Comparative Pharmacokinetics and Safety of Imrecoxib, a Novel Selective Cyclooxygenase-2 Inhibitor, in Elderly Healthy Subjects.
Imrecoxib is a novel and moderately selective cyclooxygenase-2 inhibitor with properties of anti-inflammation and alleviating pain, which is widely applied in osteoarthritis patients. The pharmacokinetic data supporting imrecoxib's rational use in elderly population are not available. The study aims to investigate the pharmacokinetics of imrecoxib and its main metabolites and explore the safety of imrecoxib in elderly healthy subjects. A total of 19 healthy subjects including 10 non-elderly and 9 elderly subjects received single dose of 100 mg imrecoxib under fasting condition. Pharmacokinetics, safety and tolerability profiles were assessed. After oral administration of single dose of 100 mg imrecoxib, it was absorbed into plasma with median time to reach peak concentration (Tmax) around 2 hours. The concentration-time curves of imrecoxib (M0) showed higher interindividual variability in elderly subjects compared with non-elderly subjects. Peak concentration (Cmax) of M0, its hydroxyl metabolite M1 and carboxylated metabolite M2 in plasma increased by 39%, 21% and 17%, and area under concentration-time curve from time 0 to time t (AUC0-t) of M0, M1 and M2 in plasma increased by 34%, 13% and 27%, respectively, in elderly subjects compared with non-elderly subjects. The 90% CIs of geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of M0, M1 and M2 between the two groups were not located within 80-125%, indicating Cmax, AUC0-t and AUC0-∞ were not completely equivalent between non-elderly and elderly healthy subjects. However, comparison of pharmacokinetic data of M0, M1 and M2 between the two groups showed no significant difference (P>0.05). Imrecoxib was well tolerated in both non-elderly and elderly healthy subjects, especially with favorable gastrointestinal and cardiovascular safety profiles. Pharmacokinetic and safety profiles of imrecoxib in elderly healthy subjects indicated that no dose adjustment should be required for elderly population.


Multi-stage segmentation of white matter hyperintensity, cortical and lacunar infarcts.
Cerebral abnormalities such as white matter hyperintensity (WMH), cortical infarct (CI), and lacunar infarct (LI) are of clinical importance and frequently present in patients with stroke and dementia. Up to date, there are limited algorithms available to automatically delineate these cerebral abnormalities partially due to their complex appearance in MR images. In this paper, we describe an automated multi-stage segmentation approach for labeling the WMH, CI, and LI using multi-modal MR images. We first automatically segment brain tissues (white matter, gray matter, and CSF) based on the T1-weighted image and then identify hyperintense voxels based on the fluid attenuated inversion recovery (FLAIR) image. We finally label the WMH, CI, and LI based on the T1-weighted, T2-weighted, and FLAIR images. The segmentation accuracy is evaluated using a community-based sample of 272 old adults. Our results show that the automated segmentation of the WMH, CI, and LI is comparable with manual labeling in terms of spatial location, volume, and the number of lacunes. Additionally, the WMH volume is highly correlated with the visual grading score based on the Age-Related White Matter Changes (ARWMC) protocol. The evaluations against the manual labeling and ARWMC visual grading suggest that our algorithm provides reasonable segmentation accuracy for the WMH, CI, and LI.


Assessment of Novel Antioxidant Therapy in Atherosclerosis by Contrast Ultrasound Molecular Imaging.
Ultrasound molecular imaging was used to evaluate the therapeutic effects of antioxidant therapy with EUK-207, which has superoxide dismutase and catalase activities, on suppressing high-risk atherosclerotic features. Mice with age-dependent atherosclerosis produced by deletion of the low-density lipoprotein receptor and Apobec-1 were studied at 20 and 40 weeks of age. EUK-207 or vehicle was administered for the preceding 8 weeks. Therapy for 28 weeks was also studied for 40-week-old mice. Ultrasound molecular imaging of the thoracic aorta was performed with contrast agents targeted to endothelial P-selectin, von Willebrand factor A1-domain, and platelet glycoprotein Ibα or control agent. Aortic plaque area and macrophage content were assessed by histology. In 20-week-old double-knockout mice, EUK-207 compared with sham therapy produced only nonsignificant trends for reduction in molecular imaging signal for endothelial P-selectin, von Willebrand factor A1-domain, and platelet adhesion. At 40 weeks, EUK-207 given for 8 or 28 weeks significantly (P < .05) reduced signal for all three endothelial-associated events essentially to background levels, with the exception of glycoprotein Ibα signal after 8 weeks (P = .06). On aortic histology, EUK-207 therapy for 8 weeks did not affect plaque area or macrophage content at either age. However, EUK-207 for 28 weeks almost completely suppressed plaque development (350 ± 258 vs 4 ± 6 × 103 μm2, P = .014) and macrophage content (136 ± 103 vs 3 ± 2 × 103 μm2, P = .002) compared with control mice at 40 weeks. Molecular imaging can be used to assess vascular responses to antioxidants and has demonstrated that certain antioxidants reduce vascular endothelial activation and platelet adhesion, but reductions in plaque size and macrophage content occurs only with long-duration therapy that is started early.


[Long-term results after multiple trauma with ISS ≥ 25. Outcome and predictors of quality of life].
The survival chances of multiple trauma patients have continually improved over the last decades; therefore, it is often not a question of whether a patient survives a severe accident but rather how the patient survives. In a retrospective study 127 patients were questioned regarding quality of life and health and possible influencing factors using the POLO chart an average of 70 months after suffering severe trauma (ISS Ø 35.6). The quality of life of severely injured patients is significantly reduced compared with the normal population even years after the trauma. In addition to four pretraumatic factors (older age, female gender, low education and previous illnesses) four posttraumatic variables (difficulties with authorities/institutions and unemployment as a consequence of the accident, long duration and subjectively inadequate treatment in hospital) were identified that have a negative impact on long-term quality of life. The self-reported quality of life after multiple trauma no longer permanently achieves the original level despite extensive rehabilitation measures. Post-traumatic factors have a greater impact on the long-term quality of life than the injury severity. A long-term care and specialized rehabilitation services are needed to improve outcome further.


Airways obstruction in survivors of thoracoplasty: reversibility is greater in non-smokers.
Before the advent of antituberculous chemotherapy, thoracoplasty (TPL) was the definitive form of therapy for cavitary pulmonary tuberculosis. This study aimed to characterize the late functional sequelae of TPL, and to establish the degree of reversibility of any consequent airway obstruction. Pulmonary function was studied in 21 long-term (mean 35 years) survivors of TPL between the years 1990-2001. A mixed obstructive/restrictive defect was found in this patient cohort. After inhalation of bronchodilator, marginal increases in FEV(1) and FVC and marginal decreases in FRC, RV and TLC were observed. Maximum mid-expiratory flow rate was severely reduced (28.8% of predicted), but reversibility after inhaled beta(2)-agonist was highest for this parameter of pulmonary function (mean 11%). Smokers had a higher RV (P = 0.04), suggesting hyperinflation, while non-smokers had a larger increase in FEV(1)/FVC ratio postbronchodilator (P = 0.004), suggesting more marked reversibility of airways obstruction in this group. Long-term survivors of TPL have an obstructive as well as a restrictive ventilatory defect. These patients have partial reversibility of the obstructive defect. The degree of reversibility found suggests that bronchodilator therapy may help these patients.


Synthesis and biological evaluation of novel 2-[substituted acetyl]-amino-5-alkyl-1,3,4-thiadiazoles [corrected].
Sixteen novel 2-substituted acetyl amino-5-alkyl-1,3,4-thiadiazole were synthesized and screened for their pharmacological activities. A few of the compounds namely 11, 12 and 16 showed anti-inflammatory activities comparable to phenylbutazone. Compound 12 also showed significant non-specific spasmolytic activity. Diuretic activity of compound 15 at a dose level of 90 mg/kg p.o. was two fold higher compared to 50 mg/kg p.o. of furosemide. Comparable diuresis was also produced by compounds 9, 10 and 16.


Copper nutriture, bioavailability, and the influence of dietary factors.
Copper is known to be an essential nutrient for human beings, but a Recommended Dietary Allowance has not yet been established. A safe and adequate range of intake was established in 1980 for copper and five other trace elements. The range for copper, 2 to 3 mg/day, is higher than the usual dietary copper intake of many individuals in this country. On the basis of balance studies, a requirement of 1.3 mg/day has been suggested. Recent data on copper intake and bioavailability should aid in reevaluating the dietary copper requirement. Copper deficiency symptoms have seldom been observed in human beings. When copper deficiency has been recognized, it has been under unusual conditions, such as in patients receiving parenteral nutrition. Interactions between copper and other dietary components may alter copper status, but the impact of those interactions is not yet well understood. Dietary factors that may affect the bioavailability of copper include the levels of copper, zinc, and molybdenum in the diet; iron deficiency; ascorbic acid intake; intake of carbohydrates, including fructose, glucose, and starch; and fiber and phytate intakes. Some drugs may also affect copper bioavailability.


Sociality of Columbian ground squirrels in relation to their seasonal energy intake.
Seasonal energy intake was estimated for ten populations of Columbian ground squirrels (Spermophilus columbianus) in northwestern Montana. We calculated daily energy intake for an average ground squirrel in each population using measurements of feeding time, consumption rates of different vegetation types (monocots vs. dicots), and the proportion of monocots and dicots in the diet. These daily energy intakes were multiplied by the length of the plant growing season for each population to estimate seasonal energy intake, i.e. over the ground squirrel active season. Amicable interaction rates measured for each population varied with seasonal energy intake, but not with environmental heterogeneity, sex ratio, or the ratio of adults to juveniles. In particular, amicable interactions among adult-juvenile and juvenile-juvenile pairs increased as seasonal energy intake decreased. The proportion of females breeding as yearlings increased as seasonal energy intake increased. This suggests that "harsh" environments reduce the energy available for juvenile growth and development, leading to delayed dispersal and age at first reproduction. These responses may promote the formation of kin groups and increased amicable interactions within those groups. The length of the plant growing season may determine environmental "harshness" across elevational gradients, but at a particular elevation, "harshness" may depend on factors determining daily food intake.


