maximal cyto-reducing surgery. In that light, the surgical exeresis of the metastatic lesions should facilitate the response to chemotherapy. In this respect, the diaphragm metastases of ovarian cancers prove to be worthy of the highest interest due to the difficulty of their surgical approach. Several techniques for the exeresis of these secondary peritoneal localizations have been reported, using various processes (electrocoagulation, laser vaporization, classic surgical exeresis) and more recently, the ultrasound dissector. After a review of the literature on 43 cases, the authors draw the attention on the approach and surgical exeresis methods for these metastases. If these techniques prove to be quite feasible, with an acceptable morbidity rate, only a great hindsight, together with more observations, will enable the assessment of the benefit in terms of survival.


Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD).
Obsessive compulsive disorder is a common and disabling disorder. A significant proportion of patients manifest a chronic course. Individual randomised controlled trials (RCTs) have shown that selective serotonin re-uptake inhibitors (SSRIs) are effective in this condition. Previous systematic reviews or meta-analyses summarising the evidence are methodologically problematic or limited in the scope of their analysis. To examine the efficacy and adverse effects of serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD) in adults. CCDANCTR-Studies and CCDANCTR-References were searched on 12/11/2007. Reference lists were checked. Experts in the field were contacted. All RCTs and quasi-RCTs examining the efficacy of SSRIs compared with placebo for OCD in adults were eligible for inclusion. Selection of studies and data extraction were carried out by two review authors independently, and quality assessment of studies was undertaken. Data analysis was conducted using Review Manager software. Summary measures were produced using the weighted mean difference (WMD) for continuous data and relative risk (RR) for dichotomous data, with 95% confidence intervals (CI). SSRIs were examined as an overall group of drugs, and as individual drugs. Seventeen studies were included in the review, involving 3097 participants. Based on all 17 studies, SSRIs as a group were more effective than placebo in reducing the symptoms of OCD between 6 and 13 weeks post-treatment, measured using the Yale-Brown Obsessive Compulsive Scale (YBOCS) (WMD -3.21, 95% CI -3.84 to -2.57). The WMD for individual SSRI drugs were similar and not statistically different. Based on 13 studies (2697 participants), SSRIs were more effective than placebo in achieving clinical response at post-treatment (RR 1.84, 95% CI 1.56 to 2.17). The pooled RR was shown to be similar between individual SSRI drugs. Although reported adverse effects data were more limited, with few exceptions, the overall and individual adverse effects for the different SSRIs were always worse than for placebo and, in the majority of cases, the difference was statistically significant. Nausea, headache and insomnia were always reported amongst the most common adverse effects in trials of each of the drugs. SSRIs are more effective than placebo for OCD, at least in the short-term, although there are differences between the adverse effects of individual SSRI drugs. The longer term efficacy and tolerability of different SSRI drugs for OCD has yet to be established.


TROPHY: A Topologically Robust Physics-Informed Tracking Framework for Tropical Cyclones.
Tropical cyclones (TCs) are among the most destructive weather systems. Realistically and efficiently detecting and tracking TCs are critical for assessing their impacts and risks. In particular, the eye is a signature feature of a mature TC. Therefore, knowing the eyes' locations and movements is crucial for both operational weather forecasts and climate risk assessments. Recently, a multilevel robustness framework has been introduced to study the critical points of time-varying vector fields. The framework quantifies the robustness (i.e., structural stability) of critical points across varying neighborhoods. By relating the multilevel robustness with critical point tracking, the framework has demonstrated its potential in cyclone tracking. An advantage is that it identifies cyclonic features using only 2D wind vector fields, which is encouraging as most tracking algorithms require multiple dynamic and thermodynamic variables at different altitudes. A disadvantage is that the framework does not scale well computationally for datasets containing a large number of cyclones. This paper introduces a topologically robust physics-informed tracking framework (TROPHY) for TC tracking. The main idea is to integrate physical knowledge of TC to drastically improve the computational efficiency of multilevel robustness framework for large-scale climate datasets. First, during preprocessing, we propose a physics-informed feature selection strategy to filter 90% of critical points that are short-lived and have low stability, thus preserving good candidates for TC tracking. Second, during in-processing, we impose constraints during the multilevel robustness computation to focus only on physics-informed neighborhoods of TCs. We apply TROPHY to 30 years of 2D wind fields from reanalysis data in ERA5 and generate a number of TC tracks. In comparison with the observed tracks, we demonstrate that TROPHY can capture TC characteristics (e.g., frequency, intensity, duration, latitudes with maximum intensity, and genesis) that are comparable to and sometimes even better than a well-validated TC tracking algorithm that requires multiple dynamic and thermodynamic scalar fields.


Replication of herpes simplex virus type I DNA in permeabilized infected cells.
Herpes simplex type 1 (HSV)-infected Vero cells can be permeabilized by a combination of hypotonic shock and a mild emulsifier, gum arabic. Permeabilized cells will incorporate triphosphate precursors into viral and host DNA in vitro in ratios similar to those seen in vivo. This reaction is ATP-dependent and is shown to be replicative by the single strand density shift of DNA synthesized in the presence of BrdUTP. The product is heterogeneous in size, and contains a significant proportion of rapidly sedimenting forms and of unit size (55S) viral DNA. The presence of polyamines and EGTA (a specific chelator of Ca2+ ions) in the labeling medium is shown to be necessary to maintain the integrity of the replicating DNA. The average size of newly synthesized single strands, however, is smaller than seen in vivo. The reaction is sensitive to phosphonoacetic acid added at the time of labeling, at concentrations which inhibit in vivo synthesis only after one hour of pre-exposure. These properties make permeabilized cell monolayers an attractive system for the study of HSV DNA replication.


Brain adenosine 5'-triphosphate-creatine phosphotransferase.
1. The purification of creatine kinase (ATP-creatine phosphotransferase, EC 184.108.40.206) from ox brain by a method that is quicker, simpler and gives much higher yields than other published procedures is described. 2. Stoicheiometric inhibition studies with iodoacetate showed that the enzyme, like that from muscle, has two reactive thiol groups that are essential for enzyme activity. 3. The amino acid sequence around the essential thiol groups was determined and found to be virtually identical with that in creatine kinases from rabbit and ox muscle, and very similar to that found in arginine kinase; the evolutionary significance of this is discussed. 4. The identification of DNS-amino acids on thin layers of silica gel was found to have, in many cases, distinct advantages over that on polyamide layers.


[Institute of Oncology during the war and the siege of Leningrad].
There is described the activities of employees of the NN Petrov Institute of Oncology during the Great Patriotic War and the siege of Leningrad.


R-Ras Regulates Murine T Cell Migration and Intercellular Adhesion Molecule-1 Binding.
The trafficking of T-lymphocytes to peripheral draining lymph nodes is crucial for mounting an adaptive immune response. The role of chemokines in the activation of integrins via Ras-related small GTPases has been well established. R-Ras is a member of the Ras-subfamily of small guanosine-5'-triphosphate-binding proteins and its role in T cell trafficking has been investigated in R-Ras null mice (Rras-/-). An examination of the lymphoid organs of Rras-/- mice revealed a 40% reduction in the cellularity of the peripheral lymph nodes. Morphologically, the high endothelial venules of Rras-/- mice were more disorganized and less mature than those of wild-type mice. Furthermore, CD4+ and CD8+ T cells from Rras-/- mice had approximately 42% lower surface expression of L-selectin/CD62L. These aberrant peripheral lymph node phenotypes were associated with proliferative and trafficking defects in Rras-/- T cells. Furthermore, R-Ras could be activated by the chemokine, CCL21. Indeed, Rras-/- T cells had approximately 14.5% attenuation in binding to intercellular adhesion molecule 1 upon CCL21 stimulation. Finally, in a graft-versus host disease model, recipient mice that were transfused with Rras-/- T cells showed a significant reduction in disease severity when compared with mice transplanted with wild-type T cells. These findings implicate a role for R-Ras in T cell trafficking in the high endothelial venules during an effective immune response.


Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)-1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model.
Recent reports indicate that dendritic cell (DC)-derived T-cell immunoglobulin and mucin domain molecule (TIM)-4 plays an important role in the initiation of T(H)2 polarization. This study aims to elucidate the mechanisms of peanut allergy mediated by microbial products and DCs and the relationship between peanut allergy and TIM4. Mouse bone marrow-derived DCs (BMDCs) were generated and exposed to cholera toxin (CT) or/and peanut extract (PE) for 24 hours and then adoptively transferred to naive mice. After re-exposure to specific antigen PE, the mice were killed; intestinal allergic status was determined. Increased expression of TIM4 and costimulatory molecules was detected in BMDCs after concurrent exposure to CT and PE. Adoptively transferred CT/PE-conditioned BMDCs resulted in the increases in serum PE-specific IgE and skewed T(H)2 polarization in the intestine. Oral challenge with specific antigen PE induced mast cell activation in the intestine. Treating with Toll-like receptor 4 small interfering RNA abolished increased expression of TIM4 and costimulatory molecules by BMDCs. Pretreatment with anti-TIM1 or anti-TIM4 antibody abolished PE-specific T(H)2 polarization and allergy in the intestine. Concurrent exposure to microbial product CT and food antigen PE increases TIM4 expression in DCs and promotes DC maturation, which plays an important role in the initiation of PE-specific T(H)2 polarization and allergy in the intestine. Modulation of TIM4 production in DCs represents a novel therapeutic approach for the treatment of peanut allergy.


Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation.
Receptor-mediated activation of both adenylate cyclase and phosphatidylinositide hydrolysis systems occurs through guanine nucleotide regulatory proteins and ultimately leads to specific activation of either cyclic AMP-dependent protein kinase A or Ca2+/phospholipid-dependent protein kinase C. Given the remarkable diversity of agents that influence cellular metabolism through these pathways and the similarities of their components, interactions between the two signalling systems could occur. In fact, stimulation of cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA), a phorbol ester that activates protein kinase C, influences hormone-sensitive adenylate cyclase. In some cells TPA induces desensitization of receptor-mediated stimulation of adenylate cyclase, whereas in others, such as frog erythrocytes, phorbol ester treatment results in increased agonist-stimulated as well as basal, guanine nucleotide- and fluoride ion-stimulated adenylate cyclase activities. We show here that TPA produces phosphorylation of the catalytic unit of adenylate cyclase in frog erythrocytes. Moreover, purified protein kinase C can directly phosphorylate in vitro the catalytic unit of adenylate cyclase purified from bovine brain. These results suggest that phosphorylation of the catalytic unit of adenylate cyclase by protein kinase C may be involved in the phorbol ester-induced enhancement of adenylate cyclase activity. In addition to providing the first direct demonstration of a covalent modification of the catalytic unit of adenylate cyclase, these results provide a potential biochemical mechanism for a regulatory link between the two major transmembrane signalling systems.


Dietary P regulates phosphate transporter expression, phosphatase activity, and effluent P partitioning in trout culture.
Phosphate utilization by fish is an important issue because of its critical roles in fish growth and aquatic environmental pollution. High dietary phosphorus (P) levels typically decrease the efficiency of P utilization, thereby increasing the amount of P excreted as metabolic waste in effluents emanating from rainbow trout aquaculture. In mammals, vitamin D3 is a known regulator of P utilization but in fish, its regulatory role is unclear. Moreover, the effects of dietary P and vitamin D3 on expression of enzymatic and transport systems potentially involved in phosphate utilization are little known. We therefore monitored production of effluent P, levels of plasma vitamin D3 metabolites, as well as expression of phosphatases and the sodium phosphate cotransporter (NaPi2) in trout fed semipu diets that varied in dietary P and vitamin D3 levels. Mean soluble P concentrations varied markedly with dietary P but not with vitamin D3, and constituted 40-70% of total effluent P production by trout. Particulate P concentrations accounted for 25-50% of effluent P production, but did not vary with dietary P or vitamin D3. P in settleable wastes accounted for <10% of effluent P. The stronger effect of dietary P on effluent P levels is paralleled by its striking effects on phosphatases and NaPi2. The mRNA abundance of the intestinal and renal sodium phosphate transporters increased in fish fed low dietary P; vitamin D3 had no effect. Low-P diets reduced plasma phosphate concentrations. Intracellular phytase activity increased but brushborder alkaline phosphatase activity decreased in the intestine, pyloric caeca, and gills of trout fed diets containing low dietary P. Vitamin D3 had no effect on enzyme activities. Moreover, plasma concentrations of 25-hydroxyvitamin D3 and of 1,25-dihydroxyvitamin D3 were unaffected by dietary P and vitamin D3 levels. The major regulator of P metabolism, and ultimately of levels of P in the effluent from trout culture, is dietary P.


Molecular basis for increased synthesis of albumin in rat liver after thioacetamide administration.
Administration of thioacetamide to rats for 4 days has been shown previously to increase the activity of liver messenger RNA (mRNA) and to disproportionately increase the activity of albumin mRNA in the wheat germ translation system. We have explored the possibility that administration of thioacetamide quantitatively alters the transcription of rat liver unique DNA. Nucleic acid hybridization between the radioactive rat liver unique DNA and RNA from untreated as well as 4-day thioacetamide-treated rat liver indicates that the normal extent of transcription is not altered by the drug treatment. We also investigated the possibility that thioacetamide treatment increases the level of mRNA in general or of albumin mRNA in particular. Albumin mRNA, which is th most abundantly represented population in rat liver cytoplasmic mRNA, was further enriched by sucrose gradient fractionation of the liver mRNA. Synthesis of complementary DNA (cDNA) and then use of the strategy of limited hybridization yielded the cDNA corresponding to albumin mRNA. Hybridization of the fractionated cDNA with mRNA from untreated livers as well as from livers with increasing days of treatment shows no change in the level of albumin mRNA. The results indicate that drug treatment induces the augmented synthesis of albumin by disproportionately increasing the translational activity of albumin mRNA. Quantitation of gene dosage by comparison of hybridization kinetics of fractionated cDNA and unique [3H]DNA with total rat cellular DNA indicates that there are not more than two copies of the albumin gene present in the rat genome.


Functional evolution of a cis-regulatory module.
Lack of knowledge about how regulatory regions evolve in relation to their structure-function may limit the utility of comparative sequence analysis in deciphering cis-regulatory sequences. To address this we applied reverse genetics to carry out a functional genetic complementation analysis of a eukaryotic cis-regulatory module-the even-skipped stripe 2 enhancer-from four Drosophila species. The evolution of this enhancer is non-clock-like, with important functional differences between closely related species and functional convergence between distantly related species. Functional divergence is attributable to differences in activation levels rather than spatiotemporal control of gene expression. Our findings have implications for understanding enhancer structure-function, mechanisms of speciation and computational identification of regulatory modules.


