The Effect of Intravenous Regional Perfusion of the Distal Limb With Amikacin Sulfate on Wounds Healing by Second Intention in Horses.
To compare the gross and histological effects of intravenous regional limb perfusion (IVRLP) using amikacin sulfate on second intention healing of distal limb wounds in adult horses with healing in untreated wounds. In vivo experimental study. Adult horses (n = 7). Two full thickness wounds (2.5 × 2.5 cm) were created aseptically on the dorsal aspect of each metacarpus and maintained under sterile bandages. One forelimb was randomly selected from each horse for IVRLP on days 2, 3, and 4 post-wounding. Sequential biopsies were taken from 1 wound on each limb to evaluate the histological effects of IVRLP. Photographs were obtained of nonbiopsied wounds from days 2 to 62 for gross assessment and wound measurement. Wound size and contraction, healing rate during and immediately after IVRLP treatment, total healing rate, and histological scores for edema, hemorrhage, inflammatory infiltrate, and fibrovascular proliferation were compared. No differences were observed between groups for wound size, wound contraction, healing rates during or after IVRLP treatment periods, or total healing rate. Wound size over time was larger in the IVRLP group compared with the control group; however, this difference did not reach statistical significance. Mononuclear cell infiltration was greater in the IVRLP group compared with controls. No differences were observed for other histological variables. All wounds healed without the formation of exuberant granulation tissue. Treatment for 3 consecutive days with IVRLP using amikacin sulfate did not negatively affect surgical wounds healing by second intention in the distal limb of horses.


Candida albicans white and opaque cells exhibit distinct spectra of organ colonization in mouse models of infection.
Candida albicans, a species of fungi, can thrive in diverse niches of its mammalian hosts; it is a normal resident of the GI tract and mucosal surfaces but it can also enter the bloodstream and colonize internal organs causing serious disease. The ability of C. albicans to thrive in these different host environments has been attributed, at least in part, to its ability to assume different morphological forms. In this work, we examine one such morphological change known as white-opaque switching. White cells are the default state of C. albicans, and most animal studies have been carried out exclusively with white cells. Here, we compared the proliferation of white and opaque cells in two murine models of infection and also monitored, using specially constructed strains, switching between the two states in the host. We found that white cells outcompeted opaque cells in many niches; however, we show for the first time that in some organs (specifically, the heart and spleen), opaque cells competed favorably with white cells and, when injected on their own, could colonize these organs. In environments where the introduced white cells outcompeted the introduced opaque cells, we observed high rates of opaque-to-white switching. We did not observe white-to-opaque switching in any of the niches we examined.


[Preventing failures and malfunction in general practice].
According to governmental regulations, general practitioners are responsible for identifying domains within their office procedures where failures may happen, or where rules are broken. Fjellsiden Health Centre has developed a simple system for prevention of professional failures, based on identification, recording and review of cases representing routine malfunction. Presuppositions, procedures, development, experiences and current functioning are described. The annual number of reported cases varied between 12 and 52. Most cases are related to lab tests, social interaction, or confidentiality. The typical case was not a serious flaw, but could--under less fortunate conditions - have had an unacceptable lapse. We have found that this system helps us to identify weak points in our procedures. Local quality assurance can be conducted by simple methods.


A Quantitative Microbiological Risk Assessment for Salmonella in Pigs for the European Union.
A farm-to-consumption quantitative microbiological risk assessment (QMRA) for Salmonella in pigs in the European Union has been developed for the European Food Safety Authority. The primary aim of the QMRA was to assess the impact of hypothetical reductions of slaughter-pig prevalence and the impact of control measures on the risk of human Salmonella infection. A key consideration during the QMRA development was the characterization of variability between E.U. Member States (MSs), and therefore a generic MS model was developed that accounts for differences in pig production, slaughterhouse practices, and consumption patterns. To demonstrate the parameterization of the model, four case study MSs were selected that illustrate the variability in production of pork meat and products across MSs. For the case study MSs the average probability of illness was estimated to be between 1 in 100,000 and 1 in 10 million servings given consumption of one of the three product types considered (pork cuts, minced meat, and fermented ready-to-eat sausages). Further analyses of the farm-to-consumption QMRA suggest that the vast majority of human risk derives from infected pigs with a high concentration of Salmonella in their feces (≥10(4) CFU/g). Therefore, it is concluded that interventions should be focused on either decreasing the level of Salmonella in the feces of infected pigs, the introduction of a control step at the abattoir to reduce the transfer of feces to the exterior of the pig, or a control step to reduce the level of Salmonella on the carcass post-evisceration.


Response of Plant-Associated Microbiome to Plant Root Colonization by Exogenous Bacterial Endophyte in Perennial Crops.
The application of bacterial inoculums for improving plant growth and production is an important component of sustainable agriculture. However, the efficiency of perennial crop inoculums depends on the ability of the introduced endophytes to exert an impact on the host-plant over an extended period of time. This impact might be evaluated by the response of plant-associated microbiome to the inoculation. In this study, we monitored the effect of a single bacterial strain inoculation on the diversity, structure, and cooperation in plant-associated microbiome over 1-year period. An endophyte (RF67) isolated from Vaccinium angustifolium (wild blueberry) roots and annotated as Rhizobium was used for the inoculation of 1-year-old Lonicera caerulea (Haskap) plants. A significant level of bacterial community perturbation was detected in plant roots after 3 months post-inoculation. About 23% of root-associated community variation was correlated with an application of the inoculant, which was accompanied by increased cooperation between taxa belonging to Proteobacteria and Actinobacteriota phyla and decreased cooperation between Firmicutes in plant roots. Additionally, a decrease in bacterial Shannon diversity and an increase in the relative abundances of Rhizobiaceae and Enterobacteriaceae were detected in the roots of inoculated plants relative to the non-inoculated control. A strong effect of the inoculation on the bacterial cooperation was also detected after 1 year of plant field growth, whereas no differences in bacterial community composition and also alpha and beta diversities were detected between bacterial communities from inoculated and non-inoculated roots. These findings suggest that while exogenous endophytes might have a short-term effect on the root microbiome structure and composition, they can boost cooperation between plant-growth-promoting endophytes, which can exist for the extended period of time providing the host-plant with long-lasting beneficial effects.


Gas production in the Barnett Shale obeys a simple scaling theory.
Natural gas from tight shale formations will provide the United States with a major source of energy over the next several decades. Estimates of gas production from these formations have mainly relied on formulas designed for wells with a different geometry. We consider the simplest model of gas production consistent with the basic physics and geometry of the extraction process. In principle, solutions of the model depend upon many parameters, but in practice and within a given gas field, all but two can be fixed at typical values, leading to a nonlinear diffusion problem we solve exactly with a scaling curve. The scaling curve production rate declines as 1 over the square root of time early on, and it later declines exponentially. This simple model provides a surprisingly accurate description of gas extraction from 8,294 wells in the United States' oldest shale play, the Barnett Shale. There is good agreement with the scaling theory for 2,057 horizontal wells in which production started to decline exponentially in less than 10 y. The remaining 6,237 horizontal wells in our analysis are too young for us to predict when exponential decline will set in, but the model can nevertheless be used to establish lower and upper bounds on well lifetime. Finally, we obtain upper and lower bounds on the gas that will be produced by the wells in our sample, individually and in total. The estimated ultimate recovery from our sample of 8,294 wells is between 10 and 20 trillion standard cubic feet.


Influence of linear expansion of two different non metallic core materials upon cervical marginal accuracy of full veneer crowns.
The effect of water sorption and linear expansion of two different non metallic core materials: 1) Composite and 2) Reinforced glass ionomer on the cervical marginal seating of cast metal crowns was investigated in this study. Thirty freshly extracted sound mandibular molar teeth were used in this study. The teeth were machined cut to simulate average dimensions of a prepared lower second premolar tooth with chamfer finish line. The teeth were decoronated 2 mm above the finish line then specially prepared to receive equal volumes of either pin retained composite or pin retained reinforced glass ionomer. The teeth after that were restored with full coverage metal crowns. Ten of each type of core samples were immersed in 37 degrees C normal saline while the remaining samples were maintained dry (control). The vertical cervical marginal accuracy of the crowns were microscopically measured with 1 micron accuracy before immersion and after 6, 12 hours and every day of the following ten days of saline immersion. The statistical analysis of the results revealed that composite core immersed in saline solution at 37 degrees C possessed dimensional instability with the maximum linear change between the first and the second day. Also the reinforced glass ionomer core showed no effect upon the cervical marginal seating of the overlying full coverage cast metal crown.


Implementation of a computationally efficient least-squares algorithm for highly under-determined three-dimensional diffuse optical tomography problems.
Three-dimensional (3D) diffuse optical tomography is known to be a nonlinear, ill-posed and sometimes under-determined problem, where regularization is added to the minimization to allow convergence to a unique solution. In this work, a generalized least-squares (GLS) minimization method was implemented, which employs weight matrices for both data-model misfit and optical properties to include their variances and covariances, using a computationally efficient scheme. This allows inversion of a matrix that is of a dimension dictated by the number of measurements, instead of by the number of imaging parameters. This increases the computation speed up to four times per iteration in most of the under-determined 3D imaging problems. An analytic derivation, using the Sherman-Morrison-Woodbury identity, is shown for this efficient alternative form and it is proven to be equivalent, not only analytically, but also numerically. Equivalent alternative forms for other minimization methods, like Levenberg-Marquardt (LM) and Tikhonov, are also derived. Three-dimensional reconstruction results indicate that the poor recovery of quantitatively accurate values in 3D optical images can also be a characteristic of the reconstruction algorithm, along with the target size. Interestingly, usage of GLS reconstruction methods reduces error in the periphery of the image, as expected, and improves by 20% the ability to quantify local interior regions in terms of the recovered optical contrast, as compared to LM methods. Characterization of detector photo-multiplier tubes noise has enabled the use of the GLS method for reconstructing experimental data and showed a promise for better quantification of target in 3D optical imaging. Use of these new alternative forms becomes effective when the ratio of the number of imaging property parameters exceeds the number of measurements by a factor greater than 2.


