Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin.
Huntington disease (HD) is an inherited neurodegenerative disease resulting from an abnormal expansion of polyglutamine in huntingtin (Htt). Compromised oxidative stress defense systems have emerged as a contributing factor to the pathogenesis of HD. Indeed activation of the Nrf2 pathway, which plays a prominent role in mediating antioxidant responses, has been considered as a therapeutic strategy for the treatment of HD. Given the fact that there is an interrelationship between impairments in mitochondrial dynamics and increased oxidative stress, in this present study we examined the effect of mutant Htt (mHtt) on these two parameters. STHdh(Q111/Q111) cells, striatal cells expressing mHtt, display more fragmented mitochondria compared to STHdh(Q7/Q7) cells, striatal cells expressing wild type Htt, concurrent with alterations in the expression levels of Drp1 and Opa1, key regulators of mitochondrial fission and fusion, respectively. Studies of mitochondrial dynamics using cell fusion and mitochondrial targeted photo-switchable Dendra revealed that mitochondrial fusion is significantly decreased in STHdh(Q111/Q111) cells. Oxidative stress leads to dramatic increases in the number of STHdh(Q111/Q111) cells containing swollen mitochondria, while STHdh(Q7/Q7) cells just show increases in the number of fragmented mitochondria. mHtt expression results in reduced activity of Nrf2, and activation of the Nrf2 pathway by the oxidant tBHQ is significantly impaired in STHdh(Q111/Q111) cells. Nrf2 expression does not differ between the two cell types, but STHdh(Q111/Q111) cells show reduced expression of Keap1 and p62, key modulators of Nrf2 signaling. In addition, STHdh(Q111/Q111) cells exhibit increases in autophagy, whereas the basal level of autophagy activation is low in STHdh(Q7/Q7) cells. These results suggest that mHtt disrupts Nrf2 signaling which contributes to impaired mitochondrial dynamics and may enhance susceptibility to oxidative stress in STHdh(Q111/Q111) cells.


Early childbearing and children's achievement and behavior over time.
Compared with children of older women, children of women who had their first birth during their teens have long been believed to be at higher risk for a host of poor health, social and economic outcomes. Recent studies have failed to confirm this belief, but none have taken into account whether children's outcomes or the effects of early childbearing on those outcomes have changed over time. Data from the National Longitudinal Survey of the Labor Market Experience of Youth and the Panel Study of Income Dynamics are used to separate the influence of changes from the 1960s through the 1990s in children's experiences from the effect of mother's age at first birth. Multivariate analyses controlling for social and demographic characteristics show that among children born to women from a particular birth cohort, those whose mothers first gave birth in their teens have significantly lower scores on a set of four achievement tests and significantly higher scores on a behavior-problem index than do children whose mothers delayed childbearing. However, when changes over time in children's outcomes and in the effect of early childbearing on those outcomes are taken into account, children born to women who began childbearing early score significantly worse than those whose mothers delayed their first birth on the behavior-problem index, but on only one achievement test. Comparisons by age at first birth among women born in the same period may misestimate the effects of early motherhood. Whether early childbearing's effects on children are overestimated or underestimated depends on whether test scores are rising or falling. Policymakers should be cautious in making decisions based on studies that do not take time trends into account.


Predictors of latent tuberculosis infection treatment completion in the US private sector: an analysis of administrative claims data.
Factors that affect latent tuberculosis infection (LTBI) treatment completion in the US have not been well studied beyond public health settings. This gap was highlighted by recent health insurance-related regulatory changes that are likely to increase LTBI treatment by private sector healthcare providers. We analyzed LTBI treatment completion in the private healthcare setting to facilitate planning around this important opportunity for tuberculosis (TB) control in the US. We analyzed a national sample of commercial insurance medical and pharmacy claims data for people ages 0 to 64 years who initiated daily dose isoniazid treatment between July 2011 and March 2014 and who had complete data. All individuals resided in the US. Factors associated with treatment completion were examined using multivariable generalized ordered logit models and bivariate Kruskal-Wallis tests or Spearman correlations. We identified 1072 individuals with complete data who initiated isoniazid LTBI treatment. Treatment completion was significantly associated with less restrictive health insurance, age < 15 years, patient location, use of interferon-gamma release assays, non-poverty, HIV diagnosis, immunosuppressive drug therapy, and higher cumulative counts of clinical risk factors. Private sector healthcare claims data provide insights into LTBI treatment completion patterns and patient/provider behaviors. Such information is critical to understanding the opportunities and limitations of private healthcare in the US to support treatment completion as this sector's role in protecting against and eliminating TB grows.


Hyperuniformity on spherical surfaces.
We study and characterize local density fluctuations of ordered and disordered hyperuniform point distributions on spherical surfaces. In spite of the extensive literature on disordered hyperuniform systems in Euclidean geometries, to date few works have dealt with the problem of hyperuniformity in curved spaces. Indeed, some systems that display disordered hyperuniformity, like the spatial distribution of photoreceptors in avian retina, actually occur on curved surfaces. Here we will focus on the local particle number variance and its dependence on the size of the sampling window (which we take to be a spherical cap) for regular and uniform point distributions, as well as for equilibrium configurations of fluid particles interacting through Lennard-Jones, dipole-dipole, and charge-charge potentials. We show that the scaling of the local number variance as a function of the window size enables one to characterize hyperuniform and nonhyperuniform point patterns also on spherical surfaces.


Outdoor light at night and postmenopausal breast cancer risk in the NIH-AARP diet and health study.
Circadian disruption may play a role in breast carcinogenesis. Previous studies reported relationships between outdoor light at night (LAN) and the breast cancer risk, but their findings are mixed. There is also a need to examine LAN and breast cancer incidence according to different individual and environmental characteristics to identify subpopulations at greater risk associated with LAN exposure. We studied residential outdoor LAN estimated from satellite imagery at baseline (1996) in relation to postmenopausal breast cancer incidence over ~16 years of follow-up in 186 981 postmenopausal women including 12 318 incident postmenopausal breast cancer cases in the NIH-AARP Diet and Health Study. We used Cox proportional hazards models to estimate hazard ratios (HR) and two-sided 95% confidence intervals (CI) of the relationship between quintiles of LAN and postmenopausal breast cancer risk, overall and by hormone receptor status and cancer stage. We found that when compared to women in the lowest quintile of baseline LAN, those in the highest quintile had a 10% increase in postmenopausal breast cancer risk (HR (95% CI), 1.10 (1.02, 1.18), P-trend, .002). The association appeared to be stronger for estrogen receptor (ER) positive breast cancer (1.12 [1.02, 1.24], .007) than for ER-negative cancer (1.07 [0.85, 1.34], .66). Our findings also suggested that the relationship between LAN and breast cancer risk may differ by individual characteristics, such as smoking, alcohol drinking, sleep duration and BMI, and neighborhood environment. In conclusion, our study suggests that higher outdoor LAN exposure may be a risk factor for postmenopausal breast cancer.


Dermatan sulphate for the prevention of postoperative venous thromboembolism in patients with cancer. DOS (Dermatan sulphate in Oncologic Surgery) Study Group.
Patients undergoing surgery for cancer are at high risk for venous thromboembolism (VTE). Agents that selectively inhibit thrombin, such as dermatan sulphate, have potential for a favourable benefit-risk ratio in the prevention of this complication. Patients scheduled for elective abdominal, thoracic, gynecologic or urologic surgery for cancer resection, were randomised to dermatan sulphate (600 mg intramuscularly on the second day before surgery, then 300 mg once daily), or calcium heparin (5,000 IU subcutaneously t.i.d., starting 2 hours before operation). Both treatments were continued until postoperative day 7 or until adequate mobilisation was achieved. Bilateral venography was scheduled at the end of treatment. Venograms were centrally assessed in blind conditions. The study outcomes were VTE (venographically proven deep vein thrombosis IDVT] or symptomatic, objectively confirmed pulmonary embolism) and bleeding complications. At 27 centres, 842 patients were randomised and underwent surgery (418 dermatan sulphate, 424 heparin). Efficacy was assessed in 521 patients with adequate venography and/or confirmed pulmonary embolism. DVT was observed in a total of 96 patients; symptomatic non-fatal pulmonary embolism developed in 2 patients (one per group), who also had DVT at venography. Postoperative VTE occurred in 40 of 267 patients on dermatan sulphate, 15.0%, versus 56 of 254 patients on heparin. 22.0% (p = 0.033). Relative risk reduction was 32.7% (95% confidence interval, 3.1 to 53.2%). The rate of bleeding complications in all operated patients was 6.9% with dermatan sulphate and 7.5% with heparin (confidence interval for the absolute risk difference, -4.1 to 2.9%). The inhospital mortality rate was 1.2% and 1.4%, respectively. In oncologic surgery, dermatan sulphate prevents VTE more effectively than heparin without increasing bleeding complications.


Primary structure of kappa-casein isolated from mares' milk.
In this work the purification and the complete primary structure of kappa-casein from equine milk are reported for the first time. Mares' milk casein was separated by RP-HPLC into four fractions. Complete primary sequence was obtained by sequence analysis of the protein in the fastest eluting peak isolated by chromatography. This sequence was 95% identical to that reported for the C-terminal portion of the zebras' kappa-casein and showed high similarity with kappa-caseins from sources other than Equidae, confirming that this protein was indeed kappa-casein in equine milk. The presence of post-translational modifications in equine kappa-casein was investigated by mass spectroscopy, after enzymic dephosphorylation. Two main components were found, the smaller component being more abundant. Equine kappa-casein was recognized by a lectin specific for one of the glucosidic bonds in the saccharide moiety of bovine kappa-casein. Sequence comparison with prevision studies showed that the distribution of charged and hydrophobic regions in equine kappa-casein was similar, but not identical, to that found in the bovine protein; these regions are associated with the role of kappa-casein in the formation and stabilization of the micellar structure of casein in milk.