Integrative prognostic analysis of tumor-infiltrating lymphocytes, CD8, CD20, programmed cell death-ligand 1, and tertiary lymphoid structures in patients with early-stage triple-negative breast cancer who did not receive adjuvant chemotherapy.
Stromal tumor-infiltrating lymphocytes (TILs) are independent prognostic factors in systemically untreated early-stage triple-negative breast cancer (TNBC). Other immune biomarkers including CD8, CD20, programmed cell death-ligand 1 (PD-L1), and tertiary lymphoid structures (TLS) are also reported to be associated with prognosis. However, whether combining other immune biomarkers with TILs would allow for further prognostic stratification is unknown. We retrospectively analyzed 125 patients with early-stage TNBC not receiving perioperative chemotherapy. Stromal TILs and TLS were evaluated on hematoxylin-eosin slides. PD-L1 expression was evaluated using the SP142 assay. CD8 and CD20 were assessed by immunohistochemistry and counted by digital pathology. Immune biomarker levels were positively correlated (p < 0.001). Adding CD8 and PD-L1 to multivariable analysis including clinicopathological factors (stage and histological grade) and TILs significantly improved the prognostic model (likelihood ratio χ2 = 9.24, p = 0.01). In Cox regression analysis, high CD8 was significantly associated with better prognosis [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.48-0.98, p = 0.04], and PD-L1 positivity was significantly associated with worse prognosis (HR 4.33, 95%CI 1.57-11.99, p = 0.005). Patients with high CD8/PD-L1 (-) tumors had the most favorable prognosis [5 year invasive disease-free survival (iDFS), 100%], while patients with low CD8/PD-L1( +) tumors had the worst prognosis (5 year iDFS, 33.3%). CD8 and PD-L1 levels add prognostic information beyond TILs for early-stage TNBC not receiving perioperative chemotherapy. CD8-positive T cells and PD-L1 may be useful for prognostic stratification and in designing future clinical trials of TNBC.


Paraoxonase 2 protects against the CML mediated mitochondrial dysfunction through modulating JNK pathway in human retinal cells.
Paraoxonase 2 (PON2) a known anti-apoptotic protein, has not been explored against Nε-(carboxymethyl)lysine (CML), induced mitochondrial dysfunction and apoptosis in human retinal cells. Hence this present study aims to investigate the potential role of PON2 in mitigating CML-induced mitochondrial dysfunction in these cells. PON2 protein was quantified in HRECs (Human retinal endothelial cells), ARPE-19 (Retinal pigment epithelial cells) cells upon CML treatment and also in cadaveric diabetic retina vs respective controls. ROS production, mitochondrial membrane potential (MMP), mitochondrial permeability transition pore (mPTP) opening, the release of Cyt-c, Bax, Caspase-3, Fis1, Mfn1, Mfn2, mitochondrial morphology, and the signaling pathway was assessed using DCFDA, JC-1, CoCl2, immunofluorescence or western blotting analysis in both loss-of-function or gain-of-function experiments. PON2 protein was downregulated in HREC and ARPE-19 cells upon CML treatment as well as in the diabetic retina (p = 0.035). Decrease in PON2 augments Fis1 expression resulting in fragmentation of mitochondria and enhances the ROS production, decreases MMP, facilitates mPTP opening, and induces the release of Cyt-c, which activates the pro-apoptotic pathway. Whereas PON2 overexpression similar to SP600125 (a specific JNK inhibitor) was able to decrease Fis1 (p = 0.036) and reverse the Bcl-2 and Bax ratio, and inhibit the JNK1/2 signaling pathway. Our results confirm that PON2 has an anti-apoptotic role against the CML mediated mitochondrial dysfunction and inhibits apoptosis through the JNK-Fis1 axis. We hypothesis that enhancing PON2 may provide a better therapeutic potential against diabetic vascular disease.


Erythrocyte and plasma cholesterol exchange in sickle cell anemia.
The effects of sickling on cholesterol exchange between red cell membranes and serum lipoproteins were studied by following the movement of tritiated cholesterol incorporated into erythrocytes. The initial rate of this exchange was greater in sickled cells than in normal cells. One quarter of the cholesterol in the sickled cells is quickly exchanged with plasma lipoproteins. After 15 minutes, the rate becomes identical for these two types of cells, reaching similar equilibrium at end. The sickling of red cells would explain the observed differences, although conditions of hypoxia and the saturation of the incubation medium with oxygen tend respectively to accentuate and to cancel this phenomenon.


Insulin sensitivity, insulin secretion and beta-cell function during puberty in overweight Hispanic children with a family history of type 2 diabetes.
To examine cross-sectional differences in insulin sensitivity, insulin secretion and beta-cell function during puberty in overweight Hispanic boys and girls with a family history of type 2 diabetes. This cross-sectional, observational study included 214 8-13-y-old Hispanic children with a BMI percentile > or = 85th percentile and family history of type 2 diabetes. Participants underwent a physical examination, body composition measures, oral glucose tolerance test (OGTT), and frequently-sampled intravenous glucose tolerance test. Unadjusted and adjusted general linear models (GLM) tested whether insulin/glucose dynamics differed by Tanner stage and gender. Unadjusted group comparisons showed that fasting insulin increased whereas insulin sensitivity (SI) and the disposition index (DI) (a measure of pancreatic beta-cell function) decreased across Tanner stage groups (all P < 0.05). No differences in the acute insulin response to glucose (AIRg), fasting glucose or 2-h glucose were found. After adjusting for covariates, there was no independent effect of Tanner stage on SI (P = 0.9) or AIRg (P = 0.2), but DI was slightly lower in later Tanner stages suggesting decreased beta-cell function in the more mature groups (P = 0.10). Overweight Hispanic children with a family history of type 2 diabetes may represent a unique population given that pubertal insulin resistance was not evident once analyses controlled for body composition. Longitudinal analyses are required to determine whether the slightly diminished beta-cell function in later Tanner stages plays a role in the development of type 2 diabetes.


Investigation of retention behavior of polychlorinated biphenyl congeners on 18 different HRGC columns using molecular surface average local ionization energy descriptors.
In this paper, based on the general interaction properties function (GIPF) family descriptors computed at the B3LYP/6-31G* level in Gaussian98 software, a significant quantitative structure-retention relationship (QSRR) models for the high resolution gas chromatographic relative retention time (HRGC-RRT) of all PCB congeners on 18 different HRGC capillary columns were constructed by using multiple linear regression (MLR) analysis, following the guidelines for development and validation of QSRR models. By means of the elimination selection stepwise regression algorithms, the molecular surface average local ionization energy was selected as one-parameter univariate linear regression to develop a QSRR model for prediction of GC-RRT of PCBs on each stationary phase. The accuracy of all developed models was confirmed using different types of internal and external procedures. A successful interpretation of the complex relationship between HRGC-RRTs of PCBs and the chemical structures was achieved by QSRR.


Epithelial vs myofibroblast differentiation in immortal rat lung cell lines--modulating effects of bleomycin.
Two alveolar epithelial cell lines R3/1 and L2 were screened by immunocytochemical and RT-PCR analysis of epithelial and mesenchymal/contractile marker proteins. R3/1 and L2 cells were tested for their sensitivity to bleomycin (BLM), an anticancer drug, which is proposed to induce changes in lung cell differentiation. Both epithelial cell lines exhibited a mixed phenotype consisting of epithelial (E-cadherin, aquaporin-5 and cytokeratin 8) and myofibroblast-like (vimentin, alpha-SMA and caveolin-3) properties suggesting that the cell lines are arrested in vitro at a certain developmental stage during epithelial-mesenchymal transition (EMT). BLM treatment of R3/1 cells resulted in a partial reversal of this process modifying the cells in an epithelial direction, e.g., upregulation of E-cadherin, aquaporin-5 and other lung epithelial antigens at the mRNA and protein level. L2 cells showed similar alterations following BLM exposure.Immunohistochemical investigation of lung tissue from two different animal models of BLM-induced fibrosis (mouse and rat), revealed no signs of EMT, e.g., myofibroblastic differentiation of alveolar epithelial cells in situ. Immunohistological analysis of tissue samples of the rat model showed a heterogeneous population of myofibroblasts (alpha-SMA+/caveolin-3+, alpha-SMA-/caveolin-3+, and alpha-SMA+/caveolin-3-). These results suggest that BLM, on one hand, induces fibrosis and on the other hand possibly suppresses EMT during fibrogenesis.


Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement.
Hepatic involvement in hereditary hemorrhagic telangiectasia is common but often asymptomatic. However, in some cases, the vascular lesions that involve the liver may lead to high-output cardiac failure and pulmonary hypertension that is predominant over hepatobiliary manifestations. Liver transplantation and treatment of these complications are described and discussed in this article. Three patients with hereditary hemorrhagic telangiectasia and hepatic involvement received transplants. They had pulmonary hypertension and chronic right-sided heart failure caused by disseminated intrahepatic telangiectasias with shunts between the hepatic artery and hepatic veins or portal vein. Left-to-right intrahepatic shunt output was estimated to range between 51% and 57.5% of cardiac output. Hyperdynamic circulation disappeared after liver transplantation in all patients. Results of computed tomography and right-sided heart catheterization performed 6 months later were normal. Follow-up periods currently are 65, 53, and 29 months, and each patient continues to be asymptomatic. This report suggests that liver transplantation can be considered as an alternative and successful curative treatment that may prevent the irreversible evolution of cardiopulmonary disease.


Development of the bile ducts: essentials for the clinical hepatologist.
Several cholangiopathies result from a perturbation of developmental processes. Most of these cholangiopathies are characterised by the persistence of biliary structures with foetal configuration. Developmental processes are also relevant in acquired liver diseases, as liver repair mechanisms exploit a range of autocrine and paracrine signals transiently expressed in embryonic life. We briefly review the ontogenesis of the intra- and extrahepatic biliary tree, highlighting the morphogens, growth factors, and transcription factors that regulate biliary development, and the relationships between developing bile ducts and other branching biliary structures. Then, we discuss the ontogenetic mechanisms involved in liver repair, and how these mechanisms are recapitulated in ductular reaction, a common reparative response to many forms of biliary and hepatocellular damage. Finally, we discuss the pathogenic aspects of the most important primary cholangiopathies related to altered biliary development, i.e. polycystic and fibropolycystic liver diseases, Alagille syndrome.


Mechanism for atrial tachyarrhythmia in chronic volume overload-induced dilated atria.
Mechanism of chronic volume overload-induced AT. Atrial dilatation associated with chronic volume overload (CVO) plays an important role in the development of atrial fibrillation (AF). However, the underlying mechanisms are unknown. CVO-induced atrial dilatation was created in Japanese white rabbits using arteriovenous shunt formation for 6 weeks. Epicardial action potentials were measured from both atria in Langendorff-perfused sham-operated control hearts (n=8) and in CVO hearts (n=8) using high-resolution optical mapping techniques. The left atrial diameter was greater in CVO hearts (16.0+/-0.4 mm) compared to control hearts (11.0+/-0.8 mm). During steady-state pacing, right and left atrial conduction velocities were significantly lower in CVO hearts compared to control hearts (P<0.01). Rapid atrial pacing did not induce atrial tachyarrhythmia (AT) in any control hearts. However, in seven of eight CVO hearts 16 episodes of AT were induced, of which 9 exhibited a single reentrant circuit. The remaining 7 episodes exhibited a focal pattern of excitation without evidence of reentry. Interestingly, the activation rate was higher during reentry (16.1+/-1.5 Hz) compared to focal AT (9.8+/-1.0 Hz). In addition, 15 of 16 episodes occurred in the posterior left atrium (PLA). In all seven CVO hearts, AT was self-sustained for more than 10 minutes. CVO caused atrial dilatation, conduction slowing, and AT associated with reentrant and focal excitation originating from the PLA. These results suggest that the PLA may play an important role in AT induction associated with CVO-induced atrial dilation.