Identification of lutein and zeaxanthin oxidation products in human and monkey retinas.
To characterize fully all the major and minor carotenoids and their metabolites in human retina and probe for the presence of the oxidative metabolites of lutein and zeaxanthin. Carotenoids of a composite of 58 pairs of human retinas and a monkey retina were elucidated by comparing their high-performance liquid chromatography (HPLC)-ultraviolet/visible absorption spectrophotometry (UV/Vis)-mass spectrometry (MS) profile with those of authentic standards prepared by organic synthesis. In addition to lutein and zeaxanthin, several oxidation products of these compounds were present in the extracts from human retina. A major carotenoid resulting from direct oxidation of lutein was identified as 3-hydroxy-beta, epsilon-caroten-3'-one. Minor carotenoids were identified as: 3'-epilutein, epsilon,epsilon-carotene-3,3'-diol, epsilon,epsilon-carotene-3,3'-dione, 3'-hydroxy-epsilon,epsilon-caroten-3-one, and 2,6-cyclolycopene-1,5-diol. Several of the geometric isomers of lutein and zeaxanthin were also detected at low concentrations. These were as follows: 9-cis-lutein, 9'-cislutein, 13-cis-lutein, 13'-cis-lutein, 9-cis-zeaxanthin, and 13-cis-zeaxanthin. Similar results were also obtained from HPLC analysis of a freshly dissected monkey retina. Lutein, zeaxanthin, 3'-epilutein, and 3-hydroxy-beta,epsilon-caroten-3'-one in human retina may be interconverted through a series of oxidation-reduction reactions similar to our earlier proposed metabolic transformation of these compounds in humans. The presence of the direct oxidation product of lutein and 3'-epilutein (metabolite of lutein and zeaxanthin) in human retina suggests that lutein and zeaxanthin may act as antioxidants to protect the macula against short-wavelength visible light. The proposed oxidative-reductive pathways for lutein and zeaxanthin in human retina, may therefore play an important role in prevention of age-related macular degeneration and cataracts.


Acute and sub-chronic toxicity of Liberin, an anti-diabetic polyherbal formulation in rats.
The polyherbal formulation (PHF) liberin, is known to exert anti-hyperglycemic effects in type 2 diabetes mellitus. Hence, it is important to study the safety profile of PHF in the current study through acute and chronic toxicity evaluation. This research aims to assess the acute and sub-chronic toxicity of PHF in rats. PHF was administered once orally (1000 mg/kg body weight), and the rats (male and female) were monitored for toxicity signs for a 14-day period. For a 28-day chronic toxicity study, rats were daily administered with PHF dose of 500 mg/kg and 1000 mg/kg body weight. Rats were followed up for mortality, weight changes, and other morbidities. Further haematological, biochemical, and histopathological changes were assessed. No death related to treatment or toxicity signs were recorded in the acute single-dose administration group. The results showed that the PHF was tolerated well up to a dose of 1000 mg/kg body weight. Even at the high dose of 1000 mg/kg body weight, sub-chronic tests did not show any significant difference between the dosed and normal groups. No significant changes were seen in the histopathological analysis of the liver, spleen, and kidney as well as haematological and biochemical parameters in acute, sub-chronic and satellite groups following the administration of PHF. The results confirmed that there was no adverse effect of this PHF at the maximum dose of 1000 mg/kg body weight in Wistar rats. Further, no adverse delayed effects related to PHF were observed in the satellite group. Therefore, this PHF appears safe for therapeutic purposes in the Ayurvedic medicinal system.


[Structural conditions for regionalization in health care: typology of Regional Management Boards].
An explanation is required for the delay in implementing the regionalization strategy and the fragile nature of the combined decentralization and regionalization initiatives in Brazil. The article raises some hypotheses to clarify this intricate issue and reviews the structural conditioning factors of the regionalization process ongoing in the states. A national typology of the health care regions is prepared, differentiating them according to the degree of socio-economic development and the characteristics of the health care network and of the municipalities that form the Regional Management Boards (CGR), formally implanted by January 2010. Factorial and cluster analysis models were used to build the typology. Five major socio-economic groups of CGRs were identified, described according to their regional distribution, population, health care spending, profile of services offered (including the public-private sector mix) and health service coverage. The results obtained serve as guidelines for the constitution of health care networks and new initiatives at the regional level, in order to improve the regionalization policy and favour the construction of diverse and flexible regulatory instruments that are more in tune with the regional state of affairs.


Safe intubation in cervical spine injury.
Traumatic spinal injury is an ongoing community problem. Anatomical stability of the cervical spine depends on the integrity of the bony and ligamentous structures forming the cervical spine. Such stabilising structures are divided into two groups. These are designated anterior and posterior columns. One or both columns may be damaged during traumatic spinal injury. Not all spinal injuries are unstable. Instability may be predicted by viewing anterior-posterior and lateral X-rays of the cervical spine. C1 and C2 injury necessitates special through-mouth views. Instability of the neck requires a different intubation technique. A safe intubation technique is described, the essence of which is to stabilise the neck with longitudinal traction and avoid extension at the fracture site.


A novel similarity-measure for the analysis of genetic data in complex phenotypes.
Recent technological advances in DNA sequencing and genotyping have led to the accumulation of a remarkable quantity of data on genetic polymorphisms. However, the development of new statistical and computational tools for effective processing of these data has not been equally as fast. In particular, Machine Learning literature is limited to relatively few papers which are focused on the development and application of data mining methods for the analysis of genetic variability. On the other hand, these papers apply to genetic data procedures which had been developed for a different kind of analysis and do not take into account the peculiarities of population genetics. The aim of our study was to define a new similarity measure, specifically conceived for measuring the similarity between the genetic profiles of two groups of subjects (i.e., cases and controls) taking into account that genetic profiles are usually distributed in a population group according to the Hardy Weinberg equilibrium. We set up a new kernel function consisting of a similarity measure between groups of subjects genotyped for numerous genetic loci. This measure weighs different genetic profiles according to the estimates of gene frequencies at Hardy-Weinberg equilibrium in the population. We named this function the "Hardy-Weinberg kernel". The effectiveness of the Hardy-Weinberg kernel was compared to the performance of the well established linear kernel. We found that the Hardy-Weinberg kernel significantly outperformed the linear kernel in a number of experiments where we used either simulated data or real data. The "Hardy-Weinberg kernel" reported here represents one of the first attempts at incorporating genetic knowledge into the definition of a kernel function designed for the analysis of genetic data. We show that the best performance of the "Hardy-Weinberg kernel" is observed when rare genotypes have different frequencies in cases and controls. The ability to capture the effect of rare genotypes on phenotypic traits might be a very important and useful feature, as most of the current statistical tools loose most of their statistical power when rare genotypes are involved in the susceptibility to the trait under study.


Towards the use of diffuse reflectance spectroscopy for real-time in vivo detection of breast cancer during surgery.
Breast cancer surgeons struggle with differentiating healthy tissue from cancer at the resection margin during surgery. We report on the feasibility of using diffuse reflectance spectroscopy (DRS) for real-time in vivo tissue characterization. Evaluating feasibility of the technology requires a setting in which measurements, imaging and pathology have the best possible correlation. For this purpose an optical biopsy needle was used that had integrated optical fibers at the tip of the needle. This approach enabled the best possible correlation between optical measurement volume and tissue histology. With this optical biopsy needle we acquired real-time DRS data of normal tissue and tumor tissue in 27 patients that underwent an ultrasound guided breast biopsy procedure. Five additional patients were measured in continuous mode in which we obtained DRS measurements along the entire biopsy needle trajectory. We developed and compared three different support vector machine based classification models to classify the DRS measurements. With DRS malignant tissue could be discriminated from healthy tissue. The classification model that was based on eight selected wavelengths had the highest accuracy and Matthews Correlation Coefficient (MCC) of 0.93 and 0.87, respectively. In three patients that were measured in continuous mode and had malignant tissue in their biopsy specimen, a clear transition was seen in the classified DRS measurements going from healthy tissue to tumor tissue. This transition was not seen in the other two continuously measured patients that had benign tissue in their biopsy specimen. It was concluded that DRS is feasible for integration in a surgical tool that could assist the breast surgeon in detecting positive resection margins during breast surgery. Trail registration NIH US National Library of Medicine-clinicaltrails.gov, NCT01730365. Registered: 10/04/2012 https://clinicaltrials.gov/ct2/show/study/NCT01730365.


Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma.
Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ's inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.


Conversational assessment following traumatic brain injury: a comparison across two control groups.
Although changes in discourse are frequently referred to in the traumatic brain injury (TBI) literature, they are difficult to objectify and measure. It is not always easy, therefore, for clinicians to differentiate between discourse behaviours which may have been present premorbidly, and those which are uniquely associated with TBI. The major aim of this study was to systematically examine and describe the nature of conversational impairment following severe TBI, with particular reference to the premorbid sociolinguistic characteristics of the TBI population. A second aim of the study was to examine the relationship between discourse impairment following TBI and severity of injury. Twenty-six TBI participants were compared with 26 non-brain-injured orthopaedic patients, and 26 university students, using Damico's Clinical Discourse Analysis (CDA). As predicted, global measures derived from the CDA did not differentiate the groups. The TBI group was, however, found to differ significantly from both control groups on a modified measure (CDA-M) which removes discourse errors that occurred with similar frequency across the three groups. Performance on this measure correlated significantly with severity of injury. Further, it was found that there were quantitative and qualitative differences between two seventy subgroups in the TBI group with respect to their CDA-M profiles. While nearly all members of the TBI group made errors associated with information transfer, only the more fundamental 'rules' of conversational interaction. The results are discussed in relation to the psychosocial implications of the findings, together with issues in sampling and measuring conversational discourse in the TBI population.


