Protein kinase C substrate and inhibitor characteristics of peptides derived from the myristoylated alanine-rich C kinase substrate (MARCKS) protein phosphorylation site domain.
The phosphorylation sites in the myristoylated alanine-rich C kinase substrate or MARCKS protein consist of four serines contained within a conserved, basic region of 25 amino acids, termed the phosphorylation site domain. A synthetic peptide comprising this domain was phosphorylated by both protein kinase C and its catalytic fragment with high affinity and apparent positive cooperativity. Tryptic phosphopeptides derived from the peptide appeared similar to phosphopeptides derived from the phosphorylated intact protein. The peptide was phosphorylated by cAMP- and cGMP-dependent protein kinases with markedly lower affinities. In peptides containing only one of the four serines, with the other three serines replaced by alanine, the affinities for protein kinase C ranged from 25 to 60 nM with Hill constants between 1.8 and 3.0. The potential pseudosubstrate peptide, in which all four serines were replaced by alanines, inhibited protein kinase C phosphorylation of histone or a peptide substrate with an IC50 of 100-200 nM with apparently non-competitive kinetics; it also inhibited the catalytic fragment of protein kinase C with a Ki of 20 nM, with kinetics of the mixed type. The peptide did not significantly inhibit the cAMP- and cGMP-dependent protein kinases. It inhibited Ca2+/calmodulin-dependent protein kinases I, II, and III by competing with the kinases for calmodulin. In addition, the peptide inhibited the Ca2+/calmodulin-independent activity of a proteolytic fragment of Ca2+/calmodulin protein kinase II, with an IC50 approximately 5 microM. Thus, the phosphorylation site domain peptide of the MARCKS protein is a high affinity substrate for protein kinase C in vitro; the cognate peptide containing no serines is a potent but not completely specific inhibitor of both protein kinase C and its catalytic fragment.


Anatomical factors associated with gender recognizability: A study on intraoral standardized photographs.
The aim of this research was to evaluate the possibility of identifying the sex of 1 subject through visual assessment of a frontal photograph of dentition, and to investigate if some morphological characteristics are related to sex determination. 5 expert dentists, 5 non-expert dentists and 5 laypeople were made to watch 100 intraoral photographs for 5 seconds each and to establish their sex. The responses of the participants and the baseline characteristics of photographed dentitions were analyzed. The proportion of right answers was 56.0% ± 8.2% in the group of expert dentists, 65.0% ± 6.0% in the group of non-expert dentists and 58.6% ± 4.5% in the group of non-expert people. The round shape of maxillary central incisors was related to the female gender (P = .006). The male condition was correlated with poor oral hygiene for 4 observers. Female sex perception was correlated with round morphology of upper central incisors for 3 observers. No difference in the ability to determine the sex was registered among groups, suggesting that sex perception is not strongly influenced by the characteristics of dentition.


Nonlinear transient responses from light-adapted wolf spider eyes to changes in background illumination.
Retinal action potentials were recorded at the corneas of light-adapted wolf spider eyes in response to large positive and negative step changes in background illumination. These incremental responses were superimposed upon the steady-state DC responses to the background illumination. Both positive and negative step responses had peaks which overshot the DC levels to which they decayed. The overshoot was greater for positive than for negative steps. Short term DC responses measured after one-half sec were larger for negative than for positive steps; these short-term DC responses were thus asymmetrical. However, responses to short positive and negative flashes were not asymmetrical; rather, they varied linearly with flash amplitude. Asymmetries were thus delayed in onset. The short-term DC responses were found to be different from the steady-state DC responses to maintained changes in background illumination. There was an approximately exponential decay or creep from the short-term to the steady-state DC responses. It is proposed that the dynamics of delayed asymmetries can explain the waveforms of the short-term transient responses.


Ableism, Human Rights, and the COVID-19 Pandemic: Healthcare-Related Barriers Experienced by Deaf People in Aotearoa New Zealand.
The COVID-19 pandemic significantly affected global healthcare access and exacerbated pre-pandemic structural barriers. Literature on disabled people's experiences accessing healthcare is limited, with even less framing healthcare access as a human rights issue. This study documents and critically analyses Deaf people's healthcare access experiences in Aotearoa New Zealand during the COVID-19 pandemic. Eleven self-identified Deaf individuals participated in semi-structured videoconferencing interviews. Discourse analysis was applied to participant narratives with discourses juxtaposed against a human rights analysis. Barriers influencing healthcare access included: (1) the inability of healthcare providers to communicate appropriately, including a rigid adherence to face mask use; (2) cultural insensitivity and limited awareness of Deaf people's unique needs; and (3) the impact of ableist assumptions and healthcare delaying care. Barriers to healthcare access represent consecutive breaches of rights guaranteed under the United Nations Convention on the Rights of Persons with Disabilities (CRPD). Such breaches delay appropriate healthcare access and risk creating future compounding effects. Action is required to address identified breaches: (1) The CRPD should also underpin all health policy and practice development, inclusive of pandemic and disaster management responsiveness. (2) Health professionals and support staff should be trained, and demonstrate competency, in Deaf cultural awareness and sensitivity.


Motivation and goal-pursuit for injury prevention training in amateur football coaches: a cross-sectional study using the Health Action Process Approach.
Adoption of injury prevention exercise programmes (IPEPs) in team sports is contingent on behaviour change among coaches. The aim was to study motivation and goal-pursuit in IPEP use among coaches of amateur football players. A cross-sectional study using web-based questionnaires was administered to coaches in one Swedish regional football district. The study was carried out one season after dissemination of the IPEP Knee Control+. The questionnaire was based on the Health Action Process Approach and covered perceptions and beliefs about using Knee Control+. Questions were rated on 1-7 Likert scales. 440 coaches participated (response rate 32%). Coaches were neutral about injury risks (median 4-5) and knowledge about preventing injuries (median 5) but had positive outcome expectancies of preventive training (median 6). Coaches who had used an IPEP perceived they had more knowledge about preventing injuries than non-users (median 5 vs 4, small effect size d=0.43). Coaches who used Knee Control+ were positive about their practical ability to use it (median 6) and had high intention to prioritise continuous use (median 7). Highly adherent coaches to higher extent believed that specific training may prevent injuries and had plans for how to instruct the players and how to work around barriers compared with low adherent coaches. Coaches need more knowledge and support on IPEP usage and how to structure training. Coaches who had adopted Knee Control+ had high belief in their abilities but may need constructive plans on how to use the programme and to overcome barriers.


Comprehensive relationship between disease activity indices, mTSS, and mHAQ and physical function evaluation and QOL in females with rheumatoid arthritis.
Rheumatoid arthritis (RA) causes significant physical disability. We comprehensively investigated the relationship between RA disease activity (Disease Activity Score 28-C-reactive protein [DAS28-CRP], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index [CDAI]), physical function (10-Meter Walk Test [10 MWT], Timed Up and Go test [TUG], Functional Reach Test [FRT], and Disabilities of the Arm, Shoulder, and Hand [DASH]), and quality of life (QOL) (Short-Form 36 [SF-36®]). We also investigated the relationship between van der Heijde's modified Total Sharp Score (mTSS), modified Health Assessment Questionnaire (mHAQ), and physical function and QOL assessments. Among 35 female patients with RA, DAS28-CRP correlated solely with DASH (r = 0.376), while SDAI and CDAI did not correlate with physical function. The mTSS-hand roentgenographic evaluation correlated with TUG (r = 0.359), FRT (r = - 0.415), and DASH (r = 0.533) among physical function assessments. The mHAQ correlated with 10 MWT (r = 0.347), TUG (r = 0.356), FRT (r = - 0.420), and DASH (r = 0.646). DAS28-CRP correlated with six of the eight subscales of SF-36®, and mTSS and mHAQ correlated with only one subscale. RA disease activity assessments may not reflect all physical functions and QOL domains of female patients with RA. Evaluating physical function and QOL in female patients with RA is essential.


Osa-miR398b boosts H2 O2 production and rice blast disease-resistance via multiple superoxide dismutases.
miRNAs contribute to plant resistance against pathogens. Previously, we found that the function of miR398b in immunity in rice differs from that in Arabidopsis. However, the underlying mechanisms are unclear. In this study, we characterized the mutants of miR398b target genes and demonstrated that multiple superoxide dismutase genes contribute to miR398b-regulated rice immunity against the blast fungus Magnaporthe oryzae. Out of the four target genes of miR398b, mutations in Cu/Zn-Superoxidase Dismutase1 (CSD1), CSD2 and Os11g09780 (Superoxide DismutaseX, SODX) led to enhanced resistance to M. oryzae and increased hydrogen peroxide (H2 O2 ) accumulation. By contrast, mutations in Copper Chaperone for Superoxide Dismutase (CCSD) resulted in enhanced susceptibility. Biochemical studies revealed that csd1, csd2 and sodx displayed altered expression of CSDs and other superoxide dismutase (SOD) family members, leading to increased total SOD enzyme activity that positively contributed to higher H2 O2 production. By contrast, the ccsd mutant showed CSD protein deletion, resulting in decreased CSD and total SOD enzyme activity. Our results demonstrate the roles of different SODs in miR398b-regulated resistance to rice blast disease, and uncover an integrative regulatory network in which miR398b boosts total SOD activity to upregulate H2 O2 concentration and thereby improve disease resistance.


Histone Chaperone Paralogs Have Redundant, Cooperative, and Divergent Functions in Yeast.
Gene duplications increase organismal robustness by providing freedom for gene divergence or by increasing gene dosage. The yeast histone chaperones Fpr3 and Fpr4 are paralogs that can assemble nucleosomes in vitro; however, the genomic locations they target and their functional relationship is poorly understood. We refined the yeast synthetic genetic array approach to enable the functional dissection of gene paralogs. Applying this method to Fpr3 and Fpr4 uncovered redundant, cooperative, and divergent functions. While Fpr3 is uniquely involved in chromosome segregation, Fpr3 and Fpr4 cooperate to regulate genes involved in polyphosphate metabolism and ribosome biogenesis. We find that the TRAMP5 RNA exosome is critical for fitness in Δfpr3Δfpr4 yeast and leverage this information to identify an important role for Fpr4 at the 5' ends of protein coding genes. Additionally, Fpr4 and TRAMP5 negatively regulate RNAs from the nontranscribed spacers of ribosomal DNA. Yeast lacking Fpr3 and Fpr4 exhibit a genome instability phenotype at the ribosomal DNA, which implies that these histone chaperones regulate chromatin structure and DNA access at this location. Taken together. we provide genetic and transcriptomic evidence that Fpr3 and Fpr4 operate separately, cooperatively, and redundantly to regulate a variety of chromatin environments.