A critical review of the literature on foot orthoses.
Many reports have been published on the value of foot orthoses in treating a variety of biomechanical problems. This article reports on the application of rules developed in the 1980s to assess the scientific rigor, and hence the clinical applicability, of these publications.


Nationwide survival after inhospital cardiac arrest before and after 2010 cardiopulmonary resuscitation guidelines: 2007-2014.
American Heart Association has been revising the cardiopulmonary resuscitation (CPR) guidelines quinquennially. We sought to study the influence of 2010 CPR guidelines on nationwide survival after inhospital cardiac arrest. Healthcare Utilization Project's National Inpatient Sample 20007-2014, was used to identify 799,741 adults aged ≥15years, who underwent inhospital CPR. We compared inhospital survival trends during period before (2007-2010) and after (2011-2014) American Heart Association 2010 CPR guidelines. Mean age of the study population was 66.5years. Females constituted 44% of the study cohort. There was a significant improvement in survival after inhospital CPR from 24.1% in 2007 to 31.1% in 2014 (Ptrend<0.001). However, we did not find any statistically significant improvement in inhospital survival after CPR, in the study period after 2010 AHA CPR guidelines in comparison to study period before the guidelines. We noted a significant improvement in inhospital survival rate after CPR from 2007 through 2014 in the United States, though there was no statistically significant improvement in survival trends after 2010 CPR guidelines during period 2011-2014, in comparison to period 2007-2010.


Determination of critical-sized defect of mandible in a rabbit model: Micro-computed tomography, and histological evaluation.
To evaluate a rabbit model of mandibular box-shaped defects created through an intraoral approach and determine the minimum size defect that would not spontaneously heal during the rabbit's natural life (or critical-sized defect, CSD). Forty-five 6-month-old rabbits were randomly divided into five defect size groups (nine each). Mandibular box-shaped defects of different sizes (4, 5, 6, 8, and 10 mm) were created in each hemimandible, with the same width and depth (3 and 2 mm, respectively). Four, 8, and 12 weeks post-surgery, three animals per group were euthanized. New bone formation was assessed using micro-computed tomography (MCT) and histomorphometric analyses. Box-shaped defects were successfully created in the buccal region between the incisor area and the anterior part of the mental foramen in rabbit mandibles. Twelve weeks post-surgery, MCT analysis showed that the defects in the 4, 5, and 6 mm groups were filled with new bone, while those in the 8 and 10 mm groups remained underfilled. Quantitative analysis revealed that the bone mass recovery percentage in the 8 and 10 mm groups was significantly lower than that in the other groups (p < 0.05). There was no significant difference in the bone mass recovery percentage between the 8 and 10 mm groups (p > 0.05). Histomorphometric analysis indicated that the area of new bone formation in the 8 and 10 mm groups was significantly lower than that in the remaining groups (p < 0.05). There was no significant difference in the new bone area between the 8 and 10 mm groups (p > 0.05). The dimensions of box-shaped CSD created in the rabbit mandible through an intraoral approach were 8 mm × 3 mm × 2 mm. This model may provide a clinically relevant base for future tissue engineering efforts in the mandible.


Maintenance of low disease activity and remission with etanercept-disease-modifying antirheumatic drug (DMARD) combination therapy compared with treatment with DMARDs alone in Latin American patients with active rheumatoid arthritis: Subset analysis of a randomized trial.
Current guidelines on the treatment of rheumatoid arthritis (RA) recommend early therapy targeting the achievement of low disease activity (LDA) or clinical remission. Little published information is available on the success of this treatment strategy in Latin America. In a subset analysis of patients from Latin America, we compared efficacy maintenance with etanercept 50 mg once weekly (ETN50) versus placebo (PBO), on a background of methotrexate (MTX) ± other non-biologic, disease-modifying antirheumatic drugs, in patients with moderate-to-severe RA who had achieved LDA with ETN50. In the Treat-to-Target trial, adult patients with active RA nonresponsive to MTX were treated with ETN50 for 24 weeks (Period 1). Patients achieving LDA were randomized to receive ETN50 or PBO for 28 additional weeks (Period 2). The proportion of patients maintaining LDA at week 52 and other efficacy and quality-of-life measures were assessed. Descriptive statistics are presented using last observation carried forward imputation of data. Of the 64 patients from Latin America treated in Period 1, 61 (95.3%) achieved LDA. Among patients receiving ETN50, 13/34 remained in LDA and 6/14 maintained remission at week 52 versus 6/27 and 4/10 patients receiving PBO. The median time to flare was 113 days and 33 days for the ETN50 and PBO groups, respectively. In the overall population, adverse events were reported in 37% and 43%, serious adverse events in 1% and 4%, and serious infections in 0% and 2% of patients in the ETN50 and PBO groups, respectively. In patients with RA from Latin America, continuing treatment with ETN50 after achieving LDA appears to result in a higher proportion of patients maintaining LDA and remission compared with switching to PBO. CLINICALTRIALS. NCT01578850.


Monitoring the location profile of fluorophores in phosphatidylcholine bilayers by the use or paramagnetic quenching.
Spin probes differing in the position of their paramagnetic centre are used to quench the fluorescence of pyrene derivatives and chlorophylls incorporated into dimyristoyl phosphatidylcholine membranes. Pyrene butyric acid and pyrene decanoic acid with known orientation relative to the membrane surface are investigated. The quenching efficiency of fatty acid spin probes is dependent on the position of the nitroxide radical group in the fatty acid chain. Using this short range interaction we developed a spectroscopic method to chlorophyll-containing vesicles, we were able to characterize the orientation of the porphyrin ring within the membrane. Moreover, the chlorophyll fluorescence is also quenched by a water-soluble spin label. Therefore the porphyrin ring appears to be orientated in the polar head group region of the lipid layer, but not to be protruding out into the water phase. This conclusion is confirmed by the use of pyrene derivatives. Fluorescence quenching by a water-soluble spin label within the lipid matrix is observed even in the rigid state of the membrane. Fluorescence lifetime measurements suggest the existence of two different quenching mechanisms: (1) a static quenching occurring below the lipid phase transition temperature, and (2) an additional dynamic quenching taking place in the fluid state of the lipid bilayer.


Medical care neglect.
Discussed in sequence in this article are: the information which must pass from doctors to patients in the United States before a medical procedure is legally authorized, the necessity for comparable information to be provided to a judge who is being asked to order medical treatment for a child over objections by parents, the factors likely to influence a judge to order treatment over parental objections, and a process for deciding when the threshold for court intervention has been reached. While the general right of parents to be informed sufficiently and then to give consent for medical procedures, or to refuse to give consent, on behalf of their children is not in question, judges to override parental refusals to agree to care which is lifesaving or prevents severe impairment. An analysis of American law reveals that the factors likely to support court orders for treatment are: sufficient data has been provided for full, informed consent; a very severe prognosis exists if treatment is not provided, for example, death, retardation, paralysis, or blindness; delay is not a reasonable alternative; the medical procedure is not experimental and is likely to succeed; there are few contraindications; the quality of the child's life, given a successful intervention, will be at least of average "quality"; a child who is older consents to the procedure; and there is no strongly conflicting medical opinion. After a thorough discussion of medical factors with parents, court intervention should be considered if it is thought by those involved that no minimally reasonable parent would refuse to consent to treatment under the circumstances.


Unravelling capability of municipal wastewater treatment plant in Thailand for microplastics: Effects of seasonality on detection, fate and transport.
Many factors can affect microplastics (MPs) behaviors in aquatic environments. The effects of seasonal and meteorological conditions on MPs are not well understood. This study demonstrates the impacts of seasonality on the fate and transport, and the efficacy of MPs removal by a wastewater treatment plant. The fate and transport of MPs at a WWTP in Nonthaburi, Thailand were tracked during the dry and wet seasons of 2019-2020. Polypropylene (PP), polyethylene (PE), and toothpaste formulations were the most abundant MP types observed. Total detected MP quantities ranged between 76 and 192 particles L-1 during the dry season, and only 36-68 particles L-1 during the wet season, indicating runoff dilution effects. T-test analysis found a statistically significant difference between MP concentrations between the dry and wet seasons of 2019-2020. Spearman's correlation showed statistically strong negative relationships between MP concentrations versus wastewater flow, and MP concentrations versus precipitation; a positive correlation between MP abundance versus temperature in the treatment system was observed. During the dry seasons, MPs were mostly found in the aeration process, and were mostly rayon or polyester particles in the shape of fibers. Contrarily, in the wet seasons, MPs were detected in both the raw influent and aeration process, with PE, polyacrylate, and polyethylene terephthalate fragments dominating the make-up. MPs were also detected in the return activated sludge, thus calling for proper sludge age and drainage management. No MPs were detected in the plant's effluent during the wet season, suggesting that the plant had sufficient MPs removal capability during normal wet-season conditions. Overall, this study suggests that municipalities should focus on increasing MPs removal efficiency of wastewater treatment plants for dry seasons, while properly managing the water flows of combined sewage systems to prevent overflows that may inevitably become point-sources of MPs release into water bodies during wet seasons.


Full cost accounting in the analysis of separated waste collection efficiency: A methodological proposal.
Recycling implies additional costs for separated municipal solid waste (MSW) collection. The aim of the present study is to propose and implement a management tool - the full cost accounting (FCA) method - to calculate the full collection costs of different types of waste. Our analysis aims for a better understanding of the difficulties of putting FCA into practice in the MSW sector. We propose a FCA methodology that uses standard cost and actual quantities to calculate the collection costs of separate and undifferentiated waste. Our methodology allows cost efficiency analysis and benchmarking, overcoming problems related to firm-specific accounting choices, earnings management policies and purchase policies. Our methodology allows benchmarking and variance analysis that can be used to identify the causes of off-standards performance and guide managers to deploy resources more efficiently. Our methodology can be implemented by companies lacking a sophisticated management accounting system.