Site-dependent N uptake from N-form mixtures by arctic plants, soil microbes and ectomycorrhizal fungi.
Soil microbes constitute an important control on nitrogen (N) turnover and retention in arctic ecosystems where N availability is the main constraint on primary production. Ectomycorrhizal (ECM) symbioses may facilitate plant competition for the specific N pools available in various arctic ecosystems. We report here our study on the N uptake patterns of coexisting plants and microbes at two tundra sites with contrasting dominance of the circumpolar ECM shrub Betula nana. We added equimolar mixtures of glycine-N, NH4+ -N and NO3(-) -N, with one N form labelled with 15N at a time, and in the case of glycine, also labelled with 13C, either directly to the soil or to ECM fungal ingrowth bags. After 2 days, the vegetation contained 5.6, 7.7 and 9.1% (heath tundra) and 7.1, 14.3 and 12.5% (shrub tundra) of the glycine-, NH4+ - and NO3 (-) -(15)N, respectively, recovered in the plant-soil system, and the major part of 15N in the soil was immobilized by microbes (chloroform fumigation-extraction). In the subsequent 24 days, microbial N turnover transferred about half of the immobilized 15N to the non-extractable soil organic N pool, demonstrating that soil microbes played a major role in N turnover and retention in both tundra types. The ECM mycelial communities at the two tundras differed in N-form preferences, with a higher contribution of glycine to total N uptake at the heath tundra; however, the ECM mycelial communities at both sites strongly discriminated against NO3 (-) . Betula nana did not directly reflect ECM mycelial N uptake, and we conclude that N uptake by ECM plants is modulated by the N uptake patterns of both fungal and plant components of the symbiosis and by competitive interactions in the soil. Our field study furthermore showed that intact free amino acids are potentially important N sources for arctic ECM fungi and plants as well as for soil microorganisms.


S-acylation of P2K1 mediates extracellular ATP-induced immune signaling in Arabidopsis.
S-acylation is a reversible protein post-translational modification mediated by protein S-acyltransferases (PATs). How S-acylation regulates plant innate immunity is our main concern. Here, we show that the plant immune receptor P2K1 (DORN1, LecRK-I.9; extracellular ATP receptor) directly interacts with and phosphorylates Arabidopsis PAT5 and PAT9 to stimulate their S-acyltransferase activity. This leads, in a time-dependent manner, to greater S-acylation of P2K1, which dampens the immune response. pat5 and pat9 mutants have an elevated extracellular ATP-induced immune response, limited bacterial invasion, increased phosphorylation and decreased degradation of P2K1 during immune signaling. Mutation of S-acylated cysteine residues in P2K1 results in a similar phenotype. Our study reveals that S-acylation effects the temporal dynamics of P2K1 receptor activity, through autophosphorylation and protein degradation, suggesting an important role for this modification in regulating the ability of plants in respond to external stimuli.


[Effect of specific inhibitors of the enzymes of the respiratory chain and ATP-synthetase on ion transport in mitochondria induced by non-enzymic peroxide reactions].
Effect of specific inhibitors of membrane proton pumps of the respiratory chain and ATP-synthetase on ionic permeability of mitochondrial membranes induced by bivalent ferrum ions or organic hydroperoxide was studied. A conclusion is made concerning the existence of functional relations between non-specific oxidative reactions of the membranes with membrane proton pumps on the one hand and transport potassium ions in mitochondria on the other.


Glucose contribution to nucleic acid base synthesis in proliferating hepatoma cells: a glycine-biosynthesis-mediated pathway.
The coupling of glycolysis to serine and glycine metabolism was studied in fast-growing Zajdela hepatoma cultured cells. During the exponential phase of growth, occurring between 12 and 72 h, cells exhibited a decreased glycogen content together with a high glycolytic activity. Glycogen labelling, evaluated by 1 h-pulse experiments with [U-14C]glucose (5.5 mM), was minimal during the first 48 h and increased 2.5-fold at 72 h and 8-fold at 96 h, at which times it was also stimulated 2-fold by 10 nM insulin. [U-14C]Glucose carbons were incorporated into nucleic acid bases, with maximal incorporation at 72 h, the rate of nucleotide base labelling exceeding that of glycogen during the first 2 days of culture. Incubation of the cells with [U-14C]glucose resulted in the release into the medium of 14C-labelled glycine, the first intermediate formed on the route from serine to DNA. The rate of release per cell decreased as a function of cell growth, concomitantly with an increased rate of glucose carbon incorporation into nucleotide bases. The latter implied the intermediary formation of amino acids since the transaminase inhibitor cycloserine (10 mM), which totally inhibited [14C]glycine release, decreased by 65% nucleotide labelling from [U-14C]glucose. A dose-dependent inhibition by serine of the rate of [U-14C]glucose carbon incorporation into nucleotide bases was observed, which was maximal at 5 mM serine. These metabolic flux measurements indicate that glucose can be used as a precursor of nucleic acid synthesis. These results strongly suggest that this process is to a large extent mediated by a serine/glycine-biosynthesis-mediated pathway, and reinforce the hypothesis that glycolysis contributes to enhancing the provision of precursors required for cell proliferation.


Primate involucrins: antigenic relatedness and detection of multiple forms.
Hominoid apes (gorilla, chimpanzee, orangutan, gibbon), Old World monkeys (rhesus, cynomolgus), New World monkeys (owl, cebus), and a prosimian (lemur) express involucrin-like proteins in cultured keratinocytes. Primate involucrins can be precipitated with trichloroacetic acid, resolubilized at pH 8, and subsequently retain aqueous solubility in 67% ethanol. Polyacrylamide gel electrophoresis of keratinocyte extracts after this rapid partial purification has revealed in each species tested one (chimpanzee, orangutan, gibbon) or two (gorilla, rhesus, owl, cebus) antigenically crossreactive proteins that migrate in the vicinity of human involucrin. In the species examined further (gorilla, chimpanzee, rhesus), poly(A)+ mRNA isolated from the cultures directed the cell-free translation of polypeptides with mobilities similar to those extracted from the cells. From five cynomolgus monkeys, three different electrophoretic profiles were obtained, suggesting the existence of different alleles. Quantitative comparisons by a sensitive enzyme-linked immunosorbent assay indicated that certain primate involucrins have a higher density of antigenic determinants than the human protein, whereas others lack some determinant(s). In contrast to those from other species, all of which showed substantial crossreactivity, the lemur protein was minimally immunoreactive by immunoblotting and not clearly detected by solid-phase assay. The electrophoretic and antigenic differences displayed throughout the primate order suggest that this protein has been subject to relatively rapid evolution.


Repeatability of in vivo 3D lamina cribrosa microarchitecture using adaptive optics spectral domain optical coherence tomography.
We demonstrate the repeatability of lamina cribrosa (LC) microarchitecture for in vivo 3D optical coherence tomography (OCT) scans of healthy, glaucoma suspects, and glaucomatous eyes. Eyes underwent two scans using a prototype adaptive optics spectral domain OCT (AO-SDOCT) device from which LC microarchitecture was semi-automatically segmented. LC segmentations were used to quantify pore and beam structure through several global microarchitecture parameters. Repeatability of LC microarchitecture was assessed qualitatively and quantitatively by calculating parameter imprecision. For all but one parameters (pore volume) measurement imprecision was <4.7% of the mean value, indicating good measurement reproducibility. Imprecision ranged between 27.3% and 54.5% of the population standard deviation for each parameter, while there was not a significant effect on imprecision due to disease status, indicating utility in testing for LC structural trends.


Extending life: scientific prospects and political obstacles.
Aging can be slowed in laboratory rodents by low-calorie diets, and changes in single genes can extend mouse life span by 40 percent or more. Therefore, despite its surface complexity and effects on multiple cells and intercellular systems, aging in mammals might also be retarded by both genetic and nongenetic means. If human aging could be slowed pharmacologically to the extent now possible in rodents, the effect on healthy life expectancy would exceed that of abolishing cancer, cardiovascular disease, and adult-onset diabetes. Why, then, is research on the biological control of aging and longevity poorly funded and shunned by both most scientists and those setting national research priorities? Economic disincentives, disease-specific lobby groups, scientific careerism, and ineffective nostrums, together with gerontologiphobia, must be overcome before such research can improve public health.


Canadian Expert Group consensus recommendations: KRAS testing in colorectal cancer.
Monoclonal antibodies against the epidermal growth factor receptor (anti-egfr) when used in the treatment of metastatic colorectal cancer are associated with improved survival. Patients whose tumours harbor a KRAS mutation in codon 12 or 13 have been shown not to benefit from anti-egfr antibodies. The importance of KRAS mutation status in the management of patients with metastatic colorectal cancer has led to the elaboration of Canadian consensus recommendations on KRAS testing, with the aim of standardizing practice across Canada and reconciling testing access with the clinical demand for testing. The present guidelines were developed at a Canadian consensus meeting held in Montreal in April 2010. The best available evidence and expertise were used to develop recommendations for various aspects of KRAS testing, including indications and timing for testing, sample requirements, recommendations for reporting requirements, and acceptable turnaround times.


Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome.
Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease.


Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat.
Tubulo-interstitial fibrosis is a constant feature of chronic renal failure and it is suspected to contribute importantly to the deterioration of renal function. In the fibrotic kidney there exists, besides normal fibroblasts, a large population of myofibroblasts, which are supposedly responsible for the increased production of intercellular matrix. It has been proposed that myofibroblasts in chronic renal failure originate from the transformation of tubular cells via epithelial-mesenchymal transition (EMT) or from infiltration by bone marrow-derived precursors. Little attention has been paid to the possibility of a transformation of resident fibroblasts into myofibroblasts in renal fibrosis. Therefore we examined the fate of resident fibroblasts in the initial phase of renal fibrosis in the classical model of unilateral ureter obstruction (UUO) in the rat. Rats were perfusion-fixed on days 1, 2, 3 and 4 after ligature of the right ureter. Starting from 1 day of UUO an increasing expression of alpha-smooth muscle actin (alphaSMA) in resident fibroblasts was revealed by immunofluorescence and confirmed by the observation of bundles of microfilaments and webs of intermediate filaments in the electron microscope. Inversely, there was a decreased expression of 5'-nucleotidase (5'NT), a marker of renal cortical fibroblasts. The RER became more voluminous, suggesting an increased synthesis of matrix. Intercellular junctions, a characteristic feature of myofibroblasts, became more frequent. The mitotic activity in fibroblasts was strongly increased. Renal tubules underwent severe regressive changes but the cells retained their epithelial characteristics and there was no sign of EMT. In conclusion, after ureter ligature, resident peritubular fibroblasts proliferated and they showed progressive alterations, suggesting a transformation in myofibroblasts. Thus the resident fibroblasts likely play a central role in fibrosis in that model.