Evidence for two distinct mitochondrial malic enzymes in human skeletal muscle: purification and properties of the NAD(P)+-dependent enzyme.
Human muscle mitochondria reduced either NADP+ or NAD+ in the presence of L-malate and Mn2+ or Mg2+. After polyacrylamide slab gel electrophoresis and agarose gel isoelectrofocusing, two bands were seen in mitochondrial extract, one strictly NADP+-dependent and the other reacting with either NAD+ or NADP+. The two mitochondrial malic enzymes were separated by DEAE-Sepharose chromatography. The NAD+/NADP+-dependent enzyme was purified 1600-fold with a final yield of 34% and a final specific activity of 32.9 units/mg of protein by employing affinity chromatography on Agarose-ATP. SDS electrophoresis revealed a single band having an apparent Mr = 64,000. Estimates of the native apparent molecular weight upon gel filtration yielded a value of 140,300. Kinetic characterization showed that succinate and ATP were activator and inhibitor, respectively. In the absence of succinate the Km values for malate, NAD+ and NADP+ were 3.7, 0.13 and 0.78 mM, respectively; in the presence of succinate the Km value for malate was 1.9 mM. ATP was found to be an inhibitor competitive with malate, with a Ki (ATP) of 0.2 mM. This is the first report to show that mammalian skeletal muscle mitochondria contains two distinct malic enzymes, one active with either NAD+ or NADP+ and the other active only with NADP+.


Anaplerotic processes in human skeletal muscle during brief dynamic exercise.
1. This study examined changes in tricarboxylic acid cycle intermediates (TCAIs) in human skeletal muscle during 5 min of dynamic knee extensor exercise (approximately 80% of maximum workload) and following 2 min of recovery. 2. The sum of the seven measured TCAIs (sigma TCAIs) increased from 1.10 +/- 0.08 mmol (kg dry weight)-1 at rest to 3.12 +/- 0.24, 3.86 +/- 0.35 and 4.33 +/- 0.30 mmol (kg dry weight)-1 after 1, 3 and 5 min of exercise, respectively (P < or = 0.05): The sigma TCAIs after 2 min of recovery (3.74 +/- 0.43 mmol (kg dry weight)-1) was not different compared with 5 min of exercise. 3. The rapid increase in sigma TCAIs during exercise was primarily mediated by large changes in succinate, malate and fumarate. These three intermediates accounted for > 90% of the net increase in sigma TCAIs during the first minute of contraction. 4. Intramuscular alanine increased after 1 min of exercise by an amount similar to the increase in the sigma TCAIs (2.33 mmol (kg dry weight)-1) (P < or = 0.05). Intramuscular pyruvate was also higher (P < or = 0.05) during exercise, while intramuscular glutamate decreased by approximately 50% within 1 min and remained low despite an uptake from the circulation (P < or = 0.05). 5. The calculated net release plus estimated muscle accumulation of ammonia after 1 min of exercise (approximately 60 mumol (kg wet weight)-1) indicated that only a minor portion of the increase in sigma TCAIs could have been mediated through the purine nucleotide cycle and/or glutamate dehydrogenase reaction. 6. It is concluded that the close temporal relationship between the increase in sigma TCAIs and changes in glutamate, alanine and pyruvate metabolism suggests that the alanine aminotransferase reaction is the most important anaplerotic process during the initial minutes of contraction in human skeletal muscle.


A Face-Aging App for Smoking Cessation in a Waiting Room Setting: Pilot Study in an HIV Outpatient Clinic.
There is strong evidence for the effectiveness of addressing tobacco use in health care settings. However, few smokers receive cessation advice when visiting a hospital. Implementing smoking cessation technology in outpatient waiting rooms could be an effective strategy for change, with the potential to expose almost all patients visiting a health care provider without preluding physician action needed. The objective of this study was to develop an intervention for smoking cessation that would make use of the time patients spend in a waiting room by passively exposing them to a face-aging, public morphing, tablet-based app, to pilot the intervention in a waiting room of an HIV outpatient clinic, and to measure the perceptions of this intervention among smoking and nonsmoking HIV patients. We developed a kiosk version of our 3-dimensional face-aging app Smokerface, which shows the user how their face would look with or without cigarette smoking 1 to 15 years in the future. We placed a tablet with the app running on a table in the middle of the waiting room of our HIV outpatient clinic, connected to a large monitor attached to the opposite wall. A researcher noted all the patients who were using the waiting room. If a patient did not initiate app use within 30 seconds of waiting time, the researcher encouraged him or her to do so. Those using the app were asked to complete a questionnaire. During a 19-day period, 464 patients visited the waiting room, of whom 187 (40.3%) tried the app and 179 (38.6%) completed the questionnaire. Of those who completed the questionnaire, 139 of 176 (79.0%) were men and 84 of 179 (46.9%) were smokers. Of the smokers, 55 of 81 (68%) said the intervention motivated them to quit (men: 45, 68%; women: 10, 67%); 41 (51%) said that it motivated them to discuss quitting with their doctor (men: 32, 49%; women: 9, 60%); and 72 (91%) perceived the intervention as fun (men: 57, 90%; women: 15, 94%). Of the nonsmokers, 92 (98%) said that it motivated them never to take up smoking (men: 72, 99%; women: 20, 95%). Among all patients, 102 (22.0%) watched another patient try the app without trying it themselves; thus, a total of 289 (62.3%) of the 464 patients were exposed to the intervention (average waiting time 21 minutes). A face-aging app implemented in a waiting room provides a novel opportunity to motivate patients visiting a health care provider to quit smoking, to address quitting at their subsequent appointment and thereby encourage physician-delivered smoking cessation, or not to take up smoking.


Enhanced recovery protocols in trauma and emergency abdominal surgery: a scoping review.
Enhanced recovery protocols (ERP) have been shown to improve patient outcomes and is now regarded as standard of care in elective surgical setting. However, the literature addressing the use of ERP in trauma and emergency abdominal surgery (EAS) is limited and heterogenous. A scoping review was conducted to comprehensively assess the literature on ERP in trauma laparotomy and EAS. Three bibliographic databases were searched for studies addressing ERP in trauma laparotomy and EAS. We extracted the study characteristics including study design, country, year, surgical procedures, ERP components used, and outcomes. Reporting was according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews. After screening of 1631 articles for eligibility, 39 studies were included in the review. There has been an increase in the number of articles in the field, with 44% of the identified studies published between 2020 and 2022. Fourteen different protocols were identified, with varying components for each operative phase (preoperative; 29, intraoperative; 20, postoperative; 27). The majority of the studies addressed the effectiveness of ERP on clinical outcomes (31/39: 79%). Only two studies (5%) included purely trauma populations. Studies on ERP implementations in the EAS populations were published across a range of countries, with improved outcomes. However, a clear gap in ERP research on trauma laparotomy was identified. This scoping review indicates that standardization of care through ERP implementation has potential to improve the quality of care in both EAS and trauma laparotomy.