Reducing NOx emissions from a biodiesel-fueled engine by use of low-temperature combustion.
Biodiesel is popularly discussed in many countries due to increased environmental awareness and the limited supply of petroleum. One of the main factors impacting general replacement of diesel by biodiesel is NOx (nitrogen oxides) emissions. Previous studies have shown higher NOx emissions relative to petroleum diesel in traditional direct-injection (DI) diesel engines. In this study, effects of injection timing and different biodiesel blends are studied for low load [2 bar IMEP (indicated mean effective pressure)] conditions. The results show that maximum heat release rate can be reduced by retarding fuel injection. Ignition and peak heat release rate are both delayed for fuels containing more biodiesel. Retarding the injection to post-TDC (top dead center) lowers the peak heat release and flattens the heat release curve. It is observed that low-temperature combustion effectively reduces NOx emissions because less thermal NOx is formed. Although biodiesel combustion produces more NOx for both conventional and late-injection strategies, with the latter leading to a low-temperature combustion mode, the levels of NOx of B20 (20 vol % soy biodiesel and 80 vol % European low-sulfur diesel), B50, and B100 all with post-TDC injection are 68.1%, 66.7%, and 64.4%, respectively, lower than pure European low-sulfur diesel in the conventional injection scenario.


Overexpression of LLT1 (OCIL, CLEC2D) on prostate cancer cells inhibits NK cell-mediated killing through LLT1-NKRP1A (CD161) interaction.
Prostate cancer is the most common type of cancer diagnosed and the second leading cause of cancer-related death in American men. Natural Killer (NK) cells are the first line of defense against cancer and infections. NK cell function is regulated by a delicate balance between signals received through activating and inhibitory receptors. Previously, we identified Lectin-like transcript-1 (LLT1/OCIL/CLEC2D) as a counter-receptor for the NK cell inhibitory receptor NKRP1A (CD161). Interaction of LLT1 expressed on target cells with NKRP1A inhibits NK cell activation. In this study, we have found that LLT1 was overexpressed on prostate cancer cell lines (DU145, LNCaP, 22Rv1 and PC3) and in primary prostate cancer tissues both at the mRNA and protein level. We further showed that LLT1 is retained intracellularly in normal prostate cells with minimal cell surface expression. Blocking LLT1 interaction with NKRP1A by anti-LLT1 mAb on prostate cancer cells increased the NK-mediated cytotoxicity of prostate cancer cells. The results indicate that prostate cancer cells may evade immune attack by NK cells by expressing LLT1 to inhibit NK cell-mediated cytolytic activity through LLT1-NKRP1A interaction. Blocking LLT1-NKRP1A interaction will make prostate cancer cells susceptible to killing by NK cells and therefore may be a new therapeutic option for treatment of prostate cancer.


The preparation of an alkali-soluble collagen from demineralized bone.
Ossein was solubilized by the action of alkali and a resulting high-molecular-weight fraction isolated. The chemical and physical properties of this fraction were studied and compared with those of an acid-soluble collagen prepared from calf skin by conventional techniques. From the results it is concluded that the alkali-soluble protein exhibits only minor differences from acid-soluble collagen, and that these differences can be ascribed for the most part to a decrease in the inter- and intramolecular cross-linking.


Prognostic values of B7-H3, B7-H4, and HHLA2 expression in human pancreatic cancer tissues based on mIHC and spatial distribution analysis.
Pancreatic cancer (PC) is one of the most malignant solid tumors and its 5-year survival rate remains poor. Although immunotherapy has achieved certain therapeutic efficacy in some clinical trials, such treatment still shows low responses and overall remission rate. Therefore, it is urgently necessary to dissect the tumor microenvironment and optimize the immunotherapeutic strategies against this malignancy. Using the multi-color immunohistochemistry assay, we investigated the expressions of B7-H3, B7-H4, HHLA2, CD8, and CD68 in 63 cases of PC tissues in a tissue microarray. Moreover, we analyzed immunolocalization features, clinical associations and prognostic values of these molecules. The expressions of B7-H3, B7-H4, and HHLA2 could be detected in cytokeratin staining positive (CK+) cancer epithelial cells, CD68+tumor-associated macrophages (TAMs), and even other cells defined as CK-CD8-CD68-. Higher expression of B7-H3 in tumor cells could predict a better survival of the PC patients. A positive correlation was found between the expressions of B7-H3 and HHLA2 in tumor cells, while there was a negative correlation between the expressions of B7-H4 and HHLA2 in tumor cells. A positive correlation was found between the expressions of B7-H3 and B7-H4 or HHLA2 in CD68+TAMs, but not B7-H4 and HHLA2. Tumor-infiltrating CD8+T cells in combination with CD68+TAMs could serve as an important predictor for the postoperative prognosis of PC patients. Higher expression of B7-H3, or HHLA2 in CD68+TAMs could serve as an important predictor for poorer prognosis of PC patients. Patients with B7-H3lowB7-H4low, B7-H3lowHHLA2low, or B7-H4lowHHLA2low on CD68+TAMs could have a better postoperative prognosis compared with the other sub-populations in the combinational analysis. Taken together, our study indicated variable expressions and prognostic values of B7-H3, B7-H4, and HHLA2, in human PC tissues, and demonstrated that these co-stimulator molecules expressed by CD68+TAMs could be used as important bio-markers for the prognostic prediction of PC patients. Moreover, these results supported that the evaluation of these markers could be used as essential candidate targets for immunotherapy against PC.


A dissociation between simple and complex span impairment in alcoholics.
We investigated whether the surprisingly good memory performance of alcoholics may result from simple memory performance being spared while performance in complex memory tasks is impaired. Simple word span was contrasted with a complex word span task involving concurrent monitoring and re-organisation of items for recall. To control for disruption of rehearsal in the complex word span task, performance on two additional tasks with disrupted rehearsal but no additional processing components was studied. As hypothesised, the alcoholics showed a deficit in the complex but not the simple word span task. They were also impaired, compared to controls, on both tasks with disrupted rehearsal. The difference between groups remained in the complex span task when scores in simple span and either of the two other tasks were used as covariates. Thus, both executive processes necessary for coping with disrupted rehearsal and additional processes scheduling processing and storage in a complex task may play a role in accounting for working memory deficits found in alcoholics.


Cyclin E Overexpression in Human Mammary Epithelial Cells Promotes Epithelial Cancer-Specific Copy Number Alterations.
Cyclin E, a key cell cycle regulatory protein, has been linked to oncogenesis when dysregulated. We have previously shown that overexpression of cyclin E causes replication stress, leading to failure to complete replication at specific chromosomal loci during S phase of the cell cycle. This in turn promotes chromosomal damage during anaphase. Here we show that non-transformed human mammary epithelial cell clones that survive such aberrant mitoses have a specific and reproducible pattern of chromosomal Copy Number Alterations (CNAs) that we have characterized and termed the cyclin E CNA signature. Using a number of computational approaches, we show that this signature resembles one specific CNA pattern enriched in differentiated epithelial-like tumors of the breast and ovary. Analysis of the CNA profile of these clones provides a potential mechanism for cyclin E-mediated oncogenesis.


Towards the Applicability of Measuring the Electrodermal Activity in the Context of Process Model Comprehension: Feasibility Study.
Process model comprehension is essential in order to understand the five Ws (i.e., who, what, where, when, and why) pertaining to the processes of organizations. However, research in this context showed that a proper comprehension of process models often poses a challenge in practice. For this reason, a vast body of research exists studying the factors having an influence on process model comprehension. In order to point research towards a neuro-centric perspective in this context, the paper at hand evaluates the appropriateness of measuring the electrodermal activity (EDA) during the comprehension of process models. Therefore, a preliminary test run and a feasibility study were conducted relying on an EDA and physical activity sensor to record the EDA during process model comprehension. The insights obtained from the feasibility study demonstrated that process model comprehension leads to an increased activity in the EDA. Furthermore, EDA-related results indicated significantly that participants were confronted with a higher cognitive load during the comprehension of complex process models. In addition, the experiences and limitations we learned in measuring the EDA during the comprehension of process models are discussed in this paper. In conclusion, the feasibility study demonstrated that the measurement of the EDA could be an appropriate method to obtain new insights into process model comprehension.


[Effects of rosuvastatin in homocysteine induced mouse vascular smooth muscle cell dedifferentiation and endoplasmic reticulum stress and its mechanisms].
To investigate the effect of rosuvastatin on homocysteine (Hcy) induced mousevascular smooth muscle cells(VSMCs) dedifferentiation and endoplasmic reticulum stress(ERS). VSMCs were co-cultured with Hcy and different concentration of rosuvastatin (0.1, 1.0 and 10 μmol/L). Cytoskeleton remodeling, VSMCs phenotype markers (smooth muscle actin-α, calponin and osteopontin) and ERS marker mRNAs (Herpud1, XBP1s and GRP78) were detected at predicted time. Tunicamycin was used to induce, respectively 4-phenylbutyrate(4-PBA) inhibition, ERS in VSMCs and cellular migration, proliferation and expression of phenotype proteins were analyzed. Mammalian target of rapamycin(mTOR)-P70S6 kinase (P70S6K) signaling agonist phosphatidic acid and inhibitor rapamycin were used in Rsv treated VSMCs. And then mTOR signaling and ERS associated mRNAs were detected. Compared with Hcy group, Hcy+ Rsv group (1.0 and 10 μmol/L) showed enhanced α-SMA and calponin expression (P<0.01), suppressed ERS mRNA levels (P<0.01) and promoted polarity of cytoskeleton. Compared with Hcy group, Hcy+Rsv group and Hcy+4-PBA group showed suppressed proliferation, migration and enhanced contractile protein expression (P<0.01); while tunicamycin could reverse the effect of Rsv on Hcy treated cells. Furthermore, alleviated mTOR-P70S6K phosphorylation and ERS (P<0.01)were observed in Hcy+Rsv group and Hcy+rapamycin group, compared with Hcy group; while phosphatidic acid inhibited the effect of Rsv on mTOR signaling activation and ERS mRNA levels (P<0.01). Rosuvastatin could inhibit Hcy induced VSMCs dedifferentiation via suppressing ERS, which might be regulated by mTOR-P70S6K signaling.


