Reconstituting protein interaction networks using parameter-dependent domain-domain interactions.
We can describe protein-protein interactions (PPIs) as sets of distinct domain-domain interactions (DDIs) that mediate the physical interactions between proteins. Experimental data confirm that DDIs are more consistent than their corresponding PPIs, lending support to the notion that analyses of DDIs may improve our understanding of PPIs and lead to further insights into cellular function, disease, and evolution. However, currently available experimental DDI data cover only a small fraction of all existing PPIs and, in the absence of structural data, determining which particular DDI mediates any given PPI is a challenge. We present two contributions to the field of domain interaction analysis. First, we introduce a novel computational strategy to merge domain annotation data from multiple databases. We show that when we merged yeast domain annotations from six annotation databases we increased the average number of domains per protein from 1.05 to 2.44, bringing it closer to the estimated average value of 3. Second, we introduce a novel computational method, parameter-dependent DDI selection (PADDS), which, given a set of PPIs, extracts a small set of domain pairs that can reconstruct the original set of protein interactions, while attempting to minimize false positives. Based on a set of PPIs from multiple organisms, our method extracted 27% more experimentally detected DDIs than existing computational approaches. We have provided a method to merge domain annotation data from multiple sources, ensuring large and consistent domain annotation for any given organism. Moreover, we provided a method to extract a small set of DDIs from the underlying set of PPIs and we showed that, in contrast to existing approaches, our method was not biased towards DDIs with low or high occurrence counts. Finally, we used these two methods to highlight the influence of the underlying annotation density on the characteristics of extracted DDIs. Although increased annotations greatly expanded the possible DDIs, the lack of knowledge of the true biological false positive interactions still prevents an unambiguous assignment of domain interactions responsible for all protein network interactions.Executable files and examples are given at: http://www.bhsai.org/downloads/padds/


Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.
Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.


A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria.
To broadly explore mitochondrial structure and function as well as the communication of mitochondria with other cellular pathways, we constructed a quantitative, high-density genetic interaction map (the MITO-MAP) in Saccharomyces cerevisiae. The MITO-MAP provides a comprehensive view of mitochondrial function including insights into the activity of uncharacterized mitochondrial proteins and the functional connection between mitochondria and the ER. The MITO-MAP also reveals a large inner membrane-associated complex, which we term MitOS for mitochondrial organizing structure, comprised of Fcj1/Mitofilin, a conserved inner membrane protein, and five additional components. MitOS physically and functionally interacts with both outer and inner membrane components and localizes to extended structures that wrap around the inner membrane. We show that MitOS acts in concert with ATP synthase dimers to organize the inner membrane and promote normal mitochondrial morphology. We propose that MitOS acts as a conserved mitochondrial skeletal structure that differentiates regions of the inner membrane to establish the normal internal architecture of mitochondria.


Community nurses and chronic disease in Israel: Professional dominance as a social justice issue.
Chronic diseases are major causes of health inequalities. Community nurses can potentially make large contributions to chronic illness prevention and management in Israel but may be obstructed by professional dominance of physicians. However, insufficient research exists about community nursing in Israel, and how it may differ from other countries. This study aims to document chronic disease-related community nursing roles in Israel, identify changes and trends in community nursing roles that may increase social justice, and understand how the roles and trends in community health nursing in Israel may differ from developments in other countries. In-depth interviews were performed with 55 Israeli health system professionals, and 692 nurse care-givers were asked open-ended questions. Interview answers were analyzed to find themes and trends. The study found that community nurse roles in Israel have expanded, especially for chronic disease control. Commonalities exist with countries such as the United States and the UK, albeit with important differences. However, continued conflicts with physicians exist, which can limit nurses' contributions to reducing health inequalities. Community nurses' importance is growing. Enabling them to overcome professional dominance and improve chronic disease control can help reduce health inequalities in Israel and elsewhere.


[Genetic risk factors of thrombosis].
Genetic risk factors became a frequent predisposing cause of venous thromboembolism (VTE) since the discovery of two mutations: factor V Leiden and G20210A mutation of prothrombin gene. One of these both mutations is associated with around 25% of VTE events. Interaction of genetic risk factors, such as interaction of FV Leiden or G20210A mutation of prothrombin with antithrombin, protein C or protein S deficiencies, as well as interaction with acquired risk factors, have demonstrated that venous thrombosis is a multifactorial disease. The search for thrombophilia must be done in VTE occurring before the age of 45, in case of recurrencies and in case of familial history of VTE.


[Residual stomach, duodenum, and continual jejunal interposition after subtotal gastrectomy].
To investigate the clinical effect of residual stomach, duodenum, and continual jejunal interposition on the patients of gastric cancer after subtotal gastrectomy. Fifty-four patients with gastric cancer after subtotal gastrectomy were randomly divided into 2 groups: Group A (n = 26, receiving digestive tract reconstruction by manual end-to-side anastomosis of residual stomach and jejunum, end-to-side anastomosis of residual duodenum and jejunum, and side-to-side anastomosis of jejunum and jejunum, then the jejunum proximal to the stomach-jejunum anastomosis and the jejunum distal to the duodenum-jejunum anastomosis were ligated so as to form an integral continual jejunal interposition; and Group B (n = 28, receiving Bilroth digestive tract reconstruction. The operation time, body weight, prognosis nutrition index (PNI), and Visick score 3 and 6 months after the operation were observed. All patients recovered quickly and no complicating anastomosis leakage and obstruction was found. It took 53 +/- 9 minutes to finish the reconstruction in Group A, significantly shorter than that in Group B (57 +/- 6 minutes, t = -2.145, P = 0.037). The body weight and PNI of both groups decreased significantly 3 months after the operation in comparison with those before the operation (both P < 0.05). The body weight and PNI of Group A returned to the levels before operation. Although the body weight and PNI of Group B recovered to some extent 6 months after operation, they remained significantly lower than those before operation both P < 0.05). The Visick score 6 months after operation of Group A was superior to that of Group B (t = 2.1 P < 0.05). Residual stomach, duodenum, and continual jejunal interposition after subtotal gastrectomy helps overcome the difficulty in the procedure of digestive tract reconstruction and restore the physiological passage through duodenum, thus avoiding reflux and improving patients' quality of life.


Cloning and inactivation of genes encoding ferredoxin- and NADH-dependent glutamate synthases in the cyanobacterium plectonema boryanum. Imbalances In nitrogen and carbon assimilations caused by deficiency of the ferredoxin-dependent enzyme
Glutamate synthase (GOGAT) is a key enzyme in the assimilation of inorganic nitrogen in photosynthetic organisms. We found that, like higher plants, the facultative heterotrophic cyanobacterium Plectonema boryanum had ferredoxin (Fd)- and NADH-dependent GOGATs. The genes glsF, gltB, and gltD were cloned, and structural analyses and target mutageneses demonstrated that glsF encoded Fd-GOGAT and that gltB and gltD encoded the two subunits of NADH-GOGAT. All three mutants lacking one of the GOGAT genes were able to grow photosynthetically and heterotrophically. However, the Fd-GOGAT mutant exhibited a phenotype of marked nitrogen deficiency when grown under conditions of saturating illumination and CO2 supply. In these conditions the rate of the ammonia uptake from the culture medium was slower in the Fd-GOGAT mutant than in the wild type or in the NADH-GOGAT mutant, but no significant differences were found in the rate of the CO2 fixation-dependent O2 evolution among these strains. Our results suggest that, although both Fd- and NADH-GOGATs were operative in the cells growing in light, the contribution of Fd-GOGAT, which directly utilizes photoreducing power for the catalytic reaction, is essential for balancing photosynthetic nitrogen and carbon assimilation.


The work environment of haemodialysis nurses and its mediating role in burnout.
The work environment can contribute to the occurrence of nurses' burnout. This study assessed the work environment of haemodialysis nurses and the extent of burnout they have suffered, and it explored the connection between work environment and burnout. A multicentre cross-sectional study was conducted in 53 public, hospital-based haemodialysis units in Greece. A total of 537 haemodialysis nurses participated. The majority consisted of females (90.8%) who possessed a university degree or a degree from a technological institute (72.6%). They had an average of 15 years of experience in dialysis. The Practice Environment Scale of the Nursing Work Index and the Copenhagen Burnout Inventory (CBI) were used. The demographic characteristics of the participants were also collected. Although the nurses rated their work environment as healthy, they were experiencing a moderate degree of burnout. The multivariate linear regression analysis with the CBI scales as dependent variables was applied. The increased nurses' participation in hospital affairs was associated with decreased personal (coefficient β = -9.4, 95% confidence interval [CI] = -17.4 to -1.3, p = 0.023), work-related (coefficient β = -12.9, 95% CI = -22.5 to -3.5, p = 0.008) and patient-related burnout (coefficient β = -15.9, 95% CI = -24.5 to -7.4, p = < 0.001). The better collegial nurse-physician relationships were associated with decreased personal (coefficient β = -10.7, 95% CI = -18.3 to -3.0, p = .007) and work-related burnout (coefficient β = -15.1, 95% CI = -23.3 to -7.0, p = < 0.001). The work environment of haemodialysis nurses was associated with burnout. Its improvement is an important tool in administrations' effort to ensure the nursing staff's well-being.


Nanophotothermolysis of multiple scattered cancer cells with carbon nanotubes guided by time-resolved infrared thermal imaging.
Nanophotothermolysis with long laser pulses for treatment of scattered cancer cells and their clusters is introduced with the main focus on real-time monitoring of temperature dynamics inside and around individual cancer cells labeled with carbon nanotubes. This technique utilizes advanced time- and spatially-resolved thermal radiometry imaging for the visualization of laser-induced temperature distribution in multiple-point absorbing targets. The capability of this approach was demonstrated for monitoring of thermal effects under long laser exposure (from millisecond to seconds, wavelength 1,064 nm, maximum power 1 W) of cervical cancer HeLa cells labeled with carbon nanotubes in vitro. The applications are discussed with a focus on the nanophotothermolysis of small tumors, tumor margins, or micrometastases under the guidance of near-IR and microwave radiometry.