Serine 2481-autophosphorylation of mammalian target of rapamycin (mTOR) couples with chromosome condensation and segregation during mitosis: confocal microscopy characterization and immunohistochemical validation of PP-mTOR(Ser2481) as a novel high-contrast mitosis marker in breast cancer core biopsies.
The prognostic abilities of breast cancer gene expression signatures are due mostly to the detection of proliferation activity. One of the strongest, yet simple and well-reproducible proliferation-associated prognostic factors is the mitotic activity index (MAI). However: a) counting mitotic figures is regarded by many histopathologists as cumbersome and time-consuming, and b) most available immunohistochemical markers are much weaker predictors than the MAI. We have investigated the spatio-temporal sub-cellular distribution of the Serine 2481-autophosphorylated form of mTOR (PP-mTOR(Ser2481)) during the G(1)/S-to-M-phase transition both in cultured cancer cells and in cancer tissue specimens. Using a high-resolution, automated confocal high-content imaging system, we observed that mitotic cells notably accumulated a distinct pattern of nuclear and cytoplasmic immunolabelings of PP-mTOR(Ser2481). Parallel experiments examining site-specific phosphorylation (i.e., Serine 10 and Serine 28) of the G(2)/M marker Histone H3 (PP-H3) revealed that PP-H3(Ser10/Ser28) staining efficiently detected mitotic cells from prophase until the beginning of anaphase, but not during late anaphase, telophase and cytokinesis. PP-mTOR(Ser2481) staining associated near and between separating chromosomes not only during early mitotic stages but also to the midzone and to midbody at ana/telophase through cytokinesis. We then evaluated the usefulness of PP-mTOR(Ser2481) immunostaining for improving the efficiency of mitotic counting using. Anti-PP-mTOR(Ser2481)-labeled mitotic figures (MFs) were easily seen and permitted a quick identification of mitotic hotspots in formalin-fixed cancer tissues, even at low magnification. Importantly, average mitotic counts were significantly higher when using PP-mTOR(Ser2481) staining than with the hematoxylin and eosin (H&E) protocol in breast cancer core biopsies. Mitotic count based on PP-mTOR(Ser2481) immunostaining increased tumor grade by one grade in 2 of 9 breast carcinomas. These findings warrant forthcoming studies to confirm both the accuracy and the prognostic value of PP-mTOR(Ser2481) as a novel high-contrast immunohistochemical mitosis marker in larger populations of human breast carcinomas.


Asymptomatic Left Bundle Branch Block Predicts New-Onset Congestive Heart Failure and Death From Cardiovascular Diseases.
Left bundle branch block (LBBB) has been proposed as a risk factor for cardiovascular morbidity and mortality. We sought to characterize the strength of these associations in a population without preexisting clinical heart disease. The association between LBBB and new-onset congestive heart failure (CHF) or death from cardiovascular diseases was examined in 1,688 participants enrolled in the SPPARCS study who were free of known CHF or previous myocardial infarction. SPPARCS is a community-based cohort study in residents of Sonoma, California that are > 55 years. Medical history and 12-lead ECGs were obtained every 2 years for up to 6 years of follow-up. LBBB at enrollment or year 2 was considered "baseline" and assessed as a predictor of CHF and cardiovascular death ascertained at years 4 and 6. The prevalence of LBBB at baseline was 2.5% (n = 42). During 6 years of follow-up, 70 (4.8%) people developed new CHF. Incidence of CHF was higher in patients with LBBB than in participants without LBBB. This association persisted after controlling for potential confounders (odds ratio (OR): 2.85; 95% confidence interval (CI): 1.01 - 8.02; P = 0.047). A higher mortality from cardiovascular diseases was also found in participants with LBBB after adjusting for potential confounders (OR: 2.35, 95%CI: 1.02 - 5.41; P = 0.044). LBBB in the absence of a clinically detectable heart disease is associated with new-onset CHF and death from cardiovascular diseases. Further study is warranted to determine if additional diagnostic testing or earlier treatment in patients with asymptomatic LBBB can decrease cardiovascular morbidity or mortality.


Endotoxaemia is common in children with Plasmodium falciparum malaria.
Children presenting to hospital with recent or current Plasmodium falciparum malaria are at increased the risk of invasive bacterial disease, largely enteric gram-negative organisms (ENGO), which is associated with increased mortality and recurrent morbidity. Although incompletely understood, the most likely source of EGNO is the bowel. We hypothesised that as a result of impaired gut-barrier function endotoxin (lipopolysaccharide), present in the cell-wall of EGNO and in substantial quantities in the gut, is translocated into the bloodstream, and contributes to the pathophysiology of children with severe malaria. We conducted a prospective study in 257 children presenting with malaria to two hospitals in Kenya and Uganda. We analysed the clinical presentation, endotoxin and cytokine concentration. Endotoxaemia (endotoxin activity ≥0.4 EAA Units) was observed in 71 (27.6%) children but its presence was independent of both disease severity and outcome. Endotoxaemia was more frequent in children with severe anaemia but not specifically associated with other complications of malaria. Endotoxaemia was associated with a depressed inflammatory and anti-inflammatory cytokine response. Plasma endotoxin levels in severe malaria negatively correlated with IL6, IL10 and TGFβ (Spearman rho: TNFα: r=-0.122, p=0.121; IL6: r=-0.330, p<0.0001; IL10: r=-0.461, p<0.0001; TGFβ: r=-0.173, p<0.027). Endotoxaemia is common in malaria and results in temporary immune paralysis, similar to that observed in patients with sepsis and experimentally-induced endotoxaemia. Intense sequestration of P. falciparum-infected erythrocytes within the endothelial bed of the gut has been observed in pathological studies and may lead to gut-barrier dysfuction. The association of endotoxaemia with the anaemia phenotype implies that it may contribute to the dyserythropoesis accompanying malaria through inflammation. Both of these factors feasibly underpin the susceptibility to EGNO co-infection. Further research is required to investigate this initial finding, with a view to future treatment trials targeting mechanism and appropriate antimicrobial treatment.


[Germinoma of the basal ganglia and thalamus with brain stem invasion: case report].
We report an unusual case of germinoma arising from the basal ganglia and thalamus with brain stem invasion, with emphasis on computed tomography and magnetic resonance findings. Diagnosis was confirmed by histopathologic examination. Early detection of this tumor is important due to its potential response to treatment.


Prior methamphetamine self-administration attenuates the dopaminergic deficits caused by a subsequent methamphetamine exposure.
Others and we have reported that prior methamphetamine (METH) exposure attenuates the persistent striatal dopaminergic deficits caused by a subsequent high-dose "binge" METH exposure. The current study investigated intermediate neurochemical changes that may contribute to, or serve to predict, this resistance. Rats self-administered METH or saline for 7 d. On the following day (specifically, 16 h after the conclusion of the final METH self-administration session), rats received a binge exposure of METH or saline (so as to assess the impact of prior METH self-administration), or were sacrificed without a subsequent METH exposure (i.e., to assess the status of the rats at what would have been the initiation of the binge METH treatment). Results revealed that METH self-administration per se decreased striatal dopamine (DA) transporter (DAT) function and DA content, as assessed 16 h after the last self-administration session. Exposure to a binge METH treatment beginning at this 16-h time point decreased DAT function and DA content as assessed 1 h after the binge METH exposure: this effect on DA content (but not DAT function) was attenuated if rats previously self-administered METH. In contrast, 24 h after the binge METH treatment prior METH self-administration: 1) attenuated deficits in DA content, DAT function and vesicular monoamine transporter-2 function; and 2) prevented increases in glial fibrillary acidic protein and DAT complex immunoreactivity. These data suggest that changes 24 h, but not 1 h, after binge METH exposure are predictive of tolerance against the persistence of neurotoxic changes following binge METH exposures.


Purified reduced nicotinamide adenine dinucleotide: responses to lactate dehydrogenase isozymes from three cell sources.
Lactate dehydrogenase (LDH, E.C. 184.108.40.206) isozymes from three single-cell sources reacted differently with reduced nicotinamide adenine dinucleotide (NADH) purified to published chromatographic and spectrophotometric specifications and free of inhibitors of LDH, when compared with a commercial preparation of NADH. The activity of LDH-1, purified from rabbit erythrocytes, increased the most with inhibitor-free NADH; the next most stimulated were the LDH isozymes from a control hepatocyte line; but hardly responsive at all were the same isozymes from chemically transformed cells. Thus isozyme composition alone did not account for the range of responses to purified NADH. The commercial preparation of NADH used in these studies contains the Strandjörd-Clayson inhibitors, the most potent group identified in NADH preparations relative to LDH activity. The results suggest that specific molecular differences in individual isozymes contribute to the differential response to the Strandjörd-Clayson inhibitors.


