The factors that affect milk-to-serum ratio for iron during early lactation.
To determine the factors that affect milk iron content at the second week of lactation and whether the supplementation to lactating mother with iron might increase breast milk iron content between 2 weeks and 4 months postpartum. Healthy mothers were enrolled 10 to 20 days postpartum, if their babies were term, normal gestational age, and exclusive breastfed. Maternal blood samples for hemoglobin (Hb), iron, iron binding capacity, serum ferritin, and breast milk samples for iron and zinc were taken and mothers were randomized into iron supplemented and placebo groups. At the end of the fourth month, blood and milk samples were taken again. Forty-seven healthy mothers were included into the study. Milk iron content was lower; however, milk-to-serum iron ratio was higher in cases with low maternal iron reserves than cases with adequate iron reserves. Mothers with low Hb level (<12 g/dL) had higher milk zinc content and lower milk iron/zinc content than mothers with normal Hb value. Iron supplementation to lactating nonanemic mothers did not change milk iron content and the decline in milk iron content and milk-to-serum iron ratio. Milk iron content and milk-to-serum iron ratio of iron could be regulated by active transport in cooperation with maternal iron status.


Potent modulation of intestinal tumorigenesis in Apcmin/+ mice by the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase.
Intracellular polyamine pools are homeostatically maintained by processes involving biosynthesis, catabolism, and transport. Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N(1)-acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model. Herein, we examined the effects of differential SSAT expression on intestinal tumorigenesis in the Apc(Min/+) (MIN) mouse. When MIN mice were crossed with SSAT-overproducing transgenic mice, they developed 3- and 6-fold more adenomas in the small intestine and colon, respectively, than normal MIN mice. Despite accumulation of the SSAT product, N(1)-acetylspermidine, spermidine and spermine pools were only slightly decreased due to a huge compensatory increase in polyamine biosynthetic enzyme activities that gave rise to enhanced metabolic flux. When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype. Despite the loss in catabolic capability, tumor spermidine and spermine pools failed to increase significantly due to a compensatory decrease in biosynthetic enzyme activity giving rise to a reduced metabolic flux. Loss of heterozygosity at the Apc locus was observed in tumors from both SSAT-transgenic and -deficient MIN mice, indicating that loss of heterozygosity remained the predominant oncogenic mechanism. Based on these data, we propose a model in which SSAT expression alters flux through the polyamine pathway giving rise to metabolic events that promote tumorigenesis. The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers.


A simple assay method for determination of the specific radioactivity of the gamma-phosphate group of 32P-labelled ATP.
A simple and rapid assay method is described for determining the specific radioactivity of the gamma-phosphate group of 32P-labelled ATP. Labelled ATP is incubated with cyclic AMP, cyclic AMP-dependent protein kinase and histone H2A under conditions leading to maximum phosphorylation of the histone. The specific radioactivity of the gamma-phosphate group of the 32P-labelled ATP is calculated from the total amount of [32P]Pi incorporated into a standard amount of histone. This assay method uses inexpensive commercially available materials, and it yields an accurate specific radioactivity with as little as 0.25 nmol of 32P-labelled ATP.


Glutathione depletion prevents lipopolysaccharide-induced local skin inflammation.
We have previously shown that the thiol-oxidizing agent diethyl maleate prevents lipopolysaccharide (LPS)-induced up-regulation of endothelial cell intercellular adhesion molecule-1 (ICAM-1) in vitro. To determine the effect of glutathione depletion on the development of local skin inflammation in vivo, a model known to be dependent on ICAM-1. Swiss Webster mice were injected with intradermal LPS (30 micrograms) or isotonic saline solution. Mice were pretreated for 1 hour with intraperitoneal diethyl maleate (6 mmol/kg) or corn oil vehicle. Injection sites were harvested after 12 and 24 hours and evaluated for changes in vascular permeability and histological characteristics. To determine the mechanism underlying our findings, we evaluated skin ICAM-1 immunohistochemistry, levels of ICAM-1 protein and messenger RNA (mRNA), and neutrophil CD11b expression at the 24-hour point. Diethyl maleate significantly decreased the skin permeability index in a dose-dependent fashion at 24 hours but not at 12 hours. Skin histological examination under light microscopy showed a marked LPS-induced neutrophil infiltration at 24 hours, which was inhibited with diethyl maleate pretreatment. Immunohistochemical examination showed that diethyl maleate reduced ICAM-1 expression. In keeping with the hypothesized mechanism, diethyl maleate attenuated the LPS-induced up-regulation of ICAM-1 mRNA by 44%. Diethyl maleate also slightly but insignificantly reduced CD11b expression in vivo. Diethyl maleate markedly attenuates LPS-induced dermal inflammation, primarily through a reduction in ICAM-1 protein and mRNA expression. These data suggest that manipulation of the intracellular redox state may have a beneficial role in neutrophil-mediated inflammation.


Determination of vitamins A (retinol) and E (alpha-tocopherol) in foods by liquid chromatography: collaborative study.
A collaborative study was conducted for the determination of vitamins A and E. Existing AOAC liquid chromatographic (LC) methods are suited for specific vitamins A and E analytical applications. This method differs from existing methods in that it can be used to assay samples in all 9 sectors of the food matrix. Standards and test samples are saponified in basic ethanol-water solution, neutralized, and diluted, converting fats to fatty acids and retinol esters and tocopherol esters to retinol and tocopherol, respectively. Retinol and alpha-tocopherol are quantitated on separate LC systems, using UV detection at 313 or 328 nm for retinol, and fluorescence detection (excitation 290 nm, emission 330 nm) for alpha-tocopherol. Vitamin concentrations are calculated by comparison of the peak heights or peak areas of vitamins in test samples with those of standards.


Identification and analysis of expression of human VACM-1, a cullin gene family member located on chromosome 11q22-23.
We have localized the human homolog of the rabbit vasopressin-activated calcium-mobilizing receptor VACM-1 to a region close to the gene for ataxia telangiectasia ATM on chromosome 11q22-23. We have determined the complete amino acid sequence of the human Hs-VACM-1 protein, which is 780 amino acids long. The human and rabbit sequences are highly conserved, differing at only seven amino acids. Northern analysis of the human gene showed expression in a wide range of human tissues. The Hs-VACM-1 gene has homology with the Caenorhabditis elegans gene Ce-cul-5, a member of a family of cullin genes that are involved in cell cycle regulation and that might, when mutated, contribute to tumor progression.


Age of the bay of biscay: evidence from seismic profiles and bottom samples.
Paleomagnetic data and marine magnetic surveys suggest that the Bay of Biscay was created by rifting due to an anticlockwise rotation of the Iberian peninsula. The period during which movement occurred is not known precisely, but a rotation, amounting to 22 degrees, appears to have taken place in post-Eocene time. To provide independent evidence on the age of the rift, bottom samples from the Biscay abyssal plain have been related to the distribution of seismic reflectors within the sediments. The investigation shows that a large part of the Bay of Biscay was in existence in late Cretaceous times and that the data can be interpreted in terms of some early Tertiary rotation. However, the amount of possible Tertiary opening is appreciably less than the paleomagnetic results suggest. In view of the fact that reflectors of Middle-Upper Miocene age can be traced as undisturbed horizons across the bay, all tectonic movements must have ceased by the early Miocene.


How people explain their own and others' behavior: a theory of lay causal explanations.
A theoretical model is proposed that specifies lay causal theories of behavior; and supporting experimental evidence is presented. The model's basic assumption is that different types of behavior trigger different hypotheses concerning the types of causes that may have brought about the behavior. Seven categories are distinguished that are assumed to serve as both behavior types and explanation types: goals, dispositions, temporary states such as emotions, intentional actions, outcomes, events, and stimulus attributes. The model specifies inference rules that lay people use when explaining behavior (actions are caused by goals; goals are caused by higher order goals or temporary states; temporary states are caused by dispositions, stimulus attributes, or events; outcomes are caused by actions, temporary states, dispositions, stimulus attributes, or events; events are caused by dispositions or preceding events). Two experiments are reported. Experiment 1 showed that free-response explanations followed the assumed inference rules. Experiment 2 demonstrated that explanations which match the inference rules are generated faster and more frequently than non-matching explanations. Together, the findings support models that incorporate knowledge-based aspects into the process of causal explanation. The results are discussed with respect to their implications for different stages of this process, such as the activation of causal hypotheses and their subsequent selection, as well as with respect to social influences on this process.


Evaluation of bovine, cold-adapted human, and wild-type human parainfluenza type 3 viruses in adult volunteers and in chimpanzees.
In an attempt to evaluate the level of attenuation of live parainfluenza type 3 virus (PIV3) vaccine candidates, we compared the responses of partially immune adult volunteers inoculated intranasally with 10(6) to 10(7) 50% tissue culture infective dose (TCID50) of bovine PIV3 (n = 18) or cold-adapted (ca) PIV3 (n = 37) with those of 28 adults administered 10(6) to 10(7) TCID50 of wild-type PIV3. The candidate vaccine viruses and the wild-type virus were avirulent and poorly infectious for these adults even though all of them had a low level of nasal antibodies to PIV3. To determine whether the ca PIV3 was attenuated, we then administered 10(4) TCID50 of ca PIV3 (cold-passage 12) or wild-type PIV3 intranasally and intratracheally to two fully susceptible chimpanzees, respectively, and challenged the four primates with wild-type virus 1 month later. Compared with wild-type virus, which caused upper respiratory tract illness, the ca PIV3 was highly attenuated and manifested a 500-fold reduction in virus replication in both the upper and lower respiratory tracts of the two immunized animals. Despite restriction of virus replication, infection with ca PIV3 conferred a high level of protective immunity against challenge with wild-type virus. The ca PIV3 which had been passaged 12 times at 20 degrees C did not retain its ts phenotype. These findings indicate that ca PIV3 may be a promising vaccine candidate for human beings if a passage level can be identified that is genetically stable, satisfactorily attenuated, and immunogenic.