Complete degradation of carbohydrate to carbon dioxide and methane by syntrophic cultures of Acetobacterium woodii and Methanosarcina barkeri.
Methanosarcina barkeri (strain MS) grew and converted acetate to CO2 and methane after an adaption period of 20 days. Growth and metabolism were rapid with gas production being comparable to that of cells grown on H2 and CO2. After an intermediary growth cycle under a H2 and CO2 atmosphere acetate-adapted cells were capable of growth on acetate with formation of methane and CO2. When acetate-adapted Methanosarcina barkeri was co-cultured with Acetobacterium woodii on fructose or glucose as substrate, a complete conversion of the carbohydrate to gases (CO2 and CH4) was observed.


Incidence of End Stage Kidney Disease and context of dialysis initiation
On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of ESKD incidence, the following key messages were retained. Thanks to several studies conducted using data from the REIN registry, the spatial variations of incidence of stage 5 chronic kidney disease in the replacement stage could be explained, in part, by the health condition of the general population as well as by the socio-economic context and differences in practices. Just like what is observed in other countries, the incidence is stabilising, or even decreasing, especially among people who do not have diabetes. Thanks to the registry having provided an indicator on the initiation of the dialysis, a decrease in the rate of initiation of emergency dialysis (i.e., initiated less than 24 hours after a nephrology evaluation considering a vital risk for the patient) has been observed, resulting from an effort to understand and better anticipate the starting of the replacement.


Late relapse of clinical stage I testicular cancer.
The clinical presentation and treatment of late recurrence (2 or more years after initial management) of testis cancer are defined. A retrospective search was performed to identify patients treated for late relapse at our university from 1979 to 1992 who had initially presented with clinical stage 1 disease. We treated 35 patients with chemotherapy for late relapse. No patient has remained disease-free with chemotherapy alone. Subsequent surgery resulted in 43% of the patients being currently disease-free. The treatment of late relapse is surgical. Chemotherapy before late relapse for low volume disease does not uniformly prevent late recurrence.


Lectures and skills workshops as teaching formats in a history-taking skills course for medical students.
The consulting skills acquired by medical students during their training are an important determinant of their ability to conduct adequate and efficient clinical interviews. These skills comprise: the acquisition of medical knowledge and the ability to apply this; and communication skills required to obtain full, accurate clinical histories from patients and to be able to give to patients the information they need to comply with prescribed regimens. Until recently, consulting skills training has certainly not had a high profile in medical curricula, despite evidence that students do not gain sufficient expertise during their medical training. A history-taking skills course within the Austin Hospital Clinical School, utilizing mass lecture and small-group skills workshops is described. Independent evaluation of students' videotaped interviews with patients, completed before training, after mass lectures and following small-group workshops, showed that students trained in consulting skills demonstrated significant improvements in interview skills and techniques, compared with a similar group of students for whom training followed the more traditional model. Whilst there were some improvements after mass lectures, most significant gains in history-taking skills were obtained following skills workshops. Ongoing evaluation of these students will determine if these short-term improvements in consultation skills persist over their clinical training and internship.


An enzyme-linked immunosorbent assay (ELISA) for the measurement of serum antibodies to growth hormone. The Wessex Growth Study.
A solid-phase enzyme-linked immunosorbent assay for measuring antibodies to growth hormone (GH) was developed, with occasional use and long shelf-life in mind. With coating protein concentration optimised, the standard curve was linear over a 25-fold range of concentration. The interassay coefficient of variation ranged from 14.4% to 9.3%. The specificity of the assay was confirmed by the substitution of insulin for GH as coating protein and by preabsorption of sera with GH coupled covalently to Sepharose beads. There was no binding signal with insulin and absorption was dose dependent, maximum (greater than 80% complete) with 2 x 10(4) micrograms GH/ml undiluted serum. The assay was simple to perform, cheap and reliable.


Convalescent plasma and all-cause mortality of COVID-19 patients: systematic review and meta-analysis.
Insight into the clinical potential of convalescent plasma in patients with coronavirus disease (COVID-19) is important given the severe clinical courses in unvaccinated and seronegative individuals. The aim of the study was to investigate whether there is a survival benefit of convalescent plasma therapy in COVID-19 patients. The authors independently assessed randomized controlled trials (RCTs) identified by the search strategy for inclusion, extracted data, and assessed risk of bias. The binary primary outcome was all-cause mortality. Risk ratio (RR) of the convalescent plasma treatment (vs. best standard care) and its associated standard error (effect size) were calculated. A random-effects model was employed to statistically pool the effect sizes of the selected studies. We included 19 RCTs with 17,021 patients. The random-effects model resulted in an estimated pooled RR of 0.94 (95% CI 0.81-1.08, p = 0.33), showing no statistical evidence of the benefit of convalescent plasma therapy on all-cause mortality. Convalescent plasma therapy was not found to be effective in reducing all-cause mortality in COVID-19 patients. Further studies are needed to determine in which patients convalescent plasma therapy may lead to a reduction in mortality.


A procedure for the isolation of highly purified populations of B cells, T cells and monocytes from human peripheral and umbilical cord blood.
A sequential separation protocol is described which reproducibly yields biologically active populations of B cells, T cells and monocytes from human peripheral and umbilical cord blood. The purification protocol employed T lymphocyte rosetting with unmodified sheep red blood cells, monocyte adherence to microexudate-coated flasks and anti-immunoglobulin panning of B cells. Population purity was determined by cytofluorographic light scatter analysis, expression of cell surface markers, esterase activity and mitogen responsiveness. The sequential protocol reproducibly yielded viable and functionally active cell populations of greater than 95% purity from a single starting population of mononuclear cells.


Analysis of wet oxidation process after initial thermohydrolysis of excess sewage sludge.
The authors propose a new technique to analyse a complex process of wet oxidation of excess sewage sludge by separating thermohydrolysis that results in the separation of sewage sludge into hydrolysates: solid and liquid products, from the basic process of oxidation of the two products. Wet oxidation kinetics was studied at different temperatures of both products based on the measurement of total organic carbon during the process with the use of a PARR high-pressure reactor. Decomposition of the liquid product leads to the formation of non-degradable and gaseous final products, while degradation of the solid product-via an intermediate liquid product-also leads to the formation of final and gaseous products. Solution of the kinetic equations that describe the dependence of relative organic carbon concentration on time is well illustrated by experimental results. On the basis of fitting theoretical curves to the experimental results, the kinetic parameters of the process were determined.


Counterpoint: Time-series studies of acute health events and environmental conditions are not confounded by personal risk factors.
We discuss Bukowski's hypothesis that unmeasured, individual risk factors, notably stress caused by being in traffic or at work, may confound the association found in many time-series studies between air pollution and cardiovascular outcomes. In replying to these concerns, we describe the methods used to carry out time-series studies and discuss whether it is reasonable to believe that stress can confound the association. Our analysis suggests that these factors are unlikely to cause bias in time-series studies, although it may be important in panel and other longitudinal studies. Specifically, we argue that: (1) persons most likely to be susceptible to the effects of air pollution, notably the very young and the elderly, and those suffering from certain chronic diseases (e.g., congestive heart failure), are unlikely to be highly exposed to traffic and therefore to traffic-related stress and (2) over lengthy periods of time and sub-populations, levels of individual stress are unlikely to act coherently to create an association with ambient air pollution.


The cortisol awakening response is related to executive function in older age.
Changes in the cortisol awakening response (CAR) have been reportedly associated with older age and may reflect changes in cognitive performance. However methodological issues around adherence, in regard to careful timing of the CAR, suggest caution in drawing firm conclusions. More investigation is also needed regarding which cognitive domains may be most relevant. Executive Function (EF) is linked strongly to functioning of the frontal cortex, itself linked to cortisol secretion via regulation of the Hypothalamic Adrenocortical Axis. In this study, cortisol profiles, cognitive performance and adherence were carefully assessed in a sample of 50 older participants, aged 60-91 years (mean=74 years). Key aspects of EF were assessed using Form B of the standard Trail-making Test controlling for time taken to complete the simpler Trail-A form of the test. Strong associations between CAR profiles and EF were evident. Cortisol measures significantly predictive of superior EF-related performance in a regression analysis were: earlier peaking and greater magnitude of the CAR. Together these measures explained fully a quarter of all the variance in test performance (R(2)=0.25; F=7.90; df=2,47; p<.001). Cognitive tests of declarative memory, often linked to hippocampal functioning, were not associated with CAR profiles. We conclude that in a population of healthy older adults aspects of the CAR may be strongly, and perhaps with some degree of specificity, associated with that domain of cognitive functioning, EF, which seems to depend crucially on the integrity of frontal cortex circuitry.


Hygienic and cosmetic care habits in polish women during COVID-19 pandemic.
COVID-19 pandemic influences a lot of aspects of human life. Particularly, hygienic habits are affected. Changes in washing and cosmetic standards during the pandemic toward the past are in the focus of our interest. The questionnaire study was conducted anonymously in 140 women. The examination concerned pre- and during-pandemic routine hygiene activities such as hands washing, hair washing, bathing, the use of disinfectants, and use of specific type of cosmetics. Compared were data before and during pandemic. Responders declared increased handwashing and taking shower after coming back home and after using local city transportation. We found also that increased use of disinfectants during COVID-19 pandemic. In contrary to that, number of people washing their hair decreased slightly. Work documents that profile of used cosmetics was changed; increasing hand cream use and decreasing in makeup cosmetics. Nearly, half of the respondents declare that they will maintain new habits also after the pandemic has ended.


Imaging amyloid precursor protein in vivo: an axonal transport assay.
Fusion of fluorescent probes to axonally transported proteins represents an established approach that enables live imaging of axonal transport. In this approach, in vivo examination of fluorescent particle dynamics provides information about the length, directionality, and the velocity by which axonally transported proteins travel along axons. Analysis of these parameters provides information about the distribution of axonal proteins and their dynamics in and between different subcellular compartments. Establishing the movement behavior of amyloid precursor protein within axons indicated that live imaging approaches offer the opportunity to significantly enhance our understanding of the biology as well as pathology of axonal transport. This chapter provides a fluorescence-based procedure for measuring axonal transport of APP in cultured newborn mouse hippocampal neurons.