A structural equation model of patient-healthcare provider relationships and HIV-infected patient outcomes in Chinese populations.
Obtaining maximum antiretroviral therapy (ART) adherence is critical for maintaining a high CD4 count and strong immune function in PLWHA. Key factors for achieving optimum adherence include good medication self-efficacy, decreased medication-taking difficulties, and positive patient-healthcare provider (HCP) relationships. Limited studies have analyzed the correlation of these factors and ART adherence in Chinese population. In this paper, structural equation modeling was performed to assess the proposed model of relations between patient-HCP relationships and adherence. Audio Computer-Assisted Self-Interview (ACASI) software was used to collect data on ART adherence and patient variables among 227 PLWHA in Shanghai and Taipei. Participants completed a one-time 60-minute ACASI survey that consisted of standardized measures to assess demographics, recent CD4 counts, self-efficacy, patient-HCP relationship, adherence, and medication-taking difficulties. The data shown the relationship between patient-HCP relationships and adherence was significantly consistent with mediation by medication self-efficacy. However, patient-HCP interaction did not directly influence medication-taking difficulties, and medication-taking difficulties did not significantly affect CD4 counts. Furthermore, patient-HCP interactions did not directly impact CD4 counts; rather, the relation was consistent with mediation (by either better medication self-efficacy or better adherence) or by improved adherence alone. Future interventions should be designed to enhance self-management and provide better patient-HCP communication. This improved communication will enhance medication self-efficacy and decrease medication-taking difficulties. This in turn will improve medication adherence and immune function among PLWHA.


Solvent compatibility of poly(dimethylsiloxane)-based microfluidic devices.
This paper describes the compatibility of poly(dimethylsiloxane) (PDMS) with organic solvents; this compatibility is important in considering the potential of PDMS-based microfluidic devices in a number of applications, including that of microreactors for organic reactions. We considered three aspects of compatibility: the swelling of PDMS in a solvent, the partitioning of solutes between a solvent and PDMS, and the dissolution of PDMS oligomers in a solvent. Of these three parameters that determine the compatibility of PDMS with a solvent, the swelling of PDMS had the greatest influence. Experimental measurements of swelling were correlated with the solubility parameter, delta (cal(1/2) cm(-3/2)), which is based on the cohesive energy densities, c (cal/cm(3)), of the materials. Solvents that swelled PDMS the least included water, nitromethane, dimethyl sulfoxide, ethylene glycol, perfluorotributylamine, perfluorodecalin, acetonitrile, and propylene carbonate; solvents that swelled PDMS the most were diisopropylamine, triethylamine, pentane, and xylenes. Highly swelling solvents were useful for extracting contaminants from bulk PDMS and for changing the surface properties of PDMS. The feasibility of performing organic reactions in PDMS was demonstrated by performing a Diels-Alder reaction in a microchannel.


Pediatric response to a large-scale child protection intervention.
In a rural area of the US state of Texas, in April 2008, the Texas Department of Family and Protective Services (DFPS) responded to evidence of widespread child abuse in an isolated religious compound by removing 463 individuals into state custody. This mass child protection intervention is the largest such action that has ever occurred in the United States. The objective of this paper is to characterize the burdens placed on the area's community resources, healthcare providers, and legal system, the limitations encountered by the forensic and public health professionals, and how these might be minimized in future large-scale child protection interventions. Drawing on publicly available information, this article describes the child abuse investigation, legal outcomes, experiences of pediatric healthcare providers directly affected by the mass removal, and the roles of regional child abuse pediatric specialists. Because the compound's residents refused to cooperate with the investigation and the population of the compound was eight times higher than expected, law enforcement and child protection resources were insufficient to conduct standard child abuse investigations. Local medical and public health resources were also quickly overwhelmed. Consulting child abuse pediatricians were asked to recommend laboratory and radiologic studies that could assist in identifying signs of child abuse, but the lack of cooperation from patients and parents, inadequate medical histories, and limited physical examinations precluded full implementation of the recommendations. Although most children in danger of abuse were removed from the high-risk environment for several months and some suspected abusers were found guilty in criminal trials, the overall success of the child protection intervention was reduced by the limitations imposed by insufficient resources and lack of cooperation from the compound's residents. Recommendations for community and child abuse pediatricians who may become involved in future large child-protection interventions are presented.


IKK epsilon regulates F actin assembly and interacts with Drosophila IAP1 in cellular morphogenesis.
Differentiated cells assume complex shapes through polarized cell migration and growth. These processes require the restricted organization of the actin cytoskeleton at limited subcellular regions. IKK epsilon is a member of the IkappaB kinase family, and its developmental role has not been clear. Drosophila IKK epsilon was localized to the ruffling membrane of cultured cells and was required for F actin turnover at the cell margin. In IKK epsilon mutants, tracheal terminal cells, bristles, and arista laterals, which require accurate F actin assembly for their polarized elongation, all exhibited aberrantly branched morphology. These phenotypes were sensitive to a change in the dosage of Drosophila inhibitor of apoptosis protein 1 (DIAP1) and the caspase DRONC without apparent change in cell viability. In contrast to this, hyperactivation of IKK epsilon destabilized F actin-based structures. Expression of a dominant-negative form of IKK epsilon increased the amount of DIAP1. The results suggest that at the physiological level, IKK epsilon acts as a negative regulator of F actin assembly and maintains the fidelity of polarized elongation during cell morphogenesis. This IKK epsilon function involves the negative regulation of the nonapoptotic activity of DIAP1.


Metabolic adaptation to high-starch diet in largemouth bass (Micropterus salmoides) was associated with the restoration of metabolic functions via inflammation, bile acid synthesis and energy metabolism.
A short-term 2-week (2w) and long-term 8-week (8w) feeding trial was conducted to investigate the effects of low-starch (LS) and high-starch (HS) diets on the growth performance, metabolism and liver health of largemouth bass (Micropterus salmoides). Two isonitrogenous and isolipidic diets containing two levels of starch (LS, 9·06 %; HS, 13·56 %) were fed to largemouth bass. The results indicated that HS diet had no significant effects on specific growth rate during 2w, whereas significantly lowered specific growth rate at 8w. HS diet significantly increased hepatic glycolysis and gluconeogenesis at postprandial 24 h in 2w. The hepatosomatic index, plasma alkaline phosphatase, total bile acid (TBA) levels, and hepatic glycogen, TAG, total cholesterol, TBA, and NEFA contents were significantly increased in the HS group at 2w. Moreover, HS diet up-regulated fatty acid and TAG synthesis-related genes and down-regulated TAG hydrolysis and β-oxidation-related genes. Therefore, the glucolipid metabolism disorders resulted in metabolic liver disease induced by HS diet at 2w. However, the up-regulation of bile acid synthesis, inflammation and energy metabolism-related genes in 2w indicated that largemouth bass was still in a state of 'self-repair' response. Interestingly, all the metabolic parameters were returned to homoeostasis, with up-regulation of intestinal glucose uptake and transport-related genes, even hepatic histopathological analysis showed no obvious abnormality in the HS group in 8w. In conclusion, HS feed induced short-term acute metabolic disorder, but long-term metabolic adaptation to HS diet was related to repairing metabolism disorders via improving inflammatory responses, bile acid synthesis and energy metabolism. These results strongly indicated that the largemouth bass owned certain adaptability to HS diet.