[Sarcoidosis of the central and peripheral nervous system].
The authors report two cases of Besnier -Boeck- Schaumann sarcoidosis with a neurological presentation. The first case was a 25 year old woman with a 5 year history of polyneuritis affecting the cranial and spinal nerves with very low nerve conduction times and without any detectable visceral disease. The diagnosis was made by distal bronchial biopsy. The second case was of an elderly man with tremor, difficulty in keeping his balance and deafness with chronic meningitis. The diagnosis was made by proximal bronchial biopsy, chest X-Ray showing a benign hilar lymphoma. In the first case, therapy comprised two three months courses of high dose intravenous steroids followed by oral corticosteroid therapy tailing off over three weeks. In the second case, the same intravenous steroid therapy was relayed by continuous oral steroids. The therapeutic effect was spectacular in the first case, but incomplete in the second, the intravenous steroids seeming to be more effective than the oral steroids.


The effects of embryo stage and cell number on the composition of mouse aggregation chimaeras.
Studies with intact preimplantation mouse embryos and some types of chimaeric aggregates have shown that the most advanced cells are preferentially allocated to the inner cell mass (ICM) rather than the trophectoderm. Thus, differences between 4-cell and 8-cell stage embryos could contribute to the tendency for tetraploid cells to colonise the trophectoderm more readily than the ICM in 4-cell tetraploid<-->8 cell diploid chimaeras. The aim of the present study was to test whether 4-cell stage embryos in 4-cell diploid<-->8-cell diploid aggregates contributed equally to all lineages present in the E12.5 conceptus. These chimaeras were compared with those produced from standard aggregates of two whole 8-cell embryos and aggregates of half an 8-cell embryo with a whole 8-cell embryo. As expected, the overall contribution of 4-cell embryos was lower than that of 8-cell embryos and similar to that of half 8-cell stage embryos. In the 4-cell<-->8-cell chimaeras the 4-cell stage embryos did not contribute more to the trophectoderm than the ICM derivatives. Thus, differences between 4-cell and 8-cell embryos cannot explain the restricted tissue distribution of tetraploid cells previously reported for 4-cell tetraploid<-->8-cell diploid chimaeras. It is suggested that cells from the more advanced embryo are more likely to contribute to the ICM but, for technical reasons, are prevented from doing so in simple aggregates of equal numbers of whole 4-cell and whole 8-cell stage embryos.


A potassium channel mutation in neonatal human epilepsy.
Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene (KCNQ2) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog (Xenopus laevis) oocytes led to potassium-selective currents that activated slowly with depolarization. In a large pedigree with BFNC, a five-base pair insertion would delete more than 300 amino acids from the KCNQ2 carboxyl terminus. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.


Burden of Peripheral Artery Disease in Sub-Saharan Africa and the Caribbean 1990 to 2015.
The estimated global prevalence of Peripheral artery disease (PAD) increased by 24% in span of 10 years (2000-2010) from 164 to 202 million. Despite scarcity of data on PAD in sub-Saharan Africa (SSA) and the Caribbean, estimates for PAD from these regions may be helpful for health-care providers. The Global Burden of Disease Study 2015 quantified health loss from hundreds of diseases using systematic reviews and multilevel computer modeling. Estimated rates with 95% uncertainty intervals (UI) for PAD (ICD-10 I70.2) were examined for SSA and the Caribbean and compared to high-income North America (HINA). Disability-adjusted life years (DALYs) are years of healthy life lost representing total disease burden by combining years of life lost and years lived disabled. In 2015, estimated age-standardized DALYs per 100,000 due to PAD for males were as follows: Caribbean (34, UI: 29-39), HINA (36, UI: 30-42), and SSA (20, UI: 14-30). In contrast, DALYs in females were as follows: Caribbean (25, UI: 20-30), HINA (28, UI: 22-36), and SSA (17, UI: 11-26). For both sexes combined, the rate in Southern SSA was 55 (46-67). This reflects the extremely high rates in South Africa (males 90, UI: 77-107; females 63, UI: 53-75). Estimated rate of DALYs per 100,000 was lowest in SSA. Within SSA, the rate in South Africa was highest, exceeding even HINA. Caribbean rates were intermediate.


Surgeon's role in ethical decisions.
Three clinical cases are summarized to provide examples of reasonably common dilemmas in decision making. Instead of a focus on the solutions, the issue of "who decides" is raised. Contrary to frequent practice, the position is taken that, legally and ethically, substantive patient involvement is required. Factors implicated in physician dominance are briefly discussed, including subjectivity, medical care environments, and notions of the proper role of the physician. Suggestions for the surgeon's role include professional competence, patient education (including effective communication), and separation of the medical/technical aspects of decisions from the ethical/personal ones.


Diffusion weighted magnetic resonance imaging (DW-MRI) as a non-invasive, tissue cellularity marker to monitor cancer treatment response.
Diffusion weighted magnetic resonance imaging (DW-MRI) holds great potential for monitoring treatment response in cancer patients shortly after initiation of radiotherapy. It is hypothesized that a decrease in cellular density of irradiated cancerous tissue will lead to an increase in quantitative apparent diffusion coefficient (ADC) values. DW-MRI can therefore serve as a non-invasive marker of cell death and apoptosis in response to treatment. In the present study, we aimed to investigate the applicability of DW-MRI in preclinical models to monitor radiation-induced treatment response. In addition, we compared DW-MRI with ex vivo measures of cell density, cell death and apoptosis. DW-MRI was tested in two different syngeneic mouse models, a colorectal cancer (CT26) and a breast cancer (4 T1). ADC values were compared with quantitative determinations of apoptosis and cell death by flow cytometry. Furthermore, ADC-values were also compared to histological measurement of cell density on tumor sections. We found a significant correlation between ADC-values and apoptotic state in the CT26 model (P = 0.0031). A strong correlation between the two measurements of ADC-value and apoptotic state was found in both models, which were also present when comparing ADC-values to cell densities. Our findings demonstrate that DW-MRI can be used for non-invasive monitoring of radiation-induced changes in cell state during cancer therapy. ADC values reflect ex vivo cell density and correlates well with apoptotic state, and can hereby be described as a marker for the cell state after therapy and used as a non-invasive response marker.


Mapping functional interactions in a heterodimeric phospholipid pump.
Type 4 P-type ATPases (P(4)-ATPases) catalyze phospholipid transport to generate phospholipid asymmetry across membranes of late secretory and endocytic compartments, but their kinship to cation-transporting P-type transporters raised doubts about whether P(4)-ATPases alone are sufficient to mediate flippase activity. P(4)-ATPases form heteromeric complexes with Cdc50 proteins. Studies of the enzymatic properties of purified P(4)-ATPase·Cdc50 complexes showed that catalytic activity depends on direct and specific interactions between Cdc50 subunit and transporter, whereas in vivo interaction assays suggested that the binding affinity for each other fluctuates during the transport reaction cycle. The structural determinants that govern this dynamic association remain to be established. Using domain swapping, site-directed, and random mutagenesis approaches, we here show that residues throughout the subunit contribute to forming the heterodimer. Moreover, we find that a precise conformation of the large ectodomain of Cdc50 proteins is crucial for the specificity and functionality to transporter/subunit interactions. We also identified two highly conserved disulfide bridges in the Cdc50 ectodomain. Functional analysis of cysteine mutants that disrupt these disulfide bridges revealed an inverse relationship between subunit binding and P(4)-ATPase-catalyzed phospholipid transport. Collectively, our data indicate that a dynamic association between subunit and transporter is crucial for the transport reaction cycle of the heterodimer.


From primordial germ cells to spermatids in Caenorhabditis elegans.
Development of a syncytial germline for gamete formation requires complex regulation of cytokinesis and cytoplasmic remodeling. Recently, several uncovered cellular events have been investigated in the Caenorhabditis elegans (C. elegans) germline. In these cellular processes, the factors involved in contractility are highly conserved with those of mitosis and meiosis. However, the underlying regulatory mechanisms are far more complicated than previously thought, likely due to the single syncytial germline structure. In this review, we highlight how the proteins involved in contractility ensure faithful cell division in different cellular contexts and how they contribute to maintaining intercellular bridge stability. In addition, we discuss the current understanding of the cellular events of cytokinesis and cytoplasmic remodeling during the development of the C. elegans germline, including progenitor germ cells, germ cells, and spermatocytes. Comparisons are made with relevant systems in Drosophila melanogaster (D. melanogaster) and other animal models.


Application of Titanium Alloy 3D-Printed Artificial Vertebral Body for Stage III Kümmell's Disease Complicated by Neurological Deficits.
The current study aimed to compare the clinical and radiographic results of the 3D-printed artificial vertebral body (3DP-AVB) and titanium mesh cage (TMC) for the treatment of Kümmell's disease (KD) complicated by neurological deficits. From January 2014 to July 2018, 28 consecutive patients diagnosed with KD and nerve injuries in our department were treated by posterior vertebral column resection and internal fixation. The patients were divided into two groups (3DP-AVB group and TMC group) based on the different anterior column reconstruction implants. Clinical and radiographic parameters were used to evaluate the outcomes. The two groups achieved excellent clinical and radiographic results 1 month after surgery with no significant difference (P>0.05), while 3DP-AVB group showed better outcomes compared with TMC group during the follow-up after 6 months (P<0.05). The risk of subsidence in 3DP-AVB group was lower than that in TMC group (41.6% vs 87.5%, P<0.05), and severe subsidence (≥5 mm) was correlated with the recurrence of back pain and bad daily life function. No significant difference was found in the improvement of neurological function between the two groups (P>0.05). The blood loss and operation time in 3DP-AVB group were significantly less than both in TMC group (P<0.05). The lower incidence of cage subsidence, with a better long-term efficacy in maintaining the height of the fused segment, relieving back pain, and improving daily life function indicates that the 3DP-AVB may be a superior alternative for KD with neurological deficits.