Geochemistry of the lunar highlands as revealed by measurements of thermal neutrons.
Thermal neutron emissions from the lunar surface provide a direct measure of bulk elemental composition that can be used to constrain the chemical properties of near-surface (depth <1 m) lunar materials. We present a new calibration of the Lunar Prospector thermal neutron map, providing a direct link between measured count rates and bulk elemental composition. The data are used to examine the chemical and mineralogical composition of the lunar surface, with an emphasis on constraining the plagioclase concentration across the highlands. We observe that the regions of lowest neutron absorption, which correspond to estimated plagioclase concentrations of >85%, are generally associated with large impact basins and are colocated with clusters of nearly pure plagioclase identified with spectral reflectance data.


Label-free imaging of redox status and collagen deposition showing metabolic differences in the heart.
The heart has high metabolic demand to maintain function. The primary source of energy supply to support correct contractile muscle function differs between a fetus and an adult. In fetal life, ATP is primarily generated by glycolysis and lactate oxidation, whereas following birth, there is a shift towards a reliance on mitochondrial metabolism and fatty acid oxidation. This change in metabolic status is an adaptation to different fuel availability, oxygenation and growth patterns. In this study, we have employed 2-photon excitation fluorescence microscopy to define the relationship between two critical metabolic cofactors nicotinamide adenine dinucleotide(P)H and flavin adenine dinucleotide, effectively utilizing a redox ratio to differentiate between the metabolic status in fetal (proliferative) and adult (quiescent/hypertrophic) hearts. Two-photon imaging was also used to visually confirm the known increase in collagen deposition in the adult heart. The changes observed were consistent with a hypertrophic growth profile and greater availability of fatty acids in the adult heart, compared to the proliferative fetal heart. Two-photon excitation fluorescence microscopy is therefore a convenient imaging technology that enables the monitoring of striated muscle architecture and the metabolic status of heart tissue. This imaging technology can potentially be employed to visualize cardiac and other muscle pathologies.


Sex- and SERT-mediated differences in stimulated serotonin revealed by fast microdialysis.
In vivo microdialysis is widely used to investigate how neurotransmitter levels in the brain respond to biologically relevant challenges. Here, we combined recent improvements in the temporal resolution of online sampling and analysis for serotonin with a brief high-K(+) stimulus paradigm to study the dynamics of evoked release. We observed stimulated serotonin overflow with high-K(+) pulses as short as 1 min when determined with 2-min dialysate sampling in ventral striatum. Stimulated serotonin levels in female mice during the high estrogen period of the estrous cycle were similar to serotonin levels in male mice. By contrast, stimulated serotonin overflow during the low estrogen period in female mice was increased to levels similar to those in male mice with local serotonin transporter (SERT) inhibition. Stimulated serotonin levels in mice with constitutive loss of SERT were considerably higher yet, pointing to neuroadaptive potentiation of serotonin release. When combined with brief K(+) stimulation, fast microdialysis reveals dynamic changes in extracellular serotonin levels associated with normal hormonal cycles and pharmacologic vs genetic loss of SERT function.


Instrumentation to measure the oil thickness on a wavy water surface.
The instrumentation developed to measure the thickness of an oil layer on water in the presence of waves is described. It consists of a probe which follows the surface of water; a light-sensitive gauge attached to the probe measures the extent to which it is submerged in opaque oil, thus determining the oil thickness. In transparent petroleum products motion pictures may be used for this purpose. The results of performance tests of components and the preliminary tests on actual waves are presented.


Agricultural machinery injuries in Ontario, 1985-1996: a comparison of males and females.
Males and females on farms perform different types of work. This study investigated whether certain injuries experienced by women and men on farms also differed. Gender-based comparisons were made of fatal and hospitalized agricultural machinery injuries that took place in Ontario, Canada, between 1985 and 1996. Data compiled by the Canadian Agricultural Injury Surveillance Program (CAISP) were used. Comparisons were based on 2,333 injury records and six descriptors: age group, time period, agricultural season in which the injury occurred, machinery involved, mechanism of injury, type of machinery, and admission category (where applicable). Distributions of injuries between males and females were statistically different by age group, agricultural production season, and mechanism of injury. These and other differences suggest that gender-specific injury patterns exist. Future studies should examine thefactors contributing to these differences, including degree and duration of exposure to agricultural machinery.


Neurocircuit function in eating disorders.
Eating disorders are serious psychosomatic disorders with high morbidity and lifetime mortality. Inadequate response to current therapeutic interventions constitutes a challenging clinical problem. A better understanding of the underlying neurobiological mechanisms could improve psychotherapeutic and drug treatment strategies. A review highlighting the current state of brain imaging in eating disorders related to the anxiety and pathological fear learning model of anorexia nervosa (AN) and the impulsivity model of binge eating in bulimia nervosa (BN). Available neuroimaging studies in patients with acute AN primarily suggest a hyper-responsive emotional and fear network to food, but not necessarily to eating disorder-unrelated, salient stimuli. Furthermore, patients with AN show decreased activation in the ventral fronto-striatal circuits during the performance of a cognitive flexibility task. Results in patients with BN primarily suggest a hypo-responsive reward system to food stimuli, especially to taste reward. Additionally, patients with BN exhibit impaired brain activation in the inhibitory control network during the performance of general response-inhibition tasks. Anxiety and pathological fear learning may lead to conditioned neural stimulus-response patterns to food stimuli and increased cognitive rigidity, which could account for the phobic avoidance of food intake in patients with acute AN. However, further neurobiological studies are required to investigate pathological fear learning in patients with AN. Patients with BN may binge eat to compensate for a hypo-responsive reward system. The impaired brain activation in the inhibitory control network may facilitate the loss of control over food intake in patients with BN.


Compounded gabapentin for neuropathic pain: Stability and beyond-use date (BUD) in some commonly used bases.
To investigate the stability and beyond-use date (BUD) of topical gabapentin in 3 commonly used bases. Lipoderm cream, Versabase gel, and Emollient cream were used to compound gabapentin (10%). The products were stored in Ecolojars, kept at 25°C, 4°C, and 40°C, and samples were collected on different days (days 0, 14, 28, and 90). Potency, stability, and organoleptic changes were monitored. At 25°C and 40°C, the potency of gabapentin in Lipoderm cream significantly increased (P < 0.05) after 28 and 90 days, respectively. In contrast, gabapentin degraded in Emollient cream (P < 0.05). At 25°C, the organoleptic properties of the drug compounded with Lipoderm cream (25°C) remained consistent for up to 28 days but showed signs of physical changes in other bases. Gabapentin recrystallized from Versabase gel and Emollient cream within 14 days. Gabapentin compounded with Lipoderm cream for topical use was stable in Ecolojars for 28 days at 25°C. Under the same conditions, the drug was not stable in Versabase gel and Emollient cream. Based on our stability and potency data, the beyond-use date of currently dispensed gabapentin (10%) formulations with Lipoderm cream should not be extended beyond the currently assigned 30-day mark, even when refrigerated. It is unclear whether the stability of these formulations is improved if stored in air-tight containers.


Examining the Long-Term Association of Personality With Cause-Specific Mortality in London: Four Decades of Mortality Surveillance in the Original Whitehall Smoking Cessation Trial.
The personality domains of extraversion and neuroticism are regarded as being stable individual psychological characteristics, yet it remains unclear whether they are associated with chronic disease over an extended period of time. In a randomized controlled trial of smoking cessation nested within the original prospective Whitehall Study (1967-2012), the Eysenck Personality Questionnaire was administered to 832 male self-declared smokers who had undergone a medical examination during which their levels of extraversion and neuroticism were quantified. In the 42-year follow-up period, there were 781 deaths. In analyses in which participants from both trial arms were pooled, there was little evidence of a robust relation of either personality domain with death from all causes, coronary heart disease, stroke, respiratory disease, or cancer in any of our analyses. We therefore found no support for a role of either extraversion or neuroticism as determinants of long-term mortality risk.


Vermicomposting of sewage sludge: a new technology for Mexico.
In Mexico 31% of the treatment plants have a flow less than 60 l/s. This study offers a simple and economical alternative through vermicomposting to resolve the management of sewage sludge and water hyacinth for these small treatment plants. This study was developed with laboratory and pilot scale systems. In the laboratory Eisenia foetida survival was quantified. They were fed three doses of sludge and water hyacinth and different percentages of humidity were applied. The production of worm cocoons was quantified as biomass production and the reduction in the TV/STS ratio as an indicator of stability. To install the pilot system the mixture with the highest cocoon production was chosen. In the pilot test the effect of the worm population density on the waste degradation was observed, the experiment was divided into five modules, four with densities from 2.5 to 15 kg/m2 and one module without worms that served as a blank test. the best mixture was 70% sewage sludge and 30% water hyacinth, with 80% humidity and an average production of 298 cocoons/kg of vermicompost. There were no significant differences in the TVS/TS reduction between the different modules with worms, but in the blank test module there was no reduction. The Type A vermicompost obtained, with non-restricted use, 900 fecal coliforms NMP/g, 0.0 helminth ova/g, highly organic (60% M.O.), high concentration of total nitrogen (2.5%), phosphorus (0.96%) and cationic exchange capacity (60.2 meq/100 g), which indicates that soil fertility would increase if used in agriculture.


Leukotrienes modulate cytokine release from dendritic cells.
Leukotriene B(4) (LTB(4)) and cysteinyl leukotrienes (CysLTs) are known as potent mediators of inflammation, whereas their role in the regulation of adaptive immunity remains poorly characterized. Dendritic cells (DCs) are specialized antigen-presenting cells, uniquely capable to initiate primary immune responses. We have found that zymosan, but not lipopolysaccharide (LPS) stimulates murine bone marrow-derived dendritic cells (BM-DCs) to produce large amounts of CysLTs and LTB(4) from endogenous substrates. A selective inhibitor of leukotriene synthesis MK886 as well as an antagonist of the high affinity LTB(4) receptor (BLT(1)) U-75302 slightly inhibited zymosan-, but not LPS-stimulated interleukin (IL)-10 release from BM-DCs. In contrast, U-75302 increased zymosan-stimulated release of IL-12 p40 by approximately 23%. Pre-treatment with transforming growth factor-beta1 enhanced both stimulated leukotriene synthesis and the inhibitory effect of U-75302 and MK886 on IL-10 release from DCs. Consistent with the effects of leukotriene antagonists, exogenous LTB(4) enhanced LPS-stimulated IL-10 release by approximately 39% and inhibited IL-12 p40 release by approximately 22%. Both effects were mediated by the BLT(1) receptor. Ligands of the high affinity CysLTs receptor (CysLT(1)), MK-571 and LTD(4) had little or no effect on cytokine release. Agonists of the nuclear LTB(4) receptor peroxisome proliferator-activated receptor-alpha, 8(S)-hydroxyeicosatetraenoic acid and 5,8,11,14-eicosatetraynoic acid, inhibited release of both IL-12 p40 and IL-10. Our results indicate that both autocrine and paracrine leukotrienes may modulate cytokine release from DCs, in a manner that is consistent with previously reported T helper 2-polarizing effects of leukotrienes.


