Colorectal cancer incidence and mortality after negative fecal immunochemical tests by age 70: A prospective observational study.
Limited endoscopy capacity usually represents the main barrier to the extension of screening to subjects older than 70, given the high positivity rate in this age group. We assessed CRC incidence and mortality by number of previous negative fecal immunochemical tests (FIT) among subjects turning 70. We selected persons aged 70 years who had received their last screening invitation when they were 68 or 69 years old within the population-based screening program in the Veneto region of Italy. Subjects with a positive FIT were excluded. We calculated 10-year cumulative CRC incidence and mortality in cohorts of subjects having performed zero, one, two or three negative FITs over the last three screening rounds before turning 70. Out of 117 858 subjects included in the study (46.4% men), 33.7% had never participated in screening (zero negative FITs), 23.3% had had one-negative FIT, 20.1% two-negative FITs and 22.9% three negative FITs. The 10-year cumulative CRC incidence was 29.7 per 1000 subjects with zero FITs, and respectively, 14.5, 11.7 and 9.6 per 1000 subjects with one, two and three negative FITs. The corresponding figures for 10-year cumulative mortality were 9.3, 3.5, 2.2 and 2.1 per 1000 in the four study cohorts. Figures were roughly double for men than for women for all the study cohorts. In order to use more efficiently limited endoscopy resources, and to minimize the potential harms related to false positive results in the elderly, screening among people aged 70 to 74 might be restricted to those with zero previous negative FITs.


Strain variation in the adaptation of C57Bl6 and BALBc mice to chronic hypobaric hypoxia.
The interplay of environmental and genetic factors may lead to a spectrum of physiological and behavioral outcomes. How environmental stress factors interact with the diverse mouse genomes is still poorly understood and elucidating the underlying interactions requires specific stress models that can target integrated physiological systems. Here, we employ behavioral tests and whole-body plethysmography to examine the effects of 12 weeks of simulated high altitude (HA) exposure on two inbred mouse strains, BALBc and C57Bl6. We find that HA induced- weight loss recovers at significantly different rates in these two strains. Even at 12 weeks, however, both strains fail to reach body weight levels of controls. Performance on two motor tasks, rotarod and treadmill, improve with HA exposure but more prominently in BALBc mice. Whole-body plethysmography outcomes indicate that compensation to chronic HA includes increased respiratory frequencies and tidal volumes in both strains. However, the effects on tidal volume are significantly greater in BALBc mice and showed a biphasic course. Whole- body metabolic rates are also increased in both strains with prolonged HA exposure, but were more pronounced in BALBc mice suggestive of less successful adaptation in this strain. These adaptations occur in the absence of gross pathological changes in all major organs. Together these results indicate that chronic HA exposure results in environmental stressors that impact the specific physiological responses of BALBc more than C57Bl6 mice. Thus, these strains provide a promising platform for investigating how genetic backgrounds can differentially reinforce the effects of long-lasting environmental stressors and their potential to interact with psychological stressors.


[The use of laparoscopy in the staging of stomach cancer].
Laparotomy is still being resorted to on a large scale to diagnose stomach cancer. This surgical intervention causes unjustified trauma and often exacerbates patient's condition. In a comparative study, postoperative complications were recorded in 13% of cases of laparotomy. The death rate was 2%. Patients were confined to hospital for an average of 15 days. Laparoscopy was performed in 105 patients for staging stomach cancer during clinical examinations. Metastases to abdominal cavity organs were detected in 61.9%. Laparoscopy did not involve complication or lethality. Patients stayed at the hospital not more than 5 days. A retrospective analysis of 193 cases of stomach cancer who had undergone diagnostic laparotomy showed that surgery could have been avoided in 42.5%, if laparoscopy had been used during clinical examination.


Using Separable Nonnegative Matrix Factorization Techniques for the Analysis of Time-Resolved Raman Spectra.
The key challenge of time-resolved Raman spectroscopy is the identification of the constituent species and the analysis of the kinetics of the underlying reaction network. In this work we present an integral approach that allows for determining both the component spectra and the rate constants simultaneously from a series of vibrational spectra. It is based on an algorithm for nonnegative matrix factorization that is applied to the experimental data set following a few pre-processing steps. As a prerequisite for physically unambiguous solutions, each component spectrum must include one vibrational band that does not significantly interfere with the vibrational bands of other species. The approach is applied to synthetic "experimental" spectra derived from model systems comprising a set of species with component spectra differing with respect to their degree of spectral interferences and signal-to-noise ratios. In each case, the species involved are connected via monomolecular reaction pathways. The potential and limitations of the approach for recovering the respective rate constants and component spectra are discussed.


Infrared spectra of ThH2, ThH4, and the hydride bridging ThH4(H2)x (x = 1-4) complexes in solid neon and hydrogen.
Laser-ablated Th atoms react with molecular hydrogen to give thorium hydrides and their dihydrogen complexes during condensation in excess neon and hydrogen for characterization by matrix infrared spectroscopy. The ThH2, ThH4, and ThH4(H2)x (x = 1-4) product molecules have been identified through isotopic substitution (HD, D2) and comparison to frequencies calculated by density functional theory and the coupled-cluster, singles, doubles (CCSD) method and those observed previously in solid argon. Theoretical calculations show that the Th-H bond in ThH4 is the most polarized of group 4 and uranium metal tetrahydrides, and as a result, a strong attractive "dihydrogen" interaction was found between the oppositely charged hydride and H2 ligands ThH4(H2)x. This bridge-bonded dihydrogen complex structure is different from that recently computed for tungsten and uranium hydride super dihydrogen complexes but is similar to that recently called the "dihydrogen bond" (Crabtree, R. H. Science 1998, 282, 2000). Natural electron configurations show small charge flow from the Th center to the dihydrogen ligands.


Pharmacologic treatment of pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a rare, incurable disease characterized by adverse remodeling of the pulmonary vasculature, leading to increased pulmonary arterial pressures and right ventricular failure. Contemporary pharmacotherapy targets 3 distinct molecular pathways that are abnormal in PAH: deficient production of nitric oxide and prostacyclin, and over production of endothelin. Risk assessment is critical in guiding therapeutic decision making and in disease surveillance following treatment initiation. Patients with more advanced disease are best treated with continuous infusion therapy, while those less symptomatic patients may respond to oral or inhaled therapies. Combination therapy is being increasingly utilized in patients who fail to achieve treatment goals.


Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. I. Hematuria and proteinuria.
We review evidence on the value of dipstick urinalysis screening for hemoglobin and protein in asymptomatic adults. In young adults, evidence from five population-based studies indicates that fewer than 2% of those with a positive heme dipstick have a serious and treatable urinary tract disease, too few to justify screening and the risks of subsequent workup. For older populations, evidence is contradictory and no recommendation can presently be made for or against hematuria screening. A population-based randomized, controlled trial of hematuria screening in the elderly is urgently needed. Proteinuria screening is not recommended in any healthy, asymptomatic adult population, since four population-based studies have found that fewer than 1.5% of those with positive dipsticks have serious and treatable urinary tract disorders.


Positioning 3 qualitative trait loci on soybean molecular linkage group E.
In soybean (Glycine max [L.] Merr.), 3 qualitative trait loci (Pb, Y9, and Y17) are located on classical linkage group 14, which corresponds to molecular linkage group (MLG) E. The Pb locus conditions sharp/blunt pubescence tip; the y9 and y17 loci condition green/chlorotic foliage. The gene order is not known. Our objective was to determine the gene order on soybean MLG E of the Pb, Y9, and Y17 loci using previously mapped simple sequence repeat (SSR) markers. Allelism tests between y9 and y17 gave normal green foliage F(1) plants, indicating nonallelism. Our F(2) data from the allelism test could not distinguish between a 1:1 or a 9:7 ratio. The F(2:3) family segregation indicated a very close genetic linkage between the y9 and the y17 loci. Two molecular mapping populations were developed. Population-1 segregated for Pb and y9, and population-2 segregated for Pb and y17. The gene order on soybean MLG E, using SSR markers, was Pb, Y9, and Y17.


Vaginal bleeding in a patient with type C liver cirrhosis without a past history of laparotomy: successful treatment with partial splenic artery embolization.
A 47-year-old female patient with type C liver cirrhosis underwent endoscopic injection sclerotherapy for esophageal varices 13 years ago. The patient had no past history of hysterectomy or any other gynecological disorders. She was admitted to our hospital because of persistent vaginal bleeding and exacerbation of anemia. A contrast-enhanced computed tomography scan revealed marked dilation of not only the inferior mesenteric vein, but also the left ovarian vein, the uterine vein and the internal iliac vein. A celiac arteriography showed that the blood in the splenic vein was flowing almost totally hepatofugally into the dilated inferior mesenteric vein. An ovarian venography demonstrated knob-shaped dilation of the left ovarian vein draining into the left internal iliac vein. A proximally wedged left ovarian venography visualized the right ovarian vein and the right internal iliac vein with contrast medium via a palisade venous plexus from the dilated uterine and ovarian veins. Partial splenic embolization (PSE) was performed to increase platelet count and to reduce splenic venous blood flow into the ovarian vein. Following the PSE, the platelet count increased, and the blood flow in the dilated ovarian vein and uterine vein diminished. In addition, the portal blood flow became hepatopetal, and remarkably increased. There has as yet been no case report in which vaginal bleeding developed in women with liver cirrhosis without any past history of hysterectomy or other gynecological disorders. The present case report may be warranted in view of the rarity of the condition.