Carboxyl group (-CO2 H) functionalized coordination polymer nanoparticles as efficient platforms for drug delivery.
Functionalization of nanoparticles can significantly influence their properties and potential applications. Although researchers can now functionalize metal, metal oxide, and organic polymer nanoparticles with a high degree of precision, controlled surface functionalization of nanoscale coordination polymer particles (CPPs) has remained a significant challenge. The lack of methodology is perhaps one of the greatest roadblocks to the advancement of CPPs into high added-value drug delivery applications. Here, we report having achieved this goal through a stepwise formation and functionalization protocol. We fabricated robust nanoparticles with enhanced thermal and colloidal stabilities by incorporation of carboxyl groups and these surface carboxyl groups could be subsequently functionalized through well-known peptide coupling reactions. The set of chemistries that we employed as proof-of-concept enabled a plethora of new functional improvements for the application of CPPs as drug delivery carriers, including enhanced colloidal stabilities and the incorporation of additional functional groups such as polyethylene glycol (PEG) or fluorescent dyes that enabled tracking of their cellular uptake. Finally, we ascertained the cytotoxicity of the new CPP nanoparticles loaded with camptothecin to human breast adenocarcinoma (MCF-7). Efflux measurements show that the encapsulation of camptothecin enhances the potency of the drug 6.5-fold and increases the drug retention within the cell.


Modulation of functional networks related to the serotonin neurotransmitter system by citalopram: Evidence from a multimodal neuroimaging study.
Selective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of the serotonin 1A receptor (5-HT1AR). We investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge. We analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [123I]FP-CIT single-photon emission computerized tomography. 5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low-dose group compared to the high-dose group at rest and the placebo group during the emotional face-matching task. Taken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.


Physician impairment: physicians' exposure, attitudes, and beliefs.
Concern about physician impairment has resulted in increased efforts to educate physicians about its nature and scope. This study reports the results of a survey of how family physicians obtain information about impairment, which sources they value, and how exposure to impairment relates to their attitudes and beliefs. A significant association was found between involvement in group-oriented programs and recognition of risk factors unique to the profession. Important differences were found between physicians who acknowledged the role of personal vulnerability in impairment and those who attributed causality to external sources. Results also revealed that this sample of physicians was almost equally divided on whether impairment should be defined exclusively by professional conduct.


[Use of a cocultivation method for detecting cytomegalovirus contamination of cell cultures of simian origin].
At present, nonanthropoid primates are widely used as sources of cell cultures for manufacture of live viral vaccines. Simian cell cultures, particularly kidney cell cultures are also known to be frequently contaminated with cytomegaloviruses. The isolation of the latter is rather difficult due to the late appearance of the cytopathic effect in cell cultures of natural hosts. In the present study, the sensitivity of 4 methods virus isolation from the test cells was compared: the method of long-term cultivation of cells; the method of long-term cultivation with one subpassage of the cells; the method of cocultivation of the test cells by mixing with sensitive cells; and the method of co-cultivation by overlaying the test cells on an incomplete monolayer of sensitive cells. The latter method shortened the observation period and yielded a higher percentage of isolation of contaminating viruses from African green monkey kidney cell cultures. This method is supposed to be used in future for the detection of viral contamination of African group monkey kidney cell cultures utilized in manufacture of live viral vaccines.


The Efficacy of Doxycycline Treatment on Mansonella perstans Infection: An Open-Label, Randomized Trial in Ghana.
Treating Mansonella perstans is challenged by the low efficacy of registered antihelminthics. Wolbachia endobacteria provide an alternative treatment target because depletion results in amicrofilaremia in filarial infections with Wuchereria bancrofti and Onchocerca volvulus infections. This open-label, randomized study sought to confirm that i) Wolbachia are present in M. perstans in Ghana and ii) doxycycline treatment will deplete Wolbachia and cause a slow, sustained decline in microfilariae (MF). Two hundred and two Ghanaians with M. perstans infection were randomized into early (immediate) and delayed (6 months deferred) treatment groups, given doxycycline 200 mg/day for 6 weeks, and monitored for MF and Wolbachia levels at baseline, 4, 12, and 24 months after the study onset (= time of randomization and start of treatment for the early group). Per protocol analysis revealed that the median MF/mL in the early group declined from 138 at baseline to 64 at month 4 and further to 0 at month 12. In the delayed group, MF load did not change from a baseline median of 97 to 102 at month 4 but declined to 42 at month 12, that is, 6 months after receiving treatment, trailing the early group as expected. By month 24, both treatment groups had reached a median MF level of 0. After treatment, Wolbachia were depleted from MF by ≥ 1-log drop compared with baseline levels. We conclude that M. perstans in Ghana harbor Wolbachia that are effectively depleted by doxycycline with subsequent reduction in MF loads, most likely because of interruption of fertility of adult worms.


Vitamin carrier proteins during embryonic development in birds and mammals.
Egg maturation in oviparous vertebrates involves the hepatic synthesis, secretion, and deposition in the developing oocyte of several maternal proteins with specific nutrient carrier function. Thus, in the chicken, adequate yolk deposition of riboflavin, thiamin, etc. is obligatorily mediated by carrier proteins specific to each vitamin. Like vitellogenin, these are oestrogen-inducible specific gene products. Despite differences in patterns of embryonic development in mammals vis-à-vis oviparous species, immunologically and biochemically similar maternal vitamin carriers participate in the transplacental transport and fetal accumulation of these vitamins during gestation in the rat. The rodent riboflavin and thiamin carrier proteins are also oestrogen-induced maternal proteins of hepatic origin. Their functional importance in fetal development was established by in vivo passive immunoneutralization of the endogenous proteins, which precipitated fetal wastage leading to pregnancy termination, due to curtailment of the vitamin supply to the fetuses. Similarly, active immunization of female rats with the vitamin carrier proteins led to early fetal resorption without interference with maternal health, cyclicity and fecundity. The discovery of similar gestation-specific carrier proteins in higher mammals and humans suggests that carrier-mediated vitamin delivery mechanisms ensuring embryonic growth have been conserved during evolution.


Binding between insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 is not influenced by glucose or 2-deoxy-D-glucose.
A recent report (Zhong, D., Xiong, L., Liu, T., Liu, X., Liu, X., Chen, J., Sun, S. Y., Khuri, F. R., Zong, Y., Zhou, Q., and Zhou, W. (2009) J. Biol. Chem. 284, 23225-23233) details that 2-deoxy-D-glucose (2-DG), a well known inhibitor of glycolysis and a candidate antineoplastic agent, also induces insulin-like growth factor 1 receptor (IGF-1R) signaling through the inhibition of insulin-like growth factor 1-insulin-like growth factor-binding protein 3 (IGF-1-IGFBP-3) complex formation. Zhong et al. hypothesized that disrupted IGF-1/IGFBP-3 binding by 2-DG led to increased free IGF-1 concentrations and, consequently, activation of IGF-1R downstream pathways. Because their report suggests unprecedented off-target effects of 2-DG, this has profound implications for the fields of metabolism and oncology. Using ELISA, surface plasmon resonance, and novel "intensity-fading" mass spectrometry, we now provide a detailed characterization of complex formation between IGF-1 and IGFBP-3. All three of these independent methods demonstrated that there was no effect of glucose or 2-DG on the interaction between IGF-1 and IGFBP-3. Furthermore, we show examples of 2-DG exposure associated with reduced rather than increased IGF-1R and AKT activation, providing further evidence against a 2-DG increase in IGF-1R activation by IGF-1-IGFBP-3 complex disruption.


Exceptional adsorption-induced cluster and network deformation in the flexible metal-organic framework DUT-8(Ni) observed by in situ X-ray diffraction and EXAFS.
The "gate opening" mechanism in the highly flexible MOF Ni2(2,6-ndc)2dabco (DUT-8(Ni), DUT = Dresden University of Technology) with unprecedented unit cell volume change was elucidated in detail using combined single crystal X-ray diffraction, in situ XRD and EXAFS techniques. The analysis of the crystal structures of closed pore (cp) and large pore (lp) phases reveals a drastic and unique unit cell volume expansion of up to 254%, caused by adsorption of gases, surpassing other gas-pressure switchable MOFs significantly. To a certain extent, the structural deformation is specific for the guest molecule triggering the transformation due to subtle differences in adsorption enthalpy, shape, and kinetic diameter of the guest. Combined adsorption and powder diffraction experiments using nitrogen (77 K), carbon dioxide (195 K), and n-butane (272.5 K) as a probe molecules reveal a one-step structural transformation from cp to lp. In contrast, adsorption of ethane (185 K) or ethylene (169 K) results in a two-step transformation with the formation of intermediate phases. In situ EXAFS during nitrogen adsorption was used for the first time to monitor the local coordination geometry of the metal atoms during the structural transformation in flexible MOFs revealing a unique local deformation of the nickel-based paddle-wheel node.