Study of HTLV-I antibodies in CSF and serum of neurolathyrism patients in Bangladesh.
Neurolathyrism is a form of human spastic paraparesis related to the overconsumption of the legume Lathyrus sativus or grass pea (Khesari in Bangladesh) containing the neurotoxin 3-N-oxalyl-2,3-diaminopropanoic acid (beta-ODAP). The clinical symptoms of neurolathyrism are similar to those of Tropical Spastic Paraparesis. In order to eliminate the proposed causative agent of TSP (HTLV-I) as a potential cause of the symptoms ascribed to neurolathyrism, a total of 444 diagnosed lathyrism patients were screened for HTLV-I antibodies. 50 CSF and 394 serum samples were collected from male (415) and female (29) patients. Only 4 serum samples were found sero-positive for HTLV-I. This agrees with the assumption that overconsumption of beta-ODAP containing Lathyrus seeds, and not HTLV infection, is the causative agent for neurolathyrism.


The human/mouse imprinted genes IGF2, H19, SNRPN and ZNF127 map to two conserved autosomal clusters in a marsupial.
The four genes IGF2, H19, SNRPN and ZNF127 are imprinted in mouse and human. IGF2 and H19 form one conserved cluster on the distal part of mouse chromosome 7 and human chromosome 11p15.5, whereas SNRPN and ZNF127 form another on the middle of mouse chromosome 7 and on human chromosome 15q11-13. We have explored the evolution of these imprinted regions by cloning and mapping IGF2, H19, SNRPN and ZNF127 homeologues in marsupials. Specifically, we wished to determine whether the arrangements were shared in eutherian and marsupial mammals, and to determine whether they lay on autosomes, or on the X, as might be predicted by the hypothesis that imprinting evolved from X inactivation. Using fluorescence in situ hybridization, we localized the marsupial homeologues of IGF2 and H19 to the distal part of tammar wallaby chromosome 2p and the marsupial homeologues of SNRPN and ZNF127 to the middle of chromosome 1q. Thus, these genes were originally organized in two separate autosomal clusters in the therian ancestor 180 million years ago, the conservation of which may suggest a functional relationship. The autosomal location of these clusters does not suggest a recent evolutionary relationship between imprinting and X chromosome inactivation.


In vitro diazepam metabolism in horses.
There is little information about drug metabolism and pharmacokinetics in horses. Therefore, it is necessary to characterize the profiles of drug metabolites for the safe use of drugs. In this study, we focused on cytochrome P450 enzymes (CYPs), which represent an important enzyme group to determine pharmacological effects of drugs. We chose diazepam as the drug of choice for this study. The aim of this study was to elucidate the metabolic pathway of diazepam in horses in comparison with rats, and to clarify CYP subfamilies responsible for diazepam metabolism in horses. Our results showed temazepam was the major diazepam metabolite produced from microsomal reactions in horse liver, but horses produced drastically less p-hydroxydiazepam as compared with rats. Furthermore, CYP3A was a major contributor from the CYP subfamily of temazepam production.


Mechanisms that regulate localization of a DNA double-strand break to the nuclear periphery.
DNA double-strand breaks (DSBs) are among the most deleterious forms of DNA lesions in cells. Here we induced site-specific DSBs in yeast cells and monitored chromatin dynamics surrounding the DSB using Chromosome Conformation Capture (3C). We find that formation of a DSB within G1 cells is not sufficient to alter chromosome dynamics. However, DSBs formed within an asynchronous cell population result in large decreases in both intra- and interchromosomal interactions. Using live cell microscopy, we find that changes in chromosome dynamics correlate with relocalization of the DSB to the nuclear periphery. Sequestration to the periphery requires the nuclear envelope protein, Mps3p, and Mps3p-dependent tethering delays recombinational repair of a DSB and enhances gross chromosomal rearrangements. Furthermore, we show that components of the telomerase machinery are recruited to a DSB and that telomerase recruitment is required for its peripheral localization. Based on these findings, we propose that sequestration of unrepaired or slowly repaired DSBs to the nuclear periphery reflects a competition between alternative repair pathways.


Seasonal variation of xanthine oxidoreductase activity in the digestive gland cells of the mussel Mytilus galloprovincialis: a biochemical, histochemical and immunochemical study.
The activity and the tissue distribution of the oxygen radical producing enzyme xanthine oxidoreductase (XOR) were measured in the digestive gland of the common marine mussel Mytilus galloprovincialis Lmk along an annual cycle. No xanthine oxidase (XOX) activity could be measured, the enzyme only displaying xanthine dehydrogenase (XDH) activity in all the cases. This is interpreted as a mechanism to avoid the harmful effects of the oxygen radicals that would be produced by XOX during periods following anoxic conditions at low tide. The highest XDH activities coincided with the late spring/early summer months, the activity maxima being recorded from May to July. Histochemically XOR activity was very pronounced in duct and stomach epithelial cells as well as in the surrounding connective tissue and hemolymph vessels, the activity increasing towards the summer months. These seasonal variations in XDH or XOR activities are possibly linked to hormonal changes governing the reproductive cycle and to changes in food availability. The localization of the protein in the connective tissue lining the hemolymph vessels was confirmed immunohistochemically using a polyclonal antibody against rat liver protein that cross-reacted specifically with a polypeptide of 150 kDa of molecular mass in homogenates of the digestive gland. This polypeptide was linked to cytosolic fractions isolated by differential centrifugation from mussel digestive glands. In paraffin sections the antibody labeled the digestive cells of digestive tubules, as well as the connective tissue surrounding the hemolymph vessels, gonadal follicles, digestive epithelia and certain protozoan parasites. Taken together our results suggest that in the digestive gland of bivalve molluscs XOR is involved in the metabolism of purines and in the scavenging of oxygen free radicals.


[Study of prognostic factors in the hepatectomy for metastases of colorectal carcinoma--analysis of two scores].
Resection is the treatment of choice for colorectal cancer liver metastases. This is a retrospective, longitudinal, retrospective analysis of different prognostic factors for survival in a consecutive series of liver resection for metastatic colorectal carcinoma. Between October 1998 and November 2007, we performed 89 liver resections for colorectal metastases. A retrospective analysis from the liver resection database was performed and the variables analyzed were related to demography, primary tumor and surgical procedure. Survival analysis was performed according to the Fong and Basingstoke scores. The mean age of patients was 60.5 years and 67.4% were men. The primary tumor was localized in the colon in 73% of cases. In 68.5% the metastases were metachronous. The right hemiliver was involved in 46 patients (52%). Major hepatectomy was performed in 36 (40.2%), minor in 55 (59.8%) and combined procedures in 14 (15.7%). Seventy-seven (86.5%) R0 resections were achieved. Morbidity was 32.6%, with no perioperative mortality. Average follow-up was 32.5 months (range 1 to 158 months), with a median of 25.5 months. Median overall survival was 69.7 months and mean disease-free survival 58.7 months. Multivariate analysis found statistical significance for blood product requirement and margin of resection. Thirty-four patients are alive at the end of this study (45.9%). The Basingstoke predictive index for postoperative variables showed significant differences that were not demonstrated by the Fong clinical score on prognostic factors. The application of Basingstoke predictive index and Fong score with biomarkers may indicate the most appropriate therapeutic strategy in each patient with colorectal liver metastases.


Sinus pathology and anatomy in relation to complications in lateral window sinus augmentation.
Antral pathoses and anatomical variations increase the risk of surgical complications during a lateral window sinus augmentation procedure. Therefore, an understanding of maxillary sinus diseases and anatomies is imperative. In the first part of this article, common sinus diseases will be reviewed, which include acute/chronic rhinosinusitis, mucoceles, pseudocysts, retention cysts, and odontogenic diseases of the maxillary sinus. In addition, a treatment strategy will be proposed toward the management of these antral diseases. In the second part, anatomical variations of the maxillary sinus, for example, the septum and artery that is in approximation to the osteotomy site will be discussed. Knowledge of diagnosing and managing sinus pathoses and anatomies could assist surgeons in reducing the incidence of sinus augmentation complications.


Undignifying institutions.
Declarations of the importance of dignity in health care are commonplace in codes of practice and other mission statements, yet these documents never clarify dignity's meaning. Their vague aspirations are compared to comments from staff and patients about opportunities for and barriers against the promotion of dignity in elderly care institutions. These suggest that while nurses and health care assistants have an intuitive understanding of dignity, they either do not or cannot always bring it about in practice. Thus, despite stated intentions to promote dignity, it appears that the circumstances of at least some elderly care institutions cause patients to experience avoidable indignities. Such institutions are "undignifying institutions" because they fail to acknowledge dignity's basic components, focus excessively on quantifiable priorities, and have insufficient resources available to assure consistently dignifying care. As a partial solution, we argue that health workers should be taught to understand and specify the components of dignity, which will better prepare them to challenge undignifying practices and to recognise opportunities for dignity promotion.