Effects of atrazine and chlorpyrifos on activity and transcription of glutathione S-transferase in common carp (Cyprinus carpio L.).
Glutathione S-transferase isoenzymes (GSTs) play a critical role in detoxification pathways. Here we report the tissue distribution of four antioxidant GSTs gene in common carp, and their expression profiles. We also investigated the GSTs activity in different tissues after exposure to the agricultural chemicals atrazine (ATR), chlorpyrifos (CPF), and their mixture. Relative changes in the mRNA abundance of the GST isoforms were examined by real time PCR in liver, brain, kidney and gill of common carp. After exposure and recovery, we observed a statistically significant decrease in the GSTs activity in animals exposed to high concentrations of ATR (428 μg/L), CPF (116 μg/L), and their mixture (113 μg/L). At basal levels of tissue expression, four GSTs transcript were detected in liver, brain, kidney, and gill. High expression levels were found in all examined tissues. Transcription of some GST isoforms, GST kappa (GSTK), GST theta (GSTT) and GST rho (GSTR), decreased after exposure to CPF and ATR for the entire experimental period in both the kidney and gill. However, increased transcription of GST mu (GSTM) was observed in the kidney or gill 20 d after exposure to ATR or CPF, respectively. Transcription of both GSTT and GSTR was inhibited for the entire experimental period in the brain, kidney and gill of animals exposed to the ATR/CPF mixture, but transcription of GSTM was induced in the liver after 40 d of exposure. In summary, changes in the GSTs activity and their transcription varied within each organ and among organs of common carp after exposure to ATR, CPF, and their mixture.


Finding possible pharmacological effects of identified organic compounds in medicinal waters (BTEX and phenolic compounds).
Medicinal thermal waters consist of a mixture of different organic and inorganic compounds. Traditionally, these waters are only characterized and classified by their inorganic composition; however, the bioavailability of the majority of these inorganic compounds is limited. Many authors investigate the organic fractions of thermal waters. These authors propose that these compounds have a potential effect on health. To elucidate the underlying mechanisms, it is crucial to know the composition of the organic fractions. The absorption of these compounds on intact skin or mucosa is notable. Some of them have local anaesthetic effect or affect receptors in the central nervous system. In the knowledge of the chemical composition, we are able to estimate the possible pharmacological effect or might be able to assess possible toxicity risks. In the present article, we aim to review possible health effects of two of the identified organic fractions: benzene and alkylbenzenes and phenolic compounds that might correlate with the therapeutic effect on rheumatological or other diseases.


Effect on training on myocardial oxygen supply/demand balance.
In five well-trained and five sedentary control subjects potential subendocardial blood supply was estimated from the diastolic pressure time index (DPTI) and myocardial oxygen demands from the tension time index (TII) during a progressive near-maximal treadmill test. DPTI/TTi was used to assess the effects of training on myocardial oxygen supply/demand balance. DPTI/TTI was significantly higher in trained subjects at rest and comparable workloads. At 6.4 km/hr, 18% grade (maximum for the controls), TTI was significantly lower (4300 +/- 76 vs 4495 +/- 99 mm Hg-sec/min) and DPTI significantly higher (2534 +/- 86 vs 2295 +/- 91 mm Hg-sec/min) in the trained subjects; DPTI/TTI was significantly higher (0.59 +/- .02 vs 0.50 vs .03). At near-maximal heart rates both groups achieved the same supply/demand balance (0.50); however, the trained subjects were working at higher workloads. We conclude that endurance conditioning increases work capacity, reduces myocardial O2 demands, increases potential O2 supply and improves the supply/demand balance at any given submaximal workload which reduces the risk of ischemia.


To transplant, or not to transplant? That is the question. A patient advocate evaluation of autologous stem cell transplant in neuroblastoma.
High-dose chemotherapy with autologous stem cell transplant (ASCT) has been a mainstay of high-risk neuroblastoma treatment for several decades, demonstrating improvements in event-free survival but with risks of serious or even life-threatening acute toxicities, severe long-term adverse health effects for survivors, and ongoing contention regarding overall survival benefit. The merits of ASCT in the modern era of immunotherapy are a source of debate among parents, advocates, and some physicians. Here we examine evidence for and against ASCT, explore parent attitudes and their turmoil over decision-making, and strongly encourage international research consortia to develop a coordinated strategy to accelerate progress toward a future that avoids the routine use of ASCT in high-risk neuroblastoma.


Evaluation of the therapeutic efficacy of albendazole-loaded silver nanoparticles against Echinococcus granulosus infection in experimental mice.
The drug of choice for treatment of hydatid disease, albendazole (ABZ) is a poorly water-soluble drug; thus, enhancing its solubility is required. Among metal nanoparticles (NPs), silver (Ag) NPs showed antimicrobial efficacies. Therefore, this study was conducted to evaluate nanosilver particles (Ag NPs) free or combined with albendazole against Echinococcus granulosus infection in vivo. In this study, besides the normal control group (GI) (n = 5), 80 mice were infected with 2000 viable protoscoleces intraperitoneally then divided equally (n = 20) into the infected control (GII), ABZ-treated (GIII), nanosilver-treated (GIV) and ABZ-loaded-Ag NPs-treated (GV) groups. On the 90th post-infection day, treatment was started and continued for 8 weeks then the experiment was terminated. Each mouse was subjected to measurement of hydatid cysts' sizes and weights, serum IFN-γ, liver enzymes; histopathological and transmission electron microscopy studies. In all treated groups, there were significant reductions of hydatid cysts' sizes and weights; however, the highest efficacy rate (63.9%) was detected in group V associated with obvious ultrastructure alterations of the cysts. The liver tissues of group II showed intense granulomatous reactions, congestion, fibrosis, necrosis and steatosis associated with significant increases in serum IFN-γ and liver enzymes. Interestingly, the best antiparasitic effect and the most significant reduction of IFN-γ towards the normal values were found in GV. Moreover, Ag NPs had reduced the toxic effects of ABZ such as necrosis, steatosis and the elevated serum liver enzymes. Therefore, loading ABZ on Ag NPs could be a potential method to improve ABZ efficacy against hydatid disease.


Thirty minutes mobile phone use has no short-term adverse effects on central auditory pathways.
To investigate whether pulsed high-frequency electromagnetic field (pulsed EM field) emitted by a mobile phone for 30 min has short-term adverse effects on the human central auditory system. We studied the auditory brainstem response (ABR), the ABR recovery function and middle latency response (MLR) before and after using a mobile phone for 30 min in 15 normal hearing volunteers. None of the 3 measures were affected by exposure to pulsed EM field emitted by a mobile phone for 30 min. Based on the ABR and MLR methods utilized in the study, we conclude that 30 min mobile phone use has no short-term adverse effects on the human auditory system.


Prevention of sickle cell disease: observations on females with the sickle cell trait from the Manchester project, Jamaica.
Screening for haemoglobin genotype was offered to senior school students in Manchester parish in south central Jamaica to test whether this knowledge would influence choice of partner and reduce births with sickle cell disease. Over six academic years, 15,539 students, aged mostly 15-19 years, were screened with voluntary compliance rising from 56 to 92 % over this period. All subjects were given permanent genotype cards and carriers of abnormal genes were offered counselling which explained the reproductive options but avoided recommendations. Prior to screening, all had been offered illustrated lectures on the genetics and clinical features of sickle cell disease. The current study, confined to females with the sickle cell trait, interviewed 763/845 (90.3 %) subjects seeking to assess retention of this knowledge and their response to subsequent boyfriends. Of those interviewed, 42 subjects were excluded (38 emigrated, one died, three received incorrect genotype cards) leaving 721 with complete information. Knowledge of genotype was retained in 95 %, the outcome of future offspring correctly recalled in 91 %, and haemoglobin genotype cards were still possessed by 89 %. A current 'boyfriend' was acknowledged in 403 (56 %) of whom the partner's genotype was known in 88 (74 determined by the project laboratory; 14 by other laboratories) and unknown in 315 (78 %). Offers of free blood tests to all these partners were accepted by only 14 (4 %). Seventeen (2.4 %) were married but the husbands genotype was known in only five (four AA, one AS) of these. Most subjects retain knowledge of their genotype and of its significance for having affected children but the reluctance of partners to be tested was a major obstacle.


Ion range estimation by using dual energy computed tomography.
Inaccurate conversion of CT data to water-equivalent path length (WEPL) is one of the most important uncertainty sources in ion treatment planning. Dual energy CT (DECT) imaging might help to reduce CT number ambiguities with the additional information. In our study we scanned a series of materials (tissue substitutes, aluminum, PMMA, and other polymers) in the dual source scanner (Siemens Somatom Definition Flash). Based on the 80kVp/140SnkVp dual energy images, the electron densities ϱe and effective atomic numbers Zeff were calculated. We introduced a new lookup table that translates the ϱe to the WEPL. The WEPL residuals from the calibration were significantly reduced for the investigated tissue surrogates compared to the empirical Hounsfield-look-up table (single energy CT imaging) from (-1.0±1.8)% to (0.1±0.7)% and for non-tissue equivalent PMMA from -7.8% to -1.0%. To assess the benefit of the new DECT calibration, we conducted a treatment planning study for three different idealized cases based on tissue surrogates and PMMA. The DECT calibration yielded a significantly higher target coverage in tissue surrogates and phantom material (i.e. PMMA cylinder, mean target coverage improved from 62% to 98%). To verify the DECT calibration for real tissue, ion ranges through a frozen pig head were measured and compared to predictions calculated by the standard single energy CT calibration and the novel DECT calibration. By using this method, an improvement of ion range estimation from -2.1% water-equivalent thickness deviation (single energy CT) to 0.3% (DECT) was achieved. If one excludes raypaths located on the edge of the sample accompanied with high uncertainties, no significant difference could be observed.


Regional spread pattern predicts survival in patients with sporadic amyotrophic lateral sclerosis.
Sporadic amyotrophic lateral sclerosis (sALS) is a disease with a focal clinical onset and contiguous spread. We examined patterns of disease spread following symptoms onset in sALS and whether the pattern of spread predicted survival. Review of medical records (2003-2009) at London Ontario and Buenos Aires clinic cohorts retrieved 318 patients with sporadic sALS. According to patient self-report, we determined eight spread patterns: rostro-caudal, caudo-rostral, crossed, circular, superior interposed, middle interposed, inferior interposed and isolated. The variables studied were as follows: age, gender, sALS phenotypes, time from onset to diagnosis and time and direction of the spreading to the first region. Survival from symptoms onset was analysed by Kaplan-Meier, Tarone-Ware and Cox proportional hazards methods. The direction of first spread was horizontal in 33%, rostral to caudal in 32% and caudal to rostral in 21%, whereas spread to remote regions was observed in 14% of patients. Survival curves and 3- and 5-year survival rates favoured patients with an isolated and caudo-rostral pattern of spread compared to patients progressing to distant regions without involvement in the intervening region, or 'superior and inferior interposed patterns' (Tarone-Ware P = 0.001, χ(2) = 0.002 and χ(2) = 0.006, respectively). Factors affecting survival were gender, time to diagnosis, flail arm phenotype and age at diagnosis. We have provided evidence that not all spread in ALS is contiguous and that the nature of symptom progression influences survival. Patients with sALS with 'interposed patterns' had a worse prognosis, whereas patients with caudo-rostral pattern fared better than the rest.


