Weight Stigma Model on Quality of Life Among Children in Hong Kong: A Cross-Sectional Modeling Study.
We proposed a model to examine the relationship among different types of weight-related stigmas and their relationship to quality of life (QoL). We recruited 430 dyads of elementary school children [mean age = 10.07 years; nboy = 241 (56.0%); noverweight = 138 (32.1%)] and their parents. Parents completed QoL instruments about their children assessing generic QoL and weight-related QoL. Children completed QoL instruments assessing generic QoL and weight-related QoL and stigma scales assessing experienced weight stigma, weight-related self-stigma, and perceived weight stigma. Experienced weight stigma was significantly associated with perceived weight stigma, and in turn, perceived weight stigma was significantly associated with weight-related self-stigma. However, experienced weight stigma was not directly associated with weight-related self-stigma. In addition, experienced stigma was negatively associated with both child-rated and parent-rated QoL. Perceived weight stigma was associated only with parent-rated weight-related QoL but not child-rated QoL. Self-stigma was associated with child-rated QoL but not parent-rated QoL. Moreover, perceived weight stigma and weight-related self-stigma were significant mediators in the association between body weight and children's QoL; experienced weight stigma was not a significant mediator. The study findings can be used to inform healthcare providers about the relationship among different types of stigmas and their influence on child-rated and parent-rated QoL and help them develop interventions to address the global trend of overweight/obesity in youth and pediatric populations.


Advances in validating SALTIRSOIL at plot scale: first results.
SALTIRSOIL (SALTs in IRrigated SOILs) is a model for the medium to long term simulation of soil salinity in irrigated, well-drained lands. Once the algorithms were verified, the objective of our study was to validate SALTIRSOIL under one of several water quality and management scenarios in Mediterranean agriculture. Because drip and surface are the most common irrigation systems in irrigated agriculture in Valencia (Spain), the validation was performed with climate, soil, irrigation water (composition and management) and crop (species and management) information from an experimental plot surface irrigated with well water and planted with watermelon that has been monitored since the late spring of 2007. To carry out the validation, first we performed a global sensitivity analysis (GSA). Second, we compared simulated soil saturation extract composition against measured data. According to the GSA, SALTIRSOIL calculations of soil salinity seem to be most affected by climate (rainfall and evapotranspiration) with 60% of explained soil salinity variance, water salinity with 26% of explained variance, and then irrigation with 4%. According to the closeness of the first comparisons between predictions and measurements, SALTIRSOIL does not seem to be affected by any systematic error, and as a consequence, neither inclusion of new parameters nor calibration of the others already included would be needed at least for surface irrigation. The validation of SALTIRSOIL continues under other water quality and irrigation management scenarios.


Cigarette smoking in teenage girls: exploring the role of peer reputations, self-concept and coping.
Reducing the prevalence of smoking among teenagers is an important goal for health and education professionals. In the present study, self-reported cigarette smoking status was examined among 241 adolescent females from four metropolitan, independent girls' schools in suburban Melbourne, Australia. This study was particularly concerned with the role of peer reputations, coping and self-concept as influences on teenage girls' decision making with respect to smoking. Coping strategies, levels of self-concept and reputation enhancement were assessed using the High School Student Activity Questionnaire. Three separate multivariate analyses of variance (MANOVAs) revealed that six of the 11 reputation variables, three of the four self-concept variables and two of the three coping variables contributed to the main effect of smoking status. Post hoc analyses allowed some profiling of current cigarette smokers as compared to never smokers. This study offers support to reputation enhancement theory with regard to cigarette smoking in adolescent girls, and also provides continued evidence for the importance of particular aspects of self-concept and coping skills with respect to cigarette smoking. Suggestions for further research are discussed and some possible implications of the findings for school-based health education programmes are raised.


The chromosomal passenger complex and centralspindlin independently contribute to contractile ring assembly.
The chromosomal passenger complex (CPC) and centralspindlin are conserved cytokinesis regulators that localize to the spindle midzone, which forms between the separating chromosomes. Previous work placed the CPC and centralspindlin in a linear pathway that governs midzone formation. Using Caenorhabditis elegans embryos, we test whether there is a similar linear relationship between centralspindlin and the CPC in contractile ring constriction during cytokinesis. We show that simultaneous inhibition of the CPC kinase Aurora B(AIR-2) and the centralspindlin component MKLP1(ZEN-4) causes an additive constriction defect. Consistent with distinct roles for the proteins, inhibition of filamentous septin guanosine triphosphatases alleviates constriction defects in Aurora B(AIR-2)-inhibited embryos, whereas inhibition of Rac does so in MKLP1(ZEN-4)-inhibited embryos. Centralspindlin and the CPC are not required to enrich ring proteins at the cell equator but instead regulate formation of a compact mature ring. Therefore, in contrast to the linear midzone assembly pathway, centralspindlin and the CPC make independent contributions to control transformation of the sheet-like equatorial band into a ribbon-like contractile ring at the furrow tip.