Tissue factor procoagulant activity in the tumor cell lines and plasma of dogs with various malignant tumors.
Hypercoagulability is a common paraneoplastic complication in dogs with various malignant tumors. Importantly, tissue factor procoagulant activity (TF-PCA) induced by TF-bearing microparticles (TF-MPs) is associated with hypercoagulability in human patients with cancer. However, TF-PCA in tumor cells and the association between circulating TF-MPs and hypercoagulability in dogs with malignant tumors remain poorly understood. Therefore, the present study was conducted to evaluate the TF-PCA in various types of canine tumor cell lines and plasma in dogs with malignant tumors. Mammary gland tumor, hemangiosarcoma, and malignant melanoma cell lines, but not lymphoma cell lines, expressed TF on their surfaces and showed cellular surface and MP-associated TF-PCA. The plasma TF-PCA was elevated in some dogs that naturally developed such tumors. No significant difference was observed in plasma TF-PCA between the disseminated intravascular coagulation (DIC) group (median: 43.40; range: 3.47-85.19; n=5) and non-DIC group (median: 7.73; range: 1.70-16.13; n=12). However, plasma TF-PCA was remarkably elevated in three of five dogs with DIC. To the best of our knowledge, this is the first study to evaluate plasma TF-PCA in dogs with malignant tumors. Further studies must be conducted to determine the cellular origin of TF-MPs and the efficacy of plasma TF-PCA as a biomarker of DIC in dogs with malignant tumors.


Relationship between two year PSA nadir and biochemical recurrence in prostate cancer patients treated with iodine-125 brachytherap.
To evaluate the relationship between two year PSA nadir (PSAn) after brachytherapy and biochemical recurrence rates in prostate cancer patients. In the period from January 1998 to August 2007, 120 patients were treated with iodine-125 brachytherapy alone. The results analysis was based on the definition of biochemical recurrence according to the Phoenix Consensus. Biochemical control was observed in 86 patients (71.7%), and biochemical recurrence, in 34 (28.3%). Mean PSAn was 0.53 ng/ml. The mean follow-up was 98 months. The patients were divided into two groups: group 1, with two year PSAn < 0.5 ng/ml after brachytherapy (74 patients; 61.7%), and group 2, with two year PSAn ≥ 0.5 ng/ml after brachytherapy (46 patients; 38.3%). Group 1 presented biochemical recurrence in 15 patients (20.3%), and group 2, in 19 patients (43.2%) (p < 0.02). The analysis of biochemical disease-free survival at seven years, stratified by the two groups, showed values of 80% and 64% (p < 0.02), respectively. Levels of two year PSAn ≥ 0.5 ng/ml after brachytherapy are strongly correlated with a poor prognosis. This fact may help to identify patients at risk for disease recurrence.


Public education about the relative harm of tobacco products: an intervention for tobacco control professionals.
In the USA, new regulations require the collection of information on tobacco constituents by brand and variety and publication of this information in a way not likely to be misconstrued by consumers. Understanding of such information becomes increasingly important as new tobacco products are marketed and modifications are made to reduce the toxicity of some products. This pilot study assessed the current knowledge of tobacco control professionals regarding the relative harmfulness of several tobacco products, and evaluated an online educational intervention aimed at improving understanding of variations in nicotine and tobacco-specific N-nitrosamines (TSNAs). Fifty-two tobacco control professionals participated in an online intervention which presented and discussed the results of constituent analyses of Camel Snus and Marlboro Snus compared to several conventional smokeless tobacco products. Comparisons with cigarettes were also discussed. Pre- and post-intervention questions assessed understanding of the concepts. Pre-intervention responses demonstrated that 31% did not know that cigarettes are more harmful than smokeless tobacco, 67% did not know that smokeless products higher in nicotine are likely to be more effective substitutes for cigarettes, 52% did not know TSNAs are the major carcinogens in tobacco and 81% did not know new snus products tend to be lower in TSNAs than conventional spit tobacco. After intervention participation, knowledge increased on all points except one where pretest results were 100% correct. Public education campaigns are urgently needed for tobacco control professionals and consumers to increase awareness and understanding of the continuum of risk among tobacco products.


Chemopreventive potential of chlorophyllin: a review of the mechanisms of action and molecular targets.
Chlorophyllin (CHL), a water soluble semisynthetic derivative of the ubiquitous plant pigment chlorophyll used as a food additive, is recognized to confer a wide range of health benefits. CHL has been shown to exhibit potent antigenotoxic, anti-oxidant, and anticancer effects. Numerous experimental and epidemiological studies have demonstrated that dietary supple-mentation of CHL lowers the risk of cancer. CHL inhibits cancer initiation and progression by targeting multiple molecules and pathways involved in the metabolism of carcinogens, cell cycle progression, apoptosis evasion, invasion, and angiogenesis. The modulatory effects of CHL on the hallmark capabilities of cancer appear to be mediated via abrogation of key oncogenic signal transduction pathways such as nuclear factor kappa B, Wnt/β-catenin, and phosphatidylinositol-3-kinase/Akt signaling. This review provides insights into the molecular mechanisms of the anticancer effects of dietary CHL.


Top-down morphogenesis of colorectal tumors.
One of the fundamental tenets of oncology is that tumors arise from stem cells. In the colon, stem cells are thought to reside at the base of crypts. In the early stages of tumorigenesis, however, dysplastic cells are routinely found at the luminal surface of the crypts whereas the cells at the bases of these same crypts appear morphologically normal. To understand this discrepancy, we evaluated the molecular characteristics of cells isolated from the bases and orifices of the same crypts in small colorectal adenomas. We found that the dysplastic cells at the tops of the crypts often exhibited genetic alterations of adenomatous polyposis coli (APC) and neoplasia-associated patterns of gene expression. In contrast, cells located at the base of these same crypts did not contain such alterations and were not clonally related to the contiguous transformed cells above them. These results imply that development of adenomatous polyps proceeds through a top-down mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them.


Coverage of Certain Preventive Services Under the Affordable Care Act. Final rules.
This document contains final regulations regarding coverage of certain preventive services under section 2713 of the Public Health Service Act (PHS Act), added by the Patient Protection and Affordable Care Act, as amended, and incorporated into the Employee Retirement Income Security Act of 1974 and the Internal Revenue Code. Section 2713 of the PHS Act requires coverage without cost sharing of certain preventive health services by non-grandfathered group health plans and health insurance coverage. These regulations finalize provisions from three rulemaking actions: Interim final regulations issued in July 2010 related to coverage of preventive services, interim final regulations issued in August 2014 related to the process an eligible organization uses to provide notice of its religious objection to the coverage of contraceptive services, and proposed regulations issued in August 2014 related to the definition of "eligible organization,'' which would expand the set of entities that may avail themselves of an accommodation with respect to the coverage of contraceptive services.


A comparison of iron bioassay diets.
Two broiler chick experiments wer conducted to evaluate four basal diets for iron bioassay suitability. The test basal diets, identified according to their principal ingredients and iron content, were: (1) starch-skim milk - 15 p.p.m., (2) degerminated corn-skin milk - 18 p.p.m. (3) degermianted corn-fish meal-isolated soy - 45 p.p.m., and (4) degermianted corn-fish meal-dehulled soy - 59p.p.m. Significant differences between an iron source with known low availability (ferric oxide) and a highly available iron source (ferrous sulfate) were not detected with the degerminated corn-fish meal-isolated soy or the degerminated corn-fish meal-dehulled soy diets. Likewise, there were no significant differences found between supplemental iron levels, 10 and 20 p.p.m. The corn-skim milk and starch-skim milk diets were both found to be satisfactory for iron bioassays. However, the sample size needed to estimate the population mean was almost twice as great for the starch-skim milk fed groups, than was needed for the corn-skim milk fed groups which indicates the corn-skim milk diet obtained greater sensitivity in testing iron sources and levels. Mortality was excessively high in the starch-skim milk fed group. Ferrous sulfate was superior to ferric oxide as a source of iron.


TGF-beta induces IL-9 production from human Th17 cells.
The secretion of IL-9, initially recognized as a Th2 cytokine, was recently attributed to a novel CD4 T cell subset termed Th9 in the murine system. However, IL-9 can also be secreted by mouse Th17 cells and may mediate aspects of the proinflammatory activities of Th17 cells. Here we report that IL-9 is secreted by human naive CD4 T cells in response to differentiation by Th9 (TGF-beta and IL-4) or Th17 polarizing conditions. Yet, these differentiated naive cells did not coexpress IL-17 and IL-9, unless they were repeatedly stimulated under Th17 differentiation-inducing conditions. In contrast to the naive cells, memory CD4 T cells were induced to secrete IL-9 by simply providing TGF-beta during stimulation, as neither IL-4 nor proinflammatory cytokines were required. Furthermore, the addition of TGF-beta to the Th17-inducing cytokines (IL-1beta, IL-6, IL-21, IL-23) that induce memory cells to secrete IL-17, resulted in the marked coexpression of IL-9 in IL-17 producing memory cells. The proinflammatory cytokine mediating TGF-beta-dependent coexpression of IL-9 and IL-17 was identified to be IL-1beta. Moreover, circulating monocytes were potent costimulators of IL-9 production by Th17 cells via their capacity to secrete IL-1beta. Finally, to determine whether IL-9/IL-17 coproducing CD4 cells were altered in an inflammatory condition, we examined patients with autoimmune diabetes and demonstrated that these subjects exhibit a higher frequency of memory CD4 cells with the capacity to transition into IL-9(+)IL-17(+) cells. These data demonstrate the presence of IL-17(+)IL-9(+) CD4 cells induced by IL-1beta that may play a role in human autoimmune disease.


Structural and functional analyses of the human-type corrinoid adenosyltransferase (PduO) from Lactobacillus reuteri.
ATP:Co(I)rrinoid adenosyltransferase (ACA) catalyzes the conversion of cobalamin to coenzyme B12, an essential cofactor in animal metabolism. Several mutations of conserved residues in the active site of human ACA have been identified in humans with methylmalonic aciduria. However, the catalytic role of these residues remains unclear. To better understand the function of these residues and to determine how the enzyme promotes catalysis, several variants of a human-type ACA from the lactic acid bacterium Lactobacillus reuteri (LrPduO) were kinetically and structurally characterized. Kinetic analyses of a series of alternate nucleotides were also performed. Substrate inhibition was observed at subsaturating concentrations of ATP, consistent with an ordered binding scheme where ATP is bound first by the enzyme. Modification or elimination of an active site, inter-subunit salt bridge resulted in a reduced "on" rate for ATP binding, with a less significant disruption in the rate of subsequent catalytic steps. Kinetic and structural data demonstrate that residue Arg132 is not involved in orienting ATP in the active site but, rather, it stabilizes the altered substrate in the transition state. Two functional groups of ATP explain the reduced ability of the enzyme to use alternate nucleotides: the amino group at the C-6 position of ATP contributes approximately 6 kcal/mol of free energy to ground state binding, and the nitrogen at the N-7 position assists in coordinating the magnesium ion in the active site. This study provides new insight into the role of substrate binding determinants and active site residues in the reaction catalyzed by a human-type ACA.