Proton Conductive Channel Optimization in Methanol Resistive Hybrid Hyperbranched Polyamide Proton Exchange Membrane.
Based on a previously developed polyamide proton conductive macromolecule, the nano-scale structure of the self-assembled proton conductive channels (PCCs) is adjusted via enlarging the nano-scale pore size within the macromolecules. Hyperbranched polyamide macromolecules with different size are synthesized from different monomers to tune the nano-scale pore size within the macromolecules, and a series of hybrid membranes are prepared from these two micromoles to optimize the PCC structure in the proton exchange membrane. The optimized membrane exhibits methanol permeability low to 2.2 × 10-7 cm²/s, while the proton conductivity of the hybrid membrane can reach 0.25 S/cm at 80 °C, which was much higher than the value of the Nafion 117 membrane (0.192 S/cm). By considering the mechanical, dimensional, and the thermal properties, the hybrid hyperbranched polyamide proton exchange membrane (PEM) exhibits promising application potential in direct methanol fuel cells (DMFC).


Cerebello-pontine angle paraganglioma simulating an acoustic neurinoma.
An unusual case of paraganglioma arising from the internal auditory meatus and growing into the cerebello-pontine angle is reported. Clinical features, pre-operative radiological appearances and intra-operative findings were indistinguishable from those of an acoustic neurinoma. However, the paraganglionic nature of the tumour was confirmed by the electron microscopic evidence of neurosecretory features.


Prosthetic reconstruction with an obturator using swing-lock attachment for a patient underwent maxillectomy: A clinical report.
Patients who underwent resection of maxilla due to benign or malignant tumor, or accident will have defect in palatal area. They get retention, support and stability from remaining tissues which are hardly optimal. The advantage of swing-lock attachment design is having multiple contacts on labial and lingual side of the abutment teeth by retentive strut and palatal bracing component. Because the force is distributed equally to abutment teeth, abutment teeth of poor prognosis can be benefited from it. It is also more advantageous to cover soft tissue defects which are hard to reach with conventional prosthesis. A 56-year-old female patient who had undergone a maxillectomy due to malignant melanoma complaining of loose and unstable surgical obturator. Surveyed crowns were placed on #12, 26, and 27. Teeth #11, 21, 22, and 23 had lingual rest seat and #24 had mesial rest seat to improve stability and support of the obturator. This clinical report presents the prosthetic management of a patient treated with obturator on the maxilla using swing-lock attachment to the remaining teeth.


Severity of adolescent delinquency among boys with and without attention deficit hyperactivity disorder: predictions from early antisocial behavior and peer status.
This study evaluated predictors of adolescent delinquency severity (11 to 17 years of age) among a diverse group of preadolescent boys with attention deficit hyperactivity disorder (ADHD; n=100) and age-matched comparison boys (n=75). During childhood, baseline assessments yielded diagnostic information, and naturalistic summer programs provided multimethod measures of overt aggression, covert antisocial behavior (ASB), and peer status. Five years later, multi-informant measures of ASB and delinquency were gathered and independently rated. Baseline ADHD, overt aggression, and peer status were not significantly related to adolescent delinquency severity. Observed noncompliance and an objective measure of covert ASB each independently predicted delinquency. Covert ASB predicted delinquency severity more strongly for comparison boys than for probands.


Treatment of Aortic and Iliac Artery Occlusion by Catheter Thrombolysis Combined with Catheter Thrombectomy and Aortic Bifurcation Endovascular Stent Reconstruction.
Aortoiliac occlusive disease (AIOD) is an occlusive disease of the infrarenal aorta and iliac arteries usually caused by stenosis or occlusion at the end of the abdominal aorta-common iliac artery. Herein, we reported a case of Trans-Atlantic Inter-Society Consensus- (TASC-) D AIOD with pale, cool, and intangible dorsalis pedis artery treated with catheter thrombolysis combined with catheter thrombectomy and aortic bifurcation endovascular stent reconstruction, which proved to be safe, effective, and minimally invasive approach. In the present paper, we discussed the physical and imaging manifestations, as well as treatments.


New oxamidato-bridged Cu(II)-Ni(II) complexes: supramolecular structures with thiocyanate ligands and hydrogen bonds. Magnetostructural studies: DFT calculations.
Four new supramolecular compounds of Cu(II)-Ni(II) have been synthesized and characterized: [Cu(Me(2)oxpn)Ni(mu-NCS)(H(2)O)(tmen)](2)(ClO(4))(2) (1), [Cu(Me(2)oxpn)Ni(mu-NCS)(H(2)O)(tmen)](2)(PF(6))(2) (2), [Cu(oxpn)Ni(mu-NCS)(NCS) (tmen)](n) (3), and [Cu(Me(2)oxpn)Ni(mu-NCS)(NCS)(tmen)](n) (4), where oxpn = N,N'-bis(3-aminopropyl)oxamidate, Me(2)oxpn = N,N'-bis(3-amino-2,2'-dimethylpropyl)oxamidate, and tmen = N,N,N',N'-tetramethylethylenediamine. Their crystal structures were solved. Complexes 1 and 2 have the same tetranuclear cationic part but a different counteranion. The cationic part consists of two [Cu(Me(2)oxpn)Ni] moieties linked by SCN(-) bridged ligands and intra-tetranuclear hydrogen bonds. In the case of complex 3, a two-dimensional system was built, the thiocyanate ligand linking the dinuclear units gives a chain, and the chains are linked together by hydrogen bonds; intrachain hydrogen bonds are also present. For complex 4, the thiocyanate ligands produce intermolecular linkages between the dinuclear entities, giving a one-dimensional system; intrachain hydrogen bonds are also present. The magnetic properties of the four complexes were studied by susceptibility measurements vs temperature. DFT calculations were made to study the contribution of the SCN(-) and hydrogen bond bridges in the magnetic coupling.


Energy Autonomous Wireless Sensor Nodes for Freight Train Braking Systems Monitoring.
Nowadays, railway freight transportation is becoming more and more crucial since it represents the best alternative to road transport in terms of sustainability, pollution, and impact on the environment and on public health. Upgrading the potentiality of this kind of transportation, it would be possible to avoid delays in goods deliveries due to road accidents, traffic jams, and other situation occurring on roads. A key factor in this framework is therefore represented by monitoring and maintenance of the train components. Implementing a real time monitoring of the main components and a predictive maintenance approach, it would be possible to avoid unexpected breakdowns and consequently unavailability of wagons for unscheduled repair activities. As highlighted in recent statistical analysis, one of the elements more critical in case of failure is represented by the brake system. In this view, a real time monitoring of pressure values in some specific points of the system would provide significant information on its health status. In addition, since the braking actions are related to the load present on the convoy, thanks to this kind of monitoring, it would be possible to appreciate the different behavior of the system in case of loaded and unloaded trains. This paper presented an innovative wireless monitoring system to perform brake system diagnostics. A low-power system architecture, in terms of energy harvesting and wireless communication, was developed due to the difficulty in applying a wired monitoring system to a freight convoy. The developed system allows acquiring brake pressure data in critical points in order to verify the correct behavior of the brake system. Experimental results collected during a five-month field test were provided to validate the approach.


US-guided transvaginal drainage of pelvic abscesses and fluid collections.
Ultrasound (US)-guided transvaginal needle or catheter drainage was performed in 14 women for a variety of pelvic abscesses and fluid collections; tubo-ovarian abscesses and postoperative collections were most common. Diagnosis was achieved in all 14 patients (100%), including one patient with suspected ovarian carcinoma who underwent only diagnostic needle aspiration and no therapeutic drainage. Abscesses or fluid collections were evacuated in 13 of 13 patients (100%) with either needle (n = 7) or catheter (n = 6) drainage (with appropriate antibiotics). Twelve of the 14 patients (86%) were spared an operation; surgery was undertaken in two patients for a persistent tubo-ovarian phlegmon. No major complications were associated with drainage. Catheters were removed an average of 6.7 days after insertion. The success, safety, and advantages of US-guided transvaginal drainage in our early experience suggest its use as an alternative to standard percutaneous catheter procedures to diagnose and drain certain pelvic abscesses and fluid collections.


Adolescent food choice criteria: role of weight and dieting status.
The purpose of this study was to examine the relation of weight status, dieting status and several associated variables to the criteria for everyday food choice used by adolescents. Study participants were 411 students between the ages of 11 and 18, drawn from 15 schools. The adolescents rated 20 food in terms of nine food attributes (how tasty or healthful specific foods were, whether the foods were eaten by friends, and so forth). Within-person correlation coefficients were then calculated between these ratings and actual food choices as measured by a food frequency scale. The relation of weight and dieting status, as predictors of each of these correlational indices of the importance of potential food choice criteria, was then analysed using hierarchical multiple regression. In similar fashion, the relation was examined between weight and dieting status and: evaluations of food attributes (choice criteria); dietary quality; calorie, sugar and fat intake; body image; and physical activity. For a majority of food choice criteria and other variables, there was an apparent influence of weight as an independent variable. However, when dieting status was analysed simultaneously with weight, similar and stronger effects were now seen for dieting status and the effects of weight disappeared. Although some of the differences as a function of dieting status resembled differences shown previously in relation to dietary restraint, it is noteworthy that the simpler dieting variable yielded these associations. Overall, a "psychology of dieting" seems more relevant than "psychology of being fat versus being thin". This psychology appears to involve cognitive self-regulation processes. It is thus crucial that intervention programs and research studies take into account both the dieting status and the weight status of participants.


Effects of trichloroethylene and perchloroethylene on muscle contractile responses and epithelial prostaglandin release and acetylcholinesterase activity in swine trachea.
Trichloroethylene (TCE) and perchloroethylene (PERC) have been reported to induce respiratory complications such as airway hyperactivity and asthma. The present study was designed to investigate their influence on smooth muscle contraction and epithelial release of prostanoids in swine trachea. Results showed that TCE and PERC exposure did not alter the basal tone of tracheal smooth muscle. However, TCE and PERC concentration-dependently increased both ACh-induced and high K+-induced muscle contraction. In addition to potentiation of muscle contractile responses evoked by acetylcholine or histamine, pretreatment of smooth muscle with PERC at higher concentration significantly suppressed the relaxant activity of beta-adrenergic agonists. The epithelial prostaglandin (PG)E2, but not PGD2, release from tracheal epithelium was significantly increased by TCE and PERC. In addition, the acetylcholinesterse (AChE) activity of tracheal epithelia was reduced by TCE and PERC. In conclusion, our results suggest that the enhancement of spasmogen-evoked muscle contractile responses and epithelial PGE2 secretion, as well as reduction of epithelial AChE activity, may participate in airway impairment and hyperresponsiveness after TCE and PERC exposure.