Update on trauma care in Canada. 6. Update on trauma registries and trauma scoring.
Developments in microcomputer technology and user friendly software have resulted in rapidly expanding interest in trauma registries and injury scoring. The trauma registry, particularly when it is population based, is an empowering tool for epidemiologic research, planning of trauma systems, development of prevention programs, outcome evaluation and research. Injury coding performed in conjunction with trauma registry can also provide the basis for institutional quality assurance. The Major Trauma Outcome Study has played a major role in this, through the development of normative standards, permitting inter-institutional comparisons. These issues as well as some of the present Canadian and American initiatives in the trauma registry field are reviewed in this paper. Advances in injury scaling are addressed as are some of the limitations in existing coding methodologies.


Polycomb group protein expression during differentiation of human embryonic stem cells into pancreatic lineage in vitro.
Polycomb Group (PcG) proteins are chromatin modifiers involved in early embryonic development as well as in proliferation of adult stem cells and cancer cells. PcG proteins form large repressive complexes termed Polycomb Repressive Complexes (PRCs) of which PRC1 and PRC2 are well studied. Differentiation of human Embryonic Stem (hES) cells into insulin producing cells has been achieved to limited extent, but several aspects of differentiation remain unexplored. The PcG protein dynamics in human embryonic stem (hES) cells during differentiation into pancreatic lineage has not yet been reported. In the present study, the expression of RING1A, RING1B, BMI1, CBX2, SUZ12, EZH2, EED and JARID2 during differentiation of hES cells towards pancreatic lineage was examined. In-house derived hES cell line KIND1 was used to study expression of PcG protein upon spontaneous and directed differentiation towards pancreatic lineage. qRT-PCR analysis showed expression of gene transcripts for various lineages in spontaneously differentiated KIND1 cells, but no differentiation into pancreatic lineage was observed. Directed differentiation induced KIND1 cells grown under feeder-free conditions to transition from definitive endoderm (Day 4), primitive gut tube stage (Day 8) and pancreatic progenitors (Day 12-Day 16) as evident from expression of SOX17, PDX1 and SOX9 by qRT-PCR and Western blotting. In spontaneously differentiating KIND1 cells, RING1A and SUZ12 were upregulated at day 15, while other PcG transcripts were downregulated. qRT-PCR analysis showed transcripts of RING1B, BMI1, SUZ12, EZH2 and EED were upregulated, while RING1A and CBX2 expression remained low and JARID2 was downregulated during directed differentiation of KIND1 cells. Upregulation of BMI1, EZH2 and SUZ12 during differentiation into pancreatic lineage was also confirmed by Western blotting. Histone modifications such as H3K27 trimethylation and monoubiquitinylation of H2AK119 increased during differentiation into pancreatic lineage as seen by Western blotting. Our study shows expression of PcG proteins was distinct during spontaneous and directed differentiation. Differentiation into pancreatic lineage was achieved by directed differentiation approach and was associated with increased expression of PcG proteins RING1B, BMI1, EZH2 and SUZ12 accompanied by increase in monoubiquitinylation of H2AK119 and trimethylation of H3K27.


White matter microstructure in untreated first episode bipolar disorder with psychosis: comparison with schizophrenia.
White matter abnormalities have been reported in bipolar disorder. The present study aimed to investigate white matter integrity in untreated first episode patients with psychotic bipolar disorder using diffusion tensor imaging, and to compare observations with those from untreated first episode schizophrenia patients. Fractional anisotropy and mean diffusivity were measured in first episode psychotic patients with bipolar disorder (n = 13) or schizophrenia (n = 21) and healthy individuals (n = 18). Group differences were evaluated using voxel-based morphometry. Axial and radial diffusivity were examined in regions with altered fractional anisotropy in post-hoc analyses. Patients with bipolar disorder showed lower fractional anisotropy than healthy controls in several white matter tracts. Compared with schizophrenia patients, bipolar disorder patients showed lower fractional anisotropy in the cingulum, internal capsule, posterior corpus callosum, tapetum, and occipital white matter including posterior thalamic radiation and inferior longitudinal fasciculus/inferior fronto-occipital fasciculus. Lower fractional anisotropy in bipolar disorder was characterized by increased radial diffusion rather than axial diffusion along the orientation of fiber tracts. Across several white matter tracts, both patient groups showed greater mean diffusivity than healthy individuals. Selectively increased radial diffusivity in bipolar disorder patients suggests structural disorganization in fiber tract coherence of neurodevelopmental origin or alterations in myelin sheaths along fiber tracts. In contrast, increased isotropic diffusion along white matter tracts in schizophrenia patients with alterations in both radial and axial diffusivity suggests increased water content outside the axonal space. Thus, the present results suggest that different pathophysiological mechanisms may underlie white matter microstructural abnormalities in bipolar disorder and schizophrenia.


Estrogen, progesterone and epithelial ovarian cancer.
Ovarian carcinoma (OCa) continues to be the leading cause of death due to gynecologic malignancies and the vast majority of OCa is derived from the ovarian surface epithelium (OSE) and its cystic derivatives. Epidemiological evidence strongly suggests that steroid hormones, primarily estrogens and progesterone, are implicated in ovarian carcinogenesis. However, it has proved difficult to fully understand their mechanisms of action on the tumorigenic process. New convincing data have indicated that estrogens favor neoplastic transformation of the OSE while progesterone offers protection against OCa development. Specifically, estrogens, particularly those present in ovulatory follicles, are both genotoxic and mitogenic to OSE cells. In contrast, pregnancy-equivalent levels progesterone are highly effective as apoptosis inducers for OSE and OCa cells. In this regard, high-dose progestin may exert an exfoliation effect and rid an aged OSE of pre-malignant cells. A limited number of clinical studies has demonstrated efficacies of antiestrogens, aromatase inhibitors, and progestins alone or in combination with chemotherapeutic drugs in the treatment of OCa. As a result of increased life expectancy in most countries, the number of women taking hormone replacement therapies (HRT) continues to grow. Thus, knowledge of the mechanism of action of steroid hormones on the OSE and OCa is of paramount significance to HRT risk assessment and to the development of novel therapies for the prevention and treatment of OCa.


In vivo cloning of PCR products in E. coli.
This report describes an efficient method to clone PCR products exploiting endogenous Escherichia coli enzymatic activities. PCR products are engineered to contain terminal sequences identical to sequences at the two ends of a linearized vector. PCR products and vector DNA are then simply co-transfected into E. coli strain JC8679, obviating the requirement for enzymatic treatment of the PCR product or in vitro ligation. The high rate of homologous recombination in this strain results in efficient incorporation of the insert into the vector, a process we refer to as in vivo cloning (IVC).


A specific growth hormone-binding protein in human plasma: initial characterization.
Human (h) GH in plasma exists as a series of size isomers, which are in part explained by the presence of hGH oligomers. However, certain aspects of circulating large mol wt hGH, such as its high relative proportion compared to that in the pituitary, are poorly understood. To explore whether binding of hGH to plasma protein(s) could contribute to the phenomenon of large mol wt hGH, we incubated freshly prepared monomeric [125I]hGH or biosynthesized [3H]hGH with normal human plasma or serum at pH 7.4 for various time periods at 22 and 37 C. Plasma radioactive hGH patterns were then analyzed simultaneously with unincubated tracer hGH by Sephadex G-100 and G-200 chromatography. We found that part of the radioactivity was converted to a component with an apparent mol wt of 85,000, suggesting binding to a plasma protein(s). This phenomenon was inhibited in a dose-dependent fashion by unlabeled hGH. Saturation/Scatchard analysis indicated an association constant (Ka) of 2-3 X 10(8) M-1 and a maximum binding capacity of 20 ng hGH/ml plasma. Binding was rapid, reversible, and specific. A number of polypeptide hormones, including human placental lactogen, hPRL and rat GH, did not inhibit hGH binding. However, the 20K variant of hGH interacted weakly with the plasma binding component (Ka, 1.2 X 10(7) M-1; maximum binding capacity, 450 ng/ml). The binding component was heat labile and could be partially purified by gel permeation chromatography and affinity chromatography on a hGH-Sepharose column. Its estimated mol wt is 60,000-65,000, and it appears to bind one molecule of hGH to form a complex of 80,000-85,000 mol wt. The binding component is neither albumin nor an immunoglobulin. Under physiological conditions, a minimum of 15-18% of circulating hGH is presumably bound to this plasma component. We conclude that a specific, high affinity, low capacity binding protein for hGH with mol wt of 60,000-65,000 exists in normal and hypopituitary human plasma. hGH complexed with this protein forms part of big-big hGH. The biological significance of this binding protein remains to be investigated.


External barium affects the gating of KCNQ1 potassium channels and produces a pore block via two discrete sites.
The pore properties and the reciprocal interactions between permeant ions and the gating of KCNQ channels are poorly understood. Here we used external barium to investigate the permeation characteristics of homomeric KCNQ1 channels. We assessed the Ba(2+) binding kinetics and the concentration and voltage dependence of Ba(2+) steady-state block. Our results indicate that extracellular Ba(2+) exerts a series of complex effects, including a voltage-dependent pore blockade as well as unique gating alterations. External barium interacts with the permeation pathway of KCNQ1 at two discrete and nonsequential sites. (a) A slow deep Ba(2+) site that occludes the channel pore and could be simulated by a model of voltage-dependent block. (b) A fast superficial Ba(2+) site that barely contributes to channel block and mostly affects channel gating by shifting rightward the voltage dependence of activation, slowing activation, speeding up deactivation kinetics, and inhibiting channel inactivation. A model of voltage-dependent block cannot predict the complex impact of Ba(2+) on channel gating in low external K(+) solutions. Ba(2+) binding to this superficial site likely modifies the gating transitions states of KCNQ1. Both sites appear to reside in the permeation pathway as high external K(+) attenuates Ba(2+) inhibition of channel conductance and abolishes its impact on channel gating. Our data suggest that despite the high degree of homology of the pore region among the various K(+) channels, KCNQ1 channels display significant structural and functional uniqueness.