Simultaneous assessment of radial and axial myocyte mechanics by combining atomic force microscopy and carbon fibre techniques.
Cardiomyocytes sense and shape their mechanical environment, contributing to its dynamics by their passive and active mechanical properties. While axial forces generated by contracting cardiomyocytes have been amply investigated, the corresponding radial mechanics remain poorly characterized. Our aim is to simultaneously monitor passive and active forces, both axially and radially, in cardiomyocytes freshly isolated from adult mouse ventricles. To do so, we combine a carbon fibre (CF) set-up with a custom-made atomic force microscope (AFM). CF allows us to apply stretch and to record passive and active forces in the axial direction. The AFM, modified for frontal access to fit in CF, is used to characterize radial cell mechanics. We show that stretch increases the radial elastic modulus of cardiomyocytes. We further find that during contraction, cardiomyocytes generate radial forces that are reduced, but not abolished, when cells are forced to contract near isometrically. Radial forces may contribute to ventricular wall thickening during contraction, together with the dynamic re-orientation of cells and sheetlets in the myocardium. This new approach for characterizing cell mechanics allows one to obtain a more detailed picture of the balance of axial and radial mechanics in cardiomyocytes at rest, during stretch, and during contraction. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.


The Rho family guanine nucleotide exchange factor Vav-2 regulates the development of cell-mediated cytotoxicity.
Previous pharmacologic and genetic studies have demonstrated a critical role for the low molecular weight GTP-binding protein RhoA in the regulation of cell-mediated killing by cytotoxic lymphocytes. However, a specific Rho family guanine nucleotide exchange factor (GEF) that activates this critical regulator of cellular cytotoxicity has not been identified. In this study, we provide evidence that the Rho family GEF, Vav-2, is present in cytotoxic lymphocytes, and becomes tyrosine phosphorylated after the cross-linking of activating receptors on cytotoxic lymphocytes and during the generation of cell-mediated killing. In addition, we show that overexpression of Vav-2 in cytotoxic lymphocytes enhances cellular cytotoxicity, and this enhancement requires a functional Dbl homology and Src homology 2 domain. Interestingly, the pleckstrin homology domain of Vav-2 was found to be required for enhancement of killing through some, but not all activating receptors on cytotoxic lymphocytes. Lastly, although Vav and Vav-2 share significant structural homology, only Vav is able to enhance nuclear factor of activated T cells-activator protein 1-mediated gene transcription downstream of the T cell receptor. These data demonstrate that Vav-2, a Rho family GEF, differs from Vav in the control of certain lymphocyte functions and participates in the control of cell-mediated killing by cytotoxic lymphocytes.


Visual memory testing in older adults with age-related visual decline: a measure of memory performance or visual functioning?
Although we know that vision is correlated with memory performance in older adults, the implications for this in terms of neuropsychological assessment have not been investigated. Relationships among age, visual acuity, and visual and verbal memory in 89 community dwelling volunteers aged 60 to 87 years were examined. Vision was tested using the Landolt C and visual and verbal memory were assessed via the Visual Reproduction (VR) and Word List (WL) subtests from the Wechsler Memory Scale, Third Edition (WMS-III; Wechsler, 1997), respectively. Significant correlations were observed between vision and the VR and WL tasks. Hierarchical multiple regression analyses revealed that vision significantly increased the R2 for VR and WL after controlling for age and education. The effect of vision was not specific to visual memory. We conclude that vision is correlated with general memory function in older adults, and is not modality specific.


A longitudinal analysis of the vaginal microbiota and vaginal immune mediators in women from sub-Saharan Africa.
In cross-sectional studies increased vaginal bacterial diversity has been associated with vaginal inflammation which can be detrimental for health. We describe longitudinal changes at 5 visits over 8 weeks in vaginal microbiota and immune mediators in African women. Women (N = 40) with a normal Nugent score at all visits had a stable lactobacilli dominated microbiota with prevailing Lactobacillus iners. Presence of prostate-specific antigen (proxy for recent sex) and being amenorrhoeic (due to progestin-injectable use), but not recent vaginal cleansing, were significantly associated with microbiota diversity and inflammation (controlled for menstrual cycle and other confounders). Women (N = 40) with incident bacterial vaginosis (Nugent 7-10) had significantly lower concentrations of lactobacilli and higher concentrations of Gardnerella vaginalis, Atopobium vaginae, and Prevotella bivia, at the incident visit and when concentrations of proinflammatory cytokines (IL-1β, IL-12p70) were increased and IP-10 and elafin were decreased. A higher 'composite-qPCR vaginal-health-score' was directly associated with decreased concentrations of proinflammatory cytokines (IL-1α, IL-8, IL-12(p70)) and increased IP-10. This longitudinal study confirms the inflammatory nature of vaginal dysbiosis and its association with recent vaginal sex and progestin-injectable use. A potential role for proinflammatory mediators and IP-10 in combination with the vaginal-health-score as predictive biomarkers for vaginal dysbiosis merits further investigation.


X-ray diffraction, FT-IR, and (13)C CP/MAS NMR structural studies of solvated and desolvated C-methylcalix[4]resorcinarene.
Solid C-methylcalix[4]resorcinarene solvated by acetonitrile and water (CAL-Me) and then modified by slow solvent evaporation (CAL-Me*) was studied using single-crystal and powder X-ray diffraction, FT-IR, and (13)C CP/MAS NMR. The CAL-Me solvate crystallizes in the monoclinic P2(1)/n space group with three CH(3)CN and two H(2)O molecules in the asymmetric part of the unit cell. The CAL-Me molecules adopt a typical crown conformation with all of the hydroxyl groups of the aryl rings oriented up and all of the methyl groups disposed down (the rccc isomeric form). The crystalline network is formed by resorcinarene, CH(3)CN, and H(2)O molecules and assembled by intermolecular hydrogen bonds and weak C-H...A or C-H...pi interactions. The desolvated CAL-Me* loses its crystalline character and becomes partly amorphous. It is devoid of CH(3)CN and deficient in water. However, the resorcinarene molecules still remain in the crown conformation supported by intramolecular hydrogen bonds, while intermolecular hydrogen bonds are considerably disintegrated. The work directs general attention to the problem of stability and polymorphism of resorcinarene solvates. It shows that the joint use of diffractometric and spectroscopic methods is advantageous in the structural studies of complex crystalline macromolecular systems. On the other hand, the solid-state IR and NMR spectroscopic analyses applied in tandem have been found highly beneficial to elucidate the disordered structure of poorly crystalline, desolvated resorcinarene.


Pre-treatment haemoglobin concentration is a prognostic factor in patients with early-stage breast cancer.
We investigated the prevalence of anaemia (haemoglobin concentration < 12 g/dl) in 336 women with early-stage breast cancer and its association with other known prognostic factors. The median follow-up period was 60.5 months (range 9 - 123 months). Seventy-nine women (23.5%) had a low pre-treatment haemoglobin concentration, but anaemia was not correlated with age, tumour size, nodal status, histological grade or hormone receptor status. Univariate analysis revealed that disease-free survival and overall survival were shorter in patients with anaemia at the time of diagnosis than in patients with normal haemoglobin concentrations. Anaemia remained a significant prognostic factor for disease-free survival and overall survival in the multivariate analysis (relative risk, 1.884 and 1.785, respectively). These results suggest that pre-treatment haemoglobin concentration is an independent prognostic factor in patients with early-stage breast cancer.


Characteristics and treatment of geriatric patients in an osteopathic neuromusculoskeletal medicine clinic.
Osteopathic manipulative medicine (OMM) is an adjunctive treatment approach available to geriatric patients, but few studies provide details about presenting conditions, treatments, and response to osteopathic manipulative treatment (OMT) in that patient population. To provide descriptive data on the presentation and management of geriatric patients receiving OMT at an outpatient osteopathic neuromusculoskeletal medicine (ONMM) clinic. Data were retrospectively collected from electronic health records (EHR) at a single outpatient clinic for clinical encounters with patients over 60 years of age who were treated with OMT between July 1, 2016, and June 30, 2019. Records were reviewed for demographic information, insurance type, presenting concerns, assessments, regions treated, OMT techniques used, and treatment response. There were 9,155 total clinical encounters with 1,238 unique patients found during the study period. More women than men were represented for overall encounters (6,910 [75.4%] vs. 2,254 [24.6%]) and unique patients (850 [68.7%] vs. 388 [31.3%]; both p<0.001). The mean (standard deviation, SD) number of encounters per patient per year was 4.5 (4.0) and increased with increasing age by decade (p<0.001). Medicare was the most common primary insurance (7,246 [79.2%]), with private insurance the most common secondary insurance (8,440 [92.2%]). The total number of presenting concerns was 12,020, and back concerns were most common (6,406 [53.3%]). The total number of assessments was 18,290; most were neuromusculoskeletal (17,271 [94.5%]) and in the thoracolumbar region (7,109 [38.9%]). The mean (SD) number of somatic dysfunction assessments per encounter was 5 (1.7); the thoracic region was the most documented and treated (7,263 [15.8%]). With up to 19 technique types per encounter, the total number of OMT techniques documented across all encounters was 43,862, and muscle energy (7,203 [16.4%]) was the most documented. The use of high-velocity, low-amplitude (HVLA) declined as age increased (p<0.001). The overall treatment response was documented in 7,316 (79.9%) encounters, and most indicated improvement (7,290 [99.6%]). Our results showed that geriatric patients receiving OMT at our clinic were predominately presenting for neuromusculoskeletal concerns associated with back, neck, and extremity conditions, consistent with national epidemiological data for this population. The most common OMT techniques were also consistent with those used nationally by osteopathic medical students and practicing physicians. Future longitudinal studies are needed to determine the length of time improvement persists and the overall health impact experienced by geriatric patients receiving OMT.