Dopamine Enhances Item Novelty Detection via Hippocampal and Associative Recall via Left Lateral Prefrontal Cortex Mechanisms.
The involvement of fronto-striatal circuits in item and associative memory retrieval as well as in the stabilization of memories by retrieval practice suggests that both retrieval and re-encoding of stored memories might rely on dopaminergic mechanisms in humans. We tested these hypotheses in a placebo-controlled pharmacological fMRI study using 2 mg of the D2 antagonist haloperidol administered acutely before a cued associative recall task of previously encoded picture-word pairs in 53 healthy humans of both sexes. The cued associative recall was moreover repeated 3 d later outside the scanner without pharmacological intervention. Dopaminergic modulation significantly improved associative recall performance and recognition accuracy of verbal items. Moreover, we observed a significant dopamine effect on re-encoding in terms of increased specificity of associative memories from the first to the second cued associative recall. Better association memory under haloperidol was linked with higher activity in the left lateral prefrontal cortex and right parietal cortex, suggesting that dopamine facilitates associative retrieval through increased recruitment of frontoparietal monitoring processes. In contrast, improved recognition of verbal items under haloperidol was reflected by enhanced novelty detection in the hippocampus and increased activity in saliency networks. Together, these results show distinct but concomitant positive effects of dopamine on associative recall and item recognition and suggest that the specificity of associative recall through re-encoding mechanisms is likewise augmented by dopamine.SIGNIFICANCE STATEMENT Although the neurotransmitter dopamine has been linked with learning and memory for a long time, dopaminergic effects on item recognition in humans were demonstrated only recently. The involvement of fronto-striatal monitoring processes in association retrieval suggests that associative memory might be particularly affected by dopamine. Moreover, fronto-striatal dopaminergic signals have been hypothesized to determine the updating and re-encoding of previously retrieved memories. We here demonstrate clear facilitative effects of dopamine on associative recall and item recognition mediated by prefrontal and hippocampal mechanisms respectively. Additionally, effects on re-encoding were reflected by increased specificity of associative memories. These results augment our understanding of dopaminergic processes in episodic memory retrieval and offer new perspectives on memory impairments in dopamine-related disorders and their treatment.


Maternal smoking and oral clefts: the role of detoxification pathway genes.
There is evidence for an effect of cigarette smoking on risk of oral clefts. There are also hypothetical pathways for a biologic effect involving toxic chemicals in cigarette smoke. We performed a combined case-control and family-triad study of babies born with oral clefts in Norway in the period 1996 to 2001, with 88% participation among cases (n = 573) and 76% participation among controls (n = 763). Mothers completed a questionnaire 4 months after birth of the baby. DNA was collected from parents and children, and assayed for genes related to detoxification of compounds of cigarette smoke (NAT1, NAT2, CYP1A1, GSTP1, GSTT1, and GSTM1). For isolated cleft lip (with or without cleft palate) there was a dose-response effect of smoking in the first trimester. The odds ratio rose from 1.6 (95% confidence interval = 1.0-2.5) for passive smoking to 1.9 (0.9-4.0) for mothers who smoked more than 10 cigarettes per day. There was little evidence of an association with cleft palate. Genetic analyses used both case-control and family-triad data. In case-triads we found an association between a NAT2 haplotype and isolated cleft lip (relative risk of 1.6 with 1 copy of the allele and 2.5 with 2 copies), but with little evidence of interaction with smoking. Other genes did not show associations, and previously described interactions with smoking were not confirmed. First-trimester smoking was clearly associated with risk of cleft lip. This effect was not modified by variants of genes related to detoxification of compounds of cigarette smoke.


[Light adaptation properties of receptor potentials of cyprinid retina].
It was previously reported that changes in sensitivities of electroretinographic b-wave in the course of light adaptation depended on the intensity of background lights. B-wave sensitivity decreased with time by dimmer background lights, while it recovered during illumination with background lights of higher intensities. In this work we examined light adaptation properties of glutamate-isolated receptor potentials (P III components), using isolated and superfused cyprinid retinas. During dimmer background illumination, P III components were unchanged. When background lights were increased above certain levels, P III components showed partial recovery with time in the light. A detailed analysis of spectral sensitivities of P III components and their increment thresholds for several wavelengths indicated that the recovery of P III sensitivity appeared with background lights at which rod function was taken over by cone function. The results suggest that the recovery of b-wave sensitivity during brighter background illumination is partially a reflection of the adaptation property of cone photoreceptors.


Influence of different self-etching primers on the bond strength of orthodontic lingual buttons.
The aim of this study was to evaluate the influence of six self-etching primers (SEPs) on the shear/peel bond strength (SPBS) of orthodontic lingual buttons. A total of 150 extracted human premolars were randomly divided into six equal groups. In all groups, the lingual buttons were bonded with BeautyOrtho Bond and the enamel was conditioned with the following-group I (Control): Primers A & B; group II: Transbond Plus SEP; group III: Clearfil Mega Bond FA™; group IV: AdheSE; group V: Peak SE & Peak LC Bond; and group VI: Bond Force. The teeth were stored at 37°C for 24 hours and the SPBS was tested (0.5 mm/minute). The results were calculated in mega pascals (MPa) and statistically analysed [mean, standard deviation, Scheffè, analysis of variance (P < 0.05)]. The adhesive remnant index (ARI) was also evaluated and statistically analysed with a chi-square test. All groups demonstrated higher SPBS than the force suggested as necessary to accomplish orthodontic tooth movement, except group IV (7.7 ± 1.7 MPa), which showed a significantly lower value than groups I (10.7 ± 2.4 MPa), II (11.3 ± 3.1 MPa), and V (10.9 ± 2.8 MPa). The values of groups III (9.9 ± 1.6 MPa) and VI (10.5 ± 1.6 MPa) were comparable with those of groups I and V. Significant differences (P < 0.05) were found among the groups in ARI scores. The SPBS values of all groups could be clinically acceptable and lingual buttons might be successfully bonded with any of these SEPs except AdheSE since that conditioner significantly influenced bond strength. As the SPBS was lower in all groups than the value at which enamel fractures have been found, a sound enamel surface might be left after removal of lingual buttons.


Exosomes Derived from Squamous Head and Neck Cancer Promote Cell Survival after Ionizing Radiation.
Exosomes are nanometer-sized extracellular vesicles that are believed to function as intercellular communicators. Here, we report that exosomes are able to modify the radiation response of the head and neck cancer cell lines BHY and FaDu. Exosomes were isolated from the conditioned medium of irradiated as well as non-irradiated head and neck cancer cells by serial centrifugation. Quantification using NanoSight technology indicated an increased exosome release from irradiated compared to non-irradiated cells 24 hours after treatment. To test whether the released exosomes influence the radiation response of other cells the exosomes were transferred to non-irradiated and irradiated recipient cells. We found an enhanced uptake of exosomes isolated from both irradiated and non-irradiated cells by irradiated recipient cells compared to non-irradiated recipient cells. Functional analyses by exosome transfer indicated that all exosomes (from non-irradiated and irradiated donor cells) increase the proliferation of non-irradiated recipient cells and the survival of irradiated recipient cells. The survival-promoting effects are more pronounced when exosomes isolated from irradiated compared to non-irradiated donor cells are transferred. A possible mechanism for the increased survival after irradiation could be the increase in DNA double-strand break repair monitored at 6, 8 and 10 h after the transfer of exosomes isolated from irradiated cells. This is abrogated by the destabilization of the exosomes. Our results demonstrate that radiation influences both the abundance and action of exosomes on recipient cells. Exosomes transmit prosurvival effects by promoting the proliferation and radioresistance of head and neck cancer cells. Taken together, this study indicates a functional role of exosomes in the response of tumor cells to radiation exposure within a therapeutic dose range and encourages that exosomes are useful objects of study for a better understanding of tumor radiation response.


Clinical and epidemiological characterization of dengue hemorrhagic fever cases in northeastern, Brazil.
The dengue hemorrhagic dengue (DHF) remains an important public health problem in Brazil. The objective of this study was to analyze the epidemiological characteristics of DHF cases during the 2003 epidemic in Ceará. Suspected DHF cases with onset of symptoms between January and December 2003 were investigated. 37,964 classic dengue cases and 291 DHF cases were reported. Among the cases discarded, 75.5% were serologically positive but did not meet the criteria recommended by the World Health Organization (WHO). The DHF patients' median age was 30 years (2 - 88). Among the hemorrhagic manifestations, petechiae were the most (32.6%) frequent. Cases of gastrointestinal bleeding, ascites, pericardial pleural effusion, hepatomegaly, hypotension and shock showed higher risk of progression to death (p <0.05). The introduction of a new serotype (DENV-3) in Ceará, which encountered a susceptible population and high vector density, may have been the primary agent responsible for the magnitude of the epidemic. Timely and appropriate medical care, along with an organized care structure are essential for reducing its lethality.


Acute renal failure produced by combining cyclosporine and brief renal ischemia in the Munich Wistar rat.
To evaluate the combined effects of a brief ischemic insult and cyclosporine, four groups of male Munich Wistar rats were given: a) parenteral cyclosporine (60 mg/kg i.p.) for 4 days following 20 minutes of bilateral renal ischemia, b) the castor oil cyclosporine vehicle in a comparable volume and the same ischemic insult, c) saline in the same volume and ischemia, or d) saline and sham surgery. The cyclosporine animals ate and drank poorly, and therefore the other groups were pair-fed and watered with them. The cyclosporine-ischemia group developed significant renal failure. The other groups exhibited only a mild rise in blood urea nitrogen. Tubular vacuolization was a prominent feature in the cyclosporine and vehicle groups, but not in the saline groups. Vacuolization was correlated with severity of renal impairment. Lipid stains showed that many of the vacuoles contained lipid. Eosinophilic cytoplasmic inclusions were seen only in the cyclosporine or vehicle- (castor oil) treated animals. These findings emphasize the probable functional importance of tubular lesions in cyclosporine-induced acute renal failure, and suggest that the castor oil vehicle of parenteral cyclosporine may have renal effects of its own.