Intracanal placement of calcium hydroxide: a comparison of techniques, revisited.
The goal of this in vitro study was to compare the effectiveness of three different placement techniques of calcium hydroxide paste in a curved canal. An acrylic resin block with a 44-degree curvature was instrumented to a #40 Flex-R file. The canal was filled with radiopaque calcium hydroxide paste using the following techniques: group 1, the paste was injected with an Ultradent tip; group 2, the paste was injected as in group 1 and followed by a size 35 Lentulo to working length; and group 3, the paste was placed with a size 35 Lentulo only, to working length. Each technique was performed 25 times. The radiodensity of the simulated canal was measured at 1, 3, 5, and 7 mm from the canal terminus. At 1 mm, the Lentulo was significantly better than the other two techniques. At 3 mm, the Lentulo technique and the combined technique were better than the Ultradent tip alone.


Occupational Risk Prevention through Smartwatches: Precision and Uncertainty Effects of the Built-In Accelerometer.
Wearable technology has had a significant growth in the last years; this is particularly true of smartwatches, due to their potential advantages and ease of use. These smart devices integrate sensors that can be potentially used within industrial settings and for several applications, such as safety, monitoring, and the identification of occupational risks. The accelerometer is one of the main sensors integrated into these devices. However, several studies have identified that sensors integrated into smart devices may present inaccuracies during data acquisition, which may influence the performance of their potential applications. This article presents an analysis from the metrological point of view to characterize the amplitude and frequency response of the integrated accelerometers in three currently available commercial smartwatches, and it also includes an analysis of the uncertainties associated with these measurements by adapting the procedures described in several International Organization for Standardization (ISO) standards. The results show that despite the technical limitations produced by the factory configuration, these devices can be used in various applications related to occupational risk assessment. Opportunities for improvement have also been identified, which will allow us to take advantage of this technology in several innovative applications within industrial settings and, in particular, for occupational health purposes.


Transport of Neurohormones from the Corpora Cardiaca in Insects.
Evidence from electron microscope studies of aphid and cockroach nerves, and from the bioassay of extracts of the aortal nerves of cockroaches indicates that some neurohormones are distributed from the corpora cardiaca along nerve axons to their target organs.


Longitudinal study of murine microbiota activity and interactions with the host during acute inflammation and recovery.
Although alterations in gut microbiota composition during acute colitis have been repeatedly observed, associated functional changes and the recovery from dysbiosis received little attention. In this study, we investigated structure and function of the gut microbiota during acute inflammation and recovery in a dextran sodium sulfate (DSS)-colitis mouse model using metatranscriptomics, bacterial 16S rRNA gene amplicon sequencing and monitoring of selected host markers. Parallel to an increase of host markers of inflammation during acute colitis, we observed relative abundance shifts and alterations in phylotype composition of the dominant bacterial orders Clostridiales and Bacteroidales, and an increase of the low abundant Enterobacteriales, Deferribacterales, Verrucomicrobiales and Erysipelotrichales. During recovery, the microbiota began to resume, but did not reach its original composition until the end of the experiment. Microbial gene expression was more resilient to disturbance, with pre-perturbation-type transcript profiles appearing quickly after acute colitis. The decrease of Clostridiales during inflammation correlated with a reduction of transcripts related to butyrate formation, suggesting a disturbance in host-microbe signalling and mucosal nutrient provision. The impact of acute inflammation on the Clostridiales was also characterized by a significant downregulation of their flagellin-encoding genes. In contrast, the abundance of members of the Bacteroidales increased along with an increase in transcripts related to mucin degradation. We propose that acute inflammation triggered a selective reaction of the immune system against flagella of commensals and temporarily altered murine microbiota composition and functions relevant for the host. Despite changes in specific interactions, the host-microbiota homeostasis revealed a remarkable ability for recovery.


Ferroptosis in a sarcopenia model of senescence accelerated mouse prone 8 (SAMP8).
As a systemic syndrome characterized by age-associated degenerative skeletal muscle atrophy, sarcopenia leads to a risk of adverse outcomes in the elderly. Age-related iron accumulation is found in the muscles of sarcopenia animal models and patients, but the role of iron in sarcopenia remains poorly understood. It has been recently found that iron overload in several diseases is involved in ferroptosis, an iron- dependent form of programmed cell death. However, whether this excess iron can result in ferroptosis in muscles is still unclear. In our present study, we found that ferric citrate induced ferroptosis in C2C12 cells, as well as impaired their differentiation from myoblasts to myotubes. Due to the decreased muscle mass and fiber size, 40-week-old senescence accelerated mouse prone 8 (SAMP8) mice were used as a sarcopenia model, in whose muscles the iron content and markers of ferroptosis were found to increase, compared to 8-week- old SAMP8 controls. Moreover, our results showed that iron overload upregulated the expression of P53, which subsequently repressed the protein level of Slc7a11 (solute carrier family 7, member 11), a known ferroptosis-related gene. The downregulation of Slc7a11 then induced the ferroptosis of muscle cells through the accumulation of lipid peroxidation products, which may be one of the causes of sarcopenia. The findings in this study indicate that iron plays a key role in triggering P53- Slc7a11-mediated ferroptosis in muscles, and suggest that targeting iron accumulation and ferroptosis might be a therapeutic strategy for treating sarcopenia.


Variations in UV-B tolerance and germination speed of Metarhizium anisopliae conidia produced on insects and artificial substrates.
Solar ultraviolet radiation (UV-A and UV-B) is a major factor in failure of programs using the insect pathogenic fungus Metarhizium anisopliae as a biological control agent. Studies were conducted to determine if growth conditions, viz. artificial (agar media or rice grain) or natural (infected insects) substrates for conidial production affect two traits that directly influence performance of conidia after field application: tolerance to UV-B radiation and conidial germination speed. Conidia of two isolates (ARSEF 23 and ARSEF 2575) of M. anisopliae var. anisopliae produced on potato dextrose agar plus yeast extract (PDAY) or on fungus-killed larvae of two insect species, Galleria mellonella and Zophobas morio, were inactivated by exposure to UV-B radiation. Conidia of both isolates when produced on insect cadavers were significantly more sensitive to UV-B radiation than conidia produced on PDAY. Also, conidia from insect cadavers germinated slower than those from PDAY cultures. A comparison of conidia from artificial substrates showed that conidia produced on Czapek's and Emerson's YpSs agar media or rice grains had higher tolerance to UV-B radiation and germinated faster than conidia raised on PDA and PDAY. Accordingly, the growth substrate and nutritional environment in which conidia are produced influences M. anisopliae conidial UV-B tolerance and speed of germination; and manipulation of these variables could be used to obtain conidia with increased tolerance to UV-B radiation and shorter germination times.


[Antibody-containing cells in the mucosa of the large intestine of patients with acute bacterial dysentery].
The authors traced the dynamics of appearance, increase and disappearance of O-antibody-containing cells in the mucosa of the distal portion of the large intestine in patients suffering from acute Sonne and Flexner dysentery (aspiration biopsy of the mucosa). The antibodies were revealed by the indirect Coons method. The total number of cells per 1 mm2 of 4 mum of the mucosal section the number of lymphoid cells and the content of the antibody-containing cells in % per total cell count of the lymphoid tissue was calculated. It was revealed that the antibody-containing cells appeared on the 4th day of the disease, reached the maximum on the 7th--8th and disappeared on the 22nd--25th day. Cells of the plasmocytic series containing no antidysentery antibodies, were revealed in large amounts even at the remote periods (up to 6 months) after recovery.


Effects of an artificial hay aroma and compound feed formulation on feed intake pattern, rumen function and milk production in lactating dairy cows.
The Kempen system is a dairy feeding system in which diet is provided in the form of a compound feed (CF) and hay offered ad libitum. Ad libitum access to CF and hay allows cows in this system to achieve a high DM intake (DMI). Out of physiological concerns, the voluntary hay intake could be increased and the consumption pattern of CF could be manipulated to maintain proper rumen functioning and health. This study investigated the effects of an artificial hay aroma and CF formulation on feed intake pattern, rumen function and milk production in mid- to late-lactating dairy cows. Twenty Holstein-Friesian cows were assigned to four treatments in a 4 × 4 Latin square design. Diet consisted of CF and grass hay (GH), fed separately, and both offered ad libitum, although CF supply was restricted in maximum meal size and speed of supply by an electronic system. Treatments were the combination of two CF formulations - high in starch (CHS) and fibre (CHF); and two GH - untreated (UGH) and the same hay treated with an artificial aroma (TGH). Meal criteria were determined using three-population Gaussian-Gaussian-Weibull density functions. No GH × CF interaction effects on feed intake pattern characteristics were found. Total DMI and CF intake, but not GH intake, were greater (P < 0.01) in TGH treatment, and feed intake was not affected by type of CF. Total visits to feeders per day, visits to the GH feeder, visits to the CF feeder and CF eating time (all P < 0.01) were significantly greater in cows fed with TGH. Meal frequency, meal size and meal duration were unaffected by treatments. Cows fed CHF had a greater milk fat (P = 0.02), milk urea content (P < 0.01) and a greater milk fat yield (P < 0.01). Cows fed TGH had a greater milk lactose content and lactose yield (P < 0.05), and milk urea content (P < 0.01). Cows fed TGH had smaller molar proportions of acetic acid and greater molar proportions of propionic acid compared with UGH. In conclusion, treatment of GH with an artificial aroma increased CF intake and total DMI, but did not affect hay intake. Additionally, GH treatment increased the frequency of visits to both feeders, and affected rumen volatile fatty acid profile. Type of CF did not affect meal patterns, ruminal pH, nor fermentation profiles.


Effect of Pranayama on stress and cardiovascular autonomic function.
The stress either physical or mental, leads to cardiovascular morbidity. Newly admitted medical students are likely to be exposed to various stresses like change of environment, demanding medical education and different teaching protocol in a medical college. Pranayama is known since ancient times to relieve stress and stabilize autonomic function of the body. Therefore it was decided to study effect of Pranayama on stress and cardiovascular autonomic function. The subjects were first M.B.B.S students and the sample size was 59 consisting of 27 males and 32 females. The group of students thus selected was briefed about the study. After the orientation session, informed written consent was taken, stress questionnaire was put and the autonomic function tests were done. This was followed by practice of Pranayama for 2 months, 1 hour/day for 5 days/week and again stress questionnaire was put and the autonomic function tests were performed on the study group. The above tests were done before and after the practice of Pranayama. The results obtained were analyzed using SPSS software. The stress level has reduced after 2 months of practicing various pranayama as evident by decrease in total stress score which is highly significant. VLF and LF in n.u have reduced significantly after practice of pranayama signifying reduction in sympathetic drive to heart. HF in n.u has increased significantly after practice of pranayama for 2 months showing the increase in parasympathetic output to the heart. LF/ HF ratio reduced significantly after 2 months of practice of pranayama indicating a better sympatho vagal balance with resting balance tilting toward better parasympathetic control.