[Reconstruction of the pharynx after pharyngectomy].
Forty-five patients in whom a pharyngo-laryngectomy was carried out are described; in 21, the pharynx was reconstructed by gastric transposition and in 24 by primary reconstruction with a medially based cased flap. Minor complications, such as stenosis and fistulae occurred more often after the skin flap operation and the stay of the patient in hospital in this group was considerably longer compared to those patients having the pharyngeal replacement with the transposed stomach. However, the two year survival after skin flap reconstruction was 50% as against only 10% after reconstruction with the stomach.


Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a cancer and leukemia group B study.
Patients with acute nonlymphocytic leukemia were randomized to receive remission induction therapy consisting of seven days of cytosine arabinoside and three days of daunorubicin ("7 + 3") or to receive the same regimen intensified by either the addition of 6-thioguanine or by extension of the administration of cytosine arabinoside to ten days. Additionally, all patients were randomized to receive or not to receive cotrimoxazole antibacterial prophylaxis during the remission induction phase. Neither an increase in intensity of chemotherapy nor the antibacterial prophylaxis increased the remission rate above the 53% for patients treated with the standard "7 + 3" regimen. The second part of this study addressed the issue of the utility of long-term maintenance chemotherapy. To this end, patients were randomized to discontinue all treatment after 8 months of maintenance chemotherapy or to continue maintenance therapy for a total of 3 years. Although there was a transient increase in the relapse rate for patients who discontinued therapy, the proportion of long-term remitters was identical in the two patient groups. Additionally, there is a suggestion of a survival advantage for patients randomized to discontinue all therapy at 8 months.


Biodiversity monitoring at the Tonle Sap Lake of Cambodia: a comparative assessment of local methods.
This paper assesses local biodiversity monitoring methods practiced in the Tonle Sap Lake of Cambodia. For the assessment we used the following criteria: methodological rigor, perceived cost, ease of use (user friendliness), compatibility with existing activities, and effectiveness of intervention. Constraints and opportunities for execution of the methods were also considered. Information was collected by use of: (1) key informant interview, (2) focus group discussion, and (3) researcher's observation. The monitoring methods for fish, birds, reptiles, mammals and vegetation practiced in the research area have their unique characteristics of generating data on biodiversity and biological resources. Most of the methods, however, serve the purpose of monitoring biological resources rather than biodiversity. There is potential that the information gained through local monitoring methods can provide input for long-term management and strategic planning. In order to realize this potential, the local monitoring methods should be better integrated with each other, adjusted to existing norms and regulations, and institutionalized within community-based organization structures.


[Interdisciplinary ultrasound-guided, minimally invasive autopsy in COVID-19-deceased patients in the intensive care unit of a university hospital : A proof-of-concept study].
In this feasibility study, we carried out in an interdisciplinary team standardised, ultrasound-guided, minimally invasive autopsy (US-MIA) directly at the bedside of patients who died of COVID-19 in the intensive care unit of the Rechts der Isar Hospital of the Technical University Munich (TUM). The aim of the study was to verify the feasibility, time efficiency and infection hygiene aspects of the process, as well as the quality of the tissue samples. Our results show that bedside US-MIA is suitable for obtaining tissue samples before the onset of postmortem autolysis, and that it can also be carried out quickly and safely. The potential of US-MIA, which has gained little recognition so far, deserves special attention in the context of postmortem diagnosis, research and quality assurance. In the future, these strengths of US-MIA could help to lead postmortem diagnosis into the modern age of pathological deep analytics ("omics").


Mapping of functional groups in metal-organic frameworks.
We determined the heterogeneous mesoscale spatial apportionment of functional groups in a series of multivariate metal-organic frameworks (MTV-MOF-5) containing BDC (1,4-benzenedicarboxylate) linkers with different functional groups--B (BDC-NH2), E (BDC-NO2), F [(BDC-(CH3)2], H [BDC-(OC3H5)2], and I [BDC-(OC7H7)2]--using solid-state nuclear magnetic resonance measurements combined with molecular simulations. Our analysis reveals that these methods discern between random (EF), alternating (EI and EHI), and various cluster (BF) forms of functional group apportionments. This combined synthetic, characterization, and computational approach predicts the adsorptive properties of crystalline MTV-MOF systems. This methodology, developed in the context of ordered frameworks, is a first step in resolving the more general problem of spatial disorder in other ordered materials, including mesoporous materials, functionalized polymers, and defect distributions within crystalline solids.


Nonproteinuric diabetes-associated nephropathy in the Cohen rat model of type 2 diabetes.
The Cohen diabetic rat is an experimental model reminiscent of human type 2 diabetes. The aim of this study was to characterize the development of end-organ damage in this model. Cohen diabetic sensitive (CDs) and Cohen diabetic resistant (CDr) rats were fed regular diet or a diabetogenic diet. Glucose tolerance, renal function, and renal and retinal histology were studied at set intervals. CDs fed diabetogenic diet were the only strain that expressed the diabetic metabolic phenotype. In this strain, urinary protein excretion did not increase with the development of diabetes, but plasma urea and creatinine levels increased and creatinine clearance decreased. Light microscopy revealed in CDs enlarged glomeruli with increased mesangial matrix and thickening of the glomerular capillary wall; electron microscopy demonstrated thickened basement membrane and mesangial abundance. There was increased staining for type IV collagen in glomeruli and interstitium of CDs. The retinas of diabetic CDs demonstrated pathology consistent with nonproliferative diabetic retinopathy. The histological findings in the kidneys, the absence of proteinuria, the impairment in glomerular filtration, and the development of retinopathy in CDs are consistent with diabetes-associated nephropathy that is similar to a nonalbuminuric type of nephropathy associated with type 2 diabetes in humans.


A pleiotropic drug resistance transporter in Nicotiana tabacum is involved in defense against the herbivore Manduca sexta.
Pleiotropic drug resistance (PDR) transporters are a group of membrane proteins belonging to the ABCG sub-family of ATP binding cassette (ABC) transporters. There is clear evidence for the involvement of plant ABC transporters in resistance to fungal and bacterial pathogens, but not in the biotic stress response to insect or herbivore attack. Here, we describe a PDR transporter, ABCG5/PDR5, from Nicotiana tabacum. GFP fusion and subcellular fractionation studies revealed that ABCG5/PDR5 is localized to the plasma membrane. Staining of transgenic plants expressing the GUS reporter gene under the control of the ABCG5/PDR5 transcription promoter and immunoblotting of wild-type plants showed that, under standard growth conditions, ABCG5/PDR5 is highly expressed in roots, stems and flowers, but is only expressed at marginal levels in leaves. Interestingly, ABCG5/PDR5 expression is induced in leaves by methyl jasmonate, wounding, pathogen infiltration, or herbivory by Manduca sexta. To address the physiological role of ABCG5/PDR5, N. tabacum plants silenced for the expression of ABCG5/PDR5 were obtained. No phenotypic modification was observed under standard conditions. However, a small increase in susceptibility to the fungus Fusarium oxysporum was observed. A stronger effect was observed in relation to herbivory: silenced plants allowed better growth and faster development of M. sexta larvae than wild-type plants, indicating an involvement of this PDR transporter in resistance to M. sexta herbivory.


Environmental Influences on Pigeonpea-Fusarium udum Interactions and Stability of Genotypes to Fusarium Wilt.
Fusarium wilt (Fusarium udum Butler) is an important biotic constraint to pigeonpea (Cajanus cajan L.) production worldwide. Breeding for fusarium wilt resistance continues to be an integral part of genetic improvement of pigeonpea. Therefore, the study was aimed at identifying and validating resistant genotypes to fusarium wilt and determining the magnitude of genotype × environment (G × E) interactions through multi-environment and multi-year screening. A total of 976 genotypes including germplasm and breeding lines were screened against wilt using wilt sick plot at Patancheru, India. Ninety two genotypes resistant to wilt were tested for a further two years using wilt sick plot at Patancheru. A Pigeonpea Wilt Nursery (PWN) comprising of 29 genotypes was then established. PWN was evaluated at nine locations representing different agro-climatic zones of India for wilt resistance during two crop seasons 2007/08 and 2008/09. Genotypes (G), environment (E), and G × E interactions were examined by biplot which partitioned the main effect into G, E, and G × E interactions with significant levels (p ≤ 0.001) being obtained for wilt incidence. The genotype contributed 36.51% of resistance variation followed by the environment (29.32%). A GGE biplot integrated with a boxplot and multiple comparison tests enabled us to identify seven stable genotypes (ICPL 20109, ICPL 20096, ICPL 20115, ICPL 20116, ICPL 20102, ICPL 20106, and ICPL 20094) based on their performance across diverse environments. These genotypes have broad based resistance and can be exploited in pigeonpea breeding programs.


Allele-specific gene silencing in osteogenesis imperfecta.
OI is caused by mutations in the genes encoding for collagen type I COL1A1 and COL1A2, respectively. The patients suffer from bone fragility, and the severity can range from mild, with fractures in the youth, to lethal forms. Today, there is no effective treatment for the disorder. OI is caused by dominant negative mutations. A tempting approach to treat the disease would be to silence the allele carrying the mutation. This could in theory be done with siRNAs. Today, more than 800 various mutations are reported, and to create siRNA against a specific mutation is difficult. Instead, by developing siRNA against common polymorphic variations, it would be possible to silence the mutation by a standardized method regardless where the mutation is located on the allele. If the concept of allele-specific gene silencing by inhibitory RNA directed towards dominant negative mutations could be proven, this might be a novel approach to gene therapy in OI.