Computer aid for decision to biopsy breast masses on mammography: validation on new cases.
The purpose of this study was to validate the performance of a previously developed computer aid for breast mass classification for mammography on a new, independent database of cases not used for algorithm development. A computer aid (classifier) based on the likelihood ratio (LRb) was previously developed on a database of 670 mass cases. The 670 cases (245 malignant) from one medical institution were described using 16 features from the American College of Radiology Breast Imaging-Reporting and Data System lexicon and patient history findings. A separate database of 151 (43 malignant) validation cases were collected that were previously unseen by the classifier. These new validation cases were evaluated by the classifier without retraining. Performance evaluation methods included Receiver Operating Characteristic (ROC), round-robin, and leave-one-out bootstrap sampling. The performance of the classifier on the training data yielded an average ROC area of 0.90 +/- 0.02 and partial ROC area (0.90AUC) of 0.60 +/- 0.06. The exact nonparametric performance on the validation set of 151 cases yielded a ROC area of 0.88 and 0.90AUC of 0.57. Using a 100% sensitivity cutoff threshold established on the training data (100% negative predictive value), the classifier correctly identified 100% of the malignant masses in the validation test set, while potentially obviating 26% of the biopsies performed on benign masses. The LRb classifier performed consistently on new data that was not used for classifier development. The LRb classifier shows promise as a potential aid in reducing the number of biopsies performed on benign masses.


Mismatch between Conventional Femoral Arthroplasty Stems and Hip Morphology in the Elderly Chinese Hip Fracture Population.
The morphology of the proximal femur differs in various populations. Based on our clinical experience, conventional femoral stems used in hip arthroplasty do not fit the Chinese population well. Hence, this study aims to evaluate the suitability of conventional femoral stems in the elderly Chinese hip fracture population requiring hip arthroplasty and to establish if gender and age related differences exist within this population. We retrospectively analysed radiographic data of 300 patients from a tertiary hospital's geriatric hip fracture database who underwent either hip hemi-arthroplasties or total hip arthroplasties. Proximal femur morphological measurements were recorded, analysed and compared to that of commonly used femoral stems. Subgroup analysis was performed to compare age and gender related differences. A total of 18.3% of the study population had a medial femoral offset (MFO) of less than 30mm, which is the smallest available offset for the implants studied. 22.6% of female and 3% of male subjects had MFOs that were less than 30mm. In our subgroup analysis, males had significantly larger femoral head diameters, MFO and vertical femoral offsets compared to females. Older subjects (75-90 years old) had significantly smaller femoral head diameters, vertical femoral offsets and neck shaft angles compared to younger subjects (60-75 years old). Commonly used femoral stem implants have measurements that do not suit our Chinese population with small medial femoral offsets. In addition, elderly males have significantly larger femoral head diameters, medial and vertical femoral offsets whereas older subjects have significantly smaller femoral head diameters, vertical femoral offsets and neck shaft angles.


The special case of complicated grief in women at high risk for breast cancer.
Exploration of complicated grief focusing on the relationship of post-traumatic stress disorder (PTSD) and complicated grief in a population of women at high risk for developing breast cancer. Special reference is made to women who have experienced a material death. We reflected on the clinical attributes of the Revlon UCLA High Risk Clinic population in terms of their own perceived risk of developing breast cancer. For part of our population, their perceived risk was coupled with their reactions to the loss of their mothers to breast cancer. We compared and contrasted this pattern of reactions to those described by Licihtenthal et al. (2004) in their developmental review of complicated grief as a distinct disorder. We concluded that our population of women differed from Lichtenthal et al.'s (2004) model for complicated grief. Lichtenthal's group postulated that the key element of complicated grief involves the protracted nature of separation anxiety and distress and excludes PTSD. In our populations, the daughter with complicated grief experiences a combination of separation anxiety and a type of PTSD involving anxiety over the perceived certainty of her own future diagnosis of breast cancer. It was noteworthy that Lichtenthal's model population was composed of individuals caring for terminally ill spouses. Significantly, the spousal caretakers did not have an ongoing genetic link to their partners whereas our population is genetically linked. We postulate that this accounts for the unique presentation of complicated grief and ptsd in our population. We submit that this combination of complicated grief and PTSD requires a cognitive reframing of their perceived inevitability of developing breast cancer and desensitization techniques to help high risk women pursue preventative health care rather than avoiding it.


Arsenite but not arsenate inhibits general proteoglycan synthesis in cultured arterial smooth muscle cells.
Epidemiological and experimental studies have suggested that exposure to metalloid arsenic constitutes a risk factor for vascular disease associated with atherosclerosis. Since in atherosclerosis, types of proteoglycans (PGs) present change depending on the stage, we investigated the effect of 2 chemical forms of inorganic arsenic-a trivalent sodium arsenite and a pentavalent sodium arsenate-on the synthesis of PGs in cultured arterial smooth muscle cells. The results indicate that arsenite but not arsenate, at a noncytotoxic level, inhibits general PG synthesis independent of cell density. Arsenite may be one of the chemical forms of inorganic arsenic that influences the PG composition in blood vessel walls during the progression of vascular disorders such as atherosclerosis.


Up-regulated cytoplasmic expression, with reduced membranous distribution, of the src substrate p120(ctn) in gastric carcinoma.
p120(ctn) is a substrate of the tyrosine kinase pp60 src. Tyrosine kinases such as src localize to the adherens junctions and phosphorylate junctional proteins in both normal and transformed cells.(1) p120(ctn) forms a complex with E-cadherin at the adherens junction and is phosphorylated by ligands such as epidermal growth factor receptor as well as pp60 src. Phosphorylation of p120(ctn) has been shown to correlate with cell transformation. The aim of this study was to investigate in vivo expression of p120(ctn) in gastric carcinoma and to examine any relationship to pathological characteristics and patient survival. Immunohistochemical staining for p120(ctn) was performed in 68 gastric carcinoma specimens (19 diffuse, 49 intestinal type), in 22 lymph node metastases, and in gastric mucosal biopsies from 16 patients with gastric dysplasia and ten healthy controls. Up-regulation of p120(ctn) cytoplasmic staining was seen in six (37 per cent) of the gastric dysplasia cases and in 45 (66 per cent) tumours (89 per cent of diffuse and 57 per cent of intestinal tumours). Loss of membranous distribution of staining for p120(ctn) was seen in 22 (32 per cent) tumours (52 per cent of diffuse and 24 per cent of intestinal tumours). The staining pattern in the primary tumour showed no correlation with tumour type, grade, or stage, or patient survival. Of 22 lymph node metastases examined, 13 (60 per cent) showed loss of membranous staining. In conclusion, staining for p120(ctn) in gastric carcinoma and dysplasia revealed marked up-regulation of cytoplasmic staining, sometimes associated with reduced membranous expression. Up-regulation of expression of p120(ctn) has not previously been described in human epithelial malignancy. The significance of these findings is uncertain, but they may reflect a change in tyrosine kinase signal transduction pathways, and a role for p120(ctn) in ligand-induced mitogenic signalling and cell transformation.


An innovative nonpharmacological intervention combined with intravenous patient-controlled analgesia increased patient global improvement in pain and satisfaction after major surgery.
This study aimed to evaluate whether a nonpharmacological approach through implementation of a communication improvement program (named CICARE for Connect, Introduce, Communicate, Ask, Respond and Exit) into standard operating procedure (SOP) in acute pain service (APS) improved satisfaction in patients receiving intravenous patient-controlled analgesia (IV-PCA). This was a nonrandomized before-after study. Adult patients (aged between 20 and 80 years) who received IV-PCA after major surgery were included. Implementing CICARE into SOP was conducted in APS. Anonymous questionnaires were used to measure outcomes in this prospective two-part survey. The first part completed by APS nurses contained patients' characteristics, morphine dosage, delivery/demand ratios, IV-PCA side effects and pain at rest measured with an 11-point numeric rating scale (NRS, 0-10). A score of NRS ≥4 was defined as inadequately treated pain. The ten-question second part was completed by patients voluntarily after IV-PCA was discontinued. Each question was assessed with a 5-point Likert scale (1: extremely poor; 5: excellent). Patients were separated into "before" and "after" CICARE groups. Primary outcomes were patient global impression of improvement in pain (PGI-Improvement) and patient satisfaction. Secondary outcomes included quality of communication skills, instrument proficiency and accessibility/availability of IV-PCA. The response rate was 55.3%, with 187 usable questionnaires. CICARE effectively improved patient global impression of improvement in pain, patient satisfaction, communication skills and accessibility/availability of IV-PCA. No significant differences were noted in instrument proficiency, morphine dosage, delivery/demand ratios, rates of inadequately treated pain at rest and side effects of IV-PCA between groups. Paradoxical findings were noted between the rates of inadequately treated pain/side effects and PGI-Improvement in pain/patient satisfaction, which were affected by psychological factors. Nonpharmacological interventions carried out by implementing CICARE into SOP for APS effectively improved patient satisfaction and postoperative pain management quality, but this did not affect actual pain.


The BMP antagonist noggin regulates cranial suture fusion.
During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors (fgfr) are associated with syndromic forms of craniosynostosis. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning. Here we show that noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since noggin misexpression prevents cranial suture fusion in vitro and in vivo, we suggest that syndromic fgfr-mediated craniosynostoses may be the result of inappropriate downregulation of noggin expression.