Evidence for programmed cell death of self-reactive gamma delta T cell receptor-positive thymocytes.
The negative selection of T cells expressing the gamma delta T cell antigen receptor (gamma delta T cells) was studied using transgenic mice expressing a gamma delta receptor with specificity for an H-2T-linked class I major histocompatibility complex molecule from H-2b mice. The potentially self-reactive gamma delta thymocytes in H-2b/d transgenic mice are larger and have lower levels of gamma delta T cell receptor expression than gamma delta thymocytes from H-2d mice. H-2b/d gamma delta thymocytes do not respond to H-2b antigen-presenting cells, and thus are inactive compared to H-2d gamma delta thymocytes. However, the H-2b/d gamma delta thymocyte population, but not the H-2d gamma delta thymocyte population, undergoes a high rate of programmed cell death when placed in overnight culture. These observations constitute the first direct evidence that self-reactive gamma delta thymocytes undergo programmed cell death. This in vitro programmed cell death of self-reactive gamma delta thymocytes may reflect the clonal deletion process that results in a depletion of gamma delta T cells in the peripheral lymphoid organs of adult H-2b/d mice. We also present evidence that self-reactive gamma delta T cells, similarly to alpha beta T cells, undergo a lesser degree of clonal deletion in neonatal mice compared to adult mice.


Health Care Utilization and Expenditures Attributable to Smokeless Tobacco Use Among US Adults.
This study estimated the health care utilization and expenditures attributable to the use of smokeless tobacco (ST) which includes chewing tobacco, snuff, dip, snus, and dissolvable tobacco among US adults aged 18 and older. We used data from the 2012-2015 National Health Interview Surveys (n = 139451 adults) to estimate a zero-inflated Poisson (ZIP) regression model on four health care utilization measures among US adults (hospital nights, emergency room [ER] visits, doctor visits, and home care visits) specified as a function of tobacco use status, and other covariates. Tobacco use status was classified into four categories: current ST users, former ST users, non-ST tobacco users, and never tobacco users. ST-attributable utilization was calculated based on the estimated ZIP model using an "excess utilization" approach. It was then multiplied by the unit cost estimated from the 2014 Medical Expenditures Panel Survey data to derive ST-attributable health care expenditures. During 2012-2015, 2.1% of adults were current ST users and 7.7% were former ST users. ST-attributable health care utilization amounted to 681000 hospital nights, 624000 ER visits, and 4.6 million doctor visits per year (home care visits results were not significant). This resulted in annual excess expenditures of $1.8 billion for hospitalizations, $0.7 billion for ER visits, and $0.9 billion for doctor visits, totaling over $3.4 billion (in 2014 dollars). Comprehensive tobacco control policies and interventions are needed to reduce ST use and the associated health care burden. This is the first study to assess the impact of ST use on health care burden in the United States. Findings indicate that excess annual health care expenditures attributable to ST use for US adults were $3.4 billion in 2014 dollars.


Targeted three-dimensional immunohistochemistry reveals localization of presynaptic proteins Bassoon and Piccolo in the rat calyx of Held before and after the onset of hearing.
Bassoon and Piccolo contribute to the cytomatrix of active zones (AZ), the sites of neurotransmitter release in nerve terminals. Here, we examined the 3D localization of Bassoon and Piccolo in the rat calyx of Held between postnatal days 9 and 21, the period of hearing onset characterized by pronounced structural and functional changes. Bassoon and Piccolo were identified by immunohistochemistry (IHC) on slices of the brainstem harboring calyces labeled with membrane-anchored green fluorescent protein (mGFP). By using confocal microscopy and 3D reconstructions, we examined the distribution of Bassoon and Piccolo in calyces delineated by mGFP. This allowed us to discriminate calyceal IHC signals from noncalyceal signals located in the spaces between the calyceal stalks, which could mimic a calyx-like distribution. We found that both proteins were arranged in clusters resembling the size of AZs. These clusters were located along the presynaptic membrane facing the principal cell, close to or overlapping with synaptic vesicle (SV) clusters. Only about 60% of Bassoon and Piccolo clusters overlapped, whereas the remaining clusters contained predominantly Bassoon or Piccolo, suggesting differential targeting of these proteins within a single nerve terminal and potentially heterogeneous AZs functional properties. The total number of Bassoon and Piccolo clusters, which may approximate the number of AZs, was 405 +/- 35 at P9 and 601 +/- 45 at P21 (mean +/- SEM, n = 12). Normalized to calyx volume at P9 and P21, the density of clusters was similar, suggesting that the absolute number of clusters, not density, may contribute to the functional maturation associated with hearing onset.


Technical Optimization for the High-Throughput Purification of Antibodies on Automated Liquid Handlers.
Monoclonal antibodies (mAbs) are the fastest-growing segment in the drug market with eight of the top 20 selling drugs being mAbs and combined sales of close to 60 billion US$/year. The development of new therapeutic mAbs requires the purification of a large number of candidate molecules during initial screenings, subsequent affinity maturation campaigns, and finally the engineering of variants to improve half-life, functionality, or biophysical properties of potential lead molecules. A successful strategy to purify this ever-increasing number of mAbs in a timely manner has been the miniaturization and automation of the purification process using automatic liquid handlers (ALHs) such as Tecan's Evo or PerkinElmer's Janus platforms. These systems can be equipped with miniaturized columns, which are available in a wide variety of sizes and affinity matrices to cater to the need of the respective application. Various publications have described the setup of ALHs including the respective purification procedure. However, despite being very precise regarding the overall approach, most publications do not focus on the technical optimization and potential pitfalls, which can be crucial to obtain a robust process. To fill this gap, the present publication is aiming to point at some technical difficulties and suggesting potential ways to overcome these problems in order to facilitate the setup of new ALH systems for the purification of antibodies.


SLC22A2 - mapping genomic variations within South African indigenous and admixed populations.
The SLC22A2 gene is a polyspecific transporter that mediates the electrogenic transport of small organic cations with different molecular structures. Furthermore, single-nucleotide polymorphisms (SNPs) of SLC22A2 are clinically significant because they can alter the transport of substrate drugs and may, thus, influence the efficacy and toxicity thereof. Additionally, further studies have reported that SLC22A2 is responsible for 80% of the total metformin clearance. Therefore, loss-of-function variants of SLC22A2 could affect the pharmacokinetic and pharmacodynamic characteristics of metformin. Although it is widely accepted that African populations harbor a greater amount of genomic diversity compared to other populations, limited information is available regarding genetic polymorphisms in SLC genes among African populations, specifically those related to impaired functional activity of hOCT2. Therefore, the aim of this study was to map known impaired function variants in the SLC22A2 gene. Development of multiplex SNaPshot™ genotyping assay for 20 previously reported SLC22A2 nonsynonymous SNPs and the assessment of baseline allele frequencies of these variants in 140 Cape Admixed, 148 Xhosa and 152 Zulu individuals residing in Cape Town, South Africa. We identified three nonsynonymous SNPs, namely, A270S, R400C and K432Q in the population studied at minor allele frequencies of 6.1%, 3.4% and 0.7%, respectively. The most frequently observed haplotypes across all three populations were CATAATGCGTACGCGCGACG (~85%), CATAATGATTACGCGCGACG (~7%) and CATAATGAGTACGCGCGACG (~4.5%). In addition to SNPs, the haplotypes identified in this study can in future also aid in identifying associations between causative genetic variants and drug response. This study contributes in filling the gap that exists with regards to genetic information about important variations in organic cation transporter genes for the indigenous populations of South Africa.


Clinical aspects of lumbar intervertebral disc disease.
The diagnosis and management of lumbar disc disease has undergone significant changes in recent years. This is especially true for diagnostic imaging studies (MRI and CT). Currently, CT/myelography or unenhanced MRI may be used to confirm the diagnosis and the level of involvement of lumbar disc disease. The indications for lumbar disc surgery include patients with neurologic deficits and/or those in whom intractable pain does not respond to conservative measures. Conventional disc surgery and/or microdiscectomy are both good operative procedures for lumbar disc disease, and each yields excellent results when criteria for diagnosis and surgery are strictly followed.


A novel cellular prion protein isoform present in rapid anterograde axonal transport.
We studied the axonal transport of PrP(C) in hamster retinal and sciatic nerve axons. Our results show that a novel 38kDa form is the predominant form in rapid anterograde axonal transport while the 36kDa and 33kDa PrP(C) forms, abundant in nerve and brain, appear to be either stationary or slowly transported. We did not detect any significant retrograde transport of PrP(C). These results show that 38kDa PrP(C) is the form exported from the cell body to the axonal compartment where it may represent the precursor to the more abundant PrP(C) forms after its modification in nerve fibres or terminals.


Cistanches Herba, from an endangered species to a big brand of Chinese medicine.
Cistanches Herba (CH, Chinese name: Roucongrong), is a very precious, tonic Chinese medicine. Cistanche deserticola and Cistanche tubulosa are the two commonly used species and authenticated in Chinese Pharmacopoeia. Due to the parasitic nature of Cistanche plants, the wild source was once endangered and listed in the Appendix II of Convention on International Trade in Endangered Species of Wild Fauna and Flora. However, after continuously struggling in the past decades, CH has grown up to a big brand of Chinese medicine featured with the cultivation area as 1.26 million mu, the annual output as 6000 tons, and the related industrial output value as more than 20 billion China Yuan, attributing to large-scale cultivation and in-depth phytochemical and pharmacological investigations. Noteworthily, great achievements have reached concerning the research and development of relevant products, such as modern drugs, traditional Chinese medicine prescriptions, and dietary supplements. The current review summarizes the research progresses concerning the distribution and cultivation, phytochemistry, pharmacology, metabolism and product development of CH in the past decades, and the emerging challenges and developing prospects are discussed as well.