Hypolipidemic effect of Youcha in hyperlipidemia rats induced by high-fat diet.
Youcha is a novel tea drink from the northeast of Guangxi. This study aimed to investigate the hypolipidemic properties of Youcha in high-fat induced hyperlipidemic Sprague-Dawley (SD) rats. After designing the model, rats were randomly divided into six groups (n = 10): normal diet (NMD) group, high-fat diet (HFD) group, Xuezhikang (120 mg kg-1 d-1) (HFD+P) group and Youcha (150, 750 or 1500 mg kg-1 d-1) (HFD+L, HFD+M or HFD+H) groups. Youcha comprises tea polyphenols (1.51 g per 100 g), caffeine (34.80 mg per 100 g) and other functional compounds. To evaluate the lipid-lowering effects of Youcha, weight of the body, liver and fat, fat index, lipid metabolism, antioxidant properties and liver damage indices were examined. In addition, the activities of some enzymes in serum and liver tissue were examined to preliminarily study their possible mechanism. The results reveal that Youcha tends to reduce body weight, liver weight, fat index, total cholesterol (TC) and triglyceride (TG) contents, low-density lipoprotein cholesterol (LDL-C), atherogenic index (AI), malondialdehyde (MDA), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and increase high-density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD) and glutathione peroxidase (GPx) relative to the HFD group. The hypolipidemic effect was partly due to the regulation of fatty acid synthetase (FAS) and lipase (LPS) rather than lipoprotein lipase (LPL) to decrease TG markedly. These findings suggest that Youcha could be potentially used to remedy hyperlipidemia and is hence worthy of promotion as a tea drink.


Impact of combined precut techniques on selective biliary cannulation.
simple biliary cannulation techniques obtain a success rate of 80-95%. Advanced precut techniques are not immediately successful in 10-40% of cases. Between extreme options such as a second attempt a few days later or an immediate attempt by the transparietal route, an alternative precut technique may be used as a rescue strategy for the initially failed procedure. The purpose of this study was to assess the efficacy and safety of the combined use of two precut techniques when immediate biliary access is not granted by an initial procedure. a retrospective analysis of a personal series of precut (needle-knife and transpancreatic) sphincterotomies, both alone and in combination. five hundred sixty nine ERCPs (endoscopic retrograde cholangio-pancreatography) met the inclusion criteria for the analysis. Simple cannulation was obtained in 444 (78%) of them. In all, 119 (21%) precuts were attempted and 110 (92.4%) were successful, which raised the overall cannulation rate to 97.4%. Ninety-five (80%) precuts were successful with the initial technique. Rescue with the alternative technique was attempted for 20 failures with a successful outcome in 15, which raised the overall success rate to 92%. The combination of needle-knife precut plus transpancreatic precut raised the success rate from 87% to 94%. The combination of transpancreatic precut plus needle-knife precut raised the success rate from 70% to 90%. Among all 96 patients with available follow-up data, 17 (18%) complications were recorded: 9 bleeding episodes, 4 pancreatitis cases, and 4 retroperitoneal perforations. No mortality was recorded. a combination of precut techniques is effective for biliary cannulation when simple cannulation and initial precut approaches fail. The safety profile differs from that in the delayed strategy, hence both should be considered alternatives, their use depending on the technical and clinical conditions prevailing for each patient, as well as endoscopist experience.


Effect of DL-6-(N-alpha-pipecolinomethyl)-5-hydroxy-indane maleate (PMHI) on the reproductive system of a wild rat, Bandicota bengalensis.
The anti-testicular action of PMHI was investigated in a wild rodent, the bandicoot rat. Bandicoots were given a single subcutaneous injection of this compound at a dose of 150 mg/kg and were killed 2, 10, or 30 days later. PMHI induced marked and rapid testicular regression with complete arrest of spermatogenesis by day 10 such that the seminiferous tubules contained only a ring of Sertoli cells with few spermatogonia. This was also reflected by a severe depletion of the number of sperm in the cauda epididymis. However, by day 30 after PMHI injection, testicular histology indicated restoration of spermatogenesis in parallel with the time schedule of germ cell development. The results indicate that PHMI produces a reversible anti-spermatogenic effect in the bandicoot rat which appears to be time dependent.


Influence of frailty on the quality of life patients qualified for pacemaker implantation.
An important question is whether frailty syndrome affects the assessment of quality of life or whether frailty syndrome may reduce the benefits of a cardiac pacemaker implantation. Frailty syndrome is known risk factor for quality of life evaluation after selected cardiology invasive procedures. The study was designed as single-centre prospective study. The study included 171 patients aged ≥60 years who were qualified for pacemaker implantation. Quality of life was evaluated twice-before and 6 months after implantation using MLHF questionnaire. A frailty syndrome evaluation using the Tilburg Frailty Indicator (TFI) was performed prior to pacemaker implantation. A DDDR pacemaker was implanted in each patient. Frailty syndrome was identified in half of the patients with indications for cardiac pacemaker implantation. There was an improvement in quality of life in the six months after pacemaker implantation in all of the robust and frailty syndrome-affected patients that were included into the study-in general, physical and emotional domains. Implantation of cardiac pacemaker influences the compensation quality of life evaluation in patients with sinus node dysfunction. Presence of frailty influences worse quality of life of patients when evaluated before cardiac pacemaker implantation. Frailty should be evaluated in all older patients qualified for pacemaker implantation to evaluate high-risk group, optimise therapeutic approach and to intense education activities for patients and family.


Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories--indications for novel treatments of addiction.
This review discusses the evidence for the hypothesis that the development of drug addiction can be understood in terms of interactions between Pavlovian and instrumental learning and memory mechanisms in the brain that underlie the seeking and taking of drugs. It is argued that these behaviours initially are goal-directed, but increasingly become elicited as stimulus-response habits by drug-associated conditioned stimuli that are established by Pavlovian conditioning. It is further argued that compulsive drug use emerges as the result of a loss of prefrontal cortical inhibitory control over drug seeking habits. Data are reviewed that indicate these transitions from use to abuse to addiction depend upon shifts from ventral to dorsal striatal control over behaviour, mediated in part by serial connectivity between the striatum and midbrain dopamine systems. Only some individuals lose control over their drug use, and the importance of behavioural impulsivity as a vulnerability trait predicting stimulant abuse and addiction in animals and humans, together with consideration of an emerging neuroendophenotype for addiction are discussed. Finally, the potential for developing treatments for addiction is considered in light of the neuropsychological advances that are reviewed, including the possibility of targeting drug memory reconsolidation and extinction to reduce Pavlovian influences on drug seeking as a means of promoting abstinence and preventing relapse.


Arts and ageing; life expectancy of historical artists in the Low Countries.
Practising arts has been linked to lowering stress, anxiety and blood pressure. These mechanisms are all known to affect the ageing process. Therefore, we examine the relation between long-term involvement in arts and life expectancy at age 50 (LE50), in a cohort of 12,159 male acoustic, literary and visual artists, who were born between 1700 and 1899 in the Low Countries. We compared the life expectancy at age 50 of the various artists with the elite and middle class of that time. In the birth cohorts before 1850, acoustic (LE50:14.5-19.5) and literary artists (LE50:17.8-20.8) had a similar life expectancy at age 50 compared to the elite (LE50:18.0-19.0). Only visual artists (LE50:15.5-17.1) had a lower life expectancy at age 50 compared to the elite at that time. For the most recent birth cohorts from 1850 through 1899, the comparison between artists and the elite reversed and acoustic and literary artist had a lower life expectancy at age 50, while visual artists enjoyed a similar life expectancy at age 50. Although artists belonged to the middle socioeconomic class and lived predominantly in urban areas with poor living conditions, they had a life expectancy similar to the elite population. This is in line with observed favourable effects of practicing arts on health in the short-term. From our historical analysis, we hypothesize several mechanisms through which artistic creativity could influence the ageing process and life expectancy. These hypotheses, however, should be formally tested before any definite conclusions on effects of arts on ageing can be drawn.


Reliability and validity of Urdu PARENTS for assessing non-technical skills of paediatric residents in a teaching hospital in Pakistan.
The primary objective of our study is twofold. First, we assessed nontechnical skills (NTSs), such as the cognitive, social, and personal skills of postgraduate residents (PGRs), from paediatric caregivers' perspectives in a paediatric emergency department (PED) of a tertiary care hospital. Second, we evaluated the reliability and validity of the 'Parents' Assessment of Residents Enacting Non-Technical Skills' (PARENTS) instrument in its Urdu-translated version, ensuring its applicability and accuracy in the Pakistani context. This mixed-method study used an instrument translation and validation design. We translated an existing instrument, PARENTS, into Urdu, the national language of Pakistan, and administered it to paediatric caregivers in the PED of a tertiary care hospital. We collected data from 471 paediatric caregivers and coded them for analysis in AMOS and SPSS. The Urdu-translated version of the PARENTS demonstrated reliability and internal validity in our study. The findings from the assessment revealed that paediatric caregivers expressed satisfaction with the knowledge and skill of residents. However, there was comparatively lower satisfaction regarding the residents' display of patience or empathy towards the children under their care. The study findings support the validity and reliability of the PARENTS as an effective instrument for assessing the NTS of PGRs from the perspective of paediatric caregivers. With its demonstrated efficacy, medical educators can utilize PARENTS to pinpoint specific areas that require attention regarding the NTS of PGRs, thus facilitating targeted interventions for enhanced patient care outcomes.


Case study on temperature-accelerated molecular dynamics simulation of ligand dissociation: inducer dissociation from the Lac repressor protein.
We studied ligand dissociation from the inducer-binding domain of the Lac repressor protein using temperature-accelerated molecular dynamics (TAMD) simulations. With TAMD, ligand dissociation could be observed within relatively short simulation time. This allowed many dissociation trajectories to be sampled. Under the adiabatic approximation of TAMD, all but one degree of freedom of the system were sampled from usual canonical ensembles at room temperature. Thus, meaningful statistical analyses could be carried out on the trajectories. A systematic approach was proposed to analyze possible correlations between ligand dissociation and fluctuations of various protein conformational coordinates. These analyses employed relative entropies, allowing both linear and nonlinear correlations to be considered. Applying the simulation and analysis methods to the inducer binding domain of the Lac repressor protein, we found that ligand dissociation from this protein correlated mainly with fluctuations of side-chain conformations of a few residues that surround the binding pocket. In addition, the two binding sites of the dimeric protein were dynamically coupled: occupation of one site by an inducer molecule could significantly reduce or slow down conformational dynamics around the other binding pocket.