Interpretative problems due to the presence of chloromethcathinone isomers in the biological material from postmortem cases.
While many new psychoactive substances often disappear from the drug market rather quickly, some, such as synthetic cathinones (SCs), still remain due to their popularity among users. The current knowledge of SC concentrations in blood samples is based mainly on the published case reports of intoxications or fatalities caused by SC intake. The aim of the present study was to present and interpret the obtained toxicological analysis results of these cases, in which it was possible to determine or detect the presence of one of the isomers of chloromethcathinone (CMC) along with its intake biomarker-dihydro-CMC. These cases include 27 deaths reported at the Department of Forensic Medicine in Kraków in 2016-2022. CMC constitutes a major toxicological opinion challenge, in terms of toxicological evaluation of poisonings. As presented in this paper, a significant problem is its stability in the biological material and practices in the reporting of the obtained data. It is therefore important to monitor potential intake biomarkers that may show greater stability in the biological material than the parent drug. In the case of CMC isomers, the good biomarker of intake is the dihydro-CMC metabolite, which was detected in the blood sample in every case presented, even with the absence of the parent substance. Interpretation of the results obtained for CMC in terms of assessing their toxicity and possible cause of death is difficult. However, it should be taken into account that in cases of new psychoactive substance poisoning, an in-depth risk assessment is mandatory and the opinion of the unpredictability of the effects is taken as a principle.


Acidulated phosphate fluoride application changes the protein composition of human acquired enamel pellicle.
We evaluated, by proteomic analysis, whether the chemical changes provoked on enamel by acidulated phosphate fluoride (APF) application alter the protein composition of acquired enamel pellicle. Enamel slabs, pretreated with distilled water (negative control), phosphoric acid (active control) or APF solution, were immersed in human saliva for pellicle formation. The adsorbed proteins were extracted and analyzed by liquid chromatography-mass spectrometry/mass spectrometry. Fifty-six proteins were identified, 12 exclusive to APF and 11 to phosphoric acid. APF decreased the concentration of histatin-1, but increased the concentration of S100-A9, which is confirmed by immunoblotting. The findings suggest that APF application changes the acquired enamel pellicle composition.


[Impact of different surgical methods of radical cystectomy on the perioperative complications in patients over 75 years].
To analyze the impact of different surgical methods on perioperative complication rate after radical cystectomy in patients over 75 years of age. A retrospective study reviewed 1 432 patients who received radical cystectomy from January 2003 to January 2015. A total of 239 patients were ≥75 years (median age: 78 years), of whom, 74 patients (31.0%) suffered one or more perioperative complications. According to the different operation methods, patients could be divided into ileal conduit group and cutaneous ureterostomy group. The ileal conduit group included laparoscopic and open radical cystectomy with ileal conduit. The cutaneous ureterostomy group included transperitoneal laparoscopic, transperitoneal and extraperitoneal open radical cystectomy with cutaneous ureterostomy. Perioperative complications were significantly associated with the patient's age (P=0.012), American Society of Anesthesiologists (ASA) score (P=0.001), node staging (P=0.043), and different surgical methods. Perioperative complications caused a prolonged hospital stay and delayed recovery (34 d vs. 21 d, P=0.002). For different surgical methods, the perioperative complication rate of ileal conduit was higher than cutaneous ureterostomy (P=0.013). However, there were no significant differences between transperitoneal laparoscopic and open radical cystectomy with ileal conduit in perioperative complication rate (P=0.836). The perioperative complication rate was statistically significant among transperitoneal laparoscopic, transperitoneal and extraperitoneal open radical cystectomy with cutaneous ureterostomy (P=0.022). On multivariate analysis, age (hazard ratio=4.856, 95% CI: 1.465-16.103, P=0.010), ASA score (P=0.008), and different surgical methods (P=0.016) were significantly associated with the perioperative complication rate. The perioperative complication rate after radical cystectomy in elderly patients was associated with the patients' age, ASA score, and different surgical methods. Patients who received extraperitoneal open radical cystectomy with cutaneous ureterostomy suffered fewer perioperative complications, which was an appropriate choice for elderly patients.


Thyroid hormone regulates cardiac performance during cold acclimation in zebrafish (Danio rerio).
Limitations to oxygen transport reduce aerobic scope and thereby activity at thermal extremes. Oxygen transport in fish is facilitated to a large extent by cardiac function so that climate variability may reduce fitness by constraining the performance of the heart. In zebrafish (Danio rerio), thyroid hormone (TH) regulates skeletal muscle function and metabolism in response to thermal acclimation. Here, we aimed to determine whether TH also regulates cardiac function during acclimation. We used propylthiouracil and iopanoic acid to induce hypothyroidism in zebrafish over a 3 week acclimation period to either 18 or 28°C. We found that cold-acclimated fish had higher maximum heart rates and sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity than warm-acclimated fish. Hypothyroid treatment significantly decreased these responses in the cold-acclimated fish, but it did not affect the warm-acclimated fish. TH did not influence SERCA gene transcription, nor did it increase metabolic rate, of isolated whole hearts. To verify that physiological changes following hypothyroid treatment were in fact due to the action of TH, we supplemented hypothyroid fish with 3,5-diiodothryronine (T2) or 3,5,3'-triiodothyronine (T3). Supplementation of hypothyroid fish with T2 or T3 restored heart rate and SERCA activity to control levels. We also show that, in zebrafish, changes in cardiac output in response to warming are primarily mediated by heart rate, rather than by stroke volume. Thus, changes in heart rate are important for the overall aerobic capacity of the fish. In addition to its local effects on heart phenotype, we show that TH increases sympathetic tone on the heart at rest and during maximum exercise. Our findings reveal a new pathway through which fish can mitigate the limiting effects of temperature variability on oxygen transport to maintain aerobic scope and promote thermal tolerance.


A subclassification of multiple opiate receptors by means of selective tolerance development.
The chronic activation of opiate receptors results in the development of tolerance. On theoretical grounds, the appearance of cross-tolerance between different opioids should imply that these compounds exhibit an identical pattern on receptor activation. Tests with isolated tissue preparations, e.g. the guinea-pig ileum, made highly tolerant in vivo to the mu-agonist morphine proved that these were of almost unchanged sensitivity to different types of receptor agonists such as kappa-agonists. Thus, the ability to selectively induce tolerance on particular types of opiate receptors represents a reliable tool for the differentiation and characterization of multiple opiate receptors. Moreover, this technique facilitated the demonstration of subtypes of the already known opiate receptors.


Tumor-induced immunosuppression: a barrier to immunotherapy of large tumors by cytokine-secreting tumor vaccine.
An active immunotherapy strategy with cytokine-assisted tumor vaccine, although often effective for small tumor burdens, is much less so for large tumor burdens. This study examines how large tumors might suppress the T cell functions and escape from the immune responses elicited by a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine. According to our results, the T cells isolated from the tumor-bearing mice treated late with the vaccine failed to confer protective activity on naive mice against a wild-type tumor challenge, unlike those isolated from the early-treated group. Nevertheless, the antitumor activity of the inactive T cells could be restored on in vitro stimulation. Expression of transforming growth factor beta (TGF-beta) and interleukin 10 (IL-10), the potent immunosuppressive factors, was detected in the parental tumor cell line RLmale 1 (a murine T leukemia cell line), as well as in the tumor region, the levels of which correlated with tumor progression. An in vitro assay of T cell functions revealed that the TGF-beta in the conditioned medium of RLmale 1 cells mainly affected the activation, whereas the IL-1male affected the activation to a lesser extent, but significantly affected the cytolytic activity, of tumor-specific T cells. The immunosuppressive activity of IL-10 was also signified by the findings that administration of the conditioned medium of RLmale 1 cultured in a serum-free medium, in which the TGF-beta activity was then lost while the IL-10 activity still remained, or of recombinant IL-10 to the early-treated group of mice abrogated the known efficacy of tumor vaccine on the small tumors. These data suggested that the efficacy of cytokine-secreting tumor vaccine was blocked by the immunosuppressive factors secreted from the large tumors. The results have important implications for the clinical design of immunotherapeutic strategies for advanced cancer patients.


Hepatitis C virus infection and the risk of cancer among elderly US adults: A registry-based case-control study.
Hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC) and subtypes of non-Hodgkin lymphoma (NHL). Associations with other cancers are not established. The authors systematically assessed associations between HCV infection and cancers in the US elderly population. This was a registry-based case-control study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data in US adults aged ≥66 years. Cases (n = 1,623,538) were patients who had first cancers identified in SEER registries (1993-2011). Controls (n = 200,000) were randomly selected, cancer-free individuals who were frequency-matched to cases on age, sex, race, and calendar year. Associations with HCV (documented by Medicare claims) were determined using logistic regression. HCV prevalence was higher in cases than in controls (0.7% vs 0.5%). HCV was positively associated with cancers of the liver (adjusted odds ratio [aOR] = 31.5; 95% confidence interval [CI], 29.0-34.3), intrahepatic bile duct (aOR, 3.40; 95% CI, 2.52-4.58), extrahepatic bile duct (aOR, 1.90; 95% CI, 1.41-2.57), pancreas (aOR, 1.23; 95% CI, 1.09-1.40), and anus (aOR, 1.97; 95% CI, 1.42-2.73); nonmelanoma nonepithelial skin cancer (aOR, 1.53; 95% CI, 1.15-2.04); myelodysplastic syndrome (aOR, 1.56; 95% CI, 1.33-1.83); and diffuse large B-cell lymphoma (aOR, 1.57; 95% CI, 1.34-1.84). Specific skin cancers associated with HCV were Merkel cell carcinoma (aOR, 1.92; 95% CI, 1.30-2.85) and appendageal skin cancers (aOR, 2.02; 95% CI, 1.29-3.16). Inverse associations were observed with uterine cancer (aOR, 0.64; 95% CI, 0.51-0.80) and prostate cancer (aOR, 0.73; 95% CI, 0.66-0.82). Associations were maintained in sensitivity analyses conducted among individuals without documented alcohol abuse, cirrhosis, or hepatitis B or human immunodeficiency virus infections and after adjustment for socioeconomic status. Associations of HCV with other cancers were not observed. HCV is associated with increased risk of cancers other than HCC in the US elderly population, notably bile duct cancers and diffuse large B-cell lymphoma. These results support a possible etiologic role for HCV in an expanded group of cancers. Cancer 2017;123:1202-1211. © 2016 American Cancer Society.