Shared decision-making for people with asthma.
Asthma is a chronic inflammatory disease that affects the airways and is common in both adults and children. It is characterised by symptoms including wheeze, shortness of breath, chest tightness, and cough. People with asthma may be helped to manage their condition through shared decision-making (SDM). SDM involves at least two participants (the medical practitioner and the patient) and mutual sharing of information, including the patient's values and preferences, to build consensus about favoured treatment that culminates in an agreed action. Effective self-management is particularly important for people with asthma, and SDM may improve clinical outcomes and quality of life by educating patients and empowering them to be actively involved in their own health. To assess benefits and potential harms of shared decision-making for adults and children with asthma. We searched the Cochrane Airways Trials Register, which contains studies identified in several sources including CENTRAL, MEDLINE, and Embase. We also searched clinical trials registries and checked the reference lists of included studies. We conducted the most recent searches on 29 November 2016. We included studies of individual or cluster parallel randomised controlled design conducted to compare an SDM intervention for adults and children with asthma versus a control intervention. We included studies available as full-text reports, those published as abstracts only, and unpublished data, and we placed no restrictions on place, date, or language of publication. We included interventions targeting healthcare professionals or patients, their families or care-givers, or both. We included studies that compared the intervention versus usual care or a minimal control intervention, and those that compared an SDM intervention against another active intervention. We excluded studies of interventions that involved multiple components other than the SDM intervention unless the control group also received these interventions. Two review authors independently screened searches, extracted data from included studies, and assessed risk of bias. Primary outcomes were asthma-related quality of life, patient/parent satisfaction, and medication adherence. Secondary outcomes included exacerbations of asthma, asthma control, acceptability/feasibility from the perspective of healthcare professionals, and all adverse events. We graded and presented evidence in a 'Summary of findings' table.We were unable to pool any of the extracted outcome data owing to clinical and methodological heterogeneity but presented findings in forest plots when possible. We narratively described skewed data. We included four studies that compared SDM versus control and included a total of 1342 participants. Three studies recruited children with asthma and their care-givers, and one recruited adults with asthma. Three studies took place in the United States, and one in the Netherlands. Trial duration was between 6 and 24 months. One trial delivered the SDM intervention to the medical practitioner, and three trials delivered the SDM intervention directly to the participant. Two paediatric studies involved use of an online portal, followed by face-to-face consultations. One study delivered an SDM intervention or a clinical decision-making intervention through a mixture of face-to-face consultations and telephone calls. The final study randomised paediatric general practice physicians to receive a seminar programme promoting application of SDM principles. All trials were open-label, although one study, which delivered the intervention to physicians, stated that participants were unaware of their physicians' involvement in the trial. We had concerns about selection and attrition bias and selective reporting, and we noted that one study substantially under-recruited participants. The four included studies used different approaches to measure fidelity/intervention adherence and to report study findings.One study involving adults with poorly controlled asthma reported improved quality of life (QOL) for the SDM group compared with the control group, using the Asthma Quality of Life Questionnaire (AQLQ) for assessment (mean difference (MD) 1.90, 95% confidence interval (CI) 1.24 to 2.91), but two other trials did not identify a benefit. Patient/parent satisfaction with the performance of paediatricians was greater in the SDM group in one trial involving children. Medication adherence was better in the SDM group in two studies - one involving adults and one involving children (all medication adherence: MD 0.21, 95% CI 0.11 to 0.31; mean number of controlled medication prescriptions over 26 weeks: 1.1 in the SDM group (n = 26) and 0.7 in the control group (n = 27)). In one study, asthma-related visit rates were lower in the SDM group than in the usual care group (1.0/y vs 1.4/y; P = 0.016), but two other studies did not report a difference in exacerbations nor in prescriptions for short courses of oral steroids. Finally, one study described better odds of reporting no asthma problems in the SDM group than in the usual care group (odds ratio (OR) 1.90, 95% CI 1.26 to 2.87), although two other studies reporting asthma control did not identify a benefit with SDM. We found no information about acceptability of the intervention to the healthcare professional and no information on adverse events. Overall, our confidence in study results ranged from very low to moderate, and we downgraded outcomes owing to risk of bias, imprecision, and indirectness. Substantial differences between the four included randomised controlled trials (RCTs) indicate that we cannot provide meaningful overall conclusions. Individual studies demonstrated some benefits of SDM over control, in terms of quality of life; patient and parent satisfaction; adherence to prescribed medication; reduction in asthma-related healthcare visits; and improved asthma control. Our confidence in the findings of these individual studies ranges from moderate to very low, and it is important to note that studies did not measure or report adverse events.Future trials should be adequately powered and of sufficient duration to detect differences in patient-important outcomes such as exacerbations and hospitalisations. Use of core asthma outcomes and validated scales when possible would facilitate future meta-analysis. Studies conducted in lower-income settings and including an economic evaluation would be of interest. Investigators should systematically record adverse events, even if none are anticipated. Studies identified to date have not included adolescents; future trials should consider their inclusion. Measuring and reporting of intervention fidelity is also recommended.


Reliable underwater dipole source characterization in 3D space by an optimally designed artificial lateral line system.
Inspired by the lateral line of aquatic vertebrates, an artificial lateral line (ALL) system can localize and track an underwater moving object by analyzing the ambient flow caused by its motion. There are several studies on object detection, localization and tracking by ALL systems, but only a few have investigated the optimal design of the ALL system, the one that on average provides the highest characterization accuracy. Design optimization is particularly important because the uncertainties in the employed flow model and in sensor measurements deteriorate the reliability of sensing. This study investigates the optimal design of the ALL system in three-dimensional (3D) space for dipole source characterization. It highlights some challenges specific to the 3D setting and demonstrates the shortcomings of the designs in which all sensors and their sensing directions are in the same plane. As an alternative, it proposes two design concepts, called 'Offset Strategy' and 'Angle Strategy' to overcome these shortcomings. It investigates potentials of having a swarm of cooperative ALLs as well. It performs design optimization in the presence of sensor and model uncertainties and analyzes the trade-off between the number of sensors and characterization accuracy. The obtained solutions are analyzed to reveal their strategies in solving the problem efficiently. The dependency of the optimized solutions on the uncertainties is also demonstrated.


BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer.
A national study of BRCA1 and BRCA2 mutations in Danish HBOC (Hereditary Breast Ovarian Cancer) families revealed a total number of 322 mutation positive families, 206 (64%) BRCA1 and 116 (36%) BRCA2 positive families from a population of 5.5 million inhabitants. Seven hundred and twenty six mutation positive individuals were identified: 402 female BRCA1 carriers, 79 male BRCA1 carriers, 213 female BRCA2 carriers, and 32 male BRCA2 carriers by April 2006. Most of the mutations were frame shift or nonsense mutations, while large genomic rearrangements were rare. Most mutations were only identified in one family. A few mutations were detected repeatedly. In BRCA1 the most common mutations were: 2594delC in 32 families (16%), 3438G>T in 19 families (9%), 5382insC in 16 families (8%), 3829delT in 11 families (5%). In BRCA2 the most common mutations were: 6601delA in 13 families (11%), 1538del4 in 12 families (10%), 6714del4 in 10 families (9%). There was a tendency towards a higher frequency of BRCA2 mutations in West Denmark compared to East Denmark. The frequencies of specific BRCA1 and BRCA2 mutations were slightly different in the two regions. The mutations occurring in West Denmark have also been observed in other Scandinavian countries whereas the mutations occurring in East Denmark were more often reported from other European countries and the Baltic countries. The pattern of mutation distributions are comparable with observations from other Scandinavian and European studies and indicate that the Danish BRCA1 and BRCA2 mutations are a mixture of Scandinavian mutations and other European mutations including two of the Ashkenazi mutations. Even though a tendency towards founder mutations was observed most mutations were only detected once. Based on these observations we recommend that the mutation screening strategy of the BRCA1 and BRCA2 genes in Danish HBOC families comprises full screening of both genes including analysis for large genomic rearrangements.


Age effects on atrophy rates of entorhinal cortex and hippocampus.
The effects of age, subcortical vascular disease, apolipoprotein E (APOE) epsilon4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, and white matter hyperintensities (WMH) and the presence of lacunes were assessed on MR images. Age was significantly associated with increased atrophy rates of 0.04+/-0.02% per year for ERC and 0.05+/-0.02% per year for hippocampus. Atrophy rates of hippocampus, but not that of ERC increased with presence of lacunes, in addition to age. WMH, APOE epsilon4 and hypertension had no significant effect on atrophy rates. In conclusion, age and presence of lacunes should be taken into consideration in imaging studies of CN subjects and AD patients to predict AD progression and assess the response to treatment trials.


Characteristics of acoustic scattering from a double-layered micro shell for encapsulated drug delivery.
This work examines the characteristic differences in acoustic scattering between air-filled double-layered encapsulating (DLE) shells and air-filled single-layered encapsulating (SLE) shells. The analysis shows that the presence of an outer layer softer than the inner layer results in a shift of the first monopole of the reflectivity-frequency response to a higher frequency and a reduction in the monopole peak; and it leads to a frequency-separation of the two dipoles that trace the monopole. The frequency shift and the peak reduction of the monopole and the frequency separation of the two dipoles all increase with the increasing thickness of the softer outer layer. The numerical results reveal that variations in the Lame constant of the model material for the protein albumin have little effect on the low-frequency scattering characteristics, while they affect the high-frequency scattering characteristics significantly. The authors have shown that this phenomenon is due to the fact that the model material for the protein albumin has a Lame constant substantially larger than its shear modulus. Their further numerical studies conclude that, for each DLE shell, one can construct an equivalent SLE shell, using a simple scheme originated from the mechanics of composite materials in the sense that the so-constructed SLE shell has essentially the same acoustic scattering characteristics as the DLE shell within a low frequency range.


Pedunculated HCC or adrenal metastasis: a diagnostic conundrum.
Hepatocellular carcinoma (HCC) is the commonest primary liver tumour. Recurrences are common in the liver although extrahepatic metastases can occur and frequently involve the adrenals. When this occurs in the right adrenal gland, it can be confused with an exophytic HCC arising from the posterior surface of the liver. The distinction between a primary HCC and a metastasis is important but can be difficult in this clinical setting. We report a 52-year-old man with recurrent HCC presenting as an "exophytic" posterior liver surface lesion that was actually a right adrenal metastasis. Although right-sided adrenal metastases of HCC can be difficult to distinguish from intrahepatic recurrences, even with modern diagnostic imaging, management either way involves surgical exploration and resection whenever possible.


Diurnal variation in the effect of melatonin on plasma and muscle free fatty acid levels in the pigeon.
Pigeons maintained on standard diet and held under 12 h daily photo-period in a controlled environmental room, were given intravenous injections of melatonin. A low dose (1.25 mg/kg body weight) of melatonin when given in the middle of the scotophase, produced a significant increase in plasma FFA when estimated at 20 min and 90 min post-injection, whereas no significant change was seen with injections given in the middle of the photophase. No significant change in muscle FFA level was obtained either during the photophase or the scotophase when estimated at 90 min postinjection. With a higher dose (5 mg/kg body weight) of melatonin given in the scotophase, on the other hand, a significant increase in both plasma as well as muscle FFA levels was obtained at 90 min post-injection but there was no effect on plasma FFA at 20 min or 90 min post-injection in the photophase and at 20 min in the scotophase. It is concluded that melatonin has a lipid mobilizing action in the pigeon when administered during the scotophase.