The role of trophoblast binucleate cells in implantation in the goat: a quantitative study.
The number of goat trophoblastic binucleate cells, the incidence of their migration and the formation of trinucleate and syncytial cells in the maternal uterine epithelial layer was estimated quantitatively using transmission electron microscopy between 14 and 23 days postcoitum (dpc). Binucleate cells were first observed at 18 dpc and their proportions increased rapidly from less than 1 per cent to 16 per cent by 19 dpc and 22 per cent by 23 dpc. The appearance of trinucleate cells within the maternal uterine epithelial layer coincided with evidence of migration and fusion of binucleate cells with individual uterine epithelial cells, and an increased death rate among the other uninucleate uterine epithelial cells. There was also a slight increase in the incidence of intraepithelial lymphocytes close to the trinucleate cells. The quantitative studies uphold the hypothesis that at implantation in the goat, placental trinucleate cells and their subsequent multinucleate syncytial plaque derivatives are fetomaternal hybrid tissue formed by fusion of a binucleate cell(s) with a single uterine epithelial cell.


Pharmacokinetics of the active metabolite of benazepril, benazeprilat, and inhibition of plasma angiotensin-converting enzyme activity after single and repeated administrations to dogs.
Plasma pharmacokinetic variables of benazeprilat, the active metabolite of the angiotensin-converting enzyme (ACE) inhibitor benazepril, were evaluated in healthy Beagles. Benazeprilat was administered IV at a dosage of 0.5 mg/kg of body weight (n = 9). The elimination of half-life of benazeprilat was 3.5 hours, although an additional terminal phase was observed in some dogs. Vehicle (gelatin capsules) or benazepril at dosages of 0.125, 0.25, 0.5, or 1.0 mg/kg was administered orally as a single administration, then once daily for 15 consecutive days (n = 5 or 6/group). Peak benazeprilat concentrations were rapidly attained by 2 hours. Benazeprilat concentrations accumulated moderately with repeated administration, with a peak concentration that was 23% higher and an area under the concentration-time curve that was 34% higher after the 15th dose of benazepril, compared with values after a single dose. The effective half-life for accumulation for all 4 dosages was 12 hours. Steady-state concentrations at 2 hours after administration were achieved after a median (range) of 1 (1 to 6) dose(s). Pharmacodynamic variables were assessed by measurements of plasma ACE activity after oral administration of benazepril or vehicle. All dosages of benazepril caused profound inhibition of ACE, with rapid onset of activity (time to peak effect, 2 hours) and long duration of action (single administration of all 4 doses induced inhibition of ACE that was significantly different from the value in the control [vehicle-treated] dogs for all time points between 1 and 30 hours). Maximal inhibition at all time points was induced by the 0.25-mg/kg dosage at a single administration and with the lowest dosage tested (0.125 mg/kg) at steady state. At steady state, the 0.25-mg/kg dosage caused (mean +/- SEM) 96.9 +/- 2.0% inhibition of ACE activity at maximal effect and 83.6 +/- 4.2% at trough effect (24 hours after dosing), indicating minimal variation in peak/trough effect. Steady-state inhibition of ACE activity at both peak and trough drug effect was achieved after 1 to 4 doses. The data indicate that benazepril is a potent and long-acting ACE inhibitor in dogs.


The nucleotide sequence and genome structure of the geminivirus miscanthus streak virus.
A tandem dimer of miscanthus streak virus (MiSV) DNA was inserted into the T-DNA of the binary plasmid vector pBIN19 and agroinoculated into several monocotyledonous plants (monocots) using Agrobacterium tumefaciens or A. rhizogenes. Disease symptoms and geminate particles were produced in maize and Panicum milaceum plants, and MiSV-specific double-stranded and single-stranded DNAs were found in these plants. The nucleotide sequence of the infectious MiSV clone, consisting of 2672 nucleotides, was determined. Four open reading frames (ORFs) for proteins of Mr greater than 10K were identified, two (V0 and V2) in the virus (+) sense and two (C1 and C2) in the complementary (-) sense, although C2 did not have an ATG start codon. Unlike other geminiviruses infecting monocots, complementary-sense ORFs did not overlap. Potential splicing donor and acceptor sites were identified in the sequence of the border region between the C terminus of ORF C1 and the N terminus of ORF C2. Amino acid sequences predicted from three (V2, C1 and C2) of these ORFs showed significant homology with the corresponding ORFs of other geminiviruses infecting monocots. A fifth ORF (V1), which showed some homology with ORF V1 of other monocot-infecting geminiviruses despite having a coding capacity for a product of Mr 8.8K, was found just upstream of ORF V2 as observed in those geminiviruses. ORF V0 showed no significant homology with ORFs present in any other geminiviruses. A mutation of V0 indicated that the C-terminal 30% of this ORF was not necessary for infection in maize, but that sequences around the mutated LspI site might have some regulatory role.


Can we trust docking results? Evaluation of seven commonly used programs on PDBbind database.
Docking is one of the most commonly used techniques in drug design. It is used for both identifying correct poses of a ligand in the binding site of a protein as well as for the estimation of the strength of protein-ligand interaction. Because millions of compounds must be screened, before a suitable target for biological testing can be identified, all calculations should be done in a reasonable time frame. Thus, all programs currently in use exploit empirically based algorithms, avoiding systematic search of the conformational space. Similarly, the scoring is done using simple equations, which makes it possible to speed up the entire process. Therefore, docking results have to be verified by subsequent in vitro studies. The purpose of our work was to evaluate seven popular docking programs (Surflex, LigandFit, Glide, GOLD, FlexX, eHiTS, and AutoDock) on the extensive dataset composed of 1300 protein-ligands complexes from PDBbind 2007 database, where experimentally measured binding affinity values were also available. We compared independently the ability of proper posing [according to Root mean square deviation (or Root mean square distance) of predicted conformations versus the corresponding native one] and scoring (by calculating the correlation between docking score and ligand binding strength). To our knowledge, it is the first large-scale docking evaluation that covers both aspects of docking programs, that is, predicting ligand conformation and calculating the strength of its binding. More than 1000 protein-ligand pairs cover a wide range of different protein families and inhibitor classes. Our results clearly showed that the ligand binding conformation could be identified in most cases by using the existing software, yet we still observed the lack of universal scoring function for all types of molecules and protein families.


Bone microarchitecture as an important determinant of bone strength.
Structure and microarchitecture are determinant aspects of bone strength and essential elements for the assessment of bone mechanical properties. The main structural determinants of bone mechanical strength include width and porosity in the cortical bone; shape, width, connectivity, and anisotropy in the trabecular bone. There are several methods to assess bone architecture, particularly at the trabecular level. Two different approaches can be identified. The first is based on the use of optical microscopy and on the principles of quantitative histology, which evaluate microarchitecture two-dimensionally. The second applies the most modern diagnostic techniques, employing computed tomography and magnetic resonance to obtain and analyze three-dimensional images. From a clinical point of view, microarchitecture is an interesting aspect to study and define specific patterns, such as glucocorticoid-induced osteoporosis, or to evaluate bone alterations in transplanted patients. Microarchitecture seems to be a determinant of bone fragility independent of bone density. Moreover, bone microarchitecture seems to be important to understand the mechanisms of bone fragility as well as the action of the drugs used to prevent osteoporotic fractures. Several in vivo studies (on animals and humans) showed important findings on the effects of different treatments on microarchitecture. Bisphosphonates and parathyroid hormone seemed to preserve or even improve microarchitecture. These observations can provide an additional interpretation for the anti-fracture effect of drugs from a structural viewpoint. The challenge for the future will be to evaluate bone quality in vivo with the same or better resolution and accuracy than the invasive methods in use today.


Hunger in French Guiana, an endemic plague worsened by the health crisis
In 2020, food shortages occurred at the beginning of the confinement period that was supposed to curb the COVID-19 pandemic. In French Guiana, where a major part of the population lives under the poverty line, health workers voiced major concerns. Alongside massive food aid distributions, a first transversal study was carried out in August 2020 targeting poor neighborhoods in Cayenne. The results were particularly worrying. More than 80% of households had been suffering from hunger during that month, with a median decrease of 46% in revenue. Two other investigations followed in February and then in August of 2021. With the relaxing of the health measures, the situation improved in the Cayenne region, but two out of three were still affected, showing signs of quantitative deficiencies and insufficient food diversity. The situation seemed particularly grave for children. In light of this situation, we propose to create an observatory of food insecurity in Guiana, while maintaining this topic as a health priority. In addition, the fight against food insecurity cannot be limited to multi-sectorial material and strategic aide. It must be thought about in a more global manner, including health and social questions, territorial management policies, access to land and water, access to rights and social inclusion. Targeted actions helping the most exposed and vulnerable people is also an important stake, independent of the administrative situation and residency rights of the concerned people.


Entrepreneurship Education and Entrepreneurial Intentions of College Students: The Mediating Role of Entrepreneurial Self-Efficacy and the Moderating Role of Entrepreneurial Competition Experience.
This study aims to explore effective ways to improve college students' entrepreneurial self-efficacy and intentions through entrepreneurship education. The survey used a random sample of 804 college students in Zhejiang Province, China. The results show that: (1) In terms of the characteristics of entrepreneurial intention, there are significant differences in gender, entrepreneurial experience, entrepreneurial competition experience, and family background of self-employment. (2) There are significant differences in the characteristics of entrepreneurship education in gender, entrepreneurial competition experience, and the family background of self-employment. (3) In the relationship among entrepreneurship education, entrepreneurial self-efficacy, and entrepreneurial intention, entrepreneurship education is significantly and positively related to entrepreneurial self-efficacy and entrepreneurial intention. Entrepreneurial self-efficacy is significantly and positively associated with entrepreneurial intention. Entrepreneurial self-efficacy plays a complete mediating role between entrepreneurship education and entrepreneurial intention. Entrepreneurial self-efficacy also has a suppressing effect on the relationship between the two. (4) Entrepreneurial competition experience moderates the second half of the mediating effect of entrepreneurial self-efficacy. Finally, the study offers several proposals for the teaching practice of entrepreneurship education.


Using PCR to extend the limit of oligonucleotide synthesis.
A method has been developed to allow one to extend the practical limit of oligonucleotide synthesis by coupling the synthesis reaction to a subsequent PCR. Given that DNA synthesizers are capable of producing reasonable yields of oligonucleotides that are 125-150 bases in length, this method could be used to recover the minute amount of full-length product present in mixtures extended well beyond the established limits. This technology could be applied to gene synthesis and mutagenesis.