A conscious mouse model of gastric ileus using clinically relevant endpoints.
Gastric ileus is an unsolved clinical problem and current treatment is limited to supportive measures. Models of ileus using anesthetized animals, muscle strips or isolated smooth muscle cells do not adequately reproduce the clinical situation. Thus, previous studies using these techniques have not led to a clear understanding of the pathophysiology of ileus. The feasibility of using food intake and fecal output as simple, clinically relevant endpoints for monitoring ileus in a conscious mouse model was evaluated by assessing the severity and time course of various insults known to cause ileus. Delayed food intake and fecal output associated with ileus was monitored after intraperitoneal injection of endotoxin, laparotomy with bowel manipulation, thermal injury or cerulein induced acute pancreatitis. The correlation of decreased food intake after endotoxin injection with gastric ileus was validated by measuring gastric emptying. The effect of endotoxin on general activity level and feeding behavior was also determined. Small bowel transit was measured using a phenol red marker. Each insult resulted in a transient and comparable decrease in food intake and fecal output consistent with the clinical picture of ileus. The endpoints were highly sensitive to small changes in low doses of endotoxin, the extent of bowel manipulation, and cerulein dose. The delay in food intake directly correlated with delayed gastric emptying. Changes in general activity and feeding behavior were insufficient to explain decreased food intake. Intestinal transit remained unchanged at the times measured. Food intake and fecal output are sensitive markers of gastric dysfunction in four experimental models of ileus. In the mouse, delayed gastric emptying appears to be the major cause of the anorexic effect associated with ileus. Gastric dysfunction is more important than small bowel dysfunction in this model. Recovery of stomach function appears to be simultaneous to colonic recovery.


How to incorporate geriatric assessment in clinical decision-making for older patients with cancer. An implementation study.
With the accumulating evidence on the added value on prediction of outcomes of geriatric assessment (GA) in older patients with cancer, the question shifts from whether performing a GA is useful, to how to implement this into standard practice in a feasible and effective way. The effect of implementing GA, and assessment of patient preferences on treatment recommendations by an onco-geriatric multidisciplinary team (MDT), was compared to the recommendation previously made by the tumor board (care as usual). Patients aged 70 years and older with a solid malignancy who were referred to a tertiary care center for diagnosis and treatment recommendations, as provided by a tumor board, were included. The intervention consisted of: a nurse-led GA and assessment of patient preferences prior to the start of oncological treatment, discussing this in an onco-geriatric MDT, and weighing all this information in a structured, stepwise manner. Treatment recommendations formulated by this onco-geriatric MDT were compared to the treatment recommendations by the tumor board. Of 236 eligible patients, 197 were included. For 27%, treatment recommendations from the onco-geriatric MDT differed from the recommendations formulated by the tumor board. These modifications were mostly towards less intensive curative or palliative treatment. Thirteen percent of patients were subsequently referred to a geriatrician in order to reach a treatment recommendation. Implementing an onco-geriatric care trajectory, using GA and assessment of patient preferences, resulted in an adjustment of treatment recommendations for a quarter of patients. Thirteen percent needed subsequent referral to a geriatrician.


Electronically induced ferromagnetic transitions in Sm5Ge4-type magnetoresponsive phases.
The correlation between magnetic and structural transitions in Gd(5)Si(x)Ge(4-x) hampers the studies of valence electron concentration (VEC) effects on magnetism. Such studies require decoupling of the VEC-driven changes in the magnetic behavior and crystal structure. The designed compounds, Gd(5)GaSb(3) and Gd(5)GaBi(3), adopt the same Sm(5)Ge(4)-type structure as Gd(5)Ge(4) while the VEC increases from 31 e(-)/formula in Gd(5)Ge(4) to 33 e(-)/formula in Gd(5)GaPn(3) (Pn: pnictide atoms). As a result, the antiferromagnetic ground state in Gd(5)Ge(4) is tuned into the ferromagnetic one in Gd(5)GaPn(3). First-principles calculations reveal that the nature of interslab magnetic interactions is changed by introducing extra p electrons into the conduction band, forming a ferromagnetic bridge between the adjacent (∝)(2)[Gd(5)T(4)] slabs.


Questioning gender norms with men to improve health outcomes: evidence of impact.
This article describes a review of 58 evaluation studies of programmes with men and boys in sexual and reproductive health (including HIV prevention, treatment, care and support); father involvement; gender-based violence; maternal, newborn and child health; and gender socialisation more broadly. While few of the programmes go beyond the pilot stage, or a relatively short-term timeframe, they offer compelling evidence that well-designed programmes with men and boys can lead to positive changes in their behaviours and attitudes related to sexual and reproductive health; maternal, newborn and child health; their interaction with their children; their use of violence against women; their questioning of violence with other men; and their health-seeking behaviour. The evidence indicates that programmes that incorporate a gender-transformative approach and promote gender-equitable relationships between men and women are more effective in producing behaviour change than narrowly focused interventions, as are programmes which reach beyond the individual level to the social context.


[Reducing the rate of radiation exposure of technicians through lateral-surface contact with patients undergoing radionuclide examination].
During examinations using radionuclide methods, technicians sometimes need to interact directly with patients. The initial point of contact is when they assist patients onto the examination table, the second is when the patients are positioned for radionuclide examination, and the third occurs if the patients experience a sudden change in condition and assistance is deemed necessary. The dose of radiation increases proportionately to the size of the area being treated. Therefore, we verified that the lateral area received a lower dose of radiation than the anterior areas because of their smaller surface area. The doses in the anterior and lateral areas of the patients were measured following administration of (99m)Tc-hydroxymethyl enebisphosphonic acid (HMDP), (131)I, (18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG), and (99m)Tc-galactosyl-human serum albumin-diethylenetriamine-pentaacetic acid (GSA). The lateral/anterior (L/A) ratio was defined as an approximation of the ratio of measured values of the lateral and anterior areas; it was calculated as follows: L/A (%)=[(lateral dose-BG)/(anterior dose-BG)]×100. In all patients, the radiation dose rate from the lateral areas was lower than from the anterior areas. L/A was 52% with (99m)Tc-HMDP, 51% with (131)I, 58% with (18)F-FDG, and 33% with (99m)Tc-GSA, and radiation doses were found to be reduced by approximately 50% when interaction with patients was from the lateral side rather than the anterior side. Therefore, we confirmed that when interacting closely with patients undergoing radionuclide examinations, it is best to approach the patients from the lateral side in order to reduce radioactive exposure of the technicians.


Measuring human rights violations in a conflict-affected country: results from a nationwide cluster survey in Central African Republic.
Measuring human rights violations is particularly challenging during or after armed conflict. A recent nationwide survey in the Central African Republic produced estimates of rates of grave violations against children and adults affected by armed conflict, using an approach known as the "Neighborhood Method". In June and July, 2009, a random household survey was conducted based on population estimates from the 2003 national census. Clusters were assigned systematically proportional to population size. Respondents in randomly selected households were interviewed regarding incidents of killing, intentional injury, recruitment into armed groups, abduction, sexual abuse and rape between January 1, 2008 and the date of interview, occurring in their homes' and those of their three closest neighbors. Sixty of the selected 69 clusters were surveyed. In total, 599 women were interviewed about events in 2,370 households representing 13,669 persons. Estimates of annual rates of each violation occurring per 1000 people in each of two strata are provided for children between the ages of five and 17, adults 18 years of age and older and the entire population five years and older, along with a combined and weighted national rate. The national rates for children age five to 17 were estimated to be 0.98/1000/year (95% CI: 0.18 - 1.78) for recruitment, 2.56/1000/year (95% CI: 1.50 - 3.62) for abduction, 1.13/1000/year (95% CI: 0.33 - 1.93) for intentional injury, 10.72/1000 girls/year (95% CI: 7.40 - 14.04) for rape, and 4.80/1000 girls/year (95% CI: 2.61 - 6.00) for sexual abuse. No reports of any violation against a person under the age of five were recorded and there were no reports of rape or sexual abuse of males. No children were reported to have been killed during the recall period. Rape and abduction were the most frequently reported events. The population-based figures greatly augment existing information on human rights violations in CAR, and represent a step forward in quantifying the protection needs of Central Africans. Government, donors, and international organizations should make use of this data to better inform advocacy, prevention, and response programs, to assist in fundraising, and to develop surveillance activities to monitor child protection concerns.


Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program.
This paper reviews the formulation and evolution of the ethical component in one of the earliest clinical composite tissue allograft (CTA) programs, the hand transplantation program in Louisville, Kentucky, USA. The purpose was to derive lessons and define principles to give guidance for future programs and introduction of new CTA. We reviewed the initial ethical considerations, including input from respected ethical scholars, guidelines for innovative procedures transparency in public and professional scrutiny, and compliance with human studies regulations (IRB approval). We found the initial focus on ethics, scholarly input, guidelines for innovative procedures, and human studies protection regulations to be valid. Moreover, we noted the effect of autonomy in subjective, quality-of-life benefits on equipoise and effective risk-benefit analysis in effective informed consent. We found that psychiatric screening and support to be exceptionally valuable in protecting autonomy, suitability for participation, assessing personality organization, and determining compliance ability. We conclude that the program ethical principles were validated. For future CTA programs and procedures, we recommend an ethical emphasis with adherence to high standards and transpire to independence to scrutiny and oversight. We recommend protection of autonomy judgments in equipoise judgment and informed consent. We recommend skilled psychiatric screening and support. We endorse scholarship, scientific accuracy, and data sharing.