Fate of recombinant adeno-associated viral vector genomes during DNA double-strand break-induced gene targeting in human cells.
Recombinant vectors based on adeno-associated virus (rAAV) are promising tools to specifically alter complex genomes through homologous recombination (HR)-based gene targeting. In a therapeutic setting, an AAV donor vector will recombine with a mutant target locus in order to correct the mutation directly in the genome. The low frequency of HR in mammalian cells can be significantly improved by insertion of a DNA double-strand break (DSB) into the target locus through expression of a site-specific endonuclease. Here, we have scrutinized the fate of rAAV vector genomes during DSB-induced gene targeting and assessed the targeting frequency and the targeting ratio as a risk-benefit indicator. In various human cell lines carrying a mutated enhanced green fluorescent protein locus with a recognition site for the homing endonuclease I-SceI, rAAV-transduced cells were assayed by flow cytometry and by quantitative allele-specific polymerase chain reaction to assess HR and unspecific integration events. Under optimal conditions gene-targeting frequencies of 65% and targeting ratios of 2:1 were achieved, that is, more gene correction than unspecific integrations. The gene-targeting frequency was highly dependent on rAAV vector design, the cell line, and on the presence of a DSB in the target locus. Although expression of I-SceI led to a significant increase in gene targeting, it did not augment unspecific integration. In conclusion, our results reveal the side effects associated with rAAV-mediated gene targeting, but also its great potential for precise genome engineering in a therapeutic context.


Electrolytic actuators: alternative, high-performance, material-based devices.
The emerging field of materials-based actuation continues to be the focus of considerable research because of its inherent scalability and its promise to drive micromechanical devices that cannot be realized with conventional mechanical actuator strategies. The electrolytic phase transformation actuator offers a new broad-spectrum solution to the problem of direct conversion of electrical to mechanical energy. Strains of 136,000% and unoptimized work cycle efficiencies near 50% are demonstrated in a prototype device. Conceivably capable of generating stress beyond 200 MPa, this new approach promises performance orders of magnitude beyond other novel actuation strategies.


Rehabilitation with removable dentures among the dentate population in Finland.
The information available on the rehabilitation with removable dentures among dentate subjects is contradictory. In the present study, the most common type of rehabilitation was a complete maxillary denture with or without a partial one. Nineteen per cent of men and 27% of women belonged to this category. Partial denture(s) without a complete one were worn by 11% of men and 15% of women. The odds ratio of having partial denture(s) was significantly higher among women, among people with a medium level of income, with a regular dental attendance pattern, and with a shorter distance to the nearest dental clinic. The presence of a complete denture significantly decreased the odds ratio of having a partial denture. The effect of age was non-significant in the two youngest age categories. The odds ratio of having a single complete denture was significantly higher among women, among people with a medium level of income and with a shorter distance to the nearest dental clinic. The presence of a partial denture and belonging to the oldest age bracket decreased the odds ratio significantly. Regularity of use of dental services had a non-significant effect.


[Normal and pathological cardiac aging. Apropos of an exceptional case of longevity].
Born in Arles on February 21st 1875, Madame J. C. was the oldest registered human being. She died on August 4th 1997 at the age of 122 years, the record for longevity probably for a long moment. Based on this unique case and a review of the literature, the authors describe the mechanical, physiological and clinical aspects of normal cardiac ageing. The diseases of the elderly which accelerate the process of physiological ageing are then reviewed. With its participation in left ventricular hypertrophy, left atrial dilatation and the increase in valvular stress, the decreased elasticity of the great arteries seems to be the essential factor.


DNA content differences in laboratory mouse strains determined by flow cytometry.
The nuclear DNA content of seven mouse laboratory strains has been measured by flow cytometry. The differences observed between strains as well as those between sexes within the strain were all statistically significant. The highest DNA content (approximately 6.4 pg/female nucleus) was found in the Balb/c strain; the lowest (approximately 5.7 pg/male nucleus) in the C3H/he strain. The difference between sexes varied from 1.6% (in CD-1 mice) to 6.3% (in nude mice). The interest of these results is twofold. First, the mouse can now be used to study the adaptive significance of genome size variation, so far studied only in plants. Second, DNA content analysis can become a quick method for mouse strain identification.


Paralytic strabismus.
In the past 12 months there have been many interesting publications on paralytic strabismus. Many investigators have reported on various imaging techniques helping both the clinician and the basic scientist better evaluate the causes and effects of paralytic strabismus on the extraocular muscle environment. Some interesting cases of neurologic and systemic associations have also been reported, including a unilateral pupil-sparing third nerve paralysis developing after the use of sildenafil citrate (Viagra; Pfizer, New York, New York). Advances in genetics are now helping us further understand complex entities such as progressive external ophthalmoparesis and congenital fibrosis syndrome. At the other end of the spectrum, colleagues are reporting clinical findings to help specify the diagnosis of conditions as diverse as degenerative ataxic disorders and masked bilateral superior oblique muscle paresis. Unfortunately, there were very few papers on proven new effective surgical techniques for the treatment of paralytic strabismus this year. Finally, to help clarify terminology, and when at all possible depending on the reports reviewed, the following nomenclature will be used in this paper: paralysis--complete loss of function of a muscle or group of muscles innervated by a specified (when applicable) cranial nerve or branch; paresis--incomplete loss of function; and palsy--when the authors failed to specify the degree of weakness.


Selective Photocatalytic Dehydrogenation of Formic Acid by an In Situ-Restructured Copper-Postmetalated Metal-Organic Framework under Visible Light.
Formic acid is considered as one of the most promising liquid organic hydrogen carriers. Its catalytic dehydrogenation process generally suffers from low activity, low reaction selectivity, low stability of the catalysts, and/or the use of noble-metal-based catalysts. Herein we report a highly selective, efficient, and noble-metal-free photocatalyst for the dehydrogenation of formic acid. This catalyst, UiO-66(COOH)2-Cu, is built by postmetalation of a carboxylic-functionalized Zr-MOF with copper. The visible-light-driven photocatalytic dehydrogenation process through the release of hydrogen and carbon dioxide has been monitored in real-time via operando Fourier transform infrared spectroscopy, which revealed almost 100% selectivity with high stability (over 3 days) and a conversion yield exceeding 60% (around 5 mmol·gcat-1·h-1) under ambient conditions. These performance indicators make UiO-66(COOH)2-Cu among the top photocatalysts for formic acid dehydrogenation. Interestingly, the as-prepared UiO-66(COOH)2-Cu hetero-nanostructure was found to be moderately active under solar irradiation during an induction phase, whereupon it undergoes an in-situ restructuring process through intraframework cross-linking with the formation of the anhydride analogue structure UiO-66(COO)2-Cu and nanoclustering of highly active and stable copper sites, as evidenced by the operando studies coupled with steady-state isotopic transient kinetic experiments, transmission electron microscopy and X-ray photoelectron spectroscopy analyses, and Density Functional Theory calculations. Beyond revealing outstanding catalytic performance for UiO-66(COO)2-Cu, this work delivers an in-depth understanding of the photocatalytic reaction mechanism, which involves evolutive behavior of the postmetalated copper as well as the MOF framework over the reaction. These key findings pave the way toward the engineering of new and efficient catalysts for photocatalytic dehydrogenation of formic acid.


Physical temperature effects on trust behavior: the role of insula.
Trust lies at the heart of person perception and interpersonal decision making. In two studies, we investigated physical temperature as one factor that can influence human trust behavior, and the insula as a possible neural substrate. Participants briefly touched either a cold or warm pack, and then played an economic trust game. Those primed with cold invested less with an anonymous partner, revealing lesser interpersonal trust, as compared to those who touched a warm pack. In Study 2, we examined neural activity during trust-related processes after a temperature manipulation using functional magnetic resonance imaging. The left-anterior insular region activated more strongly than baseline only when the trust decision was preceded by touching a cold pack, and not a warm pack. In addition, greater activation within bilateral insula was identified during the decision phase followed by a cold manipulation, contrasted to warm. These results suggest that the insula may be a key shared neural substrate that mediates the influence of temperature on trust processes.


Multiple diffusion indices reveals white matter degeneration in Alzheimer's disease and mild cognitive impairment: a tract-based spatial statistics study.
Alzheimer's disease (AD) is a progressive neurodegenerative disease involving the decline of memory and other cognitive functions. Mild cognitive impairment (MCI) represents a transition phase between normal aging and early AD. The degeneration patterns of the white matter across the brain in AD and MCI remain largely unclear. Here we used diffusion tensor imaging and tract-based spatial statistics (TBSS) to investigate white matter changes in multiple diffusion indices (e.g., fractional anisotropy, axial, radial and mean diffusivities) in both AD and MCI patients. Compared with the normal controls, the AD patients had reduced fractional anisotropy and increased axial, radial and mean diffusivities in widespread white matter structures, including the corpus callosum and the white matter of lateral temporal cortex, the posterior cingulate cortex/precuneus and the fronto-parietal regions. Similar white matter regions with reduced anisotropy were also found in MCI patients but with a much less extent than in AD. Between the AD and MCI groups, there were significant differences in the axial and mean diffusivities of the white matter tracts adjacent to the posterior cingulate cortex/precuneus without anisotropy changes. Taken together, our findings based upon multiple diffusion indices (FA, axial, radial and mean diffusivities) suggest distinct degeneration behaviors of the white matter in AD and MCI.


Association between lifestyle, parental smoke, socioeconomic status, and academic performance in Japanese elementary school children: the Super Diet Education Project.
Health and education are closely linked. However, few studies have explored the correlates of children's academic performance in Japan. We aimed to investigate comprehensively the associations of low academic performance among school children with lifestyles, parental smoke, and socioeconomic status. In 2016, children aged 6 to 13 years from the Super Diet Education School Project were surveyed using questionnaires. The survey explored the lifestyles and subjective academic performance of 1663 children and asked their parents about parental smoke and subjective socioeconomic status. Academic performance and socioeconomic status were divided into three levels. Then, we defined subjective academic performance in the lower two levels as low academic performance. The odds ratios (OR) were analyzed by logistic regression analysis. Among all participants, 299 (18.0%) children reported low academic performance. In general, low academic performance was significantly associated with late wakeup time (OR = 1.36 for 6:30 to < 7 a.m. and OR = 2.48 for ≥ 7 a.m.), screen time ≥ 2 h (OR = 1.35), studying at home < 1 h (OR = 1.82), paternal smoke (OR = 1.47), maternal smoke (OR = 1.87), and low socioeconomic status (OR = 1.48). Analyses stratified by grade showed stronger associations between academic performance and socioeconomic status in senior (OR = 1.62 for middle, OR = 1.52 for low in grades 4 to 6) than in junior children (OR = 1.15 for middle, OR = 1.38 for low in grades 1 to 3). Children's lifestyles, parental smoke, and socioeconomic status were significantly associated with low academic performance among Japanese children. Parents and health care providers should take these findings into consideration to prevent children from having low academic performance.