Ribosomal resistance of clinical enterococcal to streptomycin isolates.
The mechanism of high-level resistance to streptomycin was studied in 12 clinical isolates of Streptococcus faecalis. Six strains produced streptomycin-modifying enzymes. Each of three enzyme-negative strains tested demonstrated ribosomal resistance to streptomycin. Lack of ribosomal susceptibility is a significant cause of high-level streptomycin resistance among clinical enterococcal isolates.


Intraoperative arteriography during femoral-popliteal bypass.
Minor technical errors may jeopardize the patency of femoral-popliteal bypass grafts. In an attempt to detect such errors, intraoperative arteriography has been routinely employed. It allows immediate recognition and correction of the most common abnormal findings: intraluminal debris, intimal dissection, distal thrombosis, arterial spasm, and kinking of the graft.


Control of allergic rhinitis and asthma test--a formal approach to the development of a measuring tool.
The concurrent management of allergic rhinitis and asthma (ARA) has been recommended by Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. However, a tool capable of assessing simultaneously the control of upper and lower airways diseases is lacking. To describe the studies conducted to design the control of ARA test (CARAT) questionnaire. We performed a literature review to generate a list of potentially important items for the assessment of control of ARA. A formal consensus development process, that used an innovative web-based application, was designed - 111 experts in ARA and 60 patients participated. At the final consensus meeting, 25 primary and secondary care physicians formulated the questions and response options. A qualitative feasibility study (n = 31 patients) was conducted to evaluate the comprehensibility of the questionnaire while testing two different designs. Thirty-four potentially important items were identified. All the steps of the consensus process were completed in 2.5 months. The opinions of experts and patients lead to the formulation of 17 questions. At the feasibility study the instructions and wording problems were corrected and a semi-tabular format was chosen. A tool to measure the control of allergic rhinitis and asthma was developed using a comprehensive set of methodological steps ensuring the design quality and the face and content validity. Additional validation studies to assess the psychometric properties of the questionnaire have started.


Combination Treatment of Cervical Cancer Using Folate-Decorated, pH-Sensitive, Carboplatin and Paclitaxel Co-Loaded Lipid-Polymer Hybrid Nanoparticles.
Cervical cancer is one of the most common causes of death among women globally. Combinations of cisplatin, paclitaxel, bevacizumab, carboplatin, topotecan, and gemcitabine are recommended as first-line therapies. This study focuses on the development of folate-decorated, pH-sensitive lipid-polymer hybrid nanoparticles (LPNs). Loading carboplatin (CBP) and paclitaxel (PTX), LPNs were expected to combine the therapeutic effects of CBP and PTX, thus show synergistic ability on cervical cancer. FA-CBP/PTX-LPNs showed the sizes of 169.9 ± 5.6 nm, with a narrow size distribution of 0.151 ± 0.023. FA-CBP/PTX-LPNs exhibited pH-responsive drug release, high cellular uptake efficiency (66.7 ± 3.1%), and prominent cell inhibition capacity (23 ± 1.1%). In vivo tumor distribution and tumor inhibition efficiency of FA-CBP/PTX-LPNs was the highest, with no obvious body weight lost. High tumor distribution and remarkable antitumor efficiency obtained using in vitro as well as in vivo models further proved the FA-CBP/PTX-LPNs is a promising tool for cervical cancer therapy.


[Comparative study of American tegumentary leishmaniasis between childhood and teenagers from the endemic areas Buriticupu, Maranhao and Corte de Pedra, Bahia, Brazil].
A comparative study on children aged 0-15 years, with American tegumentary leishmaniasis (ATL), in the endemic regions of Buriticupu (MA) and Corte de Pedra (BA), whereby 214 cases were detected between 1982 and 1993, 78 (36.4%) of them originated from Corte de Pedra and 136 (63.6%) from Buriticupu. In Corte de Pedra, most cases were observed in patients aged between 0-5 years. Twenty nine (37.2%) cases; 62% of those were male. In the Buriticupu region, 88 (64.7%) cases occurred in patients of 11-15 years of age, where in 73.8% consisted of male. In both researched regions, brunetts were predominant, with a ratio of 65.4% in Corte de Pedra and 75% in Buriticupu. Twenty six (33.3%) children in the village of Corte de Pedra were farmers, predominantly male (57.7%), generating statistical significance (chi 2 = 11.21). Twenty one (80.8%) farmers were aged 11-15 years. Thirty seven and a half per cent of the children from Buriticupu were students, however, 41 (30.2%) were farmers, representing 39 (44.3%) cases; all of them male. Both in Buriticupu and Corte de Pedra, the unique wound was predominant, corresponding to 57.7% and 53.7%, respectively. The wounding time stood out from one to three months, with 45 (69.2%) cases in Corte de Pedra and 73 (61%) in Buriticupu (chi 2 = 11.82). As to the wound locations, it has been observed that they were most constantly present on the lower limbs, with 77.2% in Corte de Pedra and 58.9% in Buriticupu (chi 2 = 27.9). The cutaneous case mostly found in Corte de Pedra was the ulcerous one (91%). IDRM was positive in 61 (78.2%) children originated from Corte de Pedra, wherein no statistical difference was detected between age ratio and positivity of the test (chi 2 = 0.0669).


Expression of human NAD(P)H: quinone oxidoreductase (DT-diaphorase) in Chinese hamster ovary cells: effect on the toxicity of antitumor quinones.
Previous studies have indicated that NAD(P)H: quinone oxidoreductase [DT-diaphorase (NQO1)] plays an important role in the bioreductive activation of quinone-containing antitumor agents. Although these studies demonstrated that purified NQO1 can reduce these compounds in vitro, the importance of NQO1 in the intracellular activation of quinone-containing antitumor agents remains controversial. In our study, we transfected human NQO1 into Chinese hamster ovary cells that do not normally express NQO1 activity and obtained stable clones that expressed NQO1 activity of 19-3527 nmol of 2,6-dichlorophenolindophenol reduced/min/mg of protein. The level of NQO1 expression correlated with an increased killing by streptonigrin, EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)-propen ol), and 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone, but mitomycin C sensitivity was independent of this activity. NQO1 expression also led to a slight decrease in the sensitivity of cells to menadione. Our data demonstrate that compounds that are efficient substrates for NQO1 in vitro are also bioactivated in cultured mammalian cells when they are transfected with human NQO1. These results are consistent with the relative abilities of mitomycin C, streptonigrin, EO9, and 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone to serve as substrates for bioreduction by human NQO1, and show that NQO1 levels are not necessarily predictive in terms of sensitivity to mitomycin C.


Skin darkening, a potential social signal in subordinate arctic charr (Salvelinus alpinus): the regulatory role of brain monoamines and pro-opiomelanocortin-derived peptides.
Arctic charr were allowed to interact in groups of three for 5 days. Skin darkness was quantified by measuring the mean brightness of individual fish before and after social interaction. Brain levels of monoamines and monoamine metabolites and plasma concentrations of cortisol, adrenocorticotropic hormone (ACTH), N-acetyl-(beta)-endorphin and alpha-melanocyte-stimulating hormone (alpha-MSH) were analysed. The results show that social subordination resulted in a significant skin darkening. Furthermore, plasma concentrations of alpha-MSH, ACTH and cortisol were elevated in subordinates, and these fish also displayed elevated levels of 5-hydroxyindoleacetic acid (5-HIAA) in the telencephalon. The ratio of [5-HIAA] to serotonin [5-HT] was increased in several brain areas. In addition, the ratio of 3-methoxy-4-hydroxyphenylglycol (MHPG) to norepinephrine (NE) concentrations was significantly increased in the optic tectum of subordinate fish. Skin darkness following social interaction showed a significant positive correlation with plasma levels of alpha-MSH. Plasma levels of ACTH and alpha-MSH were both positively correlated with that of cortisol. Brain [5-HIAA]/[5-HT] ratios were positively correlated with circulating plasma levels of ACTH, and a similar positive correlation was seen between [MHPG]/[NE] ratios in the optic tectum and plasma levels of ACTH, alpha-MSH and N-acetyl-beta-endorphin. In contrast, hypothalamic [MHPG]/[NE] ratios displayed a negative correlation with plasma alpha-MSH concentrations. The present study demonstrates that social stress induces skin darkening in Arctic charr and that this effect could be mediated by a stress-induced increase in the levels of alpha-MSH in the circulation. Furthermore, the results suggest that 5-HT and NE in the central nervous system could be factors regulating the pituitary release of ACTH and alpha-MSH.


The role of the pituitary-adrenocortical axis in reflex responses of the adrenal medulla of the dog.
1. The release of catecholamines from the adrenal medulla, in response to carotid body hypoxia, may outlast the stimulus by more than 30 min. 2. After denervation of the adrenal gland the immediate release of catecholamines in response to carotid hypoxia is abolished, but the prolonged release remains. 3. The prolonged release of catecholamines is abolished by cycloheximide. 4. Both corticotrophin in vivo and hydrocortisone in the isolated perfused adrenal gland release adrenomedullary catecholamines. 5. It is concluded that a component of the response of the adrenal medulla to carotid body hypoxia is mediated by corticotrophin and corticosteroid release.