A multiscale simulation technique for molecular electronics: design of a directed self-assembled molecular n-bit shift register memory device.
A general method useful in molecular electronics design is developed that integrates modelling on the nano-scale (using quantum-chemical software) and on the micro-scale (using finite-element methods). It is applied to the design of an n-bit shift register memory that could conceivably be built using accessible technologies. To achieve this, the entire complex structure of the device would be built to atomic precision using feedback-controlled lithography to provide atomic-level control of silicon devices, controlled wet-chemical synthesis of molecular insulating pillars above the silicon, and controlled wet-chemical self-assembly of modular molecular devices to these pillars that connect to external metal electrodes (leads). The shift register consists of n connected cells that read data from an input electrode, pass it sequentially between the cells under the control of two external clock electrodes, and deliver it finally to an output device. The proposed cells are trimeric oligoporphyrin units whose internal states are manipulated to provide functionality, covalently connected to other cells via dipeptide linkages. Signals from the clock electrodes are conveyed by oligoporphyrin molecular wires, and μ-oxo porphyrin insulating columns are used as the supporting pillars. The developed multiscale modelling technique is applied to determine the characteristics of this molecular device, with in particular utilization of the inverted region for molecular electron-transfer processes shown to facilitate latching and control using exceptionally low energy costs per logic operation compared to standard CMOS shift register technology.


Oral contraceptives and thrombotic disease: risk of venous thromboembolism.
Studies conducted in the first three decades after discovery of a link between venous thromboembolism and oral contraceptive users showed a relative risk of first thrombosis during oral contraceptive use of 2.9 (95% CI 0.5-17). In recent studies in which the sub-50 micrograms ethinyl estrodiol containing pills were investigated comparing current users with non-users, the RR is 3.8 for non-fatal deep VTE and 2.7 for superficial VTE, deep VTE and pulmonary embolism (PE) together and 2.1 for fatal VT and PE together. The association is attributed to the estrogenic component and not related to duration of pill use. The risk disappears once the pill has been stopped, and it is not elevated among past users. Smoking does not appear to be risk factor for VTE; obesity and varicose veins are, at the most, weak risk factors. Since a causal relationship between OC use and VTE is tempting, clues for unraveling the mechanism were sought in the hemostatic system. Studies of the coagulation system found changes in the activation of coagulation and fibrinolytic compartments, but within the normal range. An epidemiologic study showed that the risk of VTE among women using OCs is 30-fold increased by the presence of a mutation of factor V, called Factor V Leiden (5% prevalence in the Caucasian population). Selective screening for the mutated factor V should be limited to women with a personal or family history of VTE. Four epidemiologic studies showed a two-fold increase in risk of VTE with the use of OCs containing third-generation progestins (gestodene and desogestrel), relative to second-generations products (levonorgestrel). Biases cannot devaluate the conclusion that the increased risk of VTE in especially first-time and younger users of third-generation OCs is highly likely. The clinical consequence is therefore that second-generation OCs are the first choice in prescription to first-time users.


Habituation of the cardiac response to involuntary diving in diving and dabbling ducks.
1. Bradycardia in response to forced submergence was habituated in dabbling (Anas platyrhynchos, Linnaeus) and diving (Aythya americana, Eyton) ducks by repetitively submerging the animals, each day for several days, for periods of 40 and 20 s, respectively. The onset of pronounced bradycardia was delayed with each successive trial, until little or no bradycardia occurred during submergence. Diving bradycardia is driven by chemoreceptors in the dabbler and caused by stimulation of narial receptors in the diver. 2. Mean arterial blood pressure in dives was unchanged from pre-dive levels in both naive and trained dabbling ducks. PaO2, PaCO2 and pHa at the end of a dive were similar before and after habituation training. 3. Bradycardia occurred in dives by habituated dabbling ducks if the animal breathed 15% O2 before submergence. The ventilatory responses to breathing high and low levels of oxygen were unaffected by habituation training. 4. The changes in blood gases during dives by naive and habituated dabbling ducks were the same: therefore, in the absence of a demonstrated decrement in receptor chemosensitivity or efferent potency, the locus of habituation must reside in the central nervous system.


Stability in controlling viral replication identifies long-term nonprogressors as a distinct subgroup among human immunodeficiency virus type 1-infected persons.
Long-term nonprogressors (LTNPs) of human immunodeficiency virus type 1 (HIV-1) infection are characterized by low levels of HIV-1 replication and viral load. However, it has not been established whether they differ in this regard from progressors from the very early stage of infection. By studying peripheral blood mononuclear cell (PBMC) specimens from a longitudinally monitored cohort of HIV-1-infected men, we found that HIV-1 proviral copy numbers and HIV-1 mRNA expression levels as low or lower than those seen in seven carefully selected LTNPs were commonly observed in specimens collected soon after seroconversion from 28 subjects who became infected while under observation. However, only the LTNPs were able to stably maintain such an efficient viral control over time. Because of the instability of the early control of HIV-1 replication, the predictive value of HIV-1 mRNA expression in PBMCs at postseroconversion was found to be limited but significantly increased during the first year of infection. Besides their diagnostic implications, these data support the idea that LTNPs may be a pathophysiologically distinct subgroup among persons infected with HIV-1.


Esophageal Expression of Active IκB Kinase-β in Mice Up-Regulates Tumor Necrosis Factor and Granulocyte-Macrophage Colony-Stimulating Factor, Promoting Inflammation and Angiogenesis.
IκB kinase-β (IKKβ) mediates activation of the nuclear factor-κB, which regulates immune and inflammatory responses. Although nuclear factor-κB is activated in cells from patients with inflammatory diseases or cancer, little is known about its roles in the development and progression of esophageal diseases. We investigated whether mice that express an activated form of IKKβ in the esophageal epithelia develop esophageal disorders. We generated ED-L2-Cre/Rosa26-IKK2caSFL mice, in which the ED-L2 promoter activates expression of Cre in the esophageal epithelia, leading to expression of a constitutively active form of IKKβ (IKKβca) in epithelial cells but not in inflammatory cells or the surrounding stroma (IKKβca mice). Mice lacking the Cre transgene served as controls. Some mice were given intraperitoneal injections of neutralizing antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) or tumor necrosis factor (TNF), or immunoglobulin G1 (control), starting at 1 month of age. Epithelial tissues were collected and analyzed by immunofluorescence, immunohistochemical, and quantitative real-time polymerase chain reaction assays. Transgenes were overexpressed from retroviral vectors in primary human keratinocytes. IKKβca mice developed esophagitis and had increased numbers of blood vessels in the esophageal stroma, compared with controls. Esophageal tissues from IKKβca mice had increased levels of GM-CSF. Expression of IKKβca in primary human esophageal keratinocytes led to 11-fold overexpression of GM-CSF and 200-fold overexpression of TNF. Incubation of human umbilical vein endothelial cells with conditioned media from these keratinocytes increased endothelial cell migration by 42% and promoted formation of capillary tubes; these effects were blocked by a neutralizing antibody against GM-CSF. Injections of anti-GM-CSF reduced angiogenesis and numbers of CD31+ blood vessels in esophageal tissues of IKKβca mice, but did not alter the esophageal vasculature of control mice and did not alter recruitment of intraepithelial leukocytes to esophageal tissues of IKKβca mice. Injections of anti-TNF prevented the development of esophagitis in IKKβca mice. Constitutive activation of IKKβ in the esophageal epithelia of mice leads to inflammation and angiogenesis, mediated by TNF and GM-CSF, respectively.


Illness perceptions of Libyans with T2DM and their influence on medication adherence: a study in a diabetes center in Tripoli.
The surrounding environment influences the constitution of illness perceptions. Therefore, local research is needed to examine how Libyan diabetes patients perceive diabetes and how their perceptions influence their medication adherence. A cross-sectional study was conducted at the National Centre for Diabetes and Endocrinology in Tripoli, Libya, between October and December 2013. A total of 523 patients with type 2 diabetes participated in this study. A self-administered questionnaire was used for data collection; this included the Revised Illness Perception Questionnaire and the eight-item Morisky Medication Adherence Scale. The respondents showed moderately high personal control and treatment control perceptions and a moderate consequences perception. They reported a high perception of diabetes timeline as chronic and a moderate perception of the diabetes course as unstable. The most commonly perceived cause of diabetes was Allah's will. The prevalence of low medication adherence was 36.1%. The identified significant predictors of low medication adherence were the low treatment control perception (p=0.044), high diabetes identity perception (p=0.008), being male (p=0.026), and employed (p=0.008). Diabetes illness perceptions of type 2 diabetic Libyans play a role in guiding the medication adherence and could be considered in the development of medication adherence promotion plans.


Has regional variation in mortality rates declined since 1931, and in all age groups, in Britain? A re-analysis using formal statistical modelling.
To examine changes in regional variance in all cause mortality rates in Great Britain from 1931-91 using formal statistical modelling procedures, and to follow up the suggestion by Illsley and Le Grand that there has been a reduction over time in the regional variance in younger but not older age groups. Data were the age and sex specific death rates around each census from 1931-91 for the British regions, reconstructed to make them comparable with the 1981 regional definitions. Regional variance was modelled using bootstrap simulation tests and by age-period and age-cohort models. While there was some evidence of a decline and levelling off of the regional variance over time in older age groups (over 35), the decline in younger age groups was more marked. This broadly confirms previous findings. Parametrising the period effect into linear and quadratic components, with allowance for an increase in regional variance in the war years, gave broadly comparable fit to the data as a model with period as a factor. Models for the changes in regional variance which were based on period effects seemed to provide a better description of the observed variances than those based on birth cohort effects. In the younger (but not older) groups there was evidence of a rise in the regional variance between 1981 and 1991. The decline in regional variance is larger in younger than in older age groups when allowance is made for the increase in regional variance over the war years. Statistical modelling can provide insights into the data which are not always detected by descriptive analyses. Moreover, they provide a capacity for generalisation beyond the particular data; relationships found can form the basis for studies of replicability, for example, in other countries.