Design and synthesis of cleavable biotinylated dideoxynucleotides for DNA sequencing by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based methods have been widely explored for DNA sequencing. We report here the design, synthesis, and evaluation of a novel set of chemically cleavable biotinylated dideoxynucleotides, ddNTPs-N₃-biotin, for the DNA polymerase extension reaction and its application in DNA sequencing by mass spectrometry (MS). These nucleotide analogs have a biotin moiety attached to the 5 position of the pyrimidines (C and U) or the 7 position of the purines (A and G) via a chemically cleavable azido-based linker, with different length linker arms serving as mass tags that contribute to large mass differences among the nucleotides. We demonstrate that these modified nucleotides are efficiently incorporated by DNA polymerase, and the DNA strand bearing biotinylated nucleotides is captured by streptavidin-coated beads and efficiently released using tris(2-carboxyethyl)phosphine in aqueous solution, which is compatible with DNA and downstream procedures. We performed Sanger sequencing reactions using these nucleotides to generate DNA fragments for MALDI-TOF MS analysis. Both synthetic DNA and polymerase chain reaction (PCR) products were accurately decoded, and a read length of approximately 37 bases was achieved using these nucleotides in MS sequencing.


Aneurysmal bone cyst of the index sesamoid.
Sesamoid bone disorders are rare and usually are a result of trauma or degenerative causes. Tumors of the sesamoid bones of the hand are encountered less frequently. We report a case of an aneurysmal bone cyst of the radial index sesamoid of the hand. The tumor was treated successfully by sesamoid bone resection.


The role of kininogenases, kinin formation and kininogenase inhibition in post traumatic shock and related conditions.
The kinin system has for a long time been considered to play a role in the pathophysiology of trauma, particularly in blood pressure changes and in inflammatory effects. Recent findings necessitate a revision of this view. It is now necessary to differentiate between two kinin systems: 1. the plasma kallikrein-HMW kininogen-kinin-system, which besides forming kinin acts decisively in Hageman Factor activation, clotting and fibrinolysis; 2. the glandular and tissue kallikrein-LMW kininogen-kinin-system which is to our present day knowledge primarily involved in kinin formation. Kinins exert a variety of actions. By interfering with angiotensin II formation, kinins may contribute to blood pressure regulation. By enhancing cellular glucose uptake and/or metabolism, they regulate partly energy production. In post traumatic states death is preceded by a severe depletion of various factors of the system and an almost total loss of kinin forming capacity. Severity and time course of these phenomena suggest that early institution of direct (Trasylol) or indirect (heparins, cortocosteroids) proteinase inhibition, and if necessary a replacement of the lost factors, should be considered.


Low-temperature (180 K) crystal structure, electron paramagnetic resonance spectroscopy, and propitious anticonvulsant activities of CuII2(aspirinate)4(DMF)2 and other CuII2(aspirinate)4 chelates.
The purpose of this research was to characterize by X-ray crystallography the ternary dimethylformamide (DMF) Cu(II) complex of acetylsalicylic acid (aspirin), in an effort to compare the structure-activity relationships for the anticonvulsant activity of this and other Cu(II)aspirinate chelates. The ternary DMF Cu(II) complex of aspirin was synthesized and crystals grown from a DMF solution were characterized by single crystal X-ray diffraction. This crystalline material was analyzed for anticonvulsant activity in the Maximal Electroshock (MES) Grand Mal and subcutaneous Metrazol (scMET) Petit Mal models of seizure used to detect anticonvulsant activity. The ternary DMF complex was found to be a monomolecular binuclear complex, tetrakis-mu-(acetylsalicylato)bis(dimethylformamido)dicopper(II) [Cu(II)(2)(aspirinate)(4)(DMF)(2)] with the following parameters: monoclinic, space group P2(1)/n, a=12.259 (1), b=10.228 (1), c=16.987 (1) A, beta=92.07 (1) degrees; V=2128.5 (3) A(3); Z=2. The structure was determined at 180 K from 2903 unique reflections (I>1sigma(I)) to the final values of R=0.030 and wR=0.033 using F. This binuclear complex contains four acetylsalicylate bridging ligands which are related to each other in a two by two symmetry center. The four nearest O atoms around each Cu atom form a closely square planar arrangement with the square pyramidal coordination completed by the dimethylformamide oxygen atom occupying an apical position at a distance of 2.154 (1) A. Each Cu atom is displaced towards the DMF ligand by 0.187 A from the plane of the four O atoms. Electron paramagnetic resonance (EPR) spectra of [Cu(II)(2)(aspirinate)(4)(DMF)(2)] crystals show a strong antiferromagnetic coupling of the copper atoms, similar to that observed with other binuclear copper(II)salicylate compounds. Studies used to detect anticonvulsant activity revealed that [Cu(II)(2)(aspirinate)(4)(DMF)(2)] was an effective anticonvulsant in the MES model of seizure but ineffective against scMET-induced seizures. The monomolecular ternary binuclear [Cu(II)(2)(aspirinate)(4)(DMF)(2)] complex is more effective in inhibiting MES-induced seizures than other binuclear or mononuclear Cu(II) chelates of aspirin including: binuclear polymeric [Cu(II)(2)(aspirinate)(4)], [Cu(II)(2)(aspirinate)(4)(H(2)O)], which is anticipated to be less polymeric, and monomolecular ternary [Cu(II)(2)(aspirinate)(4)(DMSO)(2)] and [Cu(II)(aspirinate)(2)(Pyr)(2)]. These and other chelates appear to be more effective in the scMET model of seizure than [Cu(II)(2)(aspirinate)(4)(DMF)(2)]. These structure-activity relationships support the potential efficacy of Cu chelates of aspirin in treating epilepsies.


Rapid infection and proliferation of dactylogyrid monogeneans on gills of spotted rose snapper (Lutjanus guttatus) after transfer to a sea-cage.
Finfish mariculture is typically threatened by parasite and disease outbreaks. Therefore, it is important to identify parasite species of potential risk for this activity. Snappers are valuable food fish worldwide. In the Eastern Pacific, spotted rose snapper (Lutjanus guttatus [Steindachner, 1869]) is a firm candidate for sea-cage aquaculture. In the current study, the parasitism of caged L. guttatus by dactylogyrids was evaluated for the first time during a complete farming period. Twenty five thousand juvenile fish produced at the Research Center for Food and Development (CIAD, Mazatlan Unit) were reared in a sentinel sea-cage from February to November 2012 in Mazatlan Bay, Mexico. A fish sample (n=15) was obtained every month. Dactylogyrids from the left second gill arch were identified and quantified. A total of 18,704 dactylogyrids distributed in three species, Euryhaliotrema perezponcei García-Vargas, Fajer-Ávila and Lamothe-Argumedo, 2008, E. mehen (Soler-Jiménez, García-Gasca and Fajer-Ávila, 2012), and Haliotrematoides guttati García-Vargas, Fajer-Ávila and Lamothe-Argumedo, 2008 (Monogenea: Dactylogyridae) was found, which were able to infect caged L. guttatus since the first month of the farming period. Prevalence of these parasite species was 100% all the time, except for initial low values for E. mehen and H. guttati. The mean intensity of infection of each dactylogyrid species varied significantly between sampling months. Euryhaliotrema perezponcei was the most abundant parasite, reaching the highest mean intensity in May, June and July (154.3, 296.9 and 176.6 parasites/host, respectively). No clear seasonality of infection was observed; however, the influence of the water temperature on the observed infection levels is discussed. There was no mortality, change on behavior or pathological signs. However, given the rapid infection and proliferation of dactylogyrids, particularly E. perezponcei on L. guttaus reared in a sentinel sea-cage, outbreak of these parasites could be expected when this fish species is cultured on a large scale.


Extracellular RNA: Emerging roles in cancer cell communication and biomarkers.
Extracellular RNAs (exRNAs) are a type of RNA molecules that present in various biological fluids. exRNAs are heterogenous populations including small (e.g., miRNA) and long non-coding RNAs and coding RNAs (e.g., mRNA). They can exist in a free form or associate with carriers range from lipo- and ribo-proteins to extracellular vesicles such as exosomes in the extracellular fluids. exRNAs participate in cell-to-cell communication to regulate a broad array of physiological and pathological processes. exRNAs have been widely studied as a biomarker for cancer and other diseases. In this review, we will discuss the sorts of exRNAs with potential carriers as well as their roles in cancer.


Muscarinic and dopaminergic receptors in the aging human brain.
[3H]1-Quinuclidinyl(phenyl)-4-benzilate ([3H]QNB), [3H]spiroperidol and [3H]flupenthixol were used to label brain muscarinic, dopamine D2 and D1 receptors, respectively, in altogether 78 patients aged from 4 to 93 years. The binding of [3H]QNB declined with age in the frontal cortex, hippocampus, caudate nucleus and putamen. Scatchard analysis showed that the reduced binding was due to a decline in the number of receptors. The binding of the dopaminergic ligands was determined in the caudate nucleus, putamen, pallidum and substantia nigra. [3H]Spiroperidol binding showed age-dependent decline in all the brain areas examined, while no change was seen in [3H]flupenthixol binding in any brain area studied. Also the decrease in [3H]spiroperidol binding was due to the reduced number of receptors. The results of this study suggest that aging is more likely to affect certain neurotransmitter receptor systems than certain brain areas.


B-Vitamin Serum Concentrations Predicting Long-Term Overall and Stroke-Free Survival after Carotid Endarterectomy.
Both deficiency and, according to recent reports, excess of vitamin B12 (B12) are associated with increased mortality. Thus, it is difficult to estimate the effect of B12 on overall survival, which also depends on folate (FA) in homocysteine lowering. This study aimed to assess FA and B12 serum concentrations associated with long-term survival of vascular surgery patients by means of a prognostic index (PI). This single-center, prospective cohort study comprised 485 consecutive carotid surgery patients. B-vitamin baseline concentrations of B12 and FA were used to compute a PI for postoperative overall survival from January 2003 to January 2012 (mean observation period 102.3 months). Increasing B12 serum concentrations showed a nonlinear association with overall survival (P = .033). A B vitamin-based PI significantly predicted overall (hazard ratio [HR] per standard deviation = 1.97, confidence interval [CI] 1.37-2.82; P < .001), cardiovascular (HR = 3.03, CI 1.78-5.14; P < .001), and stroke-free survival (HR = 2.20, CI 1.22-3.98; P = .009), and revealed that the highest adverse event-free survival was predicted by high FA (16.3 ± 12.9 ng/mL) but only moderate B12 (360.3 ± 156.0 pmol/L) baseline concentrations. Prediction of increased long-term overall, cardiovascular, and stroke-free survival is based on high FA but only moderate B12 serum concentrations. Excessive B12 concentrations might harbor a potential harm and are no requisite for low homocysteine concentrations. The association between B vitamins and survival might serve either as a tool for risk stratification or, if causative, as effective therapy, if optimal dosing of B vitamins is provided and on-treatment concentrations, including homocysteine and renal functions, are closely monitored.