Reconstruction of total radiance spectra of fluorescent samples by means of nonlinear principal component analysis.
Nonlinear principal component analysis (NLPCA) was used for compression and reconstruction of the total radiance factors (TRFs) of fluorescent samples. The spectral dataset included a total of 358 fluorescent reflectance spectra in the visible range of the spectrum. Spectral data compression was followed by extracting the parameterized nonlinear manifolds using the NLPCA technique. To compare the performance of NLPCA-based compression with the linear method, the orthonormal feature vectors of the dataset were also extracted by the linear PCA. The spectral performance of NLPCA and PCA-based compression approaches was assessed by the root mean square error and the goodness-fitting coefficient between the real and the reconstructed spectra. The percentages of feasible spectra by each method, i.e., those with nonnegative TRFs, were also reported as other criteria for the evaluation of methods. Furthermore, the colorimetric performance of methods were appraised by the measuring the CIELAB 1976 color difference values between the actual and reconstructed spectra under illuminants D65 and A and the 1964 standard observer. The NLPCA-based compression method performed significantly better than the standard PCA-based technique particularly in the lower dimensional spaces of the spectral radiance factors of fluorescent colors.


Limitation of physical activity, dyspnea and chest pain prior to and during two years after coronary artery bypass grafting in relation to a history of hypertension.
To describe the limitation of physical activity, the cause of limitation of physical activity and symptoms of dyspnea and chest pain before and 2 years after coronary artery bypass grafting (CABG) in relation to a history of hypertension. All patients from western Sweden who underwent CABG between 1988 and 1991 were approached with a questionnaire--prior to, 3 months and 2 years after CABG--evaluating the issues raised above. Of 2121 patients, 37% had a history of hypertension. By 3 months after CABG, physical activity tolerance had improved markedly and in a similar way for both hypertensive (p<0.001) and non-hypertensive patients (p<0.001); this level was sustained for 2 years. Absence of dyspnea increased markedly and similarly among both hypertensive and non-hypertensive patients (p < 0.001) after CABG. The presence of chest pain decreased markedly and similarly among hypertensive (p<0.001) and non-hypertensive patients (p<0.001), both 3 months and 2 years after compared to prior to the operation. There was a marked improvement in terms of physical activity and cardiovascular symptoms 3 months and 2 years after CABG as compared with the situation prior to the operation. A previous history of hypertension did not seem to affect these results.


Antifungal and Anticancer Potential of Argemone mexicana L.
Background: Medicinal plants are widely used to treat infectious diseases, metabolic disorders and cancer. Argemone mexicana L. (A. mexicana), commonly found on desolate land of Marathwada (Maharashtra, India) has been used to treat oral cavity infections. Methods: In this study, cold aqueous and methanolic extracts were prepared from A. mexicana stem and leaves. These extracts were tested for their antifungal and anticancer activities. The antifungal activity was tested using the agar well diffusion method, while the anticancer activity against immortalized cell lines was assessed by trypan blue assay. Results: It was observed that both cold aqueous and methanolic extracts of A. mexicana stem and leaves inhibited the growth of Mucor indicus, Aspergillus flavus, Aspergillus niger and Penicillum notatum. Antifungal activity of the extract was comparable to that of Amphoterecin-B. A. mexicana extracts had a cytotoxic effect on A549, SiHa and KB immortalized cell lines that were similar to that of berberine. Conclusion: The A. mexicana leaf and stems exhibit strong antifungal and anticancer potential.


Monitoring cognitive change in multiple sclerosis using a computerized cognitive battery.
Cognitive monitoring that can detect short-term change in multiple sclerosis is challenging. Computerized cognitive batteries such as the CogState Brief Battery can rapidly assess commonly affected cognitive domains. The purpose of this study was to establish the acceptability and sensitivity of the CogState Brief Battery in multiple sclerosis patients compared to controls. We compared the sensitivity of the CogState Brief Battery to that of the Paced Auditory Serial Addition Test over 12 months. Demographics, Expanded Disability Status Scale scores, depression and anxiety scores were compared with CogState Brief Battery and Paced Auditory Serial Addition Test performances of 51 patients with relapsing-remitting multiple sclerosis, 19 with secondary progressive multiple sclerosis and 40 healthy controls. Longitudinal data in 37 relapsing-remitting multiple sclerosis patients were evaluated using linear mixed models. Both the CogState Brief Battery and the Paced Auditory Serial Addition Test discriminated between multiple sclerosis and healthy controls at baseline (p<0.001). CogState Brief Battery tasks were more acceptable and caused less anxiety than the Paced Auditory Serial Addition Test (p<0.001). In relapsing-remitting multiple sclerosis patients, reaction time slowed over 12 months (p<0.001) for the CogState Brief Battery Detection (mean change -34.23 ms) and Identification (-25.31 ms) tasks. Paced Auditory Serial Addition Test scores did not change over this time. The CogState Brief Battery is highly acceptable and better able to detect cognitive change than the Paced Auditory Serial Addition Test. The CogState Brief Battery could potentially be used as a practical cognitive monitoring tool in the multiple sclerosis clinic setting.