Gender and ethnic/racial disparities in health care utilization among older adults.
We examine the role of economic access in gender and ethnic/racial disparities in the use of health services among older adults. Data from the 1993-1995 study on the Asset of Health Dynamics Among the Oldest Old (AHEAD) were used to investigate differences in the 2-year use of health services by gender and among non-Hispanic White versus minority (Hispanic and African American) ethnic/racial groups. Analyses account for predisposing factors, health needs, and economic access. African American men had fewer physician contacts; minority and non-Hispanic White women used fewer hospital or outpatient surgery services; minority men used less outpatient surgery; and Hispanic women were less likely to use nursing home care, compared with non-Hispanic White men, controlling for predisposing factors and measures of need. Although economic access was related to some medical utilization, it had little effect on gender/ethnic disparities for services covered by Medicare. However, economic access accounted for minority disparities in dental care, which is not covered by Medicare. Medicare plays a significant role in providing older women and minorities access to medical services. Significant gender and ethnic/racial disparities in use of medical services covered by Medicare were not accounted for by economic access among older adults with similar levels of health needs. Other cultural and attitudinal factors merit investigation to explain these gender/ethnic disparities.


Fungal spores and pollen are correlated with meteorological variables: effects in human health at Hermosillo, Sonora, Mexico.
We conducted the first study of air pollen and fungal spores for Hermosillo, Sonora, where the human population is exposed to high temperatures and high levels of dust and suffers from diseases related to air quality. We sampled pollen and fungal spores daily in the air during 2016 using a volumetric spore trap Hirst-type sampler. We used simple linear correlation to investigate the association between pollen and spore counts and daily weather conditions. We found an Annual Pollen Integral of 16,243 pollen day/m3 and an Annual Spore Integral higher 222,365 spore day/m3. We identified 32 pollen taxa and 15 different spores. We found two periods of higher pollen and spore concentrations: March to May and August to October, the latter was the most severe. Spore and pollen concentrations in the air increased at higher temperature and higher relative humidity but decreased at higher precipitation. We detected negative impacts during summer and fall on population health, with 13,454 cases of people who presented diseases related to allergies. A peak in allergies is centered during October and correlates well with our peaks in pollen and spore concentrations; it seems that pollen of Poaceae is the one that generates most effects in allergic people.


Botulinum neurotoxin for the treatment of migraine and other primary headache disorders.
Clinical data and experience to date have demonstrated that BoNT-A is an effective and well-tolerated therapy for the prevention of migraine and other headache disorders. It has a long duration of action that may last over 4 months with no systemic or serious AEs. Several issues remain to be defined, however, including dosing, location, and number of injections; optimal dilution of BoNT-A; specific headache types that respond best to BoNT-A; and long-term efficacy and safety. Data from ongoing well-designed trials that include a larger patient population investigating these issues may confirm a role for BoNT-A as a first-line agent for migraine prevention. Neurotoxin therapy is part of a broader headache management approach. Because the injection techniques for headache are unique and vary depending on the primary headache disorder being treated and the location and pattern of pain referral, the use of BoNT-A for headache is not simply an extension of its use for cosmesis. The use of BoNT-A in the overall management of primary headache disorders should be reserved for medical practitioners who not only have experience with BoNT-A injections, but possess the expertise in the diagnosis and management of complex headache disorders. Educating patients and addressing headache triggers and optimizing acute treatment improve the outcome of any preventive program.


Co-translational assembly pathways of nuclear multiprotein complexes involved in the regulation of gene transcription.
Most factors that regulate gene transcription in eukaryotic cells are multimeric, often large, protein complexes. The understanding of the biogenesis pathways of such large and heterogeneous protein assemblies, as well as the dimerization partner choice among transcription factors, is crucial to interpret and control gene expression programs and consequent cell fate decisions. Co-translational assembly (Co-TA) is thought to play key roles in the biogenesis of protein complexes by directing complex formation during protein synthesis. In this review we discuss the principles of Co-TA with a special focus for the assembly of transcription regulatory complexes. We outline the expected molecular advantages of establishing co-translational interactions, pointing at the available, or missing, evidence for each of them. We hypothesize different molecular mechanisms based on Co-TA to explain the allocation "dilemma" of paralog proteins and subunits shared by different transcription complexes. By taking as a paradigm the different assembly pathways employed by three related transcription regulatory complexes (TFIID, SAGA and ATAC), we discuss alternative Co-TA strategies for nuclear multiprotein complexes and the widespread - yet specific - use of Co-TA for the formation of nuclear complexes involved in gene transcription. Ultimately, we outlined a series of open questions which demand well-defined lines of research to investigate the principles of gene regulation that rely on the coordinated assembly of protein complexes.


Maternal Obesity and Its Associated Factors and Outcomes in Klang Valley, Malaysia: Findings from National Obstetric Registry.
Maternal obesity presents significant health risks to mothers and their fetuses. This study aimed to determine the proportion, associated factors and outcomes of maternal obesity among pregnant women in Klang Valley, Malaysia. A retrospective cross-sectional study was conducted between January 2018 and March 2018 using secondary data from the Malaysian National Obstetric Registry (NOR) for the year 2015. All pregnant women with first-trimester booking at 12 weeks and below that were registered with the NOR and met the inclusion and exclusion criteria were included in the study. Descriptive statistics and multiple logistic regression analysis were used. Data were analysed using SPSS version 22.0. A total of 2113 respondents were included in this study to determine the proportion, associated factors and outcomes of maternal obesity. Regarding the univariate and multivariate analyses, respondents were classified into two groups: normal and obese. The obese group comprised overweight and obese mothers. The underweight group was excluded in the subsequent analysis. Out of the 2113 respondents, 7.1% were underweight, 41.7% were of normal weight, 28.6% were overweight, 15.9% were in obese class I, 4.6% were in obese class II, and 2.1% were in obese class III according to the WHO (1995) reference. However, when the MOH (2003) cutoff point was used, there was a marked increase in the proportion of respondents in the overweight categories by 2.7% and obesity class I by 12.8%. The Indian (AdjOR 2.06, 95% CI: 1.11, 3.83, p=0.021) and Malay (AdjOR 1.75, 95% CI: 1.02, 3.00, p=0.040) ethnicities, as well as both multiparity (AdjOR 1.46, 95% CI: 1.23, 1.73, p <0.001) and grand multiparity (AdjOR 2.41, 95% CI: 1.78, 3.26, p <0.001), were significantly associated with maternal obesity. There were significant association between maternal obesity with hypertensive disorder in pregnancy (p=0.025), caesarean section delivery (p=0.002) and macrosomic infant (p <0.001). The identification of risk factors for maternal obesity is important to facilitate intervention programmes focused on improving the pregnancy outcomes for a high-risk group of women.


LC-MS based plant metabolic profiles of thirteen grassland species grown in diverse neighbourhoods.
In plants, secondary metabolite profiles provide a unique opportunity to explore seasonal variation and responses to the environment. These include both abiotic and biotic factors. In field experiments, such stress factors occur in combination. This variation alters the plant metabolic profiles in yet uninvestigated ways. This data set contains trait and mass spectrometry data of thirteen grassland species collected at four time points in the growing season in 2017. We collected above-ground vegetative material of seven grass and six herb species that were grown in plant communities with different levels of diversity in the Jena Experiment. For each sample, we recorded visible traits and acquired shoot metabolic profiles on a UPLC-ESI-Qq-TOF-MS. We performed the raw data pre-processing in Galaxy-W4M and prepared the data for statistical analysis in R by applying missing data imputation, batch correction, and validity checks on the features. This comprehensive data set provides the opportunity to investigate environmental dynamics across diverse neighbourhoods that are reflected in the metabolomic profile.


Ultrastructure of bovine oocytes exposed to Taxol prior to OPS vitrification.
Our objective was to document potential subcellular consequences of treatment with the microtubule stabilizer Taxol with or without subsequent vitrification of cow and calf oocytes by the open pulled straw (OPS) method. Oocytes were divided into four experimental groups for cows and four groups for calves: (1) a control group fixed immediately after maturation; (2) an OPS group cryopreserved by conventional OPS; (3) a Taxol/CPA group exposed to 1 microM Taxol and cryoprotective agents (CPAs); and (4) a Taxol/OPS group vitrified by OPS including 1 microM Taxol to the vitrification solution. All oocytes were processed for light and transmission electron microscopy. The main injuries were observed on the metaphase plate and the spindle. In control oocytes, the metaphase appeared as condensed chromosomes arranged in a well-organized metaphase plate and the spindle showed well organized microtubules in both cow and calf oocytes. However, in cow OPS oocytes, the metaphase plate was disorganized into scattered chromosomes or the chromosomes were condensed into a single block of chromatin. In addition, microtubules were not organized as typical spindles. In contrast, cow Taxol/OPS oocytes as well as both cow and calf Taxol/CPAs oocytes showed well-organized metaphase plates and normal spindle morphology. All calf OPS and calf Taxol/OPS oocytes displayed a single block of chromatin and no microtubules could be observed around the chromosomes. In conclusion, treatment with 1 microM Taxol before and during vitrification did not induce adverse changes in the oocyte cytoplasm or metaphase spindles in adult bovine oocytes, but stabilized the metaphase and spindle morphology.