Induced non-enzymatic browning of soybean meal. II. Ruminal escape and net portal absorption of soybean protein treated with xylose.
Non-enzymatic browning was tested as a means of increasing ruminal escape of soybean meal N. Soybean meal was treated with xylose (3 mol/mol SBM-lysine), sodium hydroxide (pH 8.5) and enough water to achieve an 83% dry matter mixture and then heated at 150 C for 30 min (XTS-30). Trial 1 evaluated ruminal escape of N from XTS-30 compared with commercial soybean meal (CS) or urea (U) in a replicated 3 X 3 Latin square design using six duodenally cannulated Angus X Hereford steers (24.7 kg). Duodenal flow of dietary N was higher (P less than for steers fed XTS-30 (47.9 g/d) than for steers fed CS (39.5 g/d). The ruminal escape estimate for XTS-30 (33.7%) was higher (P less than .10) than CS (13.1%), whereas total tract apparent N digestibility was not different among treatments. In trial 2, net portal absorption of alpha-amino N was measured in Finnsheep X Suffolk ram lambs (24.7 kg) fed U, CS or XTS-30 in a 3 X 3 Latin square design. Portal blood flow was measured by primed, continuous infusion of para-aminohippuric acid. Portal blood flow was lower (P less than .05) for U.fed lambs than for lambs fed CS or XTS-30, and tended to be lower for lambs fed CS than those fed XTS-30. Net portal absorption of alpha-amino N tended to be lowest for lambs fed U (281 mmol/d) and highest for lambs fed XTS-30 (578 mmol/d). The results are interpreted to show that non-enzymatic browning increased flow of soybean meal N to the intestine.


Effects of Ion Concentration and Headgroup Chemistry on Thin Lipid Film Drainage.
While the use of lipid nanoparticles in drug delivery applications has grown over the past few decades, much work remains to be done toward the characterization and rational design of the drug carriers. A key feature of delivery is the interaction of the exterior leaflet of the LNP with the outer leaflet of the cell membrane, which relies in part on the fusogenicity of the lipids and the ionic environment. In this paper, we study the interactions between two lipid monolayers using a thin film balance to create lipid thin films and interferometry to measure film evolution. We probe the role of lipid headgroup chemistry and charge, along with ionic solution conditions, in either promoting or hindering film drainage and stability. Specific headgroups phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and phosphatidylserine (PS) are chosen to represent a combination of charge and fusogenicity. We quantify each film's drainage characteristics over a range of capillary numbers. Qualitatively, we find that films transition from drainage via a large dimple to drainage via channels and vortices as the capillary number increases. Additionally, we observe a transition from electrostatically dominated film drainage at low CaCl2 concentrations to fusogenic-dominated film drainage at higher CaCl2 concentrations for anionic fusogenic (PS) films. Understanding the role of headgroup composition, ionic composition, and ionic concentration will pave the way for the design of tunable vesicle and buffer systems that behave desirably across a range of ex vivo and in vivo environments.


Efficacy of recombinant human Hb by 31P-NMR during isovolemic total exchange transfusion.
The ability of recombinant human Hb (rHb1.1), which is being developed as an oxygen therapeutic, to support metabolism was measured by in vivo 31P-NMR surface coil spectroscopy of the rat abdomen in control animals and in animals subjected to isovolemic exchange transfusion to hematocrit of <3% with human serum albumin or 5 g/dl rHb1.1. No significant changes in metabolite levels were observed in control animals for up to 6 h. The albumin-exchange experiments, however, resulted in a more than eightfold increase in Pi and a 50% drop in phosphocreatine and ATP within 40 min. The tissue pH dropped from 7.4 to 6.8. The decrease in high-energy phosphates obeyed Michaelis-Menten kinetics, with a Michaelis-Menten constant of 3% as the hematocrit at which a 50% drop in high-energy phosphates was observed. Exchange transfusion with rHb1.1 resulted in no significant drop in high-energy phosphates, no rise in Pi, and no change in tissue pH from 7.35 +/- 0.15 for up to 5 h after exchange. By these criteria, rHb1.1 at a plasma Hb concentration of approximately 5 g/dl after total exchange transfusion was able to sustain energy metabolism of gut tissue at levels indistinguishable from control rats with a threefold higher total Hb level in erythrocytes.


Clostridium perfringens type D epsilon toxin produces a rapid and dose-dependent cytotoxic effect on cerebral microvascular endothelial cells in vitro.
Clostridium perfringens type D epsilon toxin (ETX) is responsible for a severe and frequently fatal neurologic disorder in ruminant livestock. Light microscopic, immunohistochemical, and ultrastructural studies have suggested that ETX injury to the cerebral microvasculature, with subsequent severe, generalized vasogenic edema and increased intracranial pressure, is critically important in producing neurologic dysfunction. However, the effect of ETX on brain capillary endothelial cells in vitro has not been examined previously, to our knowledge. We exposed a well-characterized human blood-brain barrier cell line to increasing concentrations of ETX, and demonstrated a direct and dose-dependent endotheliotoxic effect. Our findings are concordant with the primacy of vasculocentric brain lesions in the diagnosis of acute epsilon toxin enterotoxemia in ruminant livestock.


Identification of the nonsubstrate steroid binding site of rat liver glutathione S-transferase, isozyme 1-1, by the steroid affinity label, 3beta-(iodoacetoxy)dehydroisoandrosterone.
3beta-(Iodoacetoxy)dehydroisoandrosterone (3beta-IDA), an analogue of the electrophilic substrate, Delta5-androstene-3,17-dione, as well as an analogue of several other steroid inhibitors of glutathione S-transferase, was tested as an affinity label of rat liver glutathione S-transferase, isozyme 1-1. A time-dependent loss of enzyme activity is observed upon incubation of 3beta-IDA with the enzyme. The rate of enzyme inactivation exhibits a nonlinear dependence on 3beta-IDA concentration, yielding an apparent Ki of 21 microM. Upon complete inactivation of the enzyme, a reagent incorporation of approximately 1 mol/mol of enzyme subunit or 2 mol/mol of enzyme dimer is observed. Protection against inactivation and incorporation is afforded by alkyl glutathione derivatives and nonsubstrate steroid ligands such as 17beta-estradiol-3,17-disulfate but, surprisingly, not by Delta5-androstene-3,17-dione or any other electrophilic substrate analogues tested. These results suggest that the site of reaction is within the nonsubstrate steroid binding site of the enzyme, which is distinguishable from the electrophilic substrate binding site, near the active site of the enzyme. Two cysteine residues, Cys17 and Cys111, are modified in nearly equal amounts, despite an average reagent incorporation of 1 mol/mol enzyme subunit. Isolation of enzyme subunits indicates the presence of unmodified, singly labeled, and doubly labeled subunits, consistent with mutually exclusive modification of cysteine residues across enzyme subunits; i.e., modification of Cys111 on subunit A prevents modification of Cys111 on subunit B and similarly for Cys17. Molecular modeling analysis suggests that Cys17 and Cys111 are located in the nonsubstrate steroid binding site, within the cleft between the subunits of the dimeric enzyme.


Data consistency based rigid motion artifact reduction in fan-beam CT.
It is well known that a rigid in-plane motion can be decomposed into a translation and a rotation around an origin. Based on our previous work, we first extend the Helgason-Ludwig consistency condition (HLCC) to cover a general rigid motion in fan-beam geometry. Then, we model the general motion by several parameters, and develop an iterative scheme for estimation of the in-plane motion parameters. This scheme determines the motion parameters by numerically minimizing an objective function constructed based on the HLCC. After the motion parameters are estimated, image reconstruction can be performed to compensate for the motion effects. Finally, we implement the algorithm and evaluate its performance in numerical simulations.


Role of XRCC1 and ERCC5 polymorphisms on clinical outcomes in advanced non-small cell lung cancer.
We aimed to assess the role of polymorphisms of the XRCC1 Arg194Trp, XRCC1 Arg399Gln, ERCC5 His1104Asp, and ERCC5 His46His genes on clinical outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy regimens. A total of 378 NSCLC patients were asked to participate within 1 month after diagnosis between January 2005 and January 2006, and they were followed up until November 2011. Genomic DNA of the four genes was extracted using the Qiagen Blood Kit. Results showed that individuals with XRCC1 399A/A and ERCC5 46T/T genotypes were more likely to show positive responses to chemotherapy, with odds ratio (OR) = 2.27 and 95% confidence interval (CI) = 1.64-6.97, and OR = 1.90, CI = 1.10-3.28, respectively. The XRCC1 399A/A genotype was significantly associated with longer progression-free survival (PFS) and overall survival (OS) rates, and the hazard ratios (HRs) (95%CI) were 0.48 (0.25-0.88) and 0.51 (0.26-0.98), respectively. Similarly, NSCLC patients carrying the ERCC5 46T/T genotype were more likely to show increased PFS and OS, with HRs (95%CI) of 0.47 (0.22-0.82) and 0.52 (0.31-0.96), respectively. In conclusion, our study indicated that XRCC1 Arg399Gln and ERCC5 His46His might significantly influence the response to chemotherapy, and the two genetic polymorphisms are suggested to be routinely detected to determine NSCLC patients that are more likely to benefit from chemotherapy.


The subject of caring.
Gordon Mitchell argues that the observational skills of nurses are an important tool in helping to identify when a patient admitted with depression is, in fact, suffering from a medical condition.


Social image factors as motivators of smoking initiation in early and middle adolescence.
The social image of the smoker may be particularly important for the process of adolescent smoking initiation. With that in mind, the present study had 2 goals: (1) to assess the social image of cigarette smoking among early and middle nonsmoking adolescents, and (2) to determine whether that social image serves to motivate smoking initiation. Based on considerations of self-esteem and susceptibility to social influence, social image factors were predicted to be related to intentions to smoke more for early adolescents and for girls. Results indicated that the social image of both male and female smokers was an ambivalent one for both early and middle adolescents. Smoking models were rated as having many undesirable qualities, but also several social assets. In terms of the relationship of the social image to smoking intentions, early adolescent girls had intentions that were best predicted by the perceived negative qualities of smoking. For middle adolescents, smoking intentions were related to the positive social assets of smoking, especially interest in the opposite sex. These results suggest that prevention strategies for early adolescent girls focus on the negative results of smoking. On the other hand, strategies for middle adolescents should either attack the positive image of the smoker or provide alternative means of self-image improvement.