Bone marrow biopsy in solid cancer.
205 patients with solid cancer, underwent bone marrow biopsy using a Jamshidi needle, regular type. 32 (16%) biopsies were positive for bone marrow metastases. Results were correlated with those of skeletal radioisotope scans, X-ray films and the complaint of bone pain, alone or combined. 27 of 131 (17.5%) patients with positive X-ray film and 31 of 110 patients (28.1%) who complained of bone pain had a positive bone marrow biopsy. 17 of 46 (36.9%) patients with 3 positive parameters had a positive bone marrow biopsy as compared with none of 18 patients whose these 3 parameters were negative. Average values of Hb, WBC, serum alkaline phosphatase and calcium did not differ between patients with positive or negative bone marrow biopsy. 86 patients were diagnosed to have bone metastases and 35 more patients were diagnosed within a year following the biopsy. Of these 121 patients, 46 of 46 with positive scan, X-ray and pain were diagnosed to have bone metastases as compared to 27 of 30 patients with a positive scan with pain but negative X-ray film. Only 1 of 18 patients with negative parameters was diagnosed as having bone metastases within a year from biopsy. In our experience, it is of no value (unlike in malignant lymphoma and oat cell carcinoma of lung) to obtain a bone marrow biopsy for the detection of bone marrow micrometastases in asymptomatic cancer patients with negative skeletal radioisotope scan and negative bone X-ray films.


[The efficacy of the Childs-Phillips mesenteric plication in intestinal obstruction].
From 1975 to 1988 we studied and valued fourteen pediatric patients, treated in the Department of Pediatric Surgery at Children's Hospital La Paz, with the Childs-Phillips procedure by postoperative recurrent bowel obstruction. Ten newborn infants had the following diagnoses: intestinal atresia, 4; Bochdaleck hernia, 3; Hirschsprung disease, 2; intestinal rotation anomalies, 1. Four patients out of neonatal period had: hiatal hernia, 1; intussusception, 1; appendicitis, 2. Six patients had more than one episode of bowel obstruction. The follow-up was 6.5 years (range four months to 13 years), and no recurrent bowel obstruction occurred.


Identification of a misfolded region in superoxide dismutase 1 that is exposed in amyotrophic lateral sclerosis.
Mutations and aberrant post-translational modifications within Cu,Zn-superoxide dismutase (SOD1) cause this otherwise protective enzyme to misfold, leading to amyotrophic lateral sclerosis (ALS). The C4F6 antibody selectively binds misfolded SOD1 in spinal cord tissues from postmortem human ALS cases, as well as from an ALS-SOD1 mouse model, suggesting that the C4F6 epitope reports on a pathogenic conformation that is common to misfolded SOD1 variants. To date, the residues and structural elements that comprise this epitope have not been elucidated. Using a chemical cross-linking and mass spectrometry approach, we identified the C4F6 epitope within several ALS-linked SOD1 variants, as well as an oxidized form of WT SOD1, supporting the notion that a similar misfolded conformation is shared among pathological SOD1 proteins. Exposure of the C4F6 epitope was modulated by the SOD1 electrostatic (loop VII) and zinc binding (loop IV) loops and correlated with SOD1-induced toxicity in a primary microglia activation assay. Site-directed mutagenesis revealed Asp(92) and Asp(96) as key residues within the C4F6 epitope required for the SOD1-C4F6 binding interaction. We propose that stabilizing the functional loops within SOD1 and/or obscuring the C4F6 epitope are viable therapeutic strategies for treating SOD1-mediated ALS.


Transfer of physical understanding in a non-tool-using parrot.
Physical cognition has generally been assessed in tool-using species that possess a relatively large brain size, such as corvids and apes. Parrots, like corvids and apes, also have large relative brain sizes, yet although parrots rarely use tools in the wild, growing evidence suggests comparable performances on physical cognition tasks. It is, however, unclear whether success on such tasks is facilitated by previous experience and training procedures. We therefore investigated physical comprehension of object relationships in two non-tool-using species of captive neotropical parrots on a new means-end paradigm, the Trap-Gaps task, using unfamiliar materials and modified training procedures that precluded procedural cues. Red-shouldered macaws (Diopsittaca nobilis) and black-headed caiques (Pionites melanocephala) were presented with an initial task that required them to discriminate between pulling food trays through gaps while attending to the respective width of the gaps and size of the trays. Subjects were then presented with a novel, but functionally equivalent, transfer task. Six of eight birds solved the initial task through trial-and-error learning. Four of these six birds solved the transfer task, with one caique demonstrating spontaneous comprehension. These findings suggest that non-tool-using parrots may possess capacities for sophisticated physical cognition by generalising previously learned rules across novel problems.


Spin-Orbit Charge-Transfer Intersystem Crossing of Compact Naphthalenediimide-Carbazole Electron-Donor-Acceptor Triads.
Compact electron donor-acceptor triads based on carbazole (Cz) and naphthalenediimide (NDI) were prepared to study the spin-orbit charge-transfer intersystem crossing (SOCT-ISC). By variation of the molecular conformation and electron-donating ability of the carbazole moieties, the electronic coupling between the two units was tuned, and as a result charge-transfer (CT) absorption bands with different magnitudes were observed (ε = 4000-18 000 M-1 cm-1). Interestingly, the triads with NDI attached at the 3-C position or with a phenyl spacer at the N position of the Cz moiety, thermally activated delayed fluorescence (TADF) was observed. Femtosecond transient absorption (fs-TA) spectroscopy indicated fast electron transfer (0.8-1.5 ps) from the Cz to NDI unit, followed by population of the triplet state (150-600 ps). Long-lived triplet states (up to τT = 45-50 μs) were observed for the triads. The solvent-polarity-dependent singlet-oxygen quantum yield (ΦΔ) is 0-26%. Time-resolved electron paramagnetic resonance (TREPR) spectral study of TADF molecules indicated the presence of the 3CT state for NDI-Cz-Ph (zero-field-splitting parameter D = 21 G) and an 3LE state for NDI-Ph-Cz (D = 586 G). The triads were used as triplet photosensitizers in triplet-triplet annihilation upconversion by excitation into the CT absorption band; the upconversion quantum yield was ΦUC = 8.2%, and there was a large anti-Stokes shift of 0.55 eV. Spatially confined photoexcitation is achieved with the upconversion using focusing laser beam excitation, and not the normally used collimated laser beam, i.e., the upconversion was only observed at the focal point of the laser beam. Photo-driven intermolecular electron transfer was demonstrated with reversible formation of the NDI-• radical anion in the presence of the sacrificial electron donor triethanolamine.


The Correlation Between Copeptin and Volume Status in Chronic Hemodialysis Patients.
Currently There is no noninvasive chemical biomarker, available for evaluating volume status, in individuals with endstage kidney disease (ESKD). This study aimed to determine the relationship between copeptin level and volume status in hemodialysis patients. This clinical trial enrolled 84 patients with ESKD (Mean age ± SD: 54.31 ± 15.47) on maintenance hemodialysis (3-times weekly, 4h /session). Plasma levels of Hb, copeptin, HCT, Na, and BUN, patients' weight, systolic and diastolic blood pressure and mean arterial pressure were measured, before and after hemodialysis. Age, sex, etiology of kidney failure, and duration of dialysis were also recorded., and the correlation between copeptin level and all variables was evaluated. There was a significant positive correlation between copeptin level and Hb (r = 0.313, P < .05), and HCT (r = 0.25, P < .05), while a negative association was found between copeptin level and Na (r = -0.051, P > .05) and IDWG (r = -0.05, P > .05). Although copeptin concentration was higher in females before (929.23 pmol/L) and after dialysis (783.3 pmol/L) than male patients (657.05 and 697.45 pmol/L), the mean copeptin changes was higher in male (205 pmol/L) than female (197 pmol/L) (P > .05). The level of copeptin decreased (P > .05) but the level of Hb (P < .05), HCT (P < .05), and Na (P > .05) were increased after dialysis compared to pre-dialysis period. Copeptin could be used as a surrogate marker for the diagnosis of volume status in hemodialysis patients. DOI: 10.52547/ijkd.7119.


Kinetics of intramembrane charge movement and sodium current in frog node of Ranvier.
Intramembrane charge movement (Q) and sodium current (INa) were monitored in isolated voltage-clamped frog nodes of Ranvier, ON charge movements (QON) for pulses from the holding potential (-100 mV) to potentials V less than or equal to 0 mV followed single exponential time courses, whereas two exponentials were found for pulses to V greater than or equal to 20 mV. The voltage dependence of both QON and its time constant tauON indicated that the two ON components resolved at V greater than or equal to 20 mV were also present, though not resolvable, for pulses to V less than or equal to 0 mV. OFF charge movements (QOFF) monitored at various potentials were well described by single exponentials. When QOFF was monitored at -30 or -40 mV after a 200-microsecond pulse to +20 mV and QON was monitored at the same potential using pulses directly from -100 mV, tauON/tauOFF = 2.5 +/- 0.3. At a set OFF potential (-90 to -70 mV), tauOFF first increased with increasing duration tON of the preceding pulse to a given potential (0 to +30 mV) and then decreased with further increases in tON. The declining phase of tauOFF followed a time course similar to that of the decline in QOFF with tON. For the same pulse protocol, the OFF time constant tauNa for INA also first increased with tON but then remained constant over the tON interval during which tauOFF and QOFF were declining. After 200- or 300-microsecond pulses to +20, +20, or +50 mV, tauOFF/tauNa at -70 to -90 mV was 1.2 +/- 0.1. Similar tauOFF/tauNa ratios were predicted by channel models having three identical charged gating particles that can rapidly and reversibly form an immobile dimer or trimer after independently crossing the membrane from their OFF to their ON locations.