Engagement of CD11b and CD11c beta2 integrin by antibodies or soluble CD23 induces IL-1beta production on primary human monocytes through mitogen-activated protein kinase-dependent pathways.
beta2 integrins are involved in the recruitment of leukocytes to inflammatory sites and in cellular activation. We demonstrate that ligation of CD11b (Mac-1, CR3) or CD11c (p150, CR4) alpha chains of beta2 integrins by mAbs or soluble chimeric CD23 (sCD23) on human freshly isolated monocytes rapidly stimulates high levels of interleukin-1beta production. This induction takes place at the transcriptional level and is regulated by members of the mitogen-activated protein kinase (MAPK) family. Indeed, stimulation of monocytes through engagement of CD11b or CD11c results in the phosphorylation and activation of ERK1, ERK2, and p38/SAPK2 MAP kinases. U0126, a potent inhibitor of the upstream activator of ERK1/2, ie, MEK1/2, suppresses IL-1beta messenger RNA (mRNA) expression in a dose-dependent fashion, showing the implication of this pathway in the transcriptional control of IL-1beta production. On the other hand, inhibition of p38 by SB203580 indicates that this MAPK is involved in the control of IL-1beta production at both transcriptional and translational levels. Together these data demonstrate that ligation of CD11b and CD11c beta2 integrins by mAbs or sCD23 fusion proteins triggers the activation of 2 distinct MAPK signaling pathways that cooperate in controlling IL-1beta synthesis at different levels. (Blood. 2000;95:3868-3877)


Exploiting amino acid composition for predicting protein-protein interactions.
Computational prediction of protein interactions typically use protein domains as classifier features because they capture conserved information of interaction surfaces. However, approaches relying on domains as features cannot be applied to proteins without any domain information. In this paper, we explore the contribution of pure amino acid composition (AAC) for protein interaction prediction. This simple feature, which is based on normalized counts of single or pairs of amino acids, is applicable to proteins from any sequenced organism and can be used to compensate for the lack of domain information. AAC performed at par with protein interaction prediction based on domains on three yeast protein interaction datasets. Similar behavior was obtained using different classifiers, indicating that our results are a function of features and not of classifiers. In addition to yeast datasets, AAC performed comparably on worm and fly datasets. Prediction of interactions for the entire yeast proteome identified a large number of novel interactions, the majority of which co-localized or participated in the same processes. Our high confidence interaction network included both well-studied and uncharacterized proteins. Proteins with known function were involved in actin assembly and cell budding. Uncharacterized proteins interacted with proteins involved in reproduction and cell budding, thus providing putative biological roles for the uncharacterized proteins. AAC is a simple, yet powerful feature for predicting protein interactions, and can be used alone or in conjunction with protein domains to predict new and validate existing interactions. More importantly, AAC alone performs at par with existing, but more complex, features indicating the presence of sequence-level information that is predictive of interaction, but which is not necessarily restricted to domains.


Twelve Impacted Supernumerary Teeth in a Nonsyndromic Patient: A Rare Case Report.
Teeth in excess number than the normal count are called supernumerary teeth. They can be either unilateral or bilateral and single or multiple, found at any place in the dental arch, but most commonly found in the anterior maxillary region. Supernumerary teeth are commonly associated with syndromes when present in more numbers, but can be idiopathic. The present study shows a case report of a 16-year-old female patient who reported with overretained deciduous teeth. A panoramic radiograph showed multiple impacted supernumerary teeth. Based on clinical features and radiographic examination, a diagnosis of idiopathic hyperdontia was given. In such types of patients, management must be planned by a multidisciplinary approach.


Investigating the Effects of Mechanical Stimulation on Retinal Ganglion Cell Spontaneous Spiking Activity.
Mechanical forces are increasingly recognized as major regulators of several physiological processes at both the molecular and cellular level; therefore, a deep understanding of the sensing of these forces and their conversion into electrical signals are essential for studying the mechanosensitive properties of soft biological tissues. To contribute to this field, we present a dual-purpose device able to mechanically stimulate retinal tissue and to record the spiking activity of retinal ganglion cells (RGCs). This new instrument relies on combining ferrule-top micro-indentation, which provides local measurements of viscoelasticity, with high-density multi-electrode array (HD-MEAs) to simultaneously record the spontaneous activity of the retina. In this paper, we introduce this instrument, describe its technical characteristics, and present a proof-of-concept experiment that shows how RGC spiking activity of explanted mice retinas respond to mechanical micro-stimulations of their photoreceptor layer. The data suggest that, under specific conditions of indentation, the retina perceive the mechanical stimulation as modulation of the visual input, besides the longer time-scale of activation, and the increase in spiking activity is not only localized under the indentation probe, but it propagates across the retinal tissue.


Predicting adverse drug events from personal health messages.
Adverse drug events (ADEs) remain a large problem in the United States, being the fourth leading cause of death, despite post market drug surveillance. Much post consumer drug surveillance relies on self-reported "spontaneous" patient data. Previous work has performed datamining over the FDA's Adverse Event Reporting System (AERS) and other spontaneous reporting systems to identify drug interactions and drugs correlated with high rates of serious adverse events. However, safety problems have resulted from the lack of post marketing surveillance information about drugs, with underreporting rates of up to 98% within such systems. We explore the use of online health forums as a source of data to identify drugs for further FDA scrutiny. In this work we aggregate individuals' opinions and review of drugs similar to crowd intelligence3. We use natural language processing to group drugs discussed in similar ways and are able to successfully identify drugs withdrawn from the market based on messages discussing them before their removal.


Pancytopenia and Septic Infection Caused by Concurrent Use of Allopurinol and Mercaptopurine: A Case Report Illustrating the Importance of Clinical Pharmacist Consultation.
BACKGROUND Pancytopenia is a hematological condition which is characterized by decreases in all three cellular elements: RBC, WBC, and platelets. As a result, patients with pancytopenia are more prone to anemia, infections, and excessive bleeding. Pancytopenia can be caused by medications or drug interactions that suppress the bone marrow. This case report highlights a drug interaction between allopurinol and mercaptopurine which led to pancytopenia and septic infection, resulting in the patient's death. This could easily have been avoided if a clinical pharmacist had been consulted. CASE REPORT A 55-year-old female patient with a past medical history of gout, depression, back pain, and type 2 diabetes was recently diagnosed with ulcerative colitis and was discharged with a new prescription of mercaptopurine. After 2 months of concurrent use of allopurinol and mercaptopurine, she developed infected foot ulcers, which progressed rabidly to sepsis. At the time, her laboratory findings confirmed pancytopenia. Despite treatment, the patient died. CONCLUSIONS This case illustrates the importance of consulting a clinical pharmacist in order to avoid such medical error. The dose of mercaptopurine should be reduced to 25% of the recommended dose when it is given concurrently with allopurinol to reduce the risk of pancytopenia. Health care providers should think about the significant role of clinical pharmacy services. In our case, there were no clinical pharmacist involved in the care of this patient, and as a result of such negligence, the patient lost her life.