Restriction of Moloney murine leukemia virus replication in Moloney murine sarcoma virus-infected cells.
MuSV349 is a TB-cell line which produces infectious MuSV with little or no MuLV detectable by the XC assay. The apparent restriction of MuLV replication in MuSV349 cells was investigated. A replication-competent helper virus, with protein composition nearly identical to that of Mo-MuLV was isolated from the viruses produced by MuSV349 cells. This helper MuLV after it was separated from MuSV and upon infection of TB cells produced viral titer similar to that of Mo-MuLV-infected TB cells indicating that its replication might have been restricted in the MuSV349 cells. To find out whether the suppression of the helper virus replication is due to the genetic peculiarities of the virus or MuSV349 cells, the relative amounts of MuLV and MuSV produced by several distinct clonal MuSV isolates (derived from a common progenitor) upon superinfection with Mo-MuLV were determined. The results of these experiments showed that while both SV7 and SV15F on coinfection with Mo-MuLV produced MuSV in excess over MuLV; and ts110 and tsSV13 on coinfection with Mo-MuLV produced MuLV in excess over MuSV. Since the same Mo-MuLV is used in these experiments and since upon transfer to a different cell, SV7, SV15F, and ts110 retain the property to restrict or not restrict MuLV replication it appears that the above property is determined by the genetics of the MuSV.


Gender and regional differences in perceived job stress across Europe.
Over the last 20 years stress at work has been found to be predictive of several conditions such as coronary heart disease, high blood pressure and non-specific sick leave. The Karasek demand/control/strain concept has been the most widely used in prospective epidemiological studies. To describe distribution in Karasek's demand/control (DC) dimensions as well as prevalence of strain in samples from different parts of Europe grouped into three regions (South, Middle, Sweden), adjusting for occupation. To describe gender differences in Karasek's DC dimensions along with strain prevalence and assess the regional stability of those differences in different occupational groups. The Job stress, Absenteeism and Coronary heart disease in Europe (JACE) study, a Concerted Action (Biomed I) of the European Union, is a multicentre prospective cohort epidemiological study: 38,019 subjects at work aged 35-59 years were surveyed at baseline. Standardised techniques were used for occupation coding (International Standardised Classification of Occupations) and for the DC model (Karasek scale): five items for the psychological demand and nine items for the control or decision latitude dimensions, respectively. A total of 34,972 subjects had a complete data set. There were important regional differences in the Karasek scales and in prevalence of strain even after adjustment for occupational class. Mean demand and control were higher in the Swedish centres when compared to two centres in Milano and Barcelona (Southern region) and values observed in four centres (Ghent, Brussels, Lille and Hoofddorp) in Middle Europe were closer to those observed in the Southern cities than to those obtained in the Swedish cities. Clerks (ISCO 4) and, more specifically, office clerks (ISCO 41) exhibited the smallest regional variation. In a multivariate model, the factor 'region' explained a small fraction of total variance. In the two Southern centres as well as in the four Middle European centres, men perceived marginally less job-demand as compared to women whereas the reverse was observed in the two Swedish centres. Differences were larger for control: men appeared to perceive more control at work than did women. In a multivariate model, gender explained a small fraction whereas occupational level explained a large fraction of the variance. In this standardised multicentre European study Karasek's DC model showed large gender and occupational differences whereas geographic region explained a small fraction of the total DC variance, notwithstanding large differences in labour market and working conditions as pointed out by the European Commission as recently as 2000.


Relationships between depressive symptoms and self-reported unintentional injuries: the cross-sectional population-based FIN-D2D survey.
There is a lack of knowledge on the influence of different levels of physical activity (PA) on unintentional injuries among those with depressive symptoms (DS). The aim of this study was to evaluate the relationship between PA categories and unintentional injuries among participants with and without DS based on a cross-sectional population-based FIN-D2D survey conducted in 2007. Out of 4500, 2682 participants (60%) aged 45-74 years attended in this study. The unintentional injuries over the past year were captured in a questionnaire. DS were determined with the Beck Depression Inventory (≥ 10 points) and PA with the International Physical Activity Questionnaire. The statistical significance between DS and unintentional injury categories was evaluated by using t-test, chi-square test, or permutation test, analysis of covariance, or regression models. The factors related to unintentional injuries were estimated by univariate and multivariate logistic regression models. The proportion of subjects with unintentional injuries was higher among those with DS (17%) compared to those without DS (10%) (age- and gender-adjusted p = 0.023). The median (range) number of activity-loss days after injury was 22 (0-365) in participants with DS and 7 (0-120) in participants without DS ( p = 0.009). The percentage of subjects with unintentional injuries was not significantly different between PA categories in participants with DS and without DS. A stepwise multivariate logistic regression analysis showed that DS, functional ability, and musculoskeletal diseases were related to unintentional injuries. PA level was not related to unintentional injuries, whereas those with DS had a higher prevalence of unintentional injuries and prolonged activity-loss after injury. These results underline the importance of injury prevention, especially among those who have DS and additional risk factors.


Development of an integrated cognitive-behavioral and social skills training intervention for older patients with schizophrenia.
There is considerable evidence that psychosocial treatments benefit younger adults with schizophrenia. However, no studies have been undertaken of such interventions for older patients with schizophrenia. This report describes the development of a novel integrated treatment combining cognitive-behavioral therapy (CBT) and social skills training (SST). This intervention is designed to address the needs of older patients with schizophrenia by challenging beliefs common in this population that interfere with treatment and by providing repetitive practice of behaviors to improve retention and skill development. The authors provide two case reports and pilot data suggesting benefits of this approach.


Preoperative monocyte-to-lymphocyte ratio as a potential predictor of bladder cancer.
The aim of this study was to investigate the role of preoperative Monocyte-to-Lymphocyte ratio (MLR) as a potential predictor of bladder cancer (BC). Clinical data of patients who underwent TURBT at our institution between 2017 and 2021 were collected and retrospectively analysed. MLR was obtained from preoperative blood analyses performed within 1 month from hospital admission. The association of MLR with different clinic-pathological features obtained from histological reports was further analysed. Statistical analysis was performed using the Kruskal Wallis test for non-parametric variables, assuming p<0.05 as statistically significant. 510 patients were included in the study (81% males, 19% females), with a mean age of 71.66 ± 11.64 years. Mean MLR was higher in patients with any-type bladder cancer, reporting an MLR of 0.41 ± 0.11 compared to 0.38 ± 0.43 in patients without bladder cancer (p=0.043). In the subsequent comparison among low-grade and high-grade bladder cancer, MLR did not report statistically significant differences, with 0.29 ± 0.12 for low-grade BC and 0.51 ± 0.81 for high-grade BC (p=0.085). Our findings reported elevated preoperative MLR should be considered a potential biomarker predicting malignancy for bladder tumours. Furthermore, research are necessary to assess its role in discerning low-grade from high-grade patients.


Solid-state NMR - a complementary technique for protein framework characterization.
Protein frameworks are an emerging class of biomaterial with medical and technological applications. Frameworks are studied mainly by X-ray diffraction or scattering techniques. Complementary strategies are required. Here, we report solid-state NMR analyses of a microcrystalline protein-macrocycle framework and the rehydrated freeze-dried protein. This methodology may aid the characterization of low-crystallinity frameworks.


Selective antimicrobial modulation of the intestinal microbial flora for infection prevention in patients with hematologic malignancies. Evaluation of clinical efficacy and the value of surveillance cultures.
To confirm the results obtained in an earlier study, the incidence of infection was evaluated in 54 patients (62 periods of admission), nursed in conventional rooms and given a regimen of antimicrobial agents intended to modulate the intestinal flora selectively as a method to prevent infection during severe granulocytopenia. In 62 patients receiving selective antimicrobial modulation (SAM), 18% acquired major infections which was similar to 19% in patients on SAM in an earlier double-blind placebo controlled study and lower than 47% in the controls. Evaluation of a large number of surveillance cultures showed that the presence of specific potentially pathogenic aerobic bacteria was associated with the occurrence of major infection. If the bacterial species in question were not found in the cultures the chance of becoming infected was less than 5%, whereas the chance ranged between 42 and 62% depending on the species involved when these microorganisms were isolated.


Total percutaneous cardiopulmonary bypass with Perclose ProGlide.
Suture-mediated closure devices have been previously described as an interesting alternative to femoral cutdown during endovascular aortic procedures. The insertion of two or three devices before the cannulation (preclose technique) permits successful percutaneous access also with a large sheath up to 24 Fr diameter. The main benefit of percutaneous access is a lower rate of complication at the groin. The same technique can be applied to cardiac procedures where femoral cannulation for cardiopulmonary bypass (CPB) is required. We report a series of 12 patients in whom total percutaneous CPB was successfully established using a Perclose ProGlide for the arterial access.


Orbital neurofibromatosis: involvement of the orbital floor.
Neurofibromatosis has been reported to involve the eye and orbit by causing irregularities of the sphenoid and other facial bones and enlargement of the foramina. To our knowledge, abnormalities of the orbital floor, however, have not been attributed to this disease in the literature until now. Two patients with neurofibromatosis had orbital floor involvement. Multiple neurofibromas eroding the orbital floor threatened vision in one patient. The other case, seen after trauma, had a condition simulating that of a blow-out fracture. Diagnostic workup with adequate roentgenography, especially tomography, helped to establish the diagnosis. We believe this is of importance in modifying the surgical approach, obviating the need for surgical intervention at times.