Stable isotope ratio mass spectrometry and physical comparison for the forensic examination of grip-seal plastic bags.
Plastic bags are frequently used to package drugs, explosives and other contraband. There exists, therefore, a requirement in forensic casework to compare bags found at different locations. This is currently achieved almost exclusively by the use of physical comparisons such as birefringence patterns. This paper discusses some of the advantages and shortcomings of this approach, and presents stable isotope ratio mass spectrometry (IRMS) as a supplementary tool for effecting comparisons of this nature. Carbon and hydrogen isotopic data are presented for sixteen grip-seal plastic bags from a wide range of sources, in order to demonstrate the range of values which is likely to be encountered. Both isotopic and physical comparison (specifically birefringence) techniques are then applied to the analysis of rolls of bags from different manufacturing lots from a leading manufacturer. Both approaches are able to associate bags from a common production batch. IRMS can be applied to small fragments which are not amenable to physical comparisons, and is able to discriminate bags which could be confused using birefringence patterns alone. Similarly, in certain cases birefringence patterns discriminate bags with similar isotopic compositions. The two approaches are therefore complementary. When more than one isotopically distinct region exists within a bag (e.g. the grip-seal is distinct from the body) the ability to discriminate and associate bags is greatly increased.


Participation of international medical graduates in graduate medical education and hospital care for the poor.
To determine the impact of limiting international medical graduate (IMG) participation in US graduate medical education (GME) on the delivery of hospital care to the poor. To ascertain the pattern of IMG participation in GME and the degree to which the principal teaching hospitals with programs with large IMG enrollments provide care to the poor, we used data from the American Medical Association 1993 Annual Survey of Graduate Medical Education Programs and Teaching Institutions to analyze the pattern of IMG participation in GME in the six core specialties of internal medicine, family practice, obstetrics and gynecology, surgery, pediatrics, and psychiatry. Programs were identified as IMG dependent if at least 50% of the resident physicians enrolled in the first year of the program were IMGs. All programs were linked to their principal teaching hospitals, and hospitals were assessed according to the number of programs based at each institution, the number of IMG-dependent programs at the institution, and whether no-pay patients and/or Medicaid/public assistance beneficiaries constituted more than 20% of the patients served. Of the 20,170 first-year resident physicians in the six core specialties, 31.8% were IMGs. The proportion of programs dependent on IMG enrollment was 27.7%, ranging from 5.2% in obstetrics and gynecology programs to 49.5% in psychiatry programs. About 72% of all first-year IMGs were in IMG-dependent programs. Of the 688 hospitals serving as principal teaching sites for programs in at least one of the six core specialties, 106 were categorized as dependent on IMG programs, but only 77 of those provided a disproportionate amount of care to the poor. Finally, 40% of the IMG-dependent GME programs and 36% of first-year IMG residents were based in hospitals that did not provide a disproportionate amount of care to the poor. Based on this analysis, 77 hospitals can arguably be considered dependent on IMG resident physicians to provide care to the poor. Moreover, a large number of IMG residents and IMG-dependent programs are in hospitals that do not provide a disproportionate amount of care to the poor. These findings show the scale of the problem policymakers must address if they choose to limit IMG access to GME while maintaining access of the poor to needed hospital care.


Replication and expression of rubella virus in human lymphocyte populations.
Human mononuclear cells (lymphocytes and monocytes) from peripheral blood were examined for their ability to support the replication of rubella virus (RV) after infection in vitro. Replication was shown to occur in mixed lymphocytes and to be enhanced by stimulation with phytohaemagglutinin or pokeweek mitogen. A comparison of RV polypeptide synthesis in lymphocytes and RK13 cells showed no major differences in the polypeptides induced by infection. However, cellular translation was inhibited in the lymphocytes facilitating identification of virus polypeptides and eliminating the need for hypertonic labelling conditions used with RK13 cells. RV replication was also shown to occur in sub-populations of T-cells but not in B-cells. However, RV could be rescued from the B and monocyte population by co-cultivation with RK13 cells.


Defining adverse events in manual therapy: an exploratory qualitative analysis of the patient perspective.
Rare, serious, and common, benign adverse events (AE) are associated with MT techniques. A proposed standard for defining AE in manual therapy (MT) practise has been published but it did not include the patient perspective. Research comparing clinician and patient reporting of AE demonstrates that several differences exist; for example, the reporting of objective versus subjective events. The objective of this study was to describe how patients define AE associated with MT techniques. A descriptive qualitative design was employed. Semi-structured interviews were used with a purposive sample of patients (n = 13) receiving MT, from physiotherapy, chiropractic and osteopathic practises in Ontario, Canada. The interview guide was informed by existing evidence and consultation with content and methodological experts. Interviews were audiotaped and transcribed verbatim. Date were analysed by two independent team members using thematic content analysis. A key finding was that patients defined mild, moderate and major AE by pain/symptom severity, functional impact, duration and by ruling out of alternative causes. An overarching theme identified multiple factors that influence how the AE is perceived. These concepts differ from the previously proposed framework for defining AE that did not include the patient perspective. Future processes to create standard definitions or measures should include the patient viewpoint to provide a broader, client-centred foundation.


Canine urothelial carcinoma: a pilot study of microRNA detection in formalin-fixed, paraffin-embedded tissue samples and in normal urine.
We assessed the effects of fixation time in formalin and inclusion of surrounding tissue on microRNA (miRNA) cycle quantification (Cq) values in formalin-fixed, paraffin-embedded (FFPE) urothelial carcinoma (UC) tissue (n = 3), and the effect of conditions on miRNAs in urine from 1 healthy dog. MiRNAs were extracted using commercial kits and quantified using miRNA-specific fluorometry in normal bladder tissue scrolls, UC tissue cores, and bladder muscularis tissue cores from 4 FFPE bladder sections (3 UCs, 1 normal), plus 1 UC stored in formalin for 1, 8, 15, and 22 d before paraffin-embedding. Urine was collected from a healthy dog on 4 occasions; 1-mL aliquots were stored at 20, 4, -20, and -80°C for 4, 8, 24, and 48 h, and 1 and 2 wk. For both FFPE tissue and urine, we used reverse-transcription quantitative real-time PCR (RT-qPCR) to quantify miR-143, miR-152, miR-181a, miR-214, miR-1842, and RNU6B in each tissue or sample, using miR-39 as an exogenous control gene. The Cq values were compared with ANOVA and t-tests. The time of tissue-fixation in formalin did not alter miRNA Cq values; inclusion of the muscularis layer resulted in a statistically different miRNA Cq profile for miR-152, miR-181a, and RNU6B in bladder tissue. MiRNAs in acellular urine were stable for up to 2 wk regardless of the storage temperature. Our findings support using stored FFPE and urine samples for miRNA detection; we recommend measuring miRNA only in the tissue of interest in FFPE sections.


Herpetosiphon gulosus sp. nov., a filamentous predatory bacterium isolated from sandy soil and Herpetosiphon giganteus sp. nov., nom. rev.
Three filamentous gliding bacteria from the German Collection of Microorganisms and Cell Cultures, Hp g11, Hp g471 and Hp g472, were subjected to a phylogenetic analysis. These organisms had previously been classified as members of the genus Herpetosiphon based on their growth physiology and morphology. However, a taxonomic assignment at the species level had not been carried out. Analysis of 16S rRNA sequences now confirmed the close relationship of strain Hp g472 to Herpetosiphon aurantiacus DSM 785T (98.6 % nucleotide identity) and Herpetosiphon geysericola DSM 7119T (97.7 %). The results of DNA-DNA hybridization experiments further implied that strain Hp g472 should be classified as a distinct species. The DNA G+C content of strain Hp g472 was 49.9 mol%. The major quinone was MK-10 and the predominant cellular fatty acids were C18 : 1, C16 : 1 and C16 : 0. Based on phenotypic, chemotaxonomic and phylogenetic data it was concluded that strain Hp g472 represents a novel species of the genus Herpetosiphon, for which the name Herpetosiphon gulosus sp. nov. is proposed. The type strain is Hp g472T (=DSM 52871T=NBRC 112829T). In contrast to Hp g472T, the strains Hp g11 and Hp g471 exhibited closest 16S rRNA gene sequence similarity (>99 %) with 'Herpetosiphon giganteus' Hp a2. The distinctive genotypic and phenotypic properties of the latter supported the revival of the name as Herpetosiphon giganteus (ex Reichenbach & Golecki, 1975) sp. nov., nom. rev. We propose the previously deposited reference strain DSM 589T=NBRC 112828T as the type strain.


Stability of cyanogen chloride in the presence of free chlorine and monochloramine.
Cyanogen chloride (CNCl) is a disinfection byproduct found in chlorinated and chloraminated drinking water. Although there is an apparent greater association of CNCI with chloraminated water relative to chlorination systems, it was not clear whether these phenomenological observations are explained by differences in the stability or formation potentials of CNCI between the two disinfectants. In this study, the stability of CNCl was examined in the presence of free chlorine and monochloramine using membrane introduction mass spectrometry. CNCI decomposes relatively rapidly when free chlorine is present but is stable in the presence of monochloramine. The decomposition kinetics and observed reaction products are consistent with a hypochlorite-catalyzed hydrolysis mechanism, and the rate law is described by (d[CNCl]/dt) = - kOCl[CNCl][OCl-]. At 25 degrees C, pH 7, and a free chlorine residual of 0.5 mg/L as Cl2, the half-life of CNCl is approximately 60 min, suggesting significant decomposition is expected over disinfection time scales. Under some winter season temperature conditions, however, the decay half-life of CNCl can be longer than typical disinfection contact times. The results of this study demonstrate that the observed association of CNCl with chloramination systems can in part be explained by the differences in its stability with chlorine and chloramines.


Sensory Trichites Associated With the Food Canal of Chrysops callidus (Diptera: Tabanidae).
Twelve pairs of putative sensory trichites (= sensilla) in the food canal of Chrysops callidus Osten Sacken are described. Eight paired trichites are located in the distal half of the food canal of all flies in the sample population (n = 26 females), but paired trichites 9 through 12 were found in variable numbers in the proximal half of the canal. Trichites were more closely spaced in the distal half of the food canal, and more widely spaced in the proximal half of the canal, indicating that monitoring blood flow is more critical in the distal region of the canal. Moreover, trichites were not precisely paired, with mean position for each right wall trichite 1 through 8 being slightly anterior to its counterpart in the left wall. A short, funnel-shaped vestibule was evident at the labrum terminus, opening distally to the outside and proximally into the food canal (the vestibule/food canal junction). There were two pairs of sensilla (one pair of basicone design, the other setiform) observed at the base of the vestibule just anterior to the junction of the vestibule with the food canal. These vestibular sensilla were constant in type, number and position, in every member of the sample population.