Synthesis of a highly dispersed CuO catalyst on CoAl-HT for the epoxidation of styrene.
A highly dispersed CuO catalyst was prepared by the deposition-precipitation method and evaluated for the catalytic epoxidation of styrene with tert-butyl hydroperoxide (TBHP) as the oxidant under solvent acetonitrile conditions. Compared with MgAl hydrotalcite (MgAl-HT)-, MgO-, TiO2-, C-, and MCM-22-supported catalysts, CuO/CoAl-HT exhibited preferable activity and selectivity towards styrene oxide (72% selectivity at 99.5% styrene conversion) due to its high dispersion of CuO and surface area of Cu. The improved dispersion of CuO/CoAl-HT could be ascribed to the nature of HT support, especially the synergistic effect of acidic and basic sites on the surface, which facilitated the formation of highly dispersed CuO species. A structure-performance relationship study indicated that copper(ii) in CuO was the active site for the epoxidation and oxidation of styrene, and that CuII of rich electronic density favored the improvement of selectivity of styrene oxide. Based on these results, a reaction mechanism was proposed. Moreover, the preferred catalytic performance of CuO/CoAl-HT could be maintained in five reused cycles.


[Constrictive pericarditis and restrictive myocardiopathy].
The purpose of this study was to assess the clinical and echocardiographic characteristics of constrictive pericarditis (CP) and restrictive cardiomyopathy (RC) and to compare them with the results obtained with cardiac catheterization. Clinical history, electrocardiogram and X-ray were taken in all patients, and transthoracic and transesophageal echocardiography were performed. Cardiac catheterization with transmyocardial biopsy was performed on only 5 patients. Wall thickness and left ventricular dimensions were normal in all patients with CP. Wall thickness was increased in those with RC. No patients demonstrated alterations in segmental wall movement. The pericardium was thickened and abnormally bright in the 3 patients with CP. In patients with CP the percentage of atrioventricular, semilunar, pulmonary and hepatic flow changes with respiration were more than 10%. In patients with RC this flow variation was less notable. However, the percentage of systolic and diastolic flow velocity increase of hepatic veins during expiration was greater than in CP. We can conclude that M-mode, two dimensional and Doppler echocardiography is extremely useful noninvasive method to differentiate CP and RC with good correlation with cardiac catheterization.


Antitumor efficacy of bcl-2 and c-myc antisense oligonucleotides in combination with cisplatin in human melanoma xenografts: relevance of the administration sequence.
bcl-2 and c-myc oncogenes are frequently overexpressed in different human tumors, including melanoma. Here, we evaluate the combined efficacy of two antisense oligonucleotides targeting bcl-2 mRNA (ODN bcl-2) and c-myc mRNA (ODN c-myc) in combination with cis-diammine dichloroplatinum (cisplatin, DDP) on three human melanoma lines (LM, NG, and M20). Two different sequences were designed to treat tumor-bearing mice: in the first one, ODN bcl-2 at a dose of 0.2 mg/day x4, followed by DDP given i.p. at a dose of 3.3 mg/kg/day x3 and ODN c-myc i.v. at 0.5 mg/day x7, whereas the other sequence consisted of ODN c-myc given as first agent followed by DDP and ODN bcl-2 at the same doses. Mice received three complete cycles of treatment in 1-week intervals. The treatment sequence with ODN bcl-2/DDP/ODN c-myc combination completely inhibited growth in NG tumor and induced a 35-day delay in LM tumor growth. In contrast, the M20 tumor growth was unaffected by the combination. A discrete amount of c-Myc and bcl-2 protein expression in both LM and NG tumors was detected, whereas no detectable levels of the two proteins were observed in M20 tumors. Compared with the other combination, the sequence (ODN bcl-2/DDP/ODN c-myc) produced the most effective results, producing a significant decrease in bcl-2 and c-Myc protein expression, which in turn significantly increased the survival of NG- and LM-bearing mice, with 4 mice out of 11 and 1 out of 7 mice being cured, respectively. Finally, this combination increased the apoptotic rate and produced an antiangiogenetic effect. These results show that an antisense approach to the treatment of melanoma xenografts overexpressing either bcl-2 or c-myc oncogenes represents a successful strategy to improve the response to chemotherapy in melanoma, with particular attention to the treatment sequence.


Soft Tissue Reconstruction of Complete Circumferential Defects of the Upper Extremity.
Upper extremity soft tissue defects with complete circumferential involvement are not common. Coupled with the unique anatomy of the upper extremity, the underlying etiology of such circumferential soft tissue defects represent additional reconstructive challenges that require treatment to be tailored to both the patient and the wound. The aim of this study is to review the various options for soft tissue reconstruction of complete circumferential defects in the upper extremity. A literature review of PubMed and MEDLINE up to December 2016 was performed. The current study focuses on forearm and arm defects from the level at or proximal to the wrist and were assessed based on Tajima's classification (J Trauma 1974). Data reviewed for analysis included patient demographics, causality, defect size, reconstructive technique(s) employed, and postoperative follow-up and functional outcomes (when available). In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 14 unique articles were identified for a total of 50 patients (mean=28.1 years). Underlying etiologies varied from extensive thermal or electrical burns to high impact trauma leading to degloving or avulsion, crush injuries, or even occur iatrogenically after tumor extirpation or extensive debridement. Treatment options ranged from the application of negative pressure wound dressings to the opposite end of the spectrum in hand transplantation. With the evolution of reconstructive techniques over time, the extent of functional and aesthetic rehabilitation of these complex upper extremity injuries has also improved. The proposed management algorithm comprehensively addresses the inherent challenges associated with these complex cases.


cDNA cloning of nuclear localization signal binding protein NBP60, a rat homologue of lamin B receptor, and identification of binding sites of human lamin B receptor for nuclear localization signals and chromatin.
We previously purified and characterized a nuclear localization signal (NLS) binding protein, NBP60, in rat liver nuclear envelopes. In this study, we cloned and sequenced the cDNA of rat NBP60, and predicted an amino acid sequence comprising 620 amino acids. The sequence revealed that NBP60 is a rat homologue of lamin B receptor (LBR), and is 79 and 63% identical in amino acids to human and chicken LBR, respectively. Using three fusion proteins containing different parts of the amino-terminal domain of human LBR, it was shown that the stretch comprising amino acids 1 to 89, which contains a Ser-Arg rich region (RS region), binds to nucleoplasmin and that the binding was inhibited by a common NLS-peptide. These results suggested that the amino-terminal domain of LBR contains an NLS-binding site. Furthermore, it was shown that the stretch comprising amino acids 1 to 53, which does not contain the RS region or the predicted DNA-binding site, binds to Xenopus laevis sperm chromatin.


Short-term impact of 1997/1998 ENSO-induced disturbance on abundance and genetic variation in a tropical butterfly.
In order to assess the short-term impact of habitat loss after disturbance, we studied Arhopala epimuta (Lepidoptera: Lycaenidae) populations in 5 landscapes in Borneo that were differentially affected by the 1997/1998 El Niño Southern Oscillation-induced drought and fire. Sampling was conducted before (1997) and after (1998 and 2000) disturbance. This study combined demographic and genetic data inferred from the analysis of 5 microsatellite loci and mitochondrial DNA (mtDNA) control region sequences. Over all 5 landscapes, a total of 313 A. epimuta were sampled over the 3-year survey. Butterfly abundance varied greatly both spatially and temporally (within disturbed landscapes). After the disturbance, a 4-fold population expansion was observed in a small unburned isolate, whereas population extinction was observed in one of the severely burned areas. The analysis of mtDNA sequences in a subsample of 106 A. epimuta revealed no significant spatial or temporal genetic structure. The analysis of 5 microsatellite loci revealed high frequencies of null alleles. Genetic evidence of recent change in population size was found in all 3 unburned landscapes using microsatellites. Congruent to mtDNA, microsatellites failed to detect significant genetic structure according to sampling year or landscapes. Our results suggest that, for mobile species within recently fragmented habitat, habitat loss after disturbance may lead to local population extinction but may augment genetic diversity in remnant local populations because of increased gene flow.