Increased endothelial biomarkers are associated with HIV antiretroviral therapy and C-reactive protein among a African rural population in Limpopo Province, South Africa.
In Sub-Saharan Africa (SSA) endothelial dysfunction (ED) and chronic inflammation in the HIV-positive adults population who are on highly active antiretroviral therapy (HAART) are not fully explored. We determined the effect of HAART on chronic inflammation and ED among HAART-exposed adults in a rural setting. Weight and height were measured to quantify the body mass index (BMI). Lipid and Glucose levels were determined. C-reactive protein (CRP), L-selectin, soluble intercellular adhesion molecule (sICAM-1), and soluble vascular cell adhesion molecule (sVCAM-1) in serum samples were tested. The majority of the HAART-exposed group were on treatment for <5 years. Soluble intercellular adhesion molecules, sVCAM-1, L-selectin and CRP were elevated in the HIV-infected groups as compared to the control group. The multivariate analysis showed that HIV infection (HAART-naïve) associated with increased sICAM-1 (β = 0.350; 95% CI: 0.035-0.664, p = 0.029) and L-selectin (β = 0.236; 95% CI: 0.038-0.434, p = 0.019) but not sVCAM-1 (β = 0.009; 95% CI: 0.252-0.270, p = 0.468). The HAART-exposed group is associated with sVCAM-1 (β = 0.250; 95% CI: 0.015-0.486, p = 0.037) but not with sICAM-1- (β = 0.253; 95% CI: -0.083-0.590, p = 0.14) and L-selectin (β = 0.119; 95% CI: -0.016-0.253, p = 0.084). sVCAM-1 was associated with decreased alcohol consumption (β = -0.245; 95% CI: -0.469-0.021, p = 0.032) while L-selectin was associated with decreased total cholesterol (β = -0.061; 95% CI: -0.124-0.002, p = 0.05) and increased CRP (β = 0.015; 95% CI: 0.009-0.022, p < 0.001). Increased endothelial biomarkers were associated with HIV disease and HAART in a rural black adult population of African descent after controlling for CVD risk factors. Inflammation (as measured with CRP) may play an important role in endothelial activation. Further studies are needed to explore the association between endothelial dysfunction and inflammation especially among the HIV-positive population on HAART in similar settings.


Cobalt-catalyzed intermolecular C(sp(2))-O cross-coupling.
Cobalt(II)-catalyzed C(sp(2) )O cross-coupling between aryl/heteroaryl alcohols and vinyl/aryl halides in the presence of Cu(I) has been achieved under ligand-free conditions. In this reaction, copper plays a significant role in transmetalation rather than being directly involved in the CO coupling. This unique Co/Cu-dual catalyst system provides an easy access to a library of aryl-vinyl, heteroaryl-styryl, aryl-aryl, and heteroaryl-heteroaryl ethers in the absence of any ligand or additive.


Fission yeast Csk1 is a CAK-activating kinase (CAKAK).
Cell cycle progression is dependent on the sequential activity of cyclin-dependent kinases (CDKs). For full activity, CDKs require an activating phosphorylation of a conserved residue (corresponding to Thr160 in human CDK2) carried out by the CDK-activating kinase (CAK). Two distinct CAK kinases have been described: in budding yeast Saccharomyces cerevisiae, the Cak1/Civ1 kinase is responsible for CAK activity. In several other species including human, Xenopus, Drosophila and fission yeast Schizosaccharomyces pombe, CAK has been identified as a complex homologous to CDK7-cyclin H (Mcs6-Mcs2 in fission yeast). Here we identify the fission yeast Csk1 kinase as an in vivo activating kinase of the Mcs6-Mcs2 CAK defining Csk1 as a CAK-activating kinase (CAKAK).


Modification of potassium nitrate assimilation test for identification of clinically important yeasts.
The modification of an auxanographic method used in yeast species identification to determine potassium nitrate (KNO3) assimilation resulted in a simple and inexpensive KNO3 assimilation test medium. The medium provided accurate and reliable results in less than 24 h.


Effects of phosphorothioate oligodeoxyribonucleotide and oligoribonucleotides on human complement and coagulation.
We have synthesized and studied the effects of phosphorothioate (PS) oligodeoxyribonucleotide (DNA) and oligoribonucleotides (RNA, 2'-O-methyl-RNA and 2'-5'-RNA) on complement activation and prolongation of activated partial thromboplastin time (aPTT) in vitro. These results suggest that a PS-DNA prolongs aPTT, and inhibits complement lysis more than do the PS-RNA analogs.


Conditions of the cervix for the increase of plasma levels of 13,14-dihydro-15-keto-prostaglandin F2 alpha after amniotomy at term.
Amniotomy was performed in 12 multiparas at term but not in labor. In 6 of these patients (group I), the fetal head and cervix condition were favorable for amniotomy, and in the other 6 (group II), they were not favorable. In all group I patients, a sudden and progressive descent of the fetal head, and onset and progress of labor were noted within 5 hours. Plasma 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) levels increased significantly (P less than 0.05) in 4 of these cases with time. In group II patients, descent of the head was less than that in group I patients (P less than 0.05), and neither strong labor nor rise of PGFM levels was noted within 5 hours. These data support our view that amniotomy at an appropriate time results in the onset and progress of labor, and the rise of plasma PGFM in virtue of the sudden and exponential increase of the head to cervix force, but amniotomy at an inappropriate time does not, because this force is unchanged.


The Process of Cessation Among Current Tobacco Smokers: A Cross-Sectional Data Analysis From 21 Countries, Global Adult Tobacco Survey, 2009-2013.
We analyzed data from the Global Adult Tobacco Survey (GATS) from 21 countries to categorize smokers by stages of cessation and highlight interventions that could be tailored to each stage. GATS is a nationally representative household survey that measures tobacco use and other key indicators by using a standardized protocol. The distribution of smokers into precontemplation, contemplation, and preparation stages varied by country. Using the stages of change model, each country can design and implement effective interventions suitable to its cultural, social, and economic situations to help smokers advance successfully through the stages of cessation.


Inflammatory-like status and acute stress response in horses after road transport.
This study aimed to evaluate the change of white blood cell count, serum concentration of cortisol, C-reactive protein, albumin and globulin fractions in horse after road transport, and to assess the linkage among hypothalamic-pituitary-adrenal axis (HPA) and inflammatory reaction. From 10 horses blood samples were collected at rest, before road transport (218 km) (BT); after unloaded (AT), 30 and 60 min after unloaded (AT30 and AT60) in order to assess white blood cell count (WBC), serum cortisol, C-reactive protein (CRP), total proteins, albumin, α1-, α-2, β1-, β2- and γ-globulins. WBC, cortisol, CRP, α1-, α-2 and β2-globulins values increased after road transport than rest condition (p < 0.001). Albumin and A/G ratio showed lower values after road transport than rest (p < 0.001). Pearson's test showed a negative correlation between cortisol and the values of WBC, CRP, α1-, α2-, β1-, β2- globulins, and a positive correlation between WBC and serum concentration of CRP, α1- and α2-, β1-, β2-globulins at AT and AT30. The results showed that road transport evokes an inflammatory like-status in horses. Moreover, the activation of HPA and the onset of acute phase reaction in response to road transport seem to be interconnected with effects on horse's immune status.


beta-Adrenoceptor alterations coupled with secretory response in rat parotid tissue.
Simultaneous studies on the secretory response of amylase and the neurotransmitter receptors of rat parotid gland, after brief treatment with agonists, showed selective alteration in beta-adrenoceptors with specific change in amylase secretion, suggesting a regulatory role of the receptors in the secretory response. The beta-adrenergic agonist (+/-)-isoprenaline (IPR) stimulated amylase secretion from rat parotid tissues much more than did the same concentration of an alpha-adrenergic or cholinergic agonist. The stimulatory effects of IPR were studied by pre-treating rat parotid tissues with IPR for 10 min and then incubating the tissue in fresh medium for 10 min. Pre-treatment with 10 microM-IPR for 10 min resulted in increased amylase secretion during further incubation with IPR and also in a lower EC50 value of amylase secretion for IPR. This treatment also resulted in selective changes in the number and affinity of beta-adrenoceptors, assessed by measuring binding of [3H]dihydroalprenolol (DHA): the maximal binding sites increased from 286/357 f-mole to mg protein and the IC50 value (the concentration for 50% inhibition of specific [3H]DHA binding) of beta-agonists, not antagonists, decreased significantly. An increase in the period of pre-treatment with IPR to 30 min resulted in a decrease in the maximal binding sites of beta-adrenoceptors and a decrease in amylase secretion during further incubation with IPR. Experiments with other agonists showed that supersensitivity of the secretory response was induced specifically by beta-agonists. Binding studies with [3H]WB-4101 and [3H]quinuclidinyl benzilate showed that alpha-adrenoceptors and muscarinic ACh receptors in rat parotid did not change under the conditions tested. The alteration in beta-adrenoceptors was parallel with a change in amylase secretion after IPR pre-treatment, but not with a change in cyclic AMP content.


Hospital outreach community-based health care: the case of Chogoria, Kenya.
This article presents an analysis of the community health activities of Chogoria Hospital, Kenya, as they evolved from a typical 'outreach' programme to a heavily community-based one, and the factors that contributed to this conversion. Factors considered include family planning, being the central theme of the programme since its inception, financing, and the impact of the programme is illustrated with data from an extensive evaluation carried out in 1985. The question of long-term financial viability is addressed, contrasting the desired self-sufficiency with the need and extent of donor contributions and finally a number of key factors are listed that may have been important to the success of the programme.


1-[(E)-Anthracen-9-yl-methyl-idene]-2-(2,4-di-nitro-phen-yl)hydrazine.
In the title Schiff base, C21H14N4O4, the dihedral angle between the two nitro groups and the central benzene ring are 83.6 (5) and 2.6 (6)°. The anthracene ring system and the benzene ring make a dihedral angle of 0.7 (2)°. Intra-molecular N-H⋯O and C-H⋯N hydrogen bonds occur. In the crystal, C-H⋯O hydrogen bonds link the mol-ecules, forming chains along the b-axis direction.