New choices for central venous catheters: potential financial implications.
To determine the cost-effectiveness of the newer antiseptic and antibiotic-impregnated central venous catheters (CVCs) relative to uncoated CVCs and to each other. Decision model analysis of the cost and efficacy of CVCs coated with either chlorhexidine silver sulfadiazine (CSS) or rifampin-minocycline (RM) at preventing catheter-related bloodstream infections (CRBSIs). The primary outcome is the incremental cost (or savings) to prevent one additional CRBSI. Model estimates are derived from prospective trials of the CSS and RM CVCs and from other studies describing the costs of CRBSIs. Hypothetical cohort of 1,000 patients requiring placement of a CVC. In the model, patients were managed with either an uncoated CVC, CSS CVC, or RM CVC. The incremental cost-effectiveness of the treated CVCs was calculated as the savings resulting from CRBSIs averted less the additional costs of the newer devices. Sensitivity analysis of the effect of the major clinical inputs was performed. For the base case analysis, we assumed the incidence of CRBSIs was 3.3% with traditional catheters and that the CSS and RM CVC conferred a relative risk reduction for the development of CRBSIs of 60% and 85%, respectively. Despite their significantly higher cost than older catheters, both novel CVCs yield significant savings. Employing either of the treated CVCs saves approximately $10,000 per CRBSI prevented (relative to standard catheters). Comparing the RM CVC to the CSS CVC revealed the RM product to be economically superior, saving nearly $9,600 per CRBSI averted and $81 per patient in the cohort. For sensitivity analysis, we adjusted all model variables by 50% individually and then simultaneously. This demonstrated the model to be most sensitive to the cost of a CRBSI; however, with all inputs skewed by 50% against both the CSS CVC and the RM CVC, these devices remained economically attractive. Under this scenario, use of either treated device was less costly. Utilization of antiseptic and antibiotic-impregnated CVCs represent an attractive alternative for the prevention of CRBSIs and may lead to significant savings. Of the two newer, coated devices, the RM CVC performs better financially. These observations hold over a range of estimates for our model inputs.


International variation in ethics and contract approval processes for a low-risk observational study of mechanical ventilation discontinuation practices.
To describe international variation in ethics and contract processes, identify predictors of approval times, and reasons for nonparticipation in an international observational study of ventilation discontinuation practices. A nested cross-sectional survey of research personnel at 111 participating sites (representing 142 intensive care units [ICUs]) from six geographic regions (Canada, India, the United Kingdom, Europe, Australia/New Zealand, and the United States). We analyzed responses from 80 sites (72.1% response rate). A single local or central approval was required at 34/80 (42.5%) and 23/80 (28.75%), respectively. Of those requiring central ethics approval, 20/23 (87.0%) sites required an additional approval. Sites with central vs. other ethics approval processes had significantly longer times to ethics approval (176 vs. 42 days; P < 0.0001). The median time to contract execution was 140 days (range: 11-1,215) with sites in India and the United States having the shortest and longest times to contract execution, respectively. We did not identify independent predictors of approval times. Of 190 sites that initially agreed to participate, 78 (41%) sites (89 ICUs) were ultimately unable to participate. International ethics and contract approval times were lengthy and highly variable. Central ethics review processes significantly increased approval times.


Electronic properties of p-xylylene and p-phenylene chains subjected to finite bias voltages: a new highly conducting oligophenyl structure.
Recently, experimental and theoretical determination of electric currents induced by finite bias voltages in p-xylylene chains attached to gold contacts revealed higher conductance of these systems in comparison with p-phenylene homologous chains. To gain more insight into the conducting properties of these oligophenyl structures, ab initio studies were carried out on the electronic properties of two different p-xylylene-like chains (pX1 and pX2) and the p-phenylene (pP) chain attached to gold contacts, with molecular formulas AuCH2 (C6 H4 )n CH2 Au (n=1-5), Au2 C(C6 H4 )n CAu2 (n=1-5), and Au(C6 H4 )n Au (n=1-5), respectively. The molecules were subjected to finite bias voltages ranging from 0 to 5 V. Analysis of the intramolecular electron transfer and electron delocalization revealed a completely opposite response to electric perturbation of pX2 in comparison with pX1 and pP. Thus, in pX2 the applied voltage causes an increase in the electron delocalization within the rings together with a large electron transfer and energetic stabilization. On the contrary, the same voltages partially destroy the electron delocalization in pX1 and pP, produce a large local electron polarization in the benzene rings, and a smaller energetic stabilization. These differences can be rationalized in terms of the role played by polarized valence bond structures in the total wave function. Theoretical estimation of the I/V profiles indicates that pX2 chains are much better electronic conductors than pX1 and pP.


Weekly topotecan in a heavily pretreated patient with peritoneal papillary serous adenocarcinoma.
Peritoneal papillary serous adenocarcinoma is a rare müllerian tumor type that is histologically similar to ovarian serous carcinoma. The low incidence of peritoneal papillary serous adenocarcinoma has hindered the establishment of a standard of care for this disease. A 56-year-old woman, who had undergone an abdominal hysterectomy 25 years earlier, presented with a vaginal nodule and palpable pelvic mass. She underwent debulking surgery and was diagnosed with stage IIIC peritoneal papillary serous adenocarcinoma. After 6 cycles of paclitaxel/carboplatin and 10 cycles of liposomal doxorubicin/cyclophosphamide, laparotomy revealed microscopic disease. This heavily pretreated patient then started topotecan therapy (1.0 mg/m(2)/day, x 5 days). After several dosing adjustments because of fatigue and malaise, weekly topotecan 4.0 mg/m(2) was determined to be the best-tolerated dosage. The patient ultimately received 14 weekly cycles of topotecan. After 12 weekly cycles, she achieved a complete response, which was maintained for 25 weeks with weekly topotecan therapy with a subsequent recurrence. Topotecan was reinstated. She maintains a disease-free interval of 58 weeks. Weekly topotecan demonstrated antitumor activity and was well tolerated in a patient with recurrent peritoneal papillary serous adenocarcinoma.


Searching for Missing Binary Equiatomic Phases: Complex Crystal Chemistry in the Hf-In System.
There remain 21 systems (out of over 3500 possible combinations of the elements) in which the existence of the simple binary equiatomic phases AB has not been established experimentally. Among these, the presumed binary phase HfIn is predicted to adopt the tetragonal CuAu-type structure (space group P4/ mmm) by a recently developed machine-learning model and by structure optimization through global energy minimization. To test this prediction, the Hf-In system was investigated experimentally by reacting the elements in a 1:1 stoichiometry at 1070 K. Under the conditions investigated, the bulk and surface of the sample correspond to different crystalline phases but have nearly the same equiatomic composition, as revealed by energy-dispersive X-ray analysis. The structure of the bulk sample, which was solved from powder X-ray diffraction data through simulated annealing, corresponds to the γ-brass (Cu5Zn8) type (space group I4̅3 m) with Hf and In atoms disordered over four sites. The structure of crystals selected from the surface, which was solved using single-crystal X-ray diffraction data, corresponds to the CuPt7 type (space group Fm3̅ m) with Hf and In atoms partially disordered over three sites. The discrepancy between the predicted CuAu-type structure and the two experimentally refined crystal structures is reconciled through close inspection of structural relationships, which reveal that the γ-brass-type structure of the bulk HfIn phase is indeed derived through small distortions and defect formation within the CuAu-type structure.


[Myocardial infarction in the adult under 35 years of age].
Infarction in the adult aged less than 35 is almost always accompanied by risk factors, the most common of which are tobacco abuse, lipid disturbances, obesity, a strong family history of cardiovascular disease and, in the woman, the use of contraceptives. The coronary arteries are sometimes normal (10-15 p. cent) but coronary lesions are most often single vessel, proximal and affect the anterior interventricular branch. Actual coronary thrombosis probably plays a more important role than in the older adult. Ventricular function is often markedly impaired. The infarct is most often anterior, transmural and large in size, with ventricular arrhythmias more frequent and a higher risk of sudden death. Post-hospital complications are the same as in the older adult, with possibly less good results of aorto-coronary venous bypasses. Long term mortality depends directly upon the number of vessels affected, but is markedly better than in the older adult.


Genetic organization, length conservation, and evolution of RNA polymerase II carboxyl-terminal domain.
With a simple tandem iterated sequence, the carboxyl terminal domain (CTD) of eukaryotic RNA polymerase II (RNAP II) serves as the central coordinator of mRNA synthesis by harmonizing a diversity of sequential interactions with transcription and processing factors. Despite intense research interest, many key questions regarding functional and evolutionary constraints on the CTD remain unanswered; for example, what selects for the canonical heptad sequence, its tandem array across organismal diversity, and constant CTD length within given species and finally and how a sequence-identical, repetitive structure can orchestrate a diversity of simultaneous and sequential, stage-dependent interactions with both modifying enzymes and binding partners? Here we examine comparative sequence evolution of 58 RNAP II CTDs from diverse taxa representing all six major eukaryotic supergroups and employ integrated evolutionary genetic, biochemical, and biophysical analyses of the yeast CTD to further clarify how this repetitive sequence must be organized for optimal RNAP II function. We find that the CTD is composed of indivisible and independent functional units that span diheptapeptides and not only a flexible conformation around each unit but also an elastic overall structure is required. More remarkably, optimal CTD function always is achieved at approximately wild-type CTD length rather than number of functional units, regardless of the characteristics of the sequence present. Our combined observations lead us to advance an updated CTD working model, in which functional, and therefore, evolutionary constraints require a flexible CTD conformation determined by the CTD sequence and tandem register to accommodate the diversity of CTD-protein interactions and a specific CTD length rather than number of functional units to correctly order and organize global CTD-protein interactions. Patterns of conservation of these features across evolutionary diversity have important implications for comparative RNAP II function in eukaryotes and can more clearly direct specific research on CTD function in currently understudied organisms.


A century of observations reveals increasing likelihood of continental-scale compound dry-hot extremes.
Using over a century of ground-based observations over the contiguous United States, we show that the frequency of compound dry and hot extremes has increased substantially in the past decades, with an alarming increase in very rare dry-hot extremes. Our results indicate that the area affected by concurrent extremes has also increased significantly. Further, we explore homogeneity (i.e., connectedness) of dry-hot extremes across space. We show that dry-hot extremes have homogeneously enlarged over the past 122 years, pointing to spatial propagation of extreme dryness and heat and increased probability of continental-scale compound extremes. Last, we show an interesting shift between the main driver of dry-hot extremes over time. While meteorological drought was the main driver of dry-hot events in the 1930s, the observed warming trend has become the dominant driver in recent decades. Our results provide a deeper understanding of spatiotemporal variation of compound dry-hot extremes.