Toxic Shock Syndrome: Still a Timely Diagnosis.
Toxic shock syndrome (TSS) is an acute, severe, toxin-mediated disease, characterized by fever, hypotension, and multiorgan system involvement. Toxic shock syndrome has made headlines because of its high associated morbidity and mortality rate in previously healthy young females. Incidence peaked in the early 1980s owing to increased usage of ultra-absorbent tampons. After improved patient education and tampon labeling, the incidence of menstrual TSS has declined. A previously healthy 14-year-old girl presented to an urgent care center with a 2-day history of fever, erythematous maculopapular rash, vomiting, diarrhea, and malaise. She was found to be tachycardic and hypotensive. Investigations revealed thrombocytopenia, an elevated white count and lactate, and acute kidney injury, consistent with septic shock. Recent tampon usage with menstruation was reported, and a pelvic examination revealed purulent vaginal discharge. The patient was transferred to a pediatric intensive care unit for antibiotic and vasopressor therapy. Vaginal swabs later tested positive for Staphylococcus aureus and TSS toxin-1. Although the incidence of TSS has decreased in recent years, it is crucial that clinicians rapidly recognize and treat this life-threatening condition. Emergency physicians should always have a high index of suspicion for TSS in young females presenting without another obvious cause of shock. A pelvic examination should always be completed in these cases.


Life-prolonging treatment in nursing homes: how do physicians and nurses describe and justify their own practice?
Making the right decisions, while simultaneously showing respect for patient autonomy, represents a great challenge to nursing home staff in the issues of life-prolonging treatment, hydration, nutrition and hospitalisation to dying patents in end-of-life. To study how physicians and nurses protect nursing home patients' autonomy in end-of-life decisions, and how they justify their practice. A qualitative descriptive design with analysis of the content of transcribed in-depth interviews with physicians and nurses. Nine physicians and ten nurses in 10 nursing homes in Norway. Assessment of the patient's competence to consent to treatment is almost absent. The physicians build their practice on the principles of beneficence and nonmaleficence. Nurses tend to trust the patients' rejection of life support, even when the patients have difficulty speaking or suffer from dementia. Relatives were, according to the health personnel, included in decision-making processes to a very limited extent. However, futile life support is sometimes provided contrary to the physicians' judgement of what constitutes the patient's best interest on occasions when they are pressurised by next of kin. The study reveals a need to improve decision-making routines according to ethical ideals and legislation. Conflicts between relatives and healthcare professionals in the decision-making process deflect the focus from searching for the best possible treatment for the terminal patient. Further discussion is required as to whether the concept of autonomy is applicable in situations in which the patient is impaired and dying.


A Multi-Step Algorithm for Measuring Airway Luminal Diameter and Wall Thickness in Lung CT Images.
Accurate measurements of airway diameter and wall thickness are important parameters in understanding numerous pulmonary diseases. Here, we describe an automated method of measuring small airway luminal diameter and wall thickness over numerous contiguous computed tomography (CT) images. Using CT lung images from 22 patients and an airway phantom, a seeded region-growing algorithm was first applied to identify the lumen of the airway. The result was applied as an initial region for boundary determination using the level set method. Once found, subsequent algorithmic expansion of the luminal border was used to calculate airway wall thickness. This algorithm automatically evaluates neighboring slices of the airway and measures the airway luminal diameter and wall thickness. This approach also detects airway bifurcations. Our new procedure provides rapid, automated, accurate, and clinically important lung airway measurements that would be useful to radiologists who use CT images for pulmonary disease assessment.