Outbreak of fatal childhood lead poisoning related to artisanal gold mining in northwestern Nigeria, 2010.
In May 2010, a team of national and international organizations was assembled to investigate children's deaths due to lead poisoning in villages in northwestern Nigeria. Our goal was to determine the cause of the childhood lead poisoning outbreak, investigate risk factors for child mortality, and identify children < 5 years of age in need of emergency chelation therapy for lead poisoning. We administered a cross-sectional, door-to-door questionnaire in two affected villages, collected blood from children 2-59 months of age, and obtained soil samples from family compounds. Descriptive and bivariate analyses were performed with survey, blood lead, and environmental data. Multivariate logistic regression techniques were used to determine risk factors for childhood mortality. We surveyed 119 family compounds. Of 463 children < 5 years of age, 118 (25%) had died in the previous year. We tested 59% (204/345) of children < 5 years of age, and all were lead poisoned (≥ 10 µg/dL); 97% (198/204) of children had blood lead levels (BLLs) ≥ 45 µg/dL, the threshold for initiating chelation therapy. Gold ore was processed inside two-thirds of the family compounds surveyed. In multivariate modeling, significant risk factors for death in the previous year from suspected lead poisoning included the age of the child, the mother's work at ore-processing activities, community well as primary water source, and the soil lead concentration in the compound. The high levels of environmental contamination, percentage of children < 5 years of age with elevated BLLs (97%, > 45 µg/dL), and incidence of convulsions among children before death (82%) suggest that most of the recent childhood deaths in the two surveyed villages were caused by acute lead poisoning from gold ore-processing activities. Control measures included environmental remediation, chelation therapy, public health education, and control of mining activities.


[The monoclonal gammapathy of uncertain meaning- a premyelomatosis?].
In three cases of localised multiple myeloma the monoclonal immunoglobulin could be identified even 17, 12 and 8 years prior to clinical manifestation. These observations point again to the question of a possible "history of development" for the plasma cell disease and, thus, to the clinical validity of monoclonal gammopathy of (still) uncertain significance. As even in the relationship of membrane-associated light chains of B-lymphocytes a certain monoclonality begins to appear at an early time, more attention should be devoted to the early diagnosis of malign plasma cell dyscrasia.


Computed tomography (CT) predicts accurately the pathologic tumour size in stage I non-small-cell lung cancer (NSCLC).
In stage I non-small-cell lung cancer (NSCLC) tumour size has been the most consistent determinant of survival. The choice of therapy option is based on accurate definition of the stage. The aim of our study is to correlate tumour size by computed tomography scan (CT) with pathologic size and to determine possible prognostic factors in surgically resected pathologic stage IA and IB NSCLC patients. Retrospective review of CT scans and medical history data from 89 pathologic stage I NSCLC patients. Clinical prognostic factors analysed were age, gender, smoking status, pulmonary function, performance status (PS), surgical procedure, histopathology, vessel invasion, pleural infi ltration, tumour size and number of lymph nodes resected. According to the new TNM classification for lung cancer, tumour size was divided into five groups (I: <2 cm, II: 2-3 cm, III: 3-5 cm, IV: 5-7 cm and V: >7 cm). After a median surveillance of 55.2 months, 42 patients relapsed and 55 had died. The 5-year progressionfree survival was 55.7% and 5-year overall survival (OS) 49.9% (median 58.97 months). None of the clinical parameters analysed were predictors of OS. Significant correlation was found between tumour size in CT scan and pathologic stage (Pearson 0.75). In our analysis with 89 surgically resected stage IA and IB NSCLC patients we found a good correlation between clinical and pathologic tumour size by CT scan. The prognoses factors analysed had no significant impact on survival.


Microgel core/shell architectures as targeted agents for fibrinolysis.
We demonstrate the utility of microgel core/shell structures conjugated to fibrin-specific peptides as fibrinolytic agents. Poly(N-isopropylmethacrylamide) (pNIPMAm) based microgels conjugated to the peptide GPRPFPAC (GPRP) were observed to bring about fibrin clot erosion, merely through exploitation of the dynamic nature of the clots. These results suggest the potential utility of peptide-microgel hybrids in clot disruption and clotting modulation.


Cardiovascular effect of intravenous lipid A in rabbits.
The in vivo cardiovascular effect of intravenous administration of monophosphoryl lipid A (mp-lipid A) and diphosphoryl lipid A (dp-lipid A) in awake New Zealand white rabbits was investigated. Observed changes were evaluated in comparison to a control group and an endotoxin-treated group. Rabbits given lipid A showed a significant depression in cardiac index (p less than .025), mean arterial pressure (p less than .025, dp-lipid A only), arterial carbon dioxide tension (p less than .025), and total leukocyte count (p less than .05) compared to controls. Animals receiving lipid A tended to respond overall in a manner closely matching that of the endotoxin group. Dosages of lipid A given were approximately 3.5 times larger than the endotoxin dosages with respect to actual number of molecules administered (1.25-2.0 times larger by mass). These results indicate that lipid A is active in producing the cardiovascular and leukopenic effects characteristic of experimental septic shock.


Recent reviews. 57.
Reviews are listed in order of appearance in the sources indicated. In multidisciplinary review journals, only those reviews which fall within the scope of this Journal are included. Sources are listed alphabetically in three categories: regularly issued review journals and series volumes, contributed volumes, and other monographs. Titles are numbered serially, and these numbers are used for reference in the index. Major English-language sources of critical reviews are covered. Encyclopedic treatises, annual surveys such as Specialist Periodical Reports, and compilations of symposia proceedings are omitted. This installment of Recent Reviews covers principally the early part of the 2000 literature. Previous installment: J. Org. Chem. 2000, 65(7), 2267-76. Supporting Information Available: A file containing this Recent Review compilation in Microsoft Word and the data in rtf format. This material is available free of charge via the Internet at http://pubs. acs.org.


Cosecretion of estrogen and inhibin B by a feminizing adrenocortical adenoma: impact on gonadotropin secretion.
We describe the first reported case of a feminizing adrenocortical adenoma cosecreting estrogens and inhibin B. A 39-yr-old man, with no previous history of disease and free of treatment, complained of gynecomastia without any clinical abnormality. Plasma E2 and T were 496 pmol/liter and 8.7 nmol/liter, respectively. Testicular echography was normal, and abdominal computed tomography scan showed a 28-mm right adrenal tumor. hCG (5000 IU, im) induced a rise in plasma T levels (20.7 nmol/liter) without any change in plasma E2 levels. Basal plasma LH and FSH levels were undetectable. GnRH (100 microg, i.v.) induced an increase in plasma LH levels without a change in plasma FSH levels. The mean plasma inhibin B level was 330 +/- 45 pg/ml (normal range, 94-327). Pulsatile GnRH administration (20 microg/pulse every 90 min for 3 d) stimulated LH secretion, whereas FSH secretion remained blunted. The patient underwent surgery to remove a 12-g adrenal adenoma. Six months later, plasma E2 and T levels were normalized. LH showed a spontaneous pulsatile pattern, and the mean plasma FSH level was 4.8 U/liter. The secretion of both gonadotropins was stimulated during a pulsatile GnRH administration performed in the same manner as before surgery. The mean plasma inhibin B level was 210 +/- 25 pg/ml. Immunohistochemical studies revealed the presence of aromatase in clusters of tumor cells. Incubation of tumor sections with anti-beta(B)-inhibin antibody revealed intense staining in groups of cells that were also labeled with anti-alpha-inhibin antibody. These data show that the tumor cosecreted E2 and inhibin B, which were both responsible for inhibition of gonadotropin secretion. Tumor secretions appeared to be much more potent in suppressing FSH than LH levels.


Cellular and Tissue Selectivity of AAV Serotypes for Gene Delivery to Chondrocytes and Cartilage.
Background: Despite several studies on the effect of adeno-associated virus (AAV)-based therapeutics on osteoarthritis (OA), information on the transduction efficiency and applicable profiles of different AAV serotypes to chondrocytes in hard cartilage tissue is still limited. Moreover, the recent discovery of additional AAV serotypes makes it necessary to screen for more suitable AAV serotypes for specific tissues. Here, we compared the transduction efficiencies of 14 conventional AAV serotypes in human chondrocytes, mouse OA models, and human cartilage explants obtained from OA patients. Methods: To compare the transduction efficiency of individual AAV serotypes, green fluorescent protein (GFP) expression was detected by fluorescence microscopy or western blotting. Likewise, to compare the transduction efficiencies of individual AAV serotypes in cartilage tissues, GFP expression was determined using fluorescence microscopy or immunohistochemistry, and GFP-positive cells were counted. Results: Only AAV2, 5, 6, and 6.2 exhibited substantial transduction efficiencies in both normal and OA chondrocytes. All AAV serotypes except AAV6 and rh43 could effectively transduce human bone marrow mesenchymal stem cells. In human and mouse OA cartilage tissues, AAV2, AAV5, AAV6.2, AAV8, and AAV rh39 showed excellent tissue specificity based on transduction efficiency. These results indicate the differences in transduction efficiencies of AAV serotypes between cellular and tissue models. Conclusions: Our findings indicate that AAV2 and AAV6.2 may be the best choices for AAV-mediated gene delivery into intra-articular cartilage tissue. These AAV vectors hold the potential to be of use in clinical applications to prevent OA progression if appropriate therapeutic genes are inserted into the vector.


[Observation on the activity of superoxide dismutase and catalase of alveolar macrophage in patients with lung cancer].
The number of alveolar macrophage (AM) and activity of superoxide dismutase (SOD) and catalase (CA) in AM and obtained from bronchoalveolar lavage (BAL) were assayed in 11 lung cancer patients and 21 patients without lung cancer. The SOD, CA activities was lower in the patients with lung cancer than that in patients without lung cancer. The number of AM in BAL reduced too. It suggested that metabolism of AM was inhibited seriously in patients with lung cancer. The number of AM in BAL of smokers was significant higher than that of non-smokers, and it is postulated that the increase of AM is probably the result of stimulation induced by smoking.