[Catheter dilatation in combined and generalized arterial occlusion and stenosis of pelvic and lower limb arteries].
The article discusses the possibilities and tactics of radiologically-guided intravascular angioplasty in extended and combined occlusive-stenotic lesions of the lower limb arteries from experience gained in 116 intravascular dilatations in 78 patients. The authors show that it is really possible to perform catheter angioplasty in patients with extended and combined occlusive-stenotic lesions of arteries of the pelvis and lower limbs with compulsory use of spasmolytic and anticoagulant therapy during the operation and, in addition, also disaggregate therapy in the postoperative period. Extended occlusions of the femoral artery, beginning from the opening of the deep femoral artery, should be managed by a retrograde popliteal approach.


A hybrid FLEET model for emergency medical service system design.
Covering models have been used to locate emergency services such as ambulance and fire protection systems. As an example, in the late seventies, an analysis of the Baltimore, Maryland fire protection system was conducted with the development and use of a covering model called the Facility Location and Equipment Emplacement Technique (FLEET). The FLEET model combined the location of fire stations with the allocation of primary and special service equipment to the stations. Further, in a recent study of Austin, Texas the ambulance system was restructured based on the use of a covering model. Covering models have also been extended to handle some of the special circumstances involved in emergency service systems. One example is the maximal expected coverage problem (MEXCLP). This paper presents a new covering model which utilizes both the special coverage structure of the MEXCLP and the simultaneous station location and equipment allocation of the FLEET model. Optimal solutions are found using linear and integer programming. Results of the model applied to several planning data sets (including a form of the Austin, Texas planning problem) demonstrate that more concentrated ambulance allocation patterns exist which may lead to easier dispatching, reduced facility costs, and better crew load balancing with little or no loss of service coverage. Tradeoff curves are presented which show that significant reductions in the number of dispatching sites (keeping the number of ambulances constant) can be made without any major changes in service level.


High Magnetic Field-Engineered Bunched Zn-Co-S Yolk-Shell Balls Intercalated within S, N Codoped CNT/Graphene Films for Free-Standing Supercapacitors.
The abundant mass and charge transfer involved in Faradaic redox reactions are largely determined by microstructures including the surface area and porosity, elemental composition and electrical conductivity of bimetallic sulfides. Here, a high magnetic field (HMF) was introduced to tune these intrinsic characters for superior supercapacitor electrodes. We developed a novel HMF-controlled anion-exchange methodology to prepare the one-dimensional (1D) bunched Zn-Co-S yolk-shell balls (ZCS6T BYSBs). The HMF-induced directional growth and alignment of Zn0.76Co0.24S drive the directional 1D assembly. The as-obtained ZCS6T BYSBs possess larger surface area/pore volume, higher crystallinity and electrical conductivity, richer electroactive elements, and favorable axial electron and ion transport because of HMF-enhanced favorable ion diffusion and exchange kinetics. Flexible S, N codoped carbon nanotubes/graphene films embedded with the ZCS6T BYSBs (CZS6T/CNTs/SNGS) were fabricated by vacuum filtration and one-step S, N codoping and reduction of graphene oxides to improve structural stability and charge transport. The CZS6T/CNTs/SNGS electrode displayed impressive enhanced specific capacitance and rate capability with 78.7% capacitance retention at 30 A g-1. Furthermore, the CZS6T/CNTs/SNGS//CNTs/SNGS asymmetric supercapacitor delivered remarkable cycling stability with a high energy density of 41.1 W h kg-1 at a large power density of 9022 W kg-1.


Postoperative outcomes with neuraxial versus general anesthesia in bilateral total hip arthroplasty.
Current evidence remains limited on the postoperative outcomes of neuraxial (NA) versus general anesthesia (GA) as primary anesthesia type in patients receiving simultaneous bilateral total hip arthroplasty (BTHA). We aimed to evaluate the rates of postoperative outcomes among patients receiving NA versus GA for BTHA. Retrospective cohort study. Multi-institutional. A total of 798 patients undergoing BTHA with 519 and 279 who received GA and NA, respectively. We used the American College of Surgeons - National Surgical Quality Improvement Program database for years 2007 to 2016. Patients undergoing BTHA. We propensity-score matched on demographic factors and comorbid conditions to compare rates of postoperative outcomes among cohorts (NA versus GA). We performed Pearson chi-square and Wilcoxon rank sum test to compare NA versus GA cohorts. The final analysis included 798 BTHA patients, of which 35% received NA as the primary anesthetic. The median age was 58 years old and 50.8% were female. The rate of perioperative transfusion in the NA and GA group were 20.1% and 29.0%, respectively (p = 0.02). There were no significant differences in the rate of postoperative outcomes between patients receiving NA versus GA as their primary anesthesia type (Bonferroni corrected p < 0.006 was considered statistically significant). Our study showed no significant differences in postoperative outcomes between NA versus GA following BTHA. Further studies are needed to investigate outcomes among this surgical population.


HIV disease and pregnancy. Part 3. Postpartum care of the HIV-positive woman and her newborn.
For women with HIV infection, physical and psychosocial adaptation during the postpartum period is fraught with ambivalence. On the one hand, there is the joy of parenthood, but on the other, the burden of a chronic, terminal illness and the possibility of having an infected newborn. The nursing care of the HIV-positive woman and her newborn is discussed. Guidelines for hospital discharge teaching are included.


Mechanism of T-oligo-induced cell cycle arrest in Mia-PaCa pancreatic cancer cells.
DNA oligonucleotides with sequence homology to human telomeric DNA (T-oligo) induce cell cycle arrest, followed by apoptosis, senescence, or autophagy in a human cancer cell type-specific manner. T-oligo has potential as a new therapeutic strategy in oncology because of its ability to target certain types of tumor cells while sparing normal ones. In the present study, we demonstrate the T-oligo-induced S-phase cell cycle arrest in four pancreatic cancer cell lines. To further contribute to the mechanistic understanding of T-oligo, we also identify cyclin dependent kinase 2 (cdk2) as a functional mediator in the T-oligo-induced cell cycle arrest of pancreatic cancer cells. Ectopic expression of a constitutively active cdk2 mutant abrogates T-oligo-induced cell cycle arrest in these tumor cells while knockdown of cdk2 expression alone recapitulates the T-oligo effect. Finally, we demonstrate the dispensability of T-oligo-induced ATM/ATR-mediated DNA damage response-signaling pathways, which have long been considered functional in the T-oligo signaling mechanism.


Collapse of blastocysts is strongly related to lower implantation success: a time-lapse study.
Is there an association between blastocyst collapse patterns and implantation potential? Embryos that exhibit collapse are as likely to hatch as those that do not, but are less likely to implant and should not be replaced if alternatives are available. Studies of blastocyst collapse in different species of mammals have found that most blastocysts, that experience consecutive weak contractions, hatch successfully whereas those that exhibit strong contractions or collapse, fail to hatch. Retrospective cohort study. Seven hundred and fifteen transferred blastocysts were analyzed from July 2012 to May 2013. University-affiliated infertility center. Participant patients were recipients of oocyte donation and autologous IVF cycles (n = 460). Embryo development was analyzed with a time-lapse imaging system. Variables studied included blastocyst collapse (defined as the separation of ≥50% of the surface of the trophectoderm of the blastocyst from the zona pellucida), kinetic variables, embryo morphology, implantation and clinical pregnancy rates. A total of 139 blastocysts presented collapse (19.4%), of these 8 presented 2 collapses and 2 presented 3 collapses. The timings of embryo cleavages and the time taken to reach the morula stage and blastulation were significantly shorter in embryos with collapse than in those without. Implantation rates were compared in cycles where either all or none of the embryos replaced, implanted so that implantation data were known for every embryo. Among 408 embryos without collapse and 94 embryos with at least one collapse (94) the implantation rates were 48.5% (95% confidence intervals (CI) 46.7-53.4%) and 35% (95% CI 25.3-44.9%), respectively. The percentage of embryos that hatched was similar in both groups 28.7 and 31%, respectively. The retrospective nature of the study limits its potential value. Study the collapse pattern of the blastocyst, may assist selection of the blastocysts most likely to implant and increase IVF/ICSI success rates.


Is atrial natriuretic peptide-guanosine 3',5' cyclic monophosphate coupling a determinant of urinary sodium excretion in essential hypertension?
(1) To compare urinary guanosine 3',5' cyclic monophosphate (cyclic GMP) excretion between normotensive subjects and essential hypertensive patients; (2) to determine the influence of changes in sodium intake on urinary cyclic GMP excretion in response to the neutral endopeptidase inhibitor candoxatril in essential hypertensives. (1) Twenty-five normotensive subjects and 25 patients with established essential hypertension not on treatment; (2) Single oral dose of candoxatril in eight patients with essential hypertension after equilibration on a low- or high-sodium diet in a placebo-controlled, double-blind, randomized, crossover study. Blood pressure was measured by ultrasound sphygmomanometry. Atrial natriuretic peptide (ANP) and urinary cyclic GMP were measured by radioimmunoassay. Group comparisons were made using unpaired t-tests and two-way analysis of variance. Plasma ANP was significantly raised in patients with essential hypertension compared with the normotensive group, but there was no difference in urinary cyclic GMP excretion. Plasma ANP increased significantly on the high- compared with low-sodium diet. After candoxatril, there were significant diet-related increases in plasma ANP and urinary sodium excretion up to 6 h after drug administration. There were similar increases in urinary cyclic GMP excretion on both diets, but there were no consistent differences in this excretion between the low- and high-sodium diets. These observations not only point to the importance of ANP-cyclic GMP coupling as a determinant of the natriuretic response to endopeptidase inhibition, but also suggest that the excretion of urinary cyclic GMP can be influenced by other factors in addition to circulating ANP.


Updates on the management of gastrointestinal stromal tumors.
Despite being the most common sarcoma of the gastrointestinal tract, gastrointestinal stromal tumor (GIST) has been widely recognized as a unique entity for just over a decade. The advent of tyrosine kinase inhibitors has revolutionized the diagnosis and treatment of GIST. Although surgery remains the only chance for cure, multimodal treatment that includes molecular therapy continues to develop. Optimal management of GIST requires careful radiographic, pathologic, medical, and surgical care, emphasizing the need for a multidisciplinary approach. This review highlights recent developments in the management of GIST.


Hemostasis in Otologic and Neurotologic Surgery.
Hemostasis is a critical component of otologic and neurotologic surgery. In these surgeries the surgical field is small; thus, even a small amount of bleeding can obstruct the view of critical and extremely small structures. Additionally, relatively large vascular structures traverse the area; if they are encroached on by trauma or disease, bleeding must be controlled within a very small space in a meticulous fashion that does not encroach on structures of the middle ear and mastoid. The authors discuss several hemostatic agents in the middle ear, mastoid, and lateral skull base, highlighting their origins, mechanisms, advantages, and complications.