Distribution Pattern of Cell Division Centers on the Epidermis of Stem Segments of Torenia fournieri during de Novo Bud Formation.
The stem epidermis in Torenia fournieri, which has budding potentialialities, is composed of one cell layer which can be easily separated from the rest of the stem segment at different stages of bud formation. As the buds are formed directly from the epidermis, without intermediate callus formation, it is possible to observe simultaneously the cell division centers over the entire excised epidermal surface. The quantitative analysis at the 6-day stage of bud formation showed that the cell division centers do not have a random distribution on the epidermal surface. With respect to the length of the stem segment, the frequency of cell division centers increases toward the base which is also the direction of auxin transport. With respect to the width, the maximum number of division centers is observed on either side of the median zone. The median zone and the lateral zones have few division centers. An anatomical study showed that the zones with few division centers are the closest to underlying vascular tissue. A more uniform distribution of division centers can be obtained by addition of auxin to the medium.


Effects of theophylline, verapamil, and mannitol on oxygen consumption of ischemic rat kidneys.
This study was designed to determine, through the measurement of oxygen consumption (QO2), whether pretreatment and posttreatment with theophylline, verapamil, and mannitol provide protection from damage in the cortex and medulla of rat kidneys subjected to 60 and 120 minutes of ischemia. QO2 levels in both tissues were examined 1 day after each ischemia. After 60 minutes of ischemia, pretreatment with theophylline and verapamil primarily provided protection from ischemic change in cortical QO2. Pretreatment with mannitol provided protection from both cortical and medullary changes in QO2, but posttreatment with mannitol only protected cortical QO2. After 120 minutes of ischemia, only pretreatment with verapamil was effective in protecting cortical QO2 from ischemic injury. These observations demonstrate that theophylline, verapamil, and mannitol are effective in protecting renal QO2 in the ischemic kidney. During this study, it became clear that there were differences in the effectiveness of theophylline and verapamil on QO2 in the ischemic kidney between pretreatment and posttreatment, and also between the cortex and the medulla.


Primary ovarian cancer: prospective comparison of contrast-enhanced CT and pre-and postcontrast, fat-suppressed MR imaging, with histologic correlation.
Sixteen patients with clinically suspected malignant ovarian disease underwent contrast agent-enhanced computed tomography (CT) and magnetic resonance (MR) imaging in a prospective comparative study. MR imaging included fat-suppressed spin-echo and breath-hold FLASH (fast low-angle shot) before and after intravenous injection of gadopentetate dimeglumine. Histologic confirmation was obtained at laparotomy (n = 13) and biopsy (n = 3). Thirteen patients had histologically proven primary ovarian cancer. MR images showed the internal architecture of ovarian tumors better than CT in nine patients and equivalently in seven. MR images showed the relationship between ovarian tumors and adjacent pelvic structures (uterus [n = 9], sigmoid colon [n = 7], bladder [n = 7], and rectum [n = 3]) better than CT in nine patients and equivalently in seven. Intraabdominal extent of disease was better defined on MR than on CT images in nine patients, equivalently in six, and worse in one. Peritoneal metastases 1-2 cm in diameter were detected on MR images and missed on CT scans in six patients. In only one case did this result in a staging error with CT. The results suggest that MR imaging is at least equivalent and may be superior to CT in the evaluation of ovarian malignancy.


Eye preference for vigilance during feeding in coot Fulica atra, and geese Anser anser and Anser cygnoides.
Most research in avian brain lateralisation has been done using birds under laboratory conditions rather than natural settings. I studied eye preference during feeding in coot and geese when head position only allows use of one eye for vigilance. Birds regularly interrupt feeding to be vigilant. This behaviour is directed towards detecting predators. Recently, evidence was found that birds might perform some kind of "low-cost" vigilance even during feeding. Because coot and geese often turn their head to either side during feeding, laterality in head turning is expected to follow a consistent pattern in which the eye used for detecting predators should be less often directed towards the obstructive ground. Coot and geese were digitally videotaped and the number of pecks with either side oriented towards the ground at an angle of at least 45 degrees was counted. I found a strong bias in swan geese oriented their left eye towards the ground and thus using the right eye for vigilance during feeding. Coot showed a similar but less pronounced pattern, while in greylag geese no preference could be detected.


Systematic review and meta-analysis of randomized controlled trials evaluating primary care-based interventions to promote breastfeeding in low-income women.
Given the benefits of breastfeeding (BF), health care institutions recommend that a child should be breastfed for the first 6 months of its life. However, differences between social groups as regards BF behaviour are very prevalent. To identify effective programmes that can be implemented by GPs to promote BF in low-income women. A review of the literature was based on the Medline, Cochrane and Public Health databases (1985-2009), using index terms relating to BF, general medicine and social inequalities in health. Randomized controlled trials were included in our analysis. Two people independently selected which studies would be used by rating the quality of the articles. The results of these studies were presented in raw form and in terms of a pooled relative risk. We analysed 10 studies (of the 343 articles originally selected) involving a population of 1445 'mother and child' pairs. The studies that assessed ways of encouraging the initiation of any form of BF showed that educational programmes are effective [relative risk (RR) for starting BF, 1.46, 95% confidence interval (CI): 1.03-2.08]. As regards the studies that involved ways to encourage mothers to continue BF, the programmes used showed significant success rates after 3-month postpartum (RR: 1.15, 95% CI: 1.01-1.30). The successful programmes usually involved multiple 'short' follow-up appointments (<20 to 30 minutes). Educational programmes delivered in the context of ongoing personal contact with a health professional are effective in promoting BF in low-income women.


[Cancer incidence among petrochemical workers in the Porto Torres industrial area, 1990-2006].
Various epidemiological studies explored cancer mortality and incidence among petrochemical workers. We followed up cancer incidence in a cohort of 5350 male petrochemical workers in the industrial area of Porto Torres (Sardinia, Italy). The follow-up covered the period from 01/01/1990, when completeness of the cohort was certain and reference rates by the local Cancer Registry became available, up to 31/12/2006. Cohort members were subjects employed for six months or more in one of the chemical plants of the industrial area, alive as at 01/01/1990. Overall, a total of 81,392 person-years at risk were accumulated. The standardized incidence ratio (sir), as the ratio of observed to expected events, and its 95% confidence interval (CI) were calculated for all cancers and selected cancer sites, in the total cohort and in sub-cohorts of workers in plants where exposure to chemical agents evaluated in the IARC Monographs might have occurred. An increase in risk for all cancers was observed in the total cohort (596 cases; sir = 1.09; 95% CI 1.00-1.18), and it was highest for non-Hodgkin lymphoma (NHL, 26 cases: sir = 1.78; 95% CI 1.22-2.62). Risk for haemolymphatic cancer was highest in the sub-cohort of workers employed for 10 years or more, with a latency period of 20 years or longer, and among those employed in the manufacture and polymerization of vinyl chloride (VCM; all cancers, 51 cases: sir = 1.43; 95% CI 1.08-1.88; NHL, 4 cases: sir=4.06; 95% CI 1.64-10.0). Risk of haemolymphatic cancer was not significantly elevated in the sub-cohort potentially exposed to benzene. An excess risk of bladder cancer (RR = 1.46; 95% CI 1.09-1.96), but not of pleural cancer, was observed in the sub-cohort potentially exposed to asbestos. No significant increase in cancer risk was observed among workers potentially exposed to acrylonitrile, butadiene, or styrene. Our follow-up study of petrochemical workers showed an increase in risk for all cancers, and particularly NHL, apparently concentrated among workers potentially exposed to VCM


Fertility preservation in transgender and non-binary adolescents and young adults.
Although 37.5-51% of transgender adults state they would've considered freezing gametes before gender-affirming therapy if offered and 24-25.8% of transgender adolescents express interest in having biological children, less than 5% of transgender adolescents have opted for fertility preservation. We sought to assess fertility preservation utilization in our multidisciplinary adolescent gender clinic. We also aimed to identify fertility preservation utilization and interest among non-binary adolescents and young adults. A retrospective review was conducted of patients seen in the Stanford Pediatric & Adolescent Gender Clinic from October 2015 through March 2019 who were >10 years of age at initial visit. All individuals with documented discussion of fertility preservation were offered referral for formal fertility preservation consultation but only 24% of patients accepted. Only 6.8% of individuals subsequently underwent fertility preservation (n = 9). Transfeminine adolescents are more likely to pursue fertility preservation than transmasculine adolescents (p = 0.01). The rate of fertility preservation in non-binary adolescents did not significantly differ from those in transfeminine adolescents (p = 1.00) or transmasculine adolescents (p = 0.31). Although only one non-binary individual underwent fertility preservation, several more expressed interest with 36% accepting referral (n = 4) and 27% being seen in consultation (n = 3). Despite offering fertility preservation with designated members of a gender clinic team, utilization remains low in transgender adolescents. Additionally, non-binary adolescents and their families are interested in fertility preservation and referrals should be offered to these individuals. Further studies and advocacy are required to continue to address fertility needs of transgender adolescents.


Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification.
Despite the initial response, all patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). The EGFR-T790M secondary mutation is responsible for half of acquired resistance cases, while MET amplification has been associated with acquired resistance in about 5-15% of NSCLCs. Clinical findings indicate the retained addiction of resistant tumors on EGFR signaling. Therefore, we evaluated the molecular mechanisms supporting the therapeutic potential of gefitinib maintenance in the HCC827 GR5 NSCLC cell line harbouring MET amplification as acquired resistance mechanism. We demonstrated that resistant cells can proliferate and survive regardless of the presence of gefitinib, whereas the absence of the drug significantly enhanced cell migration and invasion. Moreover, the continuous exposure to gefitinib prevented the epithelial-mesenchymal transition (EMT) with increased E-cadherin expression and down-regulation of vimentin and N-cadherin. Importantly, the inhibition of cellular migration was correlated with the suppression of EGFR-dependent Src, STAT5 and p38 signaling as assessed by a specific kinase array, western blot analysis and silencing functional studies. On the contrary, the lack of effect of gefitinib on EGFR phosphorylation in the H1975 cells (EGFR-T790M) correlated with the absence of effects on cell migration and invasion. In conclusion, our findings suggest that certain EGFR-mutated patients may still benefit from a second-line therapy including gefitinib based on the specific mechanism underlying tumor cell resistance.


Access to health care. Part 1: Children.
This report presents national estimates of access to medical care and unmet health care needs for children through 17 years of age by selected sociodemographic variables including sex, age, race and/or ethnicity, family income, family structure, place of residence, and health status. In addition, the impact of children's health insurance status on access to care is described. Data from the 1993 Access to Care and Health Insurance questionnaires of the National Health Interview Survey (NHIS) are analyzed to examine access indicators. The NHIS is a continuing household survey of the civilian noninstitutionalized population of the United States. The sample included 16,907 children from infants through 17 years of age from 24,071 households. In 1993, over 7.3 million U.S. children had at least one unmet health care need or had medical care delayed because of worry about the cost of care. These health care needs included medical care, dental care, prescription medicine, glasses, and mental health care. In addition, almost 4.2 million children lacked a regular source of health care. Factors related to access indicators included health insurance, family income, race and/or ethnicity, family structure, and place of residence. The lack of health insurance or inability to afford care was the main reason given by respondents for children lacking a regular source of medical care. In the United States, millions of children do not receive needed health care services. Uninsured children and those in families with low income are at the greatest risk of having unmet health needs.


[APNEA OF PREMATURITY - PATHOPHYSIOLOGY, TREATMENT & PROGNOSIS].
Apnea of prematurity affects the majority of infants born before 34 weeks of complete gestation. Significant recurrent apnea of prematurity is associated with both short and long term complications and is a risk factor for increased mortality and neurodevelopmental disability. The current review discusses the recent advances in the understanding of the pathophysiology of apnea of prematurity, as well as the clinical questions relevant to physicians and staff treating infants with apnea of prematurity. Finally, we discuss monitoring and discharge decisions, and present recommendations following discharge from the neonatal intensive care unit.


Design, synthesis and properties of synthetic chlorophyll proteins.
A chemoselective method is described for coupling chlorophyll derivatives with an aldehyde group to synthetic peptides or proteins modified with an aminoxyacetyl group at the epsilon-amino group of a lysine residue. Three template-assembled antiparallel four-helix bundles were synthesized for the ligation of one or two chlorophylls. This was achieved by coupling unprotected peptides to cysteine residues of a cyclic decapeptide by thioether formation. The amphiphilic helices were designed to form a hydrophobic pocket for the chlorophyll derivatives. Chlorophyll derivatives Zn-methyl-pheophorbide b and Zn-methyl-pyropheophorbide d were used. The aldehyde group of these chlorophyll derivatives was ligated to the modified lysine group to form an oxime bond. The peptide-chlorophyll conjugates were characterized by electrospray mass spectrometry, analytical HPLC, and UV/visible spectroscopy. Two four-helix bundle chlorophyll conjugates were further characterized by size-exclusion chromatography, circular dichroism, and resonance Raman spectroscopy.


Topically applied ceramide accumulates in skin glyphs.
Ceramides (CERs), structural components of the stratum corneum (SC), impart essential barrier properties to this thin outer layer of the epidermis. Variations in CER species within this layer have been linked to several skin diseases. A recent proliferation of CER-containing topical skin-care products warrants the elucidation of CER penetration profiles in both healthy and diseased skin. In the current study, the spatial distributions of CER concentration profiles, following topical application of two species of CER, were tracked using infrared imaging. Suspensions of single-chain perdeuterated sphingosine and phytosphingosine CER in oleic acid were applied, in separate experiments, to the surface of healthy intact ex vivo human skin using Franz diffusion cells. Following either a 24- or 48-hour incubation period at 34°C, infrared images were acquired from microtomed skin sections. Both CER species accumulated in glyph regions of the skin and penetrated into the SC, to a limited extent, only in these regions. The concentration profiles observed herein were independent of the CER species and incubation time utilized in the study. As a result, a very heterogeneous, sparse, spatial distribution of CERs in the SC was revealed. In contrast, oleic acid was found to be fairly homogeneously distributed throughout the SC and viable epidermis, albeit at lower concentrations in the latter. A more uniform, lateral distribution of CERs in the SC would likely be important for barrier efficacy or enhancement.


Random Walk-Based Solution to Triple Level Stochastic Point Location Problem.
This paper considers the stochastic point location (SPL) problem as a learning mechanism trying to locate a point on a real line via interacting with a random environment. Compared to the stochastic environment in the literatures that confines the learning mechanism to moving in two directions, i.e., left or right, this paper introduces a general triple level stochastic environment which not only tells the learning mechanism to go left or right, but also informs it to stay unmoved. It is easy to understand, as we will prove in this paper, that the environment reported in the previous literatures is just a special case of the triple level environment. And a new learning algorithm, named as random walk-based triple level learning algorithm, is proposed to locate an unknown point under this new type of environment. In order to examine the performance of this algorithm, we divided the triple level SPL problems into four distinguished scenarios by the properties of the unknown point and the stochastic environment, and proved that even under the triple level nonstationary environment and the convergence condition having not being satisfied for some time, which are rarely considered in existing SPL problems, the proposed learning algorithm is still working properly whenever the unknown point is static or evolving with time. Extensive experiments validate our theoretical analyses and demonstrate that the proposed learning algorithms are quite effective and efficient.


Developmental expression patterns and regulation of connexins in the mouse mammary gland: expression of connexin30 in lactogenesis.
The mammary gland reaches a fully differentiated phenotype at lactation, a stage characterized by the abundant expression of beta-casein. We have investigated the expression and regulation of gap junction proteins (connexins, Cx) during the various developmental stages of mouse mammary gland. Immunohistochemical analysis, with specific antibodies, reveals that Cx26 and Cx32 are expressed and confined to the cell borders of luminal epithelial cells in all developmental stages of the gland. Cx26 and Cx32 expression, at the mRNA and protein levels, increases in pregnancy and peaks in lactation. Whereas Cx43 mRNA decreases in pregnancy and lactation, the functional activity of Cx43 protein, which has been localized to myoepithelial cells, is regulated (through phosphorylation) during pregnancy and peaks during lactation. Cx30 mRNA and proteins have, for the first time, been detected in mammary gland epithelia. Using reverse transcription/polymerase chain reaction and sequencing techniques, we show that Cx30 is abundant in pregnant and lactating mammary gland. Cx30 protein levels have not been detected in the mammary gland prior to day 15 of pregnancy, whereas maximum expression occurs at the onset of lactation. In mouse mammary cells in culture, Cx30 is epithelial-cell-specific and is induced by lactogenic hormones. These data identify a novel player in mammary differentiation and suggest a potential role for Cx30 in the fully differentiated gland.


Molecular cloning and characterization of the fructooligosaccharide-producing beta-fructofuranosidase gene from Aspergillus niger ATCC 20611.
The fopA gene encoding a fructooligosaccharide-producing beta-fructofuranosidase was isolated from Aspergillus niger ATCC 20611. The primary structure deduced from the nucleotide sequence showed considerable similarity to those of two other beta-fructofuranosidases from A. niger, but the fopA gene product had several amino acid insertions and an extra C-terminal polypeptide consisting of 38 amino acids that could not be found in the two others. We could successfully express the fopA gene in S. cerevisiae and the fopA gene product obtained from the culture supernatant of the S. cerevisiae transformant had similar characteristics to the beta-fructofuranosidase purified from A. niger ATCC 20611. However, we could not detect any beta-fructofuranosidase activity in either the culture supernatant or cell lysate when the C-terminal truncated fopA gene product by 38 amino acids was used to transform S. cerevisiae. In western analysis of those samples, there was no protein product that is cross-reacted with anti-beta-fructofuranosidase antibody. These results suggested that the C-terminal region of the fopA gene product consisting of 38 amino acids was essential for the enzyme production.


Impacted cancellous allografts and cement for revision total hip arthroplasty.
We report the results of using impacted cancellous allografts and cement for fixation of the femoral component when revision arthroplasty is required in the face of lost bone stock. In 56 hips reviewed after 18 to 49 months there were few complications and a majority of satisfactory results with evidence of incorporation of the graft. Further study and review are necessary, but the use of the method appears to be justified.


Glioma surgery: From preservation of motor skills to conservation of cognitive functions.
The first step of glioma treatment is surgery. Extent of resection (EOR) improves patient survival if surgery does not negatively impair a patient's neurological status. However, how surgery affects the patient's quality of life (QOL) has been less studied, especially as regards cognitive aspects. In our study, we retrospectively analyzed our cases with awake surgery. In all patients, surgical excision was stopped when active functions were intraoperatively identified. A neuropsychological assessment was performed both before and after surgery (5 days and 1 month after). Writing, motor speech, comprehension, expression, reading, pragmatics, attention, memory, problem solving and visuoperceptive functions were evaluated and scored with the NOMS scale. We found no differences in the median values of writing and motor speech, while there was a difference in the following variables: comprehension, expression, reading, pragmatics, attention, memory, problem solving and visuoperceptive functions. Moreover, the Dunn test did not show any difference between preoperative evaluation and evaluation performed 30 days after surgery regarding comprehension, expression, reading, pragmatics, attention, problem solving and visuoperceptive functions. However, there was a difference between preoperative and postoperative evaluation for memory. This retrospective study shows that awake surgery could be a reasonable possibility to preserve a patient's QOL achieving an EOR >82% of the Total Tumor Volume (Fluid-attenuated inversion recovery (FLAIR) hyperintense region in low-grade gliomas and enhancing nodules plus FLAIR hyperintense region in high-grade gliomas). In this series memory was the only aspect that had an impairment after surgery without a complete recovery at one month after surgery.