Treatments for seizures in catamenial (menstrual-related) epilepsy.
Catamenial epilepsy describes a worsening of seizures in relation to the menstrual cycle and may affect around 40% of women with epilepsy. Vulnerable days of the menstrual cycle for seizures are perimenstrually (C1 pattern), at ovulation (C2 pattern), and during the luteal phase (C3 pattern). A reduction in progesterone levels premenstrually and reduced secretion during the luteal phase is implicated in catamenial C1 and C3 patterns. A reduction in progesterone has been demonstrated to reduce sensitivity to the inhibitory neurotransmitter in preclinical studies, hence increasing risk of seizures. A pre-ovulatory surge in oestrogen has been implicated in the C2 pattern of seizure exacerbation, although the exact mechanism by which this surge increases risk is uncertain. Current treatment practices include the use of pulsed hormonal (e.g. progesterone) and non-hormonal treatments (e.g. clobazam or acetazolamide) in women with regular menses, and complete cessation of menstruation using synthetic hormones (e.g. medroxyprogesterone (Depo-Provera) or gonadotropin-releasing hormone (GnRH) analogues (triptorelin and goserelin)) in women with irregular menses.Catamenial epilepsy and seizure exacerbation is common in women with epilepsy, and may have a significant negative impact on quality of life. Women may not be receiving appropriate treatment for their seizures because of uncertainty regarding which treatment works best and when in the menstrual cycle treatment should be taken, as well as the possible impact on fertility, the menstrual cycle, bone health, and cardiovascular health. This review aimed to address these issues in order to inform clinical practice and future research. To evaluate the efficacy and tolerability of hormonal and non-hormonal treatments for seizures exacerbated by the menstrual cycle in women with regular or irregular menses. We synthesised the evidence from randomised controlled trials of hormonal and non-hormonal treatments in women with catamenial epilepsy of any pattern. We searched the following databases to 10 January 2019: Cochrane Register of Studies (CRS Web; includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL)), MEDLINE (Ovid: 1946 to 9 January 2019), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies. We included randomised and quasi-randomised controlled trials (RCTs) of blinded or opeṉlabel design that randomised participants individually (i.e. cluster-randomised trials were excluded). We included cross-over trials if each treatment period was at least 12 weeks in length and the trial had a suitable wash-out period. Types of interventions included: women with any pattern of catamenial epilepsy who received a hormonal or non-hormonal drug intervention in addition to an existing antiepileptic drug regimen for a minimum treatment duration of 12 weeks. We extracted data on study design factors and participant demographics for the included studies. The primary outcomes of interest were: proportion seizure-free, proportion of responders (at least 50% decrease in seizure frequency from baseline), and mean change in seizure frequency. Secondary outcomes included: number of withdrawals, number of women experiencing adverse events of interest (seizure exacerbation, cardiac events, thromboembolic events, osteoporosis and bone health, mood disorders, sedation, menstrual cycle disorders, and fertility issues), and quality of life outcomes. We identified 62 records from the databases and search strategies. Following title, abstract, and full-text screening, we included eight full-text articles reporting on four double-blind, placebo-controlled RCTs. We included two cross-over RCTs of pulsed norethisterone and two parallel RCTs of pulsed progesterone recruiting a total of 192 women aged between 13 and 45 years with catamenial epilepsy. We found no RCTs for non-hormonal treatments of catamenial epilepsy or for women with irregular menses.Meta-analysis was not possible for the primary outcomes, therefore we undertook a narrative synthesis. For the two RCTs evaluating norethisterone versus placebo (24 participants), there were no reported treatment differences for mean change in seizure frequency. Outcomes for the proportion seizure-free and 50% responders were not reported. For the RCTs evaluating progesterone versus placebo (168 participants), the studies reported conflicting results on the primary outcomes. One progesterone RCT reported no significant difference between progesterone 600 mg/day taken on day 14 to 28 and placebo with respect to 50% responders, seizure freedom rates, and change in seizure frequency for any seizure type. The other progesterone RCT reported that the decrease in seizure frequency from baseline in the progesterone group was significantly higher than the decrease in seizure frequency from baseline in the placebo group.Results of secondary efficacy outcomes showed no significant difference in terms of treatment withdrawal for any reason in the pooled progesterone RCTs when compared to placebo (pooled risk ratio (RR) 1.56, 95% confidence interval (CI) 0.81 to 3.00, P = 0.18, I2 = 0%) or for treatment withdrawals due to adverse events (pooled RR 2.91, 95% CI 0.53 to 16.17, P = 0.22, I2 = 0%). No treatment withdrawals from the norethisterone RCTs were reported. The RCTs reported limited information on adverse events, although one progesterone RCT reported no significant difference in the number of women experiencing adverse events (diarrhoea, dyspepsia, nausea, vomiting, fatigue, nasopharyngitis, dizziness, headache, and depression). No studies reported on quality of life.We judged the evidence from the included progesterone RCTs to be of low to moderate certainty due to risk of bias and from the included norethisterone RCTs to be of very low certainty due to serious imprecision and risk of bias. This review provides very low-certainty evidence of no treatment difference between norethisterone and placebo, and moderate- to low-certainty evidence of no treatment difference between progesterone and placebo for catamenial epilepsy. However, as all the included studies were underpowered, important clinical effects cannot be ruled out.Our review highlighted an overall deficiency in the literature base on the effectiveness of a wide range of other hormonal and non-hormonal interventions currently being used in practice, particularly for those patients who do not have regular menses. Further clinical trials are needed in this area.


Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement.
Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, age-associated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.


Infection stones. Evaluation and management.
Infection stones may be the cause of persistent or recurrent bacterial urinary infection. Evaluation of the infection and the character of the stones often aids in the selection of management and treatment options. The ultimate success of the treatment of infection stones should be measured, however, by control or removal of both the stone and the urinary infection.


Subcutaneous bupivacaine infiltration and postoperative pain perception after percutaneous nephrolithotomy.
Recent studies have shown a significant decrease in patient reported pain scores when the nephrostomy tube size is decreased from 22 to 10Fr. We hypothesize that patient reported pain and narcotic use could be further decreased for patients with post-percutaneous nephrolithotomy nephrostomy tubes if the incision is infiltrated with a local anesthetic. A randomized prospective trial was designed to assess the impact of Marcaine infiltration of the nephrostomy tract following percutaneous stone removal. Patients undergoing single access percutaneous nephrolithotomy were randomized to have a fixed volume of saline or weight based concentration of Marcaine infiltrated into the nephrostomy tube tract at the conclusion of the procedure. Postoperative narcotic use and patient reported pain scores were then obtained at 2, 4, 24 and 48 hours postoperatively. A total of 25 patients were enrolled in the study with 3 excluded from analysis due to incomplete data collection (2) or the development of hydrothorax (1). Of the 22 patients analyzed 10 were in the Marcaine cohort and 12 were in the saline cohort. Patient pain scores at 2, 4, 24 and 28 hours for the Marcaine group were 5, 4.2, 3.6 and 2.6, while for the saline group scores were 3.3, 3.1, 2.3 and 3.5. At all points differences between the groups were not statistically significant (p >0.05). Mean postoperative narcotic use was 24.7 mg morphine sulfate in the Marcaine group and 32.1 mg morphine sulfate in the control cohort (p >0.05). In this preliminary pilot study no significant differences in patient reported pain scores were observed. However, a trend toward decreased postoperative narcotic use was seen in patients receiving subcutaneous Marcaine administration around the nephrostomy tube tract. Further studies are warranted to define additional measures to reduce discomfort in those requiring nephrostomy tube drainage following percutaneous nephrolithotomy.


[Hashimoto encephalopathy: a case study].
The impact of thyroid hormones upon the proper function of central nervous system has been known for many years. The neurological symptoms and psychiatric disturbances may occur both in case of hypo- as well as hyperthyreosis. The encephalopathy Hashimoto (EH) described in this paper is a rare illness which occurs in case of patients suffering from the autoimmunological thyroid disease and increased level of antibodies in serum without any connections to the thyroid function. It is characterised by a variety of neurological symptoms and psychotic disturbances, acute state, high re-occurrence and good reaction to glicocorticosteroid treatment. Although we face encephalopathy Hashimoto extremely rarely in the clinical practice one should remember about it during the diagnostic process because when it is a long lasting untreated illness it may lead to the irreversible changes in the central nervous system.


[The Prevalence and Management of Pediculosis Capitis in Turkey: A Systematic Review].
This study aimed to examine scientific articles performed in Turkey on the prevalence and management of PK (diagnosis, contagion, prevention, treatment) from a critical perspective. The population of the systematic review consisted of total 63 published and unpublished theses or dissertations and peer-reviewed articles published in Turkish or English in national or foreign scientific journals from studies performed in Turkey between 1982 and 2012 years. It reached 578,938 people in 63 studies. Seventy-eight percent of the studies were related to the prevalence of PK and/or associated factors. The number of the studies was limited regarding diagnosis, prevention, contagion, treatment compliance, difficulties and causes of failure. Of the studies, 90.5% had been performed in public schools, almost exclusively elementary schools. The prevalence of PK was 0.3-34.1%, 0-35.4%, and it was 0.3-34.1% in elementary school children. It increased with years of education. It was double that of the boys in the girls (p<0.05). The prevalence among the subjects with low economic status were 1.9-42.3%, and it increased with worsening economic status (p<0.05). The prevalence reached up to 44.1% among children with illiterate mother. Basic recommendations include increasing the number of studies on the diagnosis, prevention, contagion, treatment compliance and efficacy, treatment failures and difficulties; public health workers also should prioritize investigation of head lice infestation.


Cost-effectiveness of tenecteplase versus alteplase for acute ischemic stroke.
Alteplase is widely used as an intravenous thrombolytic drug in acute ischemic stroke (AIS). Recently however, tenecteplase, a modified form of tissue plasminogen activator, has been shown to increase early recanalization rate and has proven to be non-inferior with a similar safety profile compared to alteplase. This study aims to evaluate the cost-effectiveness of 0.25 mg/kg tenecteplase versus 0.9 mg/kg alteplase for intravenous thrombolysis in AIS patients from the Dutch healthcare payer perspective. A Markov decision-analytic model was constructed to assess total costs, total quality-adjusted life year (QALY), an incremental cost-effectiveness ratio, and incremental net monetary benefit (INMB) of two treatments at willingness-to-pay (WTP) thresholds of €50,000/QALY and €80,000/QALY over a 10-year time horizon. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted to test the robustness of results. Clinical data were obtained from large randomized controlled trials and real-world data. Treatment with tenecteplase saved €21 per patient while gaining 0.05 QALYs, resulting in INMB of €2381, clearly rendering tenecteplase cost-effective compared to alteplase. Importantly, tenecteplase remained the cost-effective alternative in all scenarios, including AIS patients due to large vessel occlusion (LVO). Probabilistic sensitivity analysis proved tenecteplase to be cost-effective with a 71.0% probability at a WTP threshold of €50,000/QALY. Tenecteplase treatment was cost-effective for all AIS patients (including AIS patients with LVO) compared to alteplase. The finding supports the broader use of tenecteplase in acute stroke care, as health outcomes improve at acceptable costs while having practical advantages, and a similar safety profile.