Sing to me, baby: Infants show neural tracking and rhythmic movements to live and dynamic maternal singing.
Infant-directed singing has unique acoustic characteristics that may allow even very young infants to respond to the rhythms carried through the caregiver's voice. The goal of this study was to examine neural and movement responses to live and dynamic maternal singing in 7-month-old infants and their relation to linguistic development. In total, 60 mother-infant dyads were observed during two singing conditions (playsong and lullaby). In Study 1 (n = 30), we measured infant EEG and used an encoding approach utilizing ridge regressions to measure neural tracking. In Study 2 (n =40), we coded infant rhythmic movements. In both studies, we assessed children's vocabulary when they were 20 months old. In Study 1, we found above-threshold neural tracking of maternal singing, with superior tracking of lullabies than playsongs. We also found that the acoustic features of infant-directed singing modulated tracking. In Study 2, infants showed more rhythmic movement to playsongs than lullabies. Importantly, neural coordination (Study 1) and rhythmic movement (Study 2) to playsongs were positively related to infants' expressive vocabulary at 20 months. These results highlight the importance of infants' brain and movement coordination to their caregiver's musical presentations, potentially as a function of musical variability.


Picolinate-containing macrocyclic Mn2+ complexes as potential MRI contrast agents.
We report the synthesis of the ligand Hnompa (6-((1,4,7-triazacyclononan-1-yl)methyl)picolinic acid) and a detailed characterization of the Mn(2+) complexes formed by this ligand and the related ligands Hdompa (6-((1,4,7,10-tetraazacyclododecan-1-yl)methyl)picolinic acid) and Htempa (6-((1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)picolinic acid). These ligands form thermodynamically stable complexes in aqueous solution with stability constants of logKMnL = 10.28(1) (nompa), 14.48(1) (dompa), and 12.53(1) (tempa). A detailed study of the dissociation kinetics of these Mn(2+) complexes indicates that the decomplexation reaction at about neutral pH occurs mainly following a spontaneous dissociation mechanism. The X-ray structure of [Mn2(nompa)2(H2O)2](ClO4)2 shows that the Mn(2+) ion is seven-coordinate in the solid state, being directly bound to five donor atoms of the ligand, the oxygen atom of a coordinated water molecule and an oxygen atom of a neighboring nompa(-) ligand acting as a bridging bidentate carboxylate group (μ-η(1)-carboxylate). Nuclear magnetic relaxation dispersion ((1)H NMRD) profiles and (17)O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn(nompa)](+) indicate that the Mn(2+) ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the (1)H NMRD and (17)O NMR data provides a very high water exchange rate of the inner-sphere water molecule (kex(298) = 2.8 × 10(9) s(-1)) and an unusually high value of the (17)O hyperfine coupling constant of the coordinated water molecule (AO/ℏ = 73.3 ± 0.6 rad s(-1)). DFT calculations performed on the [Mn(nompa)(H2O)](+)·2H2O system (TPSSh model) provide a AO/ℏ value in excellent agreement with the one obtained experimentally.


[Pregnancy and medical follow-up of women living with HIV/AIDS in Guadeloupe and Martinique (French West Indies): medical progress and social problems].
After sub-Saharan Africa, the Caribbean is the region of the world most affected by HIV/AIDS. Guadeloupe and Martinique (French West Indies) are located in the heart of this region. Although the AIDS incidence here is lower than in other Caribbean countries, it is much higher than in mainland France. Transmission is mostly heterosexual, and the proportion of women infected is high, almost half of all those infected. Moreover, in Guadeloupe a large proportion of them are foreigners (mainly from Haïti). This qualitative study was conducted in 2009 among health professionals, advocacy and support groups, and women living with HIV/AIDS. It analysed the characteristics of women's follow-up during and after their pregnancy. It also analysed the practices that health professionals have developed to provide follow-up for these women, despite various obstacles. Antiretroviral therapy makes it possible to health professionals to reduce the risk of mother-to-child transmission of HIV infection. They inform their patients of the possibilities for infected women to have a child with less risk of infection provided that she has a medical follow-up and that she is treated. But they note that the pregnancies are rarely planned in consultation with them: patients are generally already pregnant when they discuss the subject with their doctors. The pregnancy is nevertheless a special moment for medical monitoring: women are particularly compliant during their pregnancy, because their priority is the protection of the child's health. After the child's birth, however, the social and administrative difficulties of many of these women serve as obstacles to their continued medical care. Some women stop treatment and medical follow-up after delivery, even when they make sure the child has medical follow-up. To continue the follow-up of women and their children, or to contact women who have been lost to follow-up, professionals resort to various practices: compliance consultations, house calls, hospitalization... These practices are based on multidisciplinary collaboration, between medical departments (infectious diseases, obstetrics/gynaecology, and paediatrics), as well as with social services and support groups for persons living with HIV/AIDS.


Immune responses in infants whose mothers received Tdap vaccine during pregnancy.
The effect of maternal Tdap vaccination on infant immunologic responses to routine pediatric vaccines is unknown. This was a cohort study of infants whose mothers received or did not receive Tdap vaccine during pregnancy. Maternal and cord blood samples were collected at delivery; infant blood samples were collected before and after primary series and booster dose of diphtheria, tetanus, and acellular pertussis (DTaP) and other vaccines. Geometric mean antibody concentrations or titers to pertussis, hepatitis B, tetanus, diphtheria, Haemophilus influenzae type b and polio antigens were measured. Mean maternal-to-cord blood antibody ratios were calculated. At delivery, maternal and cord antibody concentrations to pertussis antigens were higher in the Tdap group (n=16) than control group (n=54; maternal: 1.9- to 20.4-fold greater; cord: 2.7- to 35.5-fold greater). Increased antibody concentrations persisted for infants at first DTaP (3.2- to 22.8-fold greater). After primary series, antibody concentrations to pertussis antigens were lower in Tdap group (0.7- to 0.8-fold lower), except for fimbriae types 2 and 3 (FIM) (1.5-fold greater). Antibody concentrations to pertussis antigens before and after booster dose were comparable (prebooster: Tdap group 1.0- to 1.2-fold higher than controls; postbooster: 0.9- to 1.0-fold lower). Differences in FIM values at these time points are difficult to interpret, due to varying FIM content among DTaP vaccines administered to infants in both groups. Maternal Tdap immunization resulted in higher pertussis antibody concentrations during the period between birth and the first vaccine dose. Although slightly decreased immune responses following the primary series were seen compared with controls, differences did not persist following the booster.


Risk assessment regarding the use of Annona muricata in food supplements.
The current risk assessment was performed in the context of the European Food Risk Assessment Fellowship Programme (EU-FORA) supported by EFSA and was intended to evaluate possible health risks associated with the consumption of Annona muricata L. (Annonaceae) and derived food supplements. A. muricata grows as a tree and is native to the Caribbean and Central America. Preparations made from different plant parts of A. muricata (i.e. fruit, leaves, bark, roots) have been used as herbal medicine and are also marketed worldwide as over-the-counter food supplements that have been purported to support general health or to treat a wide range of health conditions, particularly cancer and parasitic infections. However, open questions remain regarding the safety of A. muricata-based food supplements, since Annonaceae have been reported to contain potentially neurotoxic compounds, i.e. acetogenins. The assessment conducted within the present fellowship programme shows that substantial uncertainties exist regarding the safe use of A. muricata-based supplements. The available data provide indications of neurotoxic potential of certain A. muricata preparations. The paucity of adequate studies, particularly related to long-term use of A. muricata supplements, currently does not allow the establishment of a safe intake level. Within this technical report a workflow of the project is presented.