Histone variants in archaea and the evolution of combinatorial chromatin complexity.
Nucleosomes in eukaryotes act as platforms for the dynamic integration of epigenetic information. Posttranslational modifications are reversibly added or removed and core histones exchanged for paralogous variants, in concert with changing demands on transcription and genome accessibility. Histones are also common in archaea. Their role in genome regulation, however, and the capacity of individual paralogs to assemble into histone-DNA complexes with distinct properties remain poorly understood. Here, we combine structural modeling with phylogenetic analysis to shed light on archaeal histone paralogs, their evolutionary history, and capacity to generate combinatorial chromatin states through hetero-oligomeric assembly. Focusing on the human commensal Methanosphaera stadtmanae as a model archaeal system, we show that the heteromeric complexes that can be assembled from its seven histone paralogs vary substantially in DNA binding affinity and tetramer stability. Using molecular dynamics simulations, we go on to identify unique paralogs in M. stadtmanae and Methanobrevibacter smithii that are characterized by unstable interfaces between dimers. We propose that these paralogs act as capstones that prevent stable tetramer formation and extension into longer oligomers characteristic of model archaeal histones. Importantly, we provide evidence from phylogeny and genome architecture that these capstones, as well as other paralogs in the Methanobacteriales, have been maintained for hundreds of millions of years following ancient duplication events. Taken together, our findings indicate that at least some archaeal histone paralogs have evolved to play distinct and conserved functional roles, reminiscent of eukaryotic histone variants. We conclude that combinatorially complex histone-based chromatin is not restricted to eukaryotes and likely predates their emergence.


Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2 Akita) diabetic mouse sympathetic ganglia.
The Akita mouse is a robust model of diabetic autonomic neuropathy which develops severe diabetes following beta cell death, which occurs reproducibly at 3-4 weeks of age, and maintains the diabetic state without therapy for as long as 11 additional months. Neuritic dystrophy and neuronopathy involving prevertebral sympathetic superior mesenteric and celiac ganglia begin to develop within the first two months of onset of diabetes and are progressive with time. We have examined the effect of insulin implants resulting in normoglycemia and injections of ARA290, a small erythropoietin peptide which has no effect on glycemic parameters, on the reversal of established neuritic dystrophy and neuronopathy. We have found that 4 weeks of insulin therapy beginning at 2 months of diabetes resulted in normalization of blood glucose, body weight and HbA1c. Insulin therapy successfully reversed established neuritic dystrophy and neuronopathy to control levels. Numbers of sympathetic neurons were not significantly changed in either 3 month diabetic or insulin-treated Akita mice. Treatment with ARA290 for 7 weeks beginning at 4 months of diabetes did not result in altered metabolic severity of diabetes as measured by blood glucose, body weight or HbA1c levels. ARA290 treatment was able to decrease neuritic dystrophy by 55-74% compared to untreated diabetics or in comparison to a separate group of diabetic animals representing the 4 month treatment onset point. Surprisingly, there was no effect of ARA290 on ganglionic neuron number or ongoing neuronopathy (pale/degenerating neurons) in diabetic Akita mice during this time period. The development of neuroprotective EPO-like peptides may provide a possible future therapy for this debilitating complication of diabetes; however, it appears that discrete elements may be differentially targeted by the diabetic state and may require selective therapy.


Prevalence, Determinants, and Consequences of Vestibular Hypofunction. Results From the KORA-FF4 Survey.
Objective: Uni- or bilateral vestibular hypofunction (VH) impairs balance and mobility, and may specifically lead to injury from falls and to disability. The extent of this problem in the general population is still unknown and most likely to be underestimated. Objective of this study was to determine the prevalence, determinants, and consequences of VH in the general population. Methods: Data originates from the cross-sectional second follow-up (FF4) in 2013/14 of the KORA (Cooperative Health Research in the Region of Augsburg)-S4 study (1999-2001) from Southern Germany. This was a random sample of the target population consisting of all residents of the region aged 25-74 years in 1999. We included all participants who reported moderate or severe vertigo or dizziness during the last 12 months and a random sub-sample of participants representative for the general population without vertigo or dizziness during the last 12 months were tested. VH was assessed with the Video-Head Impulse Test (vHIT). Trained examiners applied high-acceleration, small-amplitude passive head rotations ("head impulses") to the left and right in the plane of the horizontal semicircular canals while participants fixated a target straight ahead. During head impulses, head movements were measured with inertial sensors, eye movements with video-oculography (EyeSeeCam vHIT). Results: A total of 2,279 participants were included (mean age 60.8 years, 51.6% female), 570 (25.0%) with moderate or severe vertigo or dizziness during the last 12 months. Of these, 450 were assessed with vHIT where 26 (5.8%) had unilateral VH, and 16 (3.6%) had bilateral VH. Likewise, 190 asymptomatic participants were tested. Of these 5 (2.6%) had unilateral VH, and 2 (1.1%) had bilateral VH. Prevalence of uni- or bilateral VH among tested symptomatic participants was 2.4% in those < 48 years, and 32.1% in individuals aged 79 and over. Age-adjusted prevalence was 6.7% (95% CI 4.8%; 8.6%). VH was associated with worse health, falls, hearing loss, hearing impairment, and ear pressure. Conclusion: VH may affect between 53 and 95 million adults in Europe and the US. While not all affected persons will experience the full spectrum of symptoms and consequences, adequate diagnostic and therapeutic measures should become standard of care to decrease the burden of disease.


Cyclooxygenase-2 induction by bradykinin in aortic vascular smooth muscle cells.
Vascular smooth muscle cell proliferation and migration play an important role in the pathophysiology of several vascular diseases, including atherosclerosis. Prostaglandins that have been implicated in this process are synthesized by two isoforms of cyclooxygenase (COX), with the expression of the regulated COX-2 isoform increased in atherosclerotic plaques. Bradykinin (BK), a vasoactive peptide increased in inflammation, induces the formation of prostaglandins through specific receptor activation. We hypothesized that BK plays an important role in the regulation of COX-2, contributing to the increase in production of prostaglandins in vascular smooth muscle cells. Herein we examined the signaling pathways that participate in the BK regulation of COX-2 protein levels in primary cultured aortic vascular smooth muscle cells. We observed an increase in COX-2 protein levels induced by BK that was maximal at 24 h. This increase was blocked by a B2 kinin receptor antagonist but not a B1 receptor antagonist, suggesting that the B2 receptor is involved in this pathway. In addition, we conclude that the activation of mitogen-activated protein kinases p42/p44, protein kinase C, and nitric oxide synthase is necessary for the increase in COX-2 levels induced by BK because either of the specific inhibitors for these enzymes blocked the effect of BK. Using a similar approach, we further demonstrated that reactive oxygen species and cAMP were not mediators on this pathway. These results suggest that BK activates several intracellular pathways that act in combination to increase COX-2 protein levels. This study suggests a role for BK on the evolution of the atheromatous plaque by virtue of controlling the levels of COX-2.


Procedural Aggressiveness in Veterans with Advanced Non-Small-Cell Lung Cancer at the End of Life.
Evidence suggests that the aggressiveness of care in cancer patients at the end of life is increasing. We sought to evaluate the use of invasive procedures at the end of life in patients with advanced non-small-cell lung cancer (NSCLC). To evaluate the utilization of invasive procedures at the end of life in Veterans with advanced NSCLC. Retrospective cohort study of Veterans with newly diagnosed stage IV NSCLC who died between 2006 and 2012. Subjects were identified from the Veterans Affairs Central Cancer Registry. All Veterans Administration (VA) and Medicare fee-for-service healthcare utilization and expenditure data were assembled for all subjects. The primary outcome was the number of invasive procedures performed in the last month of life. We classified procedures into three categories: minimally invasive, life-sustaining, and major-operative procedures. Logistic regression analysis was used to evaluate factors associated with the receipt of invasive procedures. Nineteen thousand nine hundred thirty subjects were included. Three thousand (15.1%) subjects underwent 5523 invasive procedures during the last month of life. The majority of procedures (69.6%) were classified as minimally invasive. The receipt of procedures in the last month of life was associated with receipt of chemotherapy (odds ratio [OR] 3.68, 95% confidence interval [CI] 3.38-4.0) and ICU admission (OR 3.13, 95% CI 2.83-3.45) and was inversely associated with use of hospice services (OR 0.35, 95% CI 0.33-0.38). Invasive procedures are commonly performed among Veterans with stage IV NSCLC during their last month of life and are associated with other measures of aggressive end-of-life care.


Acanthocephalan infection patterns in amphipods: a reappraisal in the light of recently discovered host cryptic diversity.
Amphipods are model species in studies of pervasive biological patterns such as sexual selection, size assortative pairing and parasite infection patterns. Cryptic diversity (i.e. morphologically identical but genetically divergent lineages) has recently been detected in several species. Potential effects of such hidden diversity on biological patterns remain unclear, but potentially significant, and beg the question of whether we have missed part of the picture by involuntarily overlooking the occurrence and effects of cryptic diversity on biological patterns documented by previous studies. Here we tested for potential effects of cryptic diversity on parasite infection patterns in amphipod populations and discuss the implications of our results in the context of previously documented host-parasite infection patterns, especially amphipod-acanthocephalan associations. We assessed infection levels (prevalence and abundance) of 3 acanthocephalan species (Pomphorhynchus laevis, P. tereticollis and Polymorphus minutus) among cryptic lineages of the Gammarus pulex/G. fossarum species complex and G. roeseli from sampling sites where they occur in sympatry. We also evaluated potential differences in parasite-induced mortality among host molecular operational taxonomic units (MOTUs)-parasite species combinations. Acanthocephalan prevalence, abundance and parasite-induced mortality varied widely among cryptic MOTUs and parasite species; infection patterns were more variable among MOTUs than sampling sites. Overall, cryptic diversity in amphipods strongly influenced apparent infection levels and parasite-induced mortality. Future research on species with cryptic diversity should account for potential effects on documented biological patterns. Results from previous studies may also need to be reassessed in light of cryptic diversity and its pervasive effects.