Changes in viral suppression status among US HIV-infected patients receiving care.
To examine changes in viral suppression status among HIV patients receiving care in 2014 and the extent of viral suppression among persons with infrequent care visits. Using data reported to the National HIV Surveillance System from 33 jurisdictions with complete reporting of CD4 and viral load tests, we created four viral suppression status groups based on their first and last viral loads in 2014: both suppressed, first unsuppressed and last suppressed (improved), first suppressed and last unsuppressed (worsened), and both unsuppressed. We also calculated the number and percentage of persons whose sole viral load in 2014 was suppressed and had a suppressed viral load at their last test in 2013. Among 339 515 persons with at least two viral load tests in 2014, 72.6% had all viral loads suppressed (durably suppressed); 75.5% had the first and last tests suppressed, 10.5% improved, 4.2% worsened, and 9.9% had both unsuppressed. Among 92 309 persons who had only one viral load test in 2014, 69 960 (75.8%) were suppressed and, of those, 53 834 (76.9%) also had a suppressed viral load at their last test in 2013. National surveillance data show that the majority of patients in HIV care during 2014 were durably suppressed. More showed improved compared with worsened viral suppression status. Some patients who have less frequent care visits have sustained viral suppression. Yet one in 10 who was in regular care did not have a suppressed viral load in 2014, indicating missed opportunities for clinical interventions to help patients achieve and sustain viral suppression.


Interaction of bilirubin with sealed and human serum albumin-entrapped sealed membranes.
In order to study the mechanism of entry and localization of bilirubin (BR) into cell membrane, binding of BR to sealed and human serum albumin (HSA)-entrapped sealed membranes was studied by CD spectroscopy. An induced bisignate CD cotton effects (CDCEs) of BR-bound sealed membranes were observed with maxima at 515 nm and minima at 470 nm with a shoulder at 430 nm. BR-bound HSA-entrapped sealed membranes produced CD spectra with additional positive peaks at 450 and 475 nm and negative troughs at 390 and 415 nm. The induced CDCEs of BR-bound sealed membranes and BR-bound HSA-entrapped sealed membranes were perturbed by the addition of drugs (ceftriaxone and sodium salicylate) with the effect of ceftriaxone being more pronounced. Drugs' being the displacer of BR from albumin, their incorporation in the incubation mixture was paralleled by reduction in CDCEs. Taken together, these results suggest that BR can traverse the membrane bilayer towards the inner surface instead of remaining intercalated in the exterior half of the bilayer.


Enduring Behavioral Effects Induced by Birth by Caesarean Section in the Mouse.
Birth by Caesarean (C)-section impacts early gut microbiota colonization and is associated with an increased risk of developing immune and metabolic disorders. Moreover, alterations of the microbiome have been shown to affect neurodevelopmental trajectories. However, the long-term effects of C-section on neurobehavioral processes remain unknown. Here, we demonstrated that birth by C-section results in marked but transient changes in microbiome composition in the mouse, in particular, the abundance of Bifidobacterium spp. was depleted in early life. Mice born by C-section had enduring social, cognitive, and anxiety deficits in early life and adulthood. Interestingly, we found that these specific behavioral alterations induced by the mode of birth were also partially corrected by co-housing with vaginally born mice. Finally, we showed that supplementation from birth with a Bifidobacterium breve strain, or with a dietary prebiotic mixture that stimulates the growth of bifidobacteria, reverses selective behavioral alterations in C-section mice. Taken together, our data link the gut microbiota to behavioral alterations in C-section-born mice and suggest the possibility of developing adjunctive microbiota-targeted therapies that may help to avert long-term negative consequences on behavior associated with C-section birth mode.


Surgical management of left colon obstruction: the University of Minnesota experience.
Management of left-sided colonic obstruction is a surgical challenge. This study was performed to review our management of patients with left colon obstruction presenting to the University of Minnesota Hospitals over a 10-year period, 1985 to 1994. We did a retrospective chart review of 143 patients (48 male and 95 female; mean age 70 years). Sites of obstruction were rectosigmoid, 40%; sigmoid colon, 47%; descending colon, 5%; and splenic flexure, 8%. Fifty-two percent of patients had obstructing colorectal cancer. Two patients presented with generalized peritonitis secondary to colonic perforation. The majority (n = 121, 85%) of patients underwent resection (subtotal in 39 [32%], and segmental in 82 [68%]) and anastomosis in a single stage after appropriate resuscitation. Intraoperative colonic cleansing was undertaken in 40 patients (28%). Morbidity within 30 days of operation was 11%, including 1 anastomotic leak, and mortality was 3%. The 4 deaths occurred in patients over 75 years of age and were not from anastomotic complications. A single stage resection and an anastomosis facilitated by intraoperative colonic cleansing in one-third of cases was performed in 85% of patients presenting with left colon obstruction. One anastomotic leak occurred. Our current policy of strongly favoring a single stage, definitive operation for patients presenting with left colon obstruction appears reasonable on the basis of this retrospective review of our experience.


Superspreaders drive the largest outbreaks of hospital onset COVID-19 infections.
SARS-CoV-2 is notable both for its rapid spread, and for the heterogeneity of its patterns of transmission, with multiple published incidences of superspreading behaviour. Here, we applied a novel network reconstruction algorithm to infer patterns of viral transmission occurring between patients and health care workers (HCWs) in the largest clusters of COVID-19 infection identified during the first wave of the epidemic at Cambridge University Hospitals NHS Foundation Trust, UK. Based upon dates of individuals reporting symptoms, recorded individual locations, and viral genome sequence data, we show an uneven pattern of transmission between individuals, with patients being much more likely to be infected by other patients than by HCWs. Further, the data were consistent with a pattern of superspreading, whereby 21% of individuals caused 80% of transmission events. Our study provides a detailed retrospective analysis of nosocomial SARS-CoV-2 transmission, and sheds light on the need for intensive and pervasive infection control procedures.


Robustness evaluation of Intensity Modulated Proton Therapy plans using Dose Volume Population Histogram.
Under geometrical uncertainties, different plan evaluation methods have been suggested but the dose distribution at a specified confidence level being highly desirable is lacking. In this work, we used the DVPH (Dose Volume Population Histogram) tool to evaluate the dose distribution of CTVs and OARs (Organs at Risk) and validate the PTV concept at a certain confidence level. The plans were evaluated using PTV DVH and the DVPH approach. The DVPH approach is based on statistical analyzing of multiple CTV DVHs under geometrical errors with corresponding occurring probabilities. The random and systematic geometrical errors, assumed to follow a Gaussian distribution, are simulated by shifting the CT images. For target doses, the results showed that the minimum dose to PTV does not represent the minimum dose to the CTV. For two prostate cases, the minimum doses reduced from 98% and 95% of prescribed dose from PTV DVH to 89% and 92% of prescribed dose from CTV 90% CL-DVPH (90% Confidence Level-DVPH). This reduction was also seen in head and neck cases, from 95% to 68% and 74% of prescribed dose. For OAR doses, OAR DVHs underestimated the OAR dose receiving. With the DVPH tool, the results showed that the minimum dose to the PTV is not a representative of the minimum dose to the CTV in IMPT at the 90% confidence level. The OAR DVH does not match any OAR CL-DVPHs.


Secretion of stem cell factor and granulocyte-macrophage colony-stimulating factor by mouse embryos in culture: influence of group culture.
Previous studies showed that the addition of a growth factor to the culture medium could modulate embryo development. The possible secretion of different factors to the culture medium by the embryo itself, however, has been poorly evaluated. The present study was designed to investigate: (1) the influence of single or group culture on the development of 2-cell mouse embryos (strain CD-1) to the blastocyst stage; (2) the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF) into the culture medium by the embryo; and (3) the levels of GM-CSF and SCF in the culture medium from both single and group embryos. Two-cell CD-1 mouse embryos were cultured for 96 h singly or in groups of five embryos per drop. GM-CSF and SCF were assayed by ELISA in the complete culture medium. It was found that embryos cultured in groups gave a higher percentage of total blastocyst formation and hatched blastocyst when compared with single embryo culture. The mouse embryos secreted GM-CSF and SCF to the culture medium. The concentration of these cytokines is significantly higher in the group cultures than the level found in single cultures. In conclusion, mouse embryos in culture secrete GM-CSF and SCF to the culture medium and the concentration of these cytokines increases during communal culture. These factors may be operating in both autocrine and paracrine pathways to modulate embryo development during in vitro culture.


The core dimerization domains of histidine kinases contain recognition specificity for the cognate response regulator.
Histidine kinases DivJ and PleC initiate signal transduction pathways that regulate an early cell division cycle step and the gain of motility later in the Caulobacter crescentus cell cycle, respectively. The essential single-domain response regulator DivK functions downstream of these kinases to catalyze phosphotransfer from DivJ and PleC. We have used a yeast two-hybrid screen to investigate the molecular basis of DivJ and PleC interaction with DivK and to identify other His-Asp signal transduction proteins that interact with DivK. The only His-Asp proteins identified in the two-hybrid screen were five members of the histidine kinase superfamily. The finding that most of the kinase clones isolated correspond to either DivJ or PleC supports the previous conclusion that DivJ and PleC are cognate DivK kinases. A 66-amino-acid sequence common to all cloned DivJ and PleC fragments contains the conserved helix 1, helix 2 sequence that forms a four-helix bundle in histidine kinases required for dimerization, autophosphorylation and phosphotransfer. We present results that indicate that the four-helix bundle subdomain is not only necessary for binding of the response regulator but also sufficient for in vivo recognition specificity between DivK and its cognate histidine kinases. The other three kinases identified in this study correspond to DivL, an essential tyrosine kinase belonging to the same kinase subfamily as DivJ and PleC, and the two previously uncharacterized, soluble histidine kinases CckN and CckO. We discuss the significance of these results as they relate to kinase response regulator recognition specificity and the fidelity of phosphotransfer in signal transduction pathways.


Arylamine spider toxins antagonize NMDA receptor-mediated synaptic transmission in rat hippocampal slices.
The effects of arylamine spider toxins on synaptic transmission in rat hippocampal slices were investigated. Two different responses were monitored: the AMPA receptor-mediated population spike recorded in control buffer (selectively antagonized by DNQX) and the NMDA receptor-mediated EPSP recorded in nominally magnesium-free buffer containing 20 microM DNQX (selectively antagonized by AP5, AP7, and dizocilpine (MK-801)). The synthetic arylamine spider toxins JSTX-3, argiotoxin-636, and argiotoxin-659 were 26 to 73 times more potent at antagonizing the NMDA receptor-mediated EPSP (IC50 values ranging from 12 to 24 microM) than the AMPA receptor-mediated population spike (IC50 values ranging from 612 to 878 microM). These results indicate that arylamine spider toxins are selective antagonists of NMDA receptors in the mammalian CNS.


17beta-estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall.
Estrogens have direct effects on the vascular wall that may prevent the development of atherosclerosis. In particular, estrogens, such as 17beta-estradiol (estradiol), are known to have potent antioxidant activity. Tumor necrosis factor-alpha (TNF) is found in human atheroma and produces oxygen-derived free radicals. These oxygen-derived free radicals may modify low density lipoproteins (LDL) and increase LDL binding in the artery wall. We asked: 1) does TNF increase LDL accumulation in the artery wall and 2) can the TNF-mediated increase in LDL accumulation be prevented by the antioxidant activity of estradiol? Carotid arteries from ovariectomized 3-month-old rats were removed and perfused with fluorescently labeled LDL and arterial LDL flux was measured using quantitative fluorescence microscopy. In six arteries, addition of TNF (10 ng/ml) to the perfusate resulted in a 2.3-fold increase in the rate of LDL accumulation (1.50 +/- 0.37 ng/min per cm2 vs. 3.38 +/- 0.48 ng/min per cm2; P < 0.01). Estradiol (65 pg/ml) and alpha-tocopherol (6 mg/L) both attenuated TNF-mediated LDL accumulation (P < 0.05), indicating that TNF may exert its effects on LDL accumulation through cellular production of oxygen-derived free radicals. These results support an antioxidant role for estradiol in the protection against LDL accumulation in the artery wall and subsequent progression of atherosclerosis.


Direct manipulation of intracellular stress fibres using a hook-shaped AFM probe.
Atomic force microscopy (AFM) is a highly successful technique for imaging nanometre-sized samples and measuring pico- to nano-newton forces acting between atoms and molecules. When it comes to the manipulation of larger samples with forces of tens and hundreds of nano-newtons, however, the present chemistry-based modification protocols for functionalizing AFM cantilevers to achieve the formation of covalent/non-covalent linkages between the AFM probe and the sample surface do not produce strong enough bonds. For the purpose of measuring the fracture strength and other mechanical properties of stress fibres (SFs) in living as well as semi-intact fibroblast cells, we fabricated an AFM probe with a hooking function by focused ion beam technology and used the AFM probe hook to capture, pull and eventually sever a chosen SF labelled with green or red fluorescent protein.


Successful treatment of chronic hepatitis C virus infection in a patient receiving daily peritoneal dialysis.
Successful use of a 4-drug oral fixed-dose combination therapy to treat chronic hepatitis C in a patient receiving peritoneal dialysis (PD) is reported. New highly effective treatments for chronic hepatitis C virus (HCV) infection are now available, but safety and efficacy data on the use of anti-HCV therapies in patients with renal failure, particularly those requiring PD, remain limited. A 73-year-old black man with chronic HCV genotype 1a infection and stage 5 chronic renal disease requiring daily automated PD was referred for HCV treatment prior to renal transplantation. HCV treatment was initiated with paritaprevir-ritonavir-ombitasvir- dasabuvir, or "PrOD" (a combination tablet containing paritaprevir 75 mg, ritonavir 50 mg, and ombitasvir 12.5 mg to be taken once daily and a dasabuvir sodium 250-mg tablet to be taken twice daily), in conjunction with ribavirin 200 mg once daily. After a 12-week course of PrOD therapy, during which ribavirin therapy was tapered and then discontinued at week 10 and subcutaneous epoetin alfa was administered for anemia control from weeks 4 to 12, the patient's HCV viral load was undetectable; a sustained virologic response at 12 weeks (SVR12) was noted. A patient with end-stage renal disease requiring PD was treated successfully for HCV genotype 1a infection with PrOD fixed-dose combination therapy plus ribavirin therapy. The patient achieved an SVR12 despite withdrawal of ribavirin at treatment week 10, with minimal adverse effects reported.


[Lipid peroxidation in the blood of patients with suppurative meningitis].
It is shown that the dynamics of lipid peroxidation (LPO) in patients with purulent meningitis is unspecified in character and is encountered both in meningococcal and pneumococcal infection. The level of secondary LPO products and the degree of hyperfermentemia, which are determined according to the dynamics of changes in the activity of aspartate transaminase, are objective characteristics of the severity of the patient's condition and reach maximum on the 5th day of the disease. The correlation between the dynamics of the primary LPO products and the ceruloplasmin/transferin coefficient allows the severity of the disease to be prognosticated.


Is a quantitative risk assessment of air quality in underground parking garages possible?
Little information is available about the health risks associated with time spent in underground parking garages. The objective of this study was to determine whether it is possible to quantify the health risks associated with these garages without epidemiologic data on the subject. We followed the standard procedure for health risk assessment. We searched the literature for pollutant concentrations in the air samples of underground parking garages, the hazards associated with their inhalation, and their toxicological reference values. Conditions of occupational and user exposure were estimated by scenarios and taken into account to discuss toxicological reference values by modifying (with Haber's law) the adjustment factors for exposure frequency and duration. Risk quantification was possible for 39 pollutants. Acute exposures to CO and NO2 exceed toxicological reference values, as does chronic exposure to benzene for threshold effects. The risk of a carcinogenic effect associated with benzene may be greater than 10(-5). Excess exposure to air pollution indicators (PM and NO2) is also elevated, judging by the WHO Air Quality Guidelines, and also when comparing to levels with reported effects in epidemiologic studies. The risk associated with underground parking garages can be evaluated only in part. The information available is nonetheless sufficient to justify actions to reduce exposure. The risks associated with exposure in underground parking garages cannot be thoroughly evaluated because of inadequate knowledge of exposures and of the toxicity of pollutants. The available knowledge is nonetheless sufficient to advise that risk management measures should be taken to reduce both acute and chronic exposures.


Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission.
Prophylactic cranial irradiation halves the rate of brain metastases in patients with small cell lung cancer. Individual randomized trials conducted on patients in complete remission were unable to clarify whether this treatment improves survival. This study aims to test whether prophylactic cranial irradiation prolongs survival of patients with small cell lung cancer in complete remission. Published and unpublished trials were eligible. Electronic databases, reference lists of trial publications, review articles and relevant books were used to identify potentially eligible trials. The search was also guided by discussions with investigators and experts, and the examination of meeting proceedings and of the Physician Data Query clinical trial registry. Randomized trials comparing prophylactic cranial irradiation with no prophylactic cranial irradiation in patients with small cell lung cancer in complete remission. Meta-analysis based on updated individual data. The main endpoint was survival. The relative risk of death in the treatment group compared to the control group was 0.84 (95% confidence interval=0.73 to 0.97, P=0.01), corresponding to a 5.4 percent increase in the 3-year survival rate (from 15.3 percent in the control group to 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased disease-free survival (relative risk=0.75, 95% confidence interval=0.65 to 0.86, P<0.001) and decreased the risk of brain metastases (relative risk=0.46, 95% confidence interval=0.38 to 0.57, P<0.001). Increasing doses of irradiation decreased the risk of brain metastases when four groups (8 Gy, 24-25 Gy, 30 Gy, 36-40 Gy) were analyzed [trend test, P=0.02], but the effect on survival did not differ significantly according to the dose. We found a trend (P=0.01) for a decrease in the brain metastasis risk in favour of earlier administration of cranial irradiation after the initiation of induction treatment. Prophylactic cranial irradiation significantly improves survival and disease-free survival for patients with small cell lung cancer in complete remission. Further clinical trials are needed to confirm the potential greater benefit on brain metastasis rate suggested when cranial irradiation is given earlier or at higher doses.


Synthesis and Characterization of Novel 1,3-Diaryltriazene-Substituted Sulfaguanidine Derivatives as Selective Carbonic Anhydrase Inhibitors: Biological Evaluation, in Silico ADME/T and Molecular Docking Study.
Sulfonamide compounds known as human carbonic anhydrase (hCA) inhibitors are used in the treatment of many diseases such as epilepsy, antibacterial, glaucoma, various diseases. 1,3-diaryl-substituted triazenes and sulfaguanidine are used for therapeutic purposes in many drug structures. Based on these two groups, the synthesis of new compounds is important. In the present study, the novel 1,3-diaryltriazene-substituted sulfaguanidine derivatives (SG1-13) were synthesized and fully characterized by spectroscopic and analytic methods. Inhibitory effect of these compounds on the hCA I and hCA II was screened as in vitro. All the series of synthesized compounds have been identified as potential hCA isoenzymes inhibitory with KI values in the range of 6.44±0.74-86.85±7.01 nM for hCA I and with KI values in the range of 8.16±0.40-77.29±9.56 nM for hCA II. Moreover, the new series of compounds showed a more effective inhibition effect than the acetazolamide used as a reference. The possible binding positions of the compounds with a binding affinity to the hCA I and hCA II was demonstrated by in silico studies. In conclusion, compounds with varying degrees of affinity for hCA isoenzymes have been designed and as selective hCA inhibitors. These compounds may be potential alternative agents that can be used to treat or prevent diseases associated with glaucoma and hCA inhibition.