[Clinical and prognostic value of cardiovascular symptoms in perinatal asphyxia].
The myocardium, while selected as a preferred organ for perfusion in the asphyxiated fetus or newborn, nevertheless may suffer damage. The objectives of this study were: (1) to analyze the frequency and type of cardiovascular (CV) manifestations in perinatal asphyxia (PA); (2) to evaluate the perinatal differences in asphyxiated term infants with and without CV involvement; and (3) to know the importance of CV manifestations in relationship to neurological sequelae in PA. One hundred and fifty-six consecutive asphyxiated full-term newborns were studied prospectively. During the neonatal period, systematic CV evaluations, including clinical examination, heart rate and blood pressure monitoring, and complementary procedures (chest X-rays, electrocardiograms and echocardiograms), were performed on every infant with PA. Those with CV involvement were classified into two groups: "minor" (dysrhythmias and mild hypotension) and "major" (transient tricuspid insufficiency, myocardial ischemia, cardiogenic and/or hypovolemic shock). CV involvement was analyzed with regard to severity of PA, hypoxic-ischemic encephalopathy (based on the classification of Levene) and neurologic sequelae after a follow-up period of at least 12-months (based on the classification of Finer and Amiel-Tison). CV manifestations were observed in 31 (19.8%) of the infants and classified as minor in 27 cases (mainly mild hypotension and bradycardia) and major in 4. CV involvement was found significantly more frequently in asphyxiated newborns with severe PA (p < 0.001) and those with neurological and other extraneurological manifestations (p < 0.001). In relation to neurologic sequelae at follow-up, the only significant extraneurologic involvement in PA was CV involvement (univariant analysis by Cox's regression; RR = 3.96, CI95% = 1.50-10.45). A significant association was found between CV manifestations and all of the neurological and extraneurological dysfunctions in PA, based on the severity of the hypoxic-ischemic lesion. The incidence of severe CV damage is low, although less severe manifestations may be frequent (mainly mild hypotension and bradycardia). The results of this study indicate the need for CV assessment in asphyxiated term newborn infants based on its clinical and prognostic value in relationship to neurological sequelae.


Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol.
Patients with stage D2 prostate carcinoma are often treated initially with hormones to decrease endogenous testosterone. Therapy with diethylstilbestrol (DES), leuprolide, or bilateral orchiectomy has been reported to be equivalent. DES is the cheapest preparation, but has the potential for serious cardiovascular or thromboembolic complications. Flutamide is a novel antiandrogen with fewer side effects. The Eastern Cooperative Oncology Group (ECOG) conducted a double-blind, randomized study to compare the efficacy of flutamide (250 mg three times daily) to DES (1 mg three times daily) as the primary hormonal therapy for patients with stage D2 prostate cancer. Patients were stratified by performance status, disease sites, and history of cardiovascular disease at randomization. Forty-eight patients received DES and 44 flutamide. Patient characteristics were evenly distributed between the two treatments. The overall response rate was similar (DES, 62%; flutamide, 50%). Grade III or worse cardiovascular or thromboembolic toxicity developed in 33.3% of patients on DES and in 17.6% on flutamide (P = .051). Other toxicities were similar between the two treatment arms. However, DES produced significantly longer time to treatment failure (26.4 v 9.7 months, P = .016) and longer survival than flutamide (43.2 v 28.5 months, P = .040). As the primary hormonal therapy for stage D2 prostate cancer, DES caused more serious cardiovascular or thromboembolic complications than flutamide. Despite this, flutamide was not as active an initial agent as DES. However, the effectiveness of flutamide in conjunction with other agents compared with DES remains undetermined, and the optimal initial hormone therapy of stage D2 prostate cancer requires further studies.


Progress toward global reduction in under-five mortality: a bootstrap analysis of uncertainty in Millennium Development Goal 4 estimates.
Millennium Development Goal 4 calls for an annual rate of reduction (ARR) of the under-five mortality rate (U5MR) of 4.4% between 1990 and 2015. Progress is measured through the point estimates of the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). To facilitate evidence-based conclusions about progress toward the goal, we assessed the uncertainty in the estimates arising from sampling errors and biases in data series and the inferior quality of specific data series. We implemented a bootstrap procedure to construct 90% uncertainty intervals (UIs) for the U5MR and ARR to complement the UN IGME estimates. We constructed the bounds for all countries without a generalized HIV epidemic, where a standard estimation approach is carried out (174 countries). In the bootstrap procedure, potential biases in levels and trends of data series of different source types were accounted for. There is considerable uncertainty about the U5MR, particularly for high mortality countries and in recent years. Among 86 countries with a U5MR of at least 40 deaths per 1,000 live births in 1990, the median width of the UI, relative to the U5MR level, was 19% for 1990 and 48% for 2011, with the increase in uncertainty due to more limited data availability. The median absolute width of the 90% UI for the ARR from 1990 to 2011 was 2.2%. Although the ARR point estimate for all high mortality countries was greater than zero, for eight of them uncertainty included the possibility of no improvement between 1990 and 2011. For 13 countries, it is deemed likely that the ARR from 1990 to 2011 exceeded 4.4%. In light of the upcoming evaluation of Millennium Development Goal 4 in 2015, uncertainty assessments need to be taken into account to avoid unwarranted conclusions about countries' progress based on limited data.


Somatotopic studies on red nucleus: spinal projection level and respective receptive fields.
The somatotopic inputs into red nucleus (RN) neurons have been studied with special reference to their level of projection in the spinal cord. As inputs we employed either volleys in predominantly cutaneous nerves of forelimb and hindlimb or cutaneous mechanoreceptor discharges evoked by taps to footpads of forelimb and hindlimb. There has been physiological confirmation of the anatomical findings that RD neurons projecting to the lumbar cord are located in the ventrolateral zone of the pars magnocellularis, whereas in the dorsomedial zone are RN neurons with cervical but not lumbar projection. Somatotopically there was found to be a differentiation of input to RN neurons according as they projected to the lumbar or only to the cervical cord. This finding was presented in the form both of tables and of somatotopic maps. As expected, this discrimination was more restrictive for the more selective inputs from pad taps than for nerve inputs. Nevertheless, forelimb inputs often had a considerable excitatory and inhibitory action on lumbar-projecting RN neurons, and vice versa for cervical-projecting neurons. There were two notable somatotopic findings that suggest specificities of connectivities. First, despite the large convergence of IP neurons onto RN neurons (about 50-fold), the degree of somatotopic discrimination was about the same for interpositus and RN neurons with two testing procedures: between inputs from forelimb and hindlimb; and between inputs from pads on one foot. Second, although there was in the interpositus nucleus a considerable topographical admixture of neurons with dominant forelimb or hindlimb inputs, the axonal projections of these neurons were apparently unscrambled on the way to the target RN neurons, so as to deliver the somatotopic specificities observed for two classes of RN neurons; those projecting down the spinal cord beyond L2 level, and those projecting to C2 but not L2. Finally, there is a general discussion of motor control with reference to the pathway; pars intermedia of anterior lobe of cerebellum leads to interpositus nucleus leads to red nucleus leads to rubrospinal tract leads to spinal motoneurons.


Using best-worst scaling to rank factors affecting vaccination demand in northern Nigeria.
Understanding and ranking the reasons for low vaccination uptake among parents in northern Nigeria is critical to implement effective policies to save lives and prevent illnesses. This study applies best-worst scaling (BWS) to rank various factors affecting parents' demand for routine childhood immunization. We conducted a household survey in Nahuche, Zamfara State in northern Nigeria. Nearly two hundred parents with children under age five were asked about their views on 16 factors using a BWS technique. These factors focused on known attributes that influence the demand for childhood immunization, which were identified from a literature review and reviewed by a local advisory board. The survey systematically presented parents with subsets of six factors and asked them to choose which they think are the most and least important in decisions to vaccinate children. We used a sequential best-worst analysis with conditional logistic regression to rank factors. The perception that vaccinating a child makes one a good parent was the most important motivation for parents in northern Nigeria to vaccinate children. Statements related to trust and social norms were ranked higher in importance compared to those that highlighted perceived benefits and risks, healthcare service, vaccine information, or opportunity costs. Fathers ranked trust in the media and views of their leaders to be of greatest importance, whereas mothers placed greater importance on social perceptions and norms. Parents of children without routine immunization ranked their trust in local leaders about vaccines higher in considerations, and the media's views lower, compared to parents with children who received routine immunization. Framing immunization messages in the context of good parenting and hearing these messages from trusted information sources may motivate parental uptake of childhood vaccines. These results are useful to policymakers to prioritize resources in order to increase awareness and demand for childhood immunization.


Adaptive fuzzy output feedback dynamic surface control of interconnected nonlinear pure-feedback systems.
In this paper, an adaptive fuzzy decentralized output feedback control design is presented for a class of interconnected nonlinear pure-feedback systems. The considered nonlinear systems contain unknown nonlinear uncertainties and the states are not necessary to be measured directly. Fuzzy logic systems are employed to approximate the unknown nonlinear functions, and then a fuzzy state observer is designed and the estimations of the immeasurable state variables are obtained. Based on the adaptive backstepping dynamic surface control design technique, an adaptive fuzzy decentralized output feedback control scheme is developed. It is proved that all the variables of the resulting closed-loop system are semi-globally uniformly ultimately bounded, and also that the observer and tracking errors are guaranteed to converge to a small neighborhood of the origin. Some simulation results and comparisons with the existing results are provided to illustrate the effectiveness and merits of the proposed approach.


Association of Continuous Opioids and/or Midazolam During Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort.
To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2 years in very premature infants who were ventilated. This national observational study included premature infants born before 32 weeks of gestation intubated within 1 hour after birth and still intubated at 24 hours from the French EPIPAGE 2 cohort. Infants only treated with bolus were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7 days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n = 450) vs naive (n = 472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age 2 years. Survival at age 2 years was significantly higher in the treated group (92.5% vs 87.9%, risk difference, 4.7%; 95% CI, 0.3-9.1; P = .037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%; risk difference, 5.3%; 95% CI -0.3 to 11.0; P = .063). These results were confirmed by sensitivity analyses using 5 alternative models. Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24 hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2 years.