Effect of arsenate on chemotactic behavior of Escherichia coli.
Escherichia coli cells treated with arsenate cannot tumble. The relationship between cellular adenosine 5'-triphosphate (ATP) level and the ability to tumble has been studied. (i) Cells incubated with arsenate completely lost their tumbling ability, and the cellular ATP level was decreased to less than 0.3 nmol/mg of protein. (ii) Incubation with 10 mM arsenate-1 mM phosphate reduced the cellular ATP level to less than 0.25 nmol/mg of protein. However, the cells were still able to tumble. (iii) Tumbling of the arsenate-treated cells was completely recovered after addition of a slight amount of phosphate, although the ATP level was still as low as 0.2 nmol/mg of protein. (iv) The cellular ATP level of an arsenate-treated uncA mutant (Ca2+,Mg2+-adenosine triphosphatase defective) was lower than 0.1 nmol/mg of protein even after the addition of 5 5 mM phosphate. However, tumbling ability was almost completely restored upon addition of the phosphate.


Remodelling of airway smooth muscle in asthma: what sort do you have?
Shortening of smooth muscle around airways is the basis of symptoms and abnormal lung function in asthma. The airway wall is increased in thickness in small and large airways asthma, in relation to the clinical severity of asthma and the airway smooth muscle layer is the main contributor to this thickening. The relative contributions of more airway smooth muscle cells, bigger cells or more extracellular matrix to the increased thickness of the smooth muscle layer in asthma is not clear and has been examined in only a small number of cases, Studies of the natural history of asthma suggest that the clinical severity of asthma is relatively constant over time, deficits in lung function compared with nonasthmatic subjects occur early in the course of the disease and the decline in lung function with age is increased in asthma. The observations from studies of the quantitative pathology and the natural history of asthma might be combined in the hypothesis that the severity of asthma is determined early (in its natural history) and is related mainly to increased volume density of airways smooth muscle cells (hyperplasia) and that later deposition of extracellular matrix from larger, hypertrophic smooth muscle cells results in fixed and increasing deficits in lung function. The relative contribution of more smooth muscle cells, bigger cells and extracellular matrix will be determined by unbiased stereological measurements in many cases of asthma of varying severity. The outcomes of such studies will be methods of monitoring and of treatment that will be tailored to the sort of smooth muscle modelling that is present in individual cases.


MR features of developing periventricular white matter in preterm infants: evidence of glial cell migration.
MR imaging of the brain is increasingly used in the investigation of the newborn, but little information is available on the normal appearance of the developing brain. We scanned a series of newborn infants in an attempt to define the normal appearance of developing periventricular white matter and to assess how pathologic conditions may modify this appearance. Sixty-eight newborn infants, median postmenstrual age (PMA) 34 weeks (range, 24 to 42 weeks), were subdivided into two groups: group A (n = 33), which included those with normal clinical and sonographic examinations, and group B (n = 35), which contained those with evidence of neuroabnormality detected prior to the MR study, either clinically or by cerebral sonography. Images were acquired in two planes on a 1.5-T imager using turbo spin-echo pulse sequences. Symmetric periventricular bands of reduced signal intensity were noted in the frontal periventricular white matter on T2-weighted images in 98% of group A infants and in 97% of group B infants. The number of bands was inversely related to PMA. The reduction in number of bands with increasing PMA was delayed in group B infants. The uniform appearance of periventricular bands in a population of healthy infants and their relationship to the infants' maturity is consistent with the results of previous histologic studies. These studies demonstrate the presence of migrating glial cells within the periventricular white matter of infants beyond 20 weeks' gestation, when neuronal migration to the cortex is complete. We postulate that the bands seen on T2-weighted images represent groups of migrating glial cells, providing a further marker of cerebral maturation.


Phasing at resolution higher than the experimental resolution.
Limited experimental resolution is a unavoidable feature in macromolecular crystallography: it may hinder or make difficult the determination of the crystal structure. A novel procedure is presented which from an approximate electron-density map extrapolates the moduli and phases of non-measured reflections beyond and behind the experimental resolution limit. Applications to a set of test structures show that the extrapolation can be successfully accomplished. As a consequence, the phase estimates of the observed reflections are subsequently improved and the interpretability of the corresponding electron-density map increases. The use of the extrapolated values for the non-measured reflections provides additional information for the map, which shows a resolution higher than the experimental resolution.


Gustatory responses of single neurons in the caudolateral orbitofrontal cortex of the macaque monkey.
1. In recordings made from 3,120 single neurons, a secondary cortical taste area was found in the caudolateral part of the orbitofrontal cortex of the cynomolgus macaque monkey, Macaca fascicularis. The area is part of the dysgranular field of the orbitofrontal cortex and is situated anterior to the primary cortical taste areas in the frontal opercular and adjoining insular cortices. 2. The responses of 49 single neurons with gustatory responses in the caudolateral orbitofrontal taste cortex were analyzed using the taste stimuli glucose, NaCl, HCl, quinine HCl, water, and blackcurrant juice. 3. A breadth-of-tuning coefficient was calculated for each neuron. This is a metric that can range from 0.0 for a neuron that responds specifically to only one of the four basic taste stimuli to 1.0 for one that responds equally to all four stimuli. The mean coefficient for 49 cells in the caudolateral orbitofrontal cortex was 0.39. This tuning is much sharper than that of neurons in the nucleus of the solitary tract of the monkey, and sharper than that of neurons in the primary frontal opercular and insular taste cortices. 4. A cluster analysis showed that at least seven different groups of neurons were present. For each of the taste stimuli glucose, blackcurrant juice, NaCl, and water, there was one group of neurons that responded much more to that tastant than to the other tastants. The other groups of neurons responded to two or more of these tastants, such as glucose and blackcurrant juice. In this particular region neurons were not found with large responses to HCl or quinine HCl, although such neurons could be present in other parts of the orbitofrontal cortex. 5. On the basis of this and other evidence it is concluded that in the caudolateral orbitofrontal cortex there is a secondary cortical taste area in which the tuning of neurons has become finer than in early areas of taste processing, in which foods, water, and NaCl are strongly represented and where motivation dependence first becomes manifest in the taste system.


Modelling cellular signalling systems.
Cell signalling pathways and networks are complex and often non-linear. Signalling pathways can be represented as systems of biochemical reactions that can be modelled using differential equations. Computational modelling of cell signalling pathways is emerging as a tool that facilitates mechanistic understanding of complex biological systems. Mathematical models are also used to generate predictions that may be tested experimentally. In the present chapter, the various steps involved in building models of cell signalling pathways are discussed. Depending on the nature of the process being modelled and the scale of the model, different mathematical formulations, ranging from stochastic representations to ordinary and partial differential equations are discussed. This is followed by a brief summary of some recent modelling successes and the state of future models.


Rotavirus genetic diversity, disease association, and temporal change in hospitalized rural Kenyan children.
The effectiveness of rotavirus vaccines will be dependent on the immunity conferred against prevalent and emergent variants causing severe diarrheal disease. Longitudinal surveillance of disease-causing strains is a prerequisite to intervention. Molecular characterization was conducted on rotavirus-positive stool samples from children admitted with diarrhea to a rural district hospital during 2002-2004. Extracted viral RNA was separated by polyacrylamide gel electrophoresis, and rotavirus VP4 (P types) and VP7 (G types) specificities were determined. Among 558 investigated cases, the predominant genotype was P[8]G1 (42%), followed by P[8]G9 (15%), P[4]G8 (7%), P[6]G8 (6%), and P[8]G8 (4%), with 10% mixed strains. Overall, there were 6 different P types and 7 G types. No association was identified between genotype and child age, sex, or severity of diarrhea. The P and G genotypes and polyacrylamide gel electropherotypes showed significant temporal variation in frequency: P[8]G1 decreased from 51% (95% confidence interval [CI], 43%-58%) in 2002 to 30% (95% CI, 24%-37%) in 2004, and P[4]G8 increased from 2% (95% CI, 0%-5%) in 2002 to 13% (95% CI, 9%-19%). Quarterly data revealed seasonally endemic and emergence and/or decay patterns. Our study of rotavirus strains causing severe diarrhea in rural Kenyan children showed a predominance of P[8]G1 and confirms the importance of G8 and G9 strains in sub-Saharan Africa. Considerable genetic diversity of rotavirus strains was observed, including substantial mixed and unusual types, coupled with significant temporal strain variation and emergence. These results warn of variable vaccine efficacy and the need for long-term surveillance of circulating rotavirus genotypes.


Lipid phosphate phosphatase 3 in vascular pathophysiology.
LPP3 is an integral membrane protein belonging to a family of enzymes (LPPs) that display broad substrate specificity and catalyse dephosphorylation of several lipid substrates, including lysophosphatidic acid and sphingosine-1-phosphate. In mammals, the LPP family consists of three enzymes named LPP1, LPP2 and LPP3, which are encoded by three independent genes, PLPP1, PLPP2 and PLPP3, respectively (formerly known as PPAP2A, PPAP2C, PPAP2B). These three enzymes, in vitro, do not seem to differ for catalytic activities and substrate preferences. However, in vivo targeted inactivation of the individual genes has indicated that the enzymes do not have overlapping functions and that LPP3, specifically, plays a crucial role in vascular development. In 2011, two genome-wide association studies have identified PLPP3 as a novel locus associated with coronary artery disease susceptibility. Shortly after these reports, tissue specific inactivation of PLPP3 in mice highlighted a specific role for LPP3 in vascular pathophysiology and, more recently, in atherosclerosis development. This review is aimed at providing an updated overview on the function of LPP3 in embryonic cardiovascular development and on the experimental and clinical evidences relating this enzyme to vascular cell functions and cardiovascular disease.