SpeS: A Novel Superantigen and Its Potential as a Vaccine Adjuvant against Strangles.
Bacterial superantigens (sAgs) are powerful activators of the immune response that trigger unspecific T cell responses accompanied by the release of proinflammatory cytokines. Streptococcus equi (S. equi) and Streptococcus zooepidemicus (S. zooepidemicus) produce sAgs that play an important role in their ability to cause disease. Strangles, caused by S. equi, is one of the most common infectious diseases of horses worldwide. Here, we report the identification of a new sAg of S. zooepidemicus, SpeS, and show that mutation of the putative T cell receptor (TCR)-binding motif (YAY to IAY) abrogated TCR-binding, whilst maintaining interaction with major histocompatibility complex (MHC) class II molecules. The fusion of SpeS and SpeSY39I to six S. equi surface proteins using two different peptide linkers was conducted to determine if MHC class II-binding properties were maintained. Proliferation assays, qPCR and flow cytometry analysis showed that SpeSY39I and its fusion proteins induced less mitogenic activity and interferon gamma expression when compared to SpeS, whilst retaining Antigen-Presenting Cell (APC)-binding properties. Our data suggest that SpeSY39I-surface protein fusions could be used to direct vaccine antigens towards antigen-presenting cells in vivo with the potential to enhance antigen presentation and improve immune responses.


[The clinical evaluation of kidney trauma: the practical indications for complementary examinations].
The aim of the present work is to try to know the clinical data that can provide directions on the attitude to take with patients who seek advise with a suspicion of renal traumatism, thus allowing to select those that may require complementary examination. This is a retrospective revision of 190 cases of renal trauma admitted in our hospital between 1971 and 1992. We rated 3 large syndrome groups based on the patient's major signs and symptoms. The first indication in 71 patients was haemorrhagic syndrome (shock or anaemia); 100 patients had microscopic or gross haematuria non-associated to anaemia; and 6 patients showed painful signs and symptoms. Existence of renal injury should be suspected in patients that came to the hospital with a background of trauma, microscopic or gross haematuria, shock with or without haematuria or intraabdominal lesions; the performance of complementary examinations is necessary in patients with evidence of gross haematuria, microscopic haematuria associated to shock or suspected associated extra-renal intra-abdominal lesions, or shock whether or not associated to haematuria.


Protein-DNA interactions in vivo upstream of a cell cycle-regulated human H4 histone gene.
Cell cycle-dependent histone genes are transcribed at a basal level throughout the cell cycle, with a three- to fivefold increase during early S phase. Protein-DNA interactions in the 5' promoter region of a cell cycle-regulated human H4 histone gene have been analyzed at single-nucleotide resolution in vivo. This region contains two sites, with four potential protein-binding domains, at which the DNA is protected from reaction with dimethyl sulfate in cells and from digestion with deoxyribonuclease I in nuclei. These protein-DNA interactions persist during all phases of the cell cycle and dissociate with 0.16 to 0.2M sodium chloride.


Synthesis, Characterization, and Pharmacodynamics Study of Enrofloxacin Mesylate.
Enrofloxacin is used in the treatment of a wide variety of bacterial infections in mammals. However, its poor solubility limits the clinical use. In order to improve the solubility of enrofloxacin, the enrofloxacin mesylate (EM) were obtained by a chemical synthesis method. The characterization of EM was carried out using ultraviolet scan (UV), synchronous thermal analysis (SDT), fourier transform infrared spectrometer (FTIR) and mass spectrometry (MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction analysis (XRPD). Acute toxicity of EM in Kunming mice was studied. Besides, pharmacokinetic studies were performed in New Zealand rabbits at a single oral dose of 10 mg/kg, and the antibacterial activity of EM was also evaluated. EM was successfully synthesized and purified. The stoichiometric ratio of mesylate to enrofloxacin was 1:1 and the aqueous solubility of EM was 483.01±4.06 mg/mL, the solubility of EM was about 2000 times higher than enrofloxacin. The oral lethal dose (LD50) of EM was 1168.364 mg/kg, and the pharmacokinetics indicated that the oral relative bioavailability of EM was about 1.79 times and 1.48 times higher than that of enrofloxacin and enrofloxacin hydrochloride, respectively. In addition, the in vitro antibacterial activity of EM was not significantly changed compared with enrofloxacin and enrofloxacin hydrochloride. EM has higher solubility, low toxicity for oral use, and increases the oral bioavailability in rabbit. This study may be of benefit for the development of new enrofloxacin drugs.


[The action of sanatorium-health resort treatment on autonomic endocrine regulation in children with functional changes in cardiac activity].
During sanatorium treatment children with cardiac disturbances developed equilibrium between adrenergic and cholinergic effects on cardiac activity. Vegetative dysfunctions declined. There was a positive trend in glucocorticoid and thyroid conditions. Individual application regimens of mud and galvanic mud therapy have been designed basing on changes in the vegeto-endocrine status.


[Sulpiride and depression].
For many years the antidepressive or uninhibiting effect of sulpiride has been a subject of controversy. Following recent reports underscoring an antidepressive action of sulpiride with mood inversion, we have studied 17 patients with depression in order to build a personal opinion. With a daily dosage of 150 mg, a satisfactory response was recorded in overall pathology in 76.5% of cases, and in depressive manifestations in 82% of cases. Therefore, we believe that sulpiride does have an antidepressive action, which begins approximately on the tenth day of treatment, while the uninhibiting effect becomes noticeable on the fifth day. It is to be pointed out that, among the 12 patients who had failed to respond to prior therapy with tricyclic antidepressants, 10 responded very satisfactorily to sulpiride.


The effect of exogenous cortisol during sleep on the behavioral and neural correlates of emotional memory consolidation in humans.
A host of animal work demonstrates that the retention benefit for emotionally aversive over neutral memories is regulated by glucocorticoid action during memory consolidation. Particularly, glucocorticoids may affect systems-level processes that promote the gradual reorganization of emotional memory traces. These effects remain largely uninvestigated in humans. Therefore, in this functional magnetic resonance imaging study we administered hydrocortisone during a polysomnographically monitored night of sleep directly after healthy volunteers studied negative and neutral pictures in a double-blind, placebo-controlled, between-subjects design. The following evening memory consolidation was probed during a recognition memory test in the MR scanner by assessing the difference in brain activity associated with memory for the consolidated items studied before sleep and new, unconsolidated items studied shortly before test (remote vs. recent memory paradigm). Hydrocortisone administration resulted in elevated cortisol levels throughout the experimental night with no group difference at recent encoding or test. Behaviorally, we showed that cortisol enhanced the difference between emotional and neutral consolidated memory, effectively prioritizing emotional memory consolidation. On a neural level, we found that cortisol reduced amygdala reactivity related to the retrieval of these same consolidated, negative items. These findings show that cortisol administration during first post-encoding sleep had a twofold effect on the first 24h of emotional memory consolidation. While cortisol prioritized recognition memory for emotional items, it reduced reactivation of the neural circuitry underlying emotional responsiveness during retrieval. These findings fit recent theories on emotional depotentiation following consolidation during sleep, although future research should establish the sleep-dependence of this effect. Moreover, our data may shed light on mechanisms underlying potential therapeutic effects of cortisol administration following psychological trauma.


The influence of prenatal intimate partner violence exposure on hypothalamic-pituitary-adrenal axis reactivity and childhood internalizing and externalizing symptoms.
This prospective longitudinal study examines the long-term influence of intimate partner violence (IPV) exposure in utero. We hypothesized that (a) prenatal IPV increases risk for internalizing and externalizing problems as well as for a profile of dysregulated cortisol reactivity, and (b) patterns of cortisol hyper- and hyporeactivity are differentially associated with internalizing and externalizing problems. The participants were 119 10-year-old children. Their mothers reported their IPV experiences and distress during pregnancy. Child and maternal reports of internalizing and externalizing problems as well as lifetime IPV exposure were obtained. Salivary cortisol was assessed at baseline, 20 min, and 40 min after challenge. The results partially supported our hypotheses: Exposure to IPV during pregnancy predicted child-reported internalizing and externalizing problems, mother ratings of child externalizing problems, and a profile of high cortisol secretion before and after stress challenge. The results were significant above and beyond the influence of maternal distress during pregnancy and IPV that occurred during the child's life. In addition, a profile of high cortisol secretion was associated with maternal reports of child internalizing behaviors. Findings support the growing consensus that prenatal stress can lead to lasting disruptions in adaptation and highlight the need for more longitudinal examinations of prenatal IPV exposure.


Comparison of Carotid Endarterectomy and Stenting for Symptomatic Internal Carotid Artery Near-Occlusion.
Carotid near-occlusion is defined as severe stenosis of the internal carotid artery with partial or full collapse of the distal vessel wall. The major studies evaluating carotid revascularization excluded patients with carotid near-occlusion. Given the paucity of data in the literature, we attempted to evaluate the safety of carotid endarterectomy and carotid artery stenting in carotid near-occlusion. A retrospective data base review was performed from January 2010 to December 2018 to identify patients who underwent carotid endarterectomy or carotid artery stenting for symptomatic ICA near-occlusion and had 1-month clinical and imaging follow-up with carotid sonography. The medical records and imaging studies of patients with ICA near-occlusion were selected for analysis. Forty-five patients met the criteria for ICA near-occlusion, of whom 39 were included in the study, given insufficient 1-month follow-up on 6 patients. Of the 39 patients, 25 underwent carotid endarterectomy and 14 underwent carotid artery stenting. All patients had technically successful immediate revascularization of the ICA. Most (33 of 39) had 1-year follow-up postoperatively. Patients with carotid artery stenting had 20% restenosis and 79% vessel maturation rates, while patients with carotid endarterectomy had 17.4% restenosis and 84% vessel maturation. There was no significant difference in periprocedural complication rates between the 2 procedures. Carotid artery stenting shows similar outcomes in restenosis and vessel maturation rates compared with carotid endarterectomy for ICA near-occlusion. There were no major differences between the 2 treatments in clinical outcomes or periprocedural complications. Carotid artery stenting is a revascularization option for carotid near-occlusion if the patient is considered at high risk for carotid endarterectomy.


Vascular endothelial growth factor gene expression in human fetal lung in vitro.
Neonatal respiratory function depends on the development of a well-formed pulmonary capillary bed. Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial cell growth and angiogenesis. High levels of VEGF protein and messenger RNA (mRNA) have been detected in the developing lung, suggesting that VEGF plays a role in the development of the pulmonary capillary bed. To begin to understand the role of VEGF in human lung development, we explored the regulation of VEGF gene expression and the localization of VEGF protein and mRNA in a model of the developing human lung. VEGF protein and mRNA were detected in midtrimester human fetal lung tissue, and their levels increased with time in explant culture. VEGF protein and mRNA were increased by the maintenance of human fetal lung explants in 2% O2 environments compared with 20% O2 environments. VEGF mRNA levels were found to be increased by cyclic adenosine monophosphate (cAMP) in explants that were incubated in 20% O2, but not in those incubated in 2% O2. Immunostaining for VEGF protein demonstrated localization primarily in airway epithelial cells in midtrimester human fetal lung tissue. Immunostaining for VEGF increased with incubation of human fetal lung explants in 2% and 20% O2. Interestingly, VEGF protein was localized primarily in the basement membrane subjacent to airway epithelial cells after 4 d of incubation in 20% O2. Incubation of tissues in the presence of dibutyryl cAMP resulted in an increase in immunostaining for VEGF, primarily in the basement membranes of prealveolar ducts in 20% O2-treated tissues. In situ hybridization studies indicated that VEGF mRNA was present in both mesenchymal cells and airway epithelial cells. These data suggest that VEGF gene expression is regulated by both oxygen and cAMP in the developing human lung. The detection of VEGF mRNA and protein in distal airway epithelial cells and the detection of VEGF protein in the basement membrane subjacent to the airway epithelial cells suggest that translocation of VEGF protein occurs after its synthesis in the epithelium. Localization of VEGF to the basement membrane of airway epithelial cells may be important for directing capillary development in the human lung.


Stable formation of compositionally unique stress granules in virus-infected cells.
Stress granules are sites of mRNA storage formed in response to a variety of stresses, including viral infections. Here, the mechanisms and consequences of stress granule formation during poliovirus infection were examined. The results indicate that stress granules containing T-cell-restricted intracellular antigen 1 (TIA-1) and mRNA are stably constituted in infected cells despite lacking intact RasGAP SH3-domain binding protein 1 (G3BP) and eukaryotic initiation factor 4G. Fluorescent in situ hybridization revealed that stress granules in infected cells do not contain significant amounts of viral positive-strand RNA. Infection does not prevent stress granule formation in response to heat shock, indicating that poliovirus does not block de novo stress granule formation. A mutant TIA-1 protein that prevents stress granule formation during oxidative stress also prevents formation in infected cells. However, stress granule formation during infection is more dependent upon ongoing transcription than is formation during oxidative stress or heat shock. Furthermore, Sam68 is recruited to stress granules in infected cells but not to stress granules formed in response to oxidative stress or heat shock. These results demonstrate that stress granule formation in poliovirus-infected cells utilizes a transcription-dependent pathway that results in the appearance of stable, compositionally unique stress granules.


Highly stretchable and wearable graphene strain sensors with controllable sensitivity for human motion monitoring.
Because of their outstanding electrical and mechanical properties, graphene strain sensors have attracted extensive attention for electronic applications in virtual reality, robotics, medical diagnostics, and healthcare. Although several strain sensors based on graphene have been reported, the stretchability and sensitivity of these sensors remain limited, and also there is a pressing need to develop a practical fabrication process. This paper reports the fabrication and characterization of new types of graphene strain sensors based on stretchable yarns. Highly stretchable, sensitive, and wearable sensors are realized by a layer-by-layer assembly method that is simple, low-cost, scalable, and solution-processable. Because of the yarn structures, these sensors exhibit high stretchability (up to 150%) and versatility, and can detect both large- and small-scale human motions. For this study, wearable electronics are fabricated with implanted sensors that can monitor diverse human motions, including joint movement, phonation, swallowing, and breathing.


Negative regulation of the osteoblast function in multiple myeloma through the repressor gene E4BP4 activated by malignant plasma cells.
To explore the pathogenetic mechanisms that suppress the osteoblast function in multiple myeloma because osteogenesis results in defective new bone formation and repair. Microarray gene analysis revealed the overexpression of E4BP4, a transcriptional repressor gene, in normal osteoblasts cocultured with myeloma cells that were releasing the parathyroid hormone-related protein (PTHrP). Thus, the effect of E4BP4 was assessed in PTHrP-stimulated osteoblasts by measuring the RNA levels of both Runx2 and Osterix as major osteoblast transcriptional activators. Because E4BP4 is a negative regulator of the cyclooxygenase-2 (COX-2) pathway that drives the expression of both Runx2 and Osterix, these factors were investigated after prostaglandin E(2) treatment to overcome the COX-2 defect as well as in E4BP4-silenced osteoblasts. Finally, E4BP4, PTHrP, Osterix, and osteocalcin levels were measured in vivo in patients with bone disease together with the E4BP4 protein in bone biopsies. E4BP4 was specifically induced by PTHrP and inhibited both Runx2 and Osterix, whereas E4BP4-silenced osteoblasts expressed functional levels of both factors. The prostaglandin E(2) treatment of E4BP4-up-regulated osteoblasts promptly restored Runx2 and Osterix activities, suggesting that integrity of COX-2 pathway is essential for their transcription. Down-regulation of Osterix by E4BP4 was confirmed in vivo by its inverse levels in osteoblasts from myeloma patients with increased serum PTHrP, whose bone biopsies expressed the E4BP4 protein. Our data support the role of E4BP4 as osteoblast transcriptional repressor in inhibiting both Runx2 and Osterix in myeloma bone disease and correlate its effect with the increased PTHrP activity.


[Extragenital injuries in rape].
The documentation of extragenital injuries to verify violent cohabitation has considerable forensic relevance. 1,875 police files in Hamburg were investigated. Injuries were analysed under the following aspects: kinds, localisations and patterns. According to the most frequent conduct of the doer (manual fixation of the victim and beats in 60% of all cases), consequences of contused violence (i.e. effusions of blood, contusions, dehiscences) were found in 50% of all cases. Injuries due to semi-sharp violence, wounds of genitals or signs of choke were relatively rare (15-3-3%). An isolated state of genital organs is of minor importance. The most frequent localisations of injuries were face and arms, less frequently legs and back. Injuries as result of manual fixation, defence or abutment formed the main patterns. "Banal" hurts were also found. In numerous cases, the outer appearance of the lesions enabled conclusions regarding the instrument used (i.e. double wales after beats with a stick). Self-inflicted injuries can mostly be discerned by their kind and localisation. Rape without any injuries is conceivable as the result of missing defence in the presence of severe threat. Psychic alterations were found in 20% of the cases, half of them continuing for a long time. The medical examination of the suspected man must include the search of signs of a fight (scratch marks, bites), localised at the hands, face and neck (besides ascertainment of traces, for example, smears of semen and smegma, i.e. from the glans penis). Extent and thoroughness of medical examinations as presently practised are discussed critically. The manner in which these examinations are conducted, is considered to be the main cause of a "secondary victimisation" of the raped woman.


Emergency department management of stroke in pregnant and postpartum patients.
Maternal stroke contributes to a significant burden of disease in the pregnant and postpartum patient populations, with an incidence nearly 3-fold that of comparable nonpregnant cohorts. Emergency clinicians must maintain a high index of suspicion for cerebrovascular injury in these patients, as rapid diagnosis and emergent management can prevent devastating neurological outcomes. Data on management of cerebrovascular injury in pregnant and postpartum patients are limited, but management of maternal stroke in the emergency department aligns closely with protocols established for nonpregnant patients. This issue discusses the risk factors associated with maternal stroke, and reviews the available evidence for emergency department management of maternal stroke, including thrombolytic and interventional therapies.


Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry.
Sphingolipids constitute a dynamic metabolic network that interconnects several bioactive molecules, including ceramide (Cer), sphingosine (Sph), Sph 1-phosphate, and Cer 1-phosphate. The interconversion of these metabolites is controlled by a cohort of at least 40 enzymes, many of which respond to endogenous or exogenous stimuli. Typical probing of the sphingolipid pathway relies on sphingolipid mass levels or determination of the activity of individual enzymes. Either approach is unable to provide a complete analysis of flux through sphingolipid metabolism, which, given the interconnectivity of the sphingolipid pathway, is critical information to identify nodes of regulation. Here, we present a one-step in situ assay that comprehensively probes the flux through de novo sphingolipid synthesis, post serine palmitoyltransferase, by monitoring the incorporation and metabolism of the 17 carbon dihydrosphingosine precursor with LC/MS. Pulse labeling and analysis of precursor metabolism identified sequential well-defined phases of sphingolipid synthesis, corresponding to the activity of different enzymes in the pathway, further confirmed by the use of specific inhibitors and modulators of sphingolipid metabolism. This work establishes precursor pulse labeling as a practical tool for comprehensively studying metabolic flux through de novo sphingolipid synthesis and complex sphingolipid generation.