Costs of crowding for the transmission of malaria parasites.
The utility of using evolutionary and ecological frameworks to understand the dynamics of infectious diseases is gaining increasing recognition. However, integrating evolutionary ecology and infectious disease epidemiology is challenging because within-host dynamics can have counterintuitive consequences for between-host transmission, especially for vector-borne parasites. A major obstacle to linking within- and between-host processes is that the drivers of the relationships between the density, virulence, and fitness of parasites are poorly understood. By experimentally manipulating the intensity of rodent malaria (Plasmodium berghei) infections in Anopheles stephensi mosquitoes under different environmental conditions, we show that parasites experience substantial density-dependent fitness costs because crowding reduces both parasite proliferation and vector survival. We then use our data to predict how interactions between parasite density and vector environmental conditions shape within-vector processes and onward disease transmission. Our model predicts that density-dependent processes can have substantial and unexpected effects on the transmission potential of vector-borne disease, which should be considered in the development and evaluation of transmission-blocking interventions.


Inbreeding depression influences genet size distribution in a marine angiosperm.
Although inbreeding depression is a major genetic phenomena influencing individual fitness, it is difficult to measure in wild populations. An alternative approach is to correlate heterozygosity, measured using highly polymorphic markers, with a fitness-correlated trait. In clonal plants, genet size is predicted to be fitness correlated. Here we test the prediction that the genet size distribution of the marine clonal plant Zostera marina (eelgrass) is influenced by inbreeding depression. We used nine polymorphic microsatellite markers to access the fine scale clonal structure and to measure individual heterozygosity within 4 plots (each corresponds to 256 m2, sampled at 1-m intervals) in two populations along the German Baltic Coast. The same plots were also sampled for flowering and vegetative shoots to obtain estimates for sexual reproductive output at the level of the genetic individual. We found substantial differences in the genet size distribution between the two populations that may be explained by different disturbance frequency. In both populations, clone size was significantly positively correlated with the total number of flowering shoots, indicating that larger clones have a higher reproductive output. Individual heterozygosity was significantly positively associated with clone size. The effect was much stronger in Falkenstein (low disturbance) than in Maasholm (high disturbance). The results indicate that in a low disturbance population the relatively outbred clones occupy a higher proportion of the available space, possibly because they outcompete relatively inbred neighbours.


Human rhinovirus 3C protease as a potential target for the development of antiviral agents.
As the major cause of the common cold in children and adults, human rhinoviruses (HRVs) are a group of small single-stranded positive-sense RNA viruses. HRVs translate their genetic information into a polyprotein precursor that is mainly processed by a virally encoded 3C protease (3Cpro) to generate functional viral proteins and enzymes. It has been shown that the enzymatic activity of HRV 3Cpro is essential to viral replication. The 3Cpro is distinguished from most other proteases by the fact that it has a cysteine nucleophile but with a chymotrypsin-like serine protease folding. This unique protein structure together with its essential role in viral replication made the 3Cpro an excellent target for antiviral intervention. In recent years, considerable efforts have been made in the development of antiviral compounds targeting this enzyme. To further facilitate the design of potent 3C protease inhibitors for therapeutic use, this review summarizes the biochemical and structural characterization conducted on HRV 3C protease along with the recent progress on the development of 3C protease inhibitors.


Molecular genetic mechanisms of allelic specific regulation of murine Comt expression.
A functional allele of the mouse catechol-O-methyltransferase (Comt) gene is defined by the insertion of a B2 short interspersed repeat element in its 3'-untranslated region (UTR). This allele has been associated with a number of phenotypes, such as pain and anxiety. In comparison with mice carrying the ancestral allele (Comt+), Comt B2i mice show higher Comt mRNA and enzymatic activity levels. Here, we investigated the molecular genetic mechanisms underlying this allelic specific regulation of Comt expression. Insertion of the B2 element introduces an early polyadenylation signal generating a shorter Comt transcript, in addition to the longer ancestral mRNA. Comparative analysis and in silico prediction of Comt mRNA potential targets within the transcript 3' to the B2 element was performed and allowed choosing microRNA (miRNA) candidates for experimental screening: mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667. Cell transfection with each miRNA downregulated the expression of the ancestral transcript and COMT enzymatic activity. Our in vivo experiments showed that mmu-miR-667-3p is strongly correlated with decreasing amounts of Comt mRNA in the brain, and lentiviral injections of mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667 increase hypersensitivity in the mouse formalin model, consistent with reduced COMT activity. In summary, our data demonstrate that the Comt+ transcript contains regulatory miRNA signals in its 3'-untranslated region leading to mRNA degradation; these signals, however, are absent in the shorter transcript, resulting in higher mRNA expression and activity levels.


Omnichannel Strategy and Consumer Behavior in Distribution Channels: Trends in the Ophthalmology Sector.
Changes in consumer behavior are forcing companies to rapidly shift their distribution channels toward an omnichannel model. In the case of the ophthalmology sector, however