Assessment of iodine nutrition in pregnant north Indian subjects in three trimesters.
The cross-sectional study was carried out to assess the iodine status of pregnant women, using median urinary iodine concentration (MUI) as the measure of outcome, to document the impact of advancing gestation on the MUI in normal pregnancy. The present study assessed the MUI in casual urine samples from 50 pregnant subjects of each trimester and 50 age-matched non-pregnant controls. The median (range) of urinary iodine concentration (UIC) in pregnant women was 304 (102-859) μg/L and only 2% of the subjects had prevalence of values under 150 μg/L (iodine insufficiency). With regard to the study cohort, median (range) UIC in the first, second, and third trimesters was 285 (102-457), 318 (102-805), and 304 (172-859) μg/L, respectively. Differences between the first, second, and third trimesters were not statistically significant. The MUI in the controls (305 μg/L) was not statistically different from the study cohort. The pregnant women had no iodine deficiency, rather had high median urinary iodine concentrations indicating more than adequate iodine intake. Larger community-based studies are required in iodine-sufficient populations, to establish gestation-appropriate reference ranges for UIC in pregnancy.


Decellularized peripheral nerve supports Schwann cell transplants and axon growth following spinal cord injury.
Schwann cell (SC) transplantation has been comprehensively studied as a strategy for spinal cord injury (SCI) repair. SCs are neuroprotective and promote axon regeneration and myelination. Nonetheless, substantial SC death occurs post-implantation, which limits therapeutic efficacy. The use of extracellular matrix (ECM)-derived matrices, such as Matrigel, supports transplanted SC survival and axon growth, resulting in improved motor function. Because appropriate matrices are needed for clinical translation, we test here the use of an acellular injectable peripheral nerve (iPN) matrix. Implantation of SCs in iPN into a contusion lesion did not alter immune cell infiltration compared to injury only controls. iPN implants were larger and contained twice as many SC-myelinated axons as Matrigel grafts. SC/iPN animals performed as well as the SC/Matrigel group in the BBB locomotor test, and made fewer errors on the grid walk at 4 weeks, equalizing at 8 weeks. The fact that this clinically relevant iPN matrix is immunologically tolerated and supports SC survival and axon growth within the graft offers a highly translational possibility for improving efficacy of SC treatment after SCI. To our knowledge, it is the first time that an injectable PN matrix is being evaluated to improve the efficacy of SC transplantation in SCI repair.


Isolated microorganisms from Iranian grapes and its derivatives.
The objective of this study was to monitor the microorganisms isolated from grapes and its derivative traditional products produced in Iran. Four kinds of grapes cultivated summer of 2010 in vineyard of Takestan and also grape derived products from Shahrod, Hamedan and Takestan were used for this study. The samples were cultured in specific media to isolate the microorganisms that might grow on or pollute the products. Species of bacteria and fungi isolated from 4 kinds of grapes cultivated in Takestan graveyards and also from 2 kinds of derived traditional products; grape sap and sour grape (abe-ghure locally named), were taken from Takestan, Shahrod and Hamedan cities. Also, bacteria Bacillus spp., Micrococcus spp., Clostridium spp., and fungus of Penicillium spp., and Aspergillus spp. were isolated. The isolated bacteria were common microorganisms that grow in soil or in the organic fertilizer and may appear from the environments that samples were collected. These bacteria were not pathogenic to human. The fungus isolated from the grapes may harm humans as they produce toxin. The results suggested that bacterial diversity on grapes and its derived traditional products are expected to be monitored and described in all Iranian graveyards as Iran has been known as one of the world's biggest grape producers.


[Radioimmunological method of determining the growth hormone of rats].
The paper is concerned with working out a system of a homologous radioimmunoassay for determination of the growth hormone of rats. The obtaining of all components of the system was described including a specimen of homogeneous highly purified rat STH and a guinea-pig antiserum to it. Conditions for running the RIA which provided for getting a calibrated curve within the range of effective STH doses of 5-1000 ng/ml were described. A study of the specificity of the STH determination method demonstrated that under such conditions LH (rLH-RP-1, NIADDK) and TTH (rTSH-RP-2, NIADDK) did not show activity and rat prolactin revealed insignificant activity equal to 1.3% of STH activity. Using the above method STH levels were determined in the blood plasma of Wistar rats under the following experimental conditions: in intact animals after L-arginine load and 2 weeks after hypophysectomy. STH levels under these conditions were 42 +/- 2.6, 102 +/- 3.8 and 8.6 +/- +/- 1.2 ng/ml, respectively. The authors presented the results of comparative immunological activity of the obtained STH specimen and the STH specimens of rats, NIADDK.


Autoimmune haemolysis associated with Donath-Landsteiner antibodies.
The clinical pattern of haemolysis associated with Donath-Landsteiner antibodies has undergone a change over the years. In the current study 13 patients developed the acute form of the disease whilst only 1 presented with the classical picture of chronic paroxysmal cold haemoglobinuria. The acute illness typically occurred in young children with a male predominance of about 2.5:1; 10 patients were less than 5 years old. There was often a history of a preceding infection, the onset was sudden, prostration, haemoglobinuria and pallor were prominent. The patients were very ill but rapid and complete recovery usually occurred within a few days; however, 1 patient died. Treatment consisted of rest and warmth; in addition blood transfusion was needed in 7 patients. The chronic disease (which was non-syphilitic in origin) followed a benign course, warmth and avoidance of cold being all that were necessary to maintain the patient's well-being. It is felt that the general term for this disorder should be Donath-Landsteiner haemolysis rather than the traditional paroxysmal cold haemoglobinuria.


Nasal immunization with tetanus toxoid increases the subsequent systemic dimeric IgA1 antibody response to intramuscular immunization.
We have investigated the effects of nasal immunization with tetanus toxoid (TT) on the subsequent systemic IgA response. Healthy adult volunteers who had not had a TT boost for at least five years received either an intra-muscular (IM) TT immunization alone (n = 19) or first an intra-nasal and then two weeks later an IM immunization (n = 27). The serum and circulating B cell IgG and IgA1 antibody response to TT were measured. When compared to subjects who received only an IM immunization, those who were nasally primed had increased serum levels of dimeric IgA1 antibodies to TT and an increased number of B cells secreting IgA1 antibodies to TT. These data indicate that mucosal antigen exposure is one of the mechanisms involved in the induction of systemic serum IgA1 response.


Mitochondria as promising targets for nutritional interventions aiming to improve performance and longevity of sows.
Genetic selection and management changes during the last decades have significantly increased the average litter size of sows. However, this recent success has not correlated with an extension of longevity and reduction in replacement rate. Longevity or lifetime production of sows is determined by a combination of environmental and genetic factors. Nutrition is an environmental factor of importance, and it has long been appreciated that animals fed with specific diets may perform differently. The advent of modern science revealed that this is partly due to the ability of nutrients to act as signalling molecules that, through appropriate intracellular sensing mechanisms, can control gene expression and modulate cell functions. Based on this concept, nutrigenomics studies now aim to show that not only are certain nutrients essential for general health, but also that specific quantities of precise nutrients are necessary during critical periods of energy deficiency and oxidative stress such as gestation and lactation to ensure long-term productivity. The toxic molecules at the origin of oxidative stress, free radicals, are mainly generated as normal by-products of aerobic energy production by mitochondria. In all cells, mitochondria are dynamic organelles that are mainly known as the primary energy-generating system. Thus, when metabolic demands are elevated as it is for hyperprolific sows, mitochondria are heavily solicited for answering all energetic needs, and substantive amounts of free radicals are generated. As a result, optimal conditions in term of antioxidant protection and metabolic substrates availability are required to support mitochondrial function in these animals. This article discusses how performance and longevity of sows are linked to mitochondrial function and oxidative stress and reviews the major natural nutrients known for their antioxidant and/or energetic properties that are susceptible to impact mitochondria and likely improved sows productivity.


Mechanisms of orthostatic intolerance during heat stress.
Heat stress profoundly and unanimously reduces orthostatic tolerance. This review aims to provide an overview of the numerous and multifactorial mechanisms by which this occurs in humans. Potential causal factors include changes in arterial and venous vascular resistance and blood distribution, and the modulation of cardiac output, all of which contribute to the inability to maintain cerebral perfusion during heat and orthostatic stress. A number of countermeasures have been established to improve orthostatic tolerance during heat stress, which alleviate heat stress induced central hypovolemia (e.g., volume expansion) and/or increase peripheral vascular resistance (e.g., skin cooling). Unfortunately, these countermeasures can often be cumbersome to use with populations prone to syncopal episodes. Identifying the mechanisms of inter-individual differences in orthostatic intolerance during heat stress has proven elusive, but could provide greater insights into the development of novel and personalized countermeasures for maintaining or improving orthostatic tolerance during heat stress. This development will be especially impactful in occuational settings and clinical situations that present with orthostatic intolerance and/or central hypovolemia. Such investigations should be considered of vital importance given the impending increased incidence of heat events, and associated cardiovascular challenges that are predicted to occur with the ensuing changes in climate.


Artichoke phytocomplex modulates serum microRNAs in patients exposed to asbestos: a first step of a phase II clinical trial.
Malignant pleural mesothelioma is a highly aggressive tumor associated with asbestos exposure. There are few effective treatment options for mesothelioma, and patients have a very poor prognosis. Mesothelioma has the potential to represent an appropriate disease to prevent because of its strong association with asbestos exposure and the long latency from exposure to the disease on-set. In the present study, we tested biological activity and toxicity of an artichoke freeze-dried extract (AWPC) as potential complementary preventive/early stage treatment agent for mesothelioma. This phase II clinical study then was conducted in 18 male-patients with evidence of radiographic characteristics related to asbestos exposure such as asbestosis or benign pleural disease as surrogate disease for mesothelioma clinical model. We investigate AWPC biological activity assessing its effect on mesothelin serum level, a glycoprotein with low expression in normal mesothelial cells and high expression in mesothelioma and asbestos related diseases. We also assess the AWPC effect on circulating miRNAs, as novel biomarkers of both cancer risk and response to therapeutic targets. While we found a small and not significant effect of AWPC on mesothelin serum levels, we observed that AWPC intake modulated 11 serum miRNAs related to gene-pathways connected to mesothelioma etiology and development. In terms of toxicity, we also did not observe any severe adverse effects associated to AWPC treatment, only gastro-intestinal symptoms were reported by five study participants. We observed an interesting AWPC effect on miRNAs which targets modulate mesothelioma development. New and much larger clinical studies based on follow-up of workers exposed to asbestos are needed to corroborate the role of AWPC in prevention and early treatment of mesothelioma. ClinicalTrials.gov, NCT02076672 . Registered 03/03/2014.


Dose-response and risk assessment of airborne hexavalent chromium and lung cancer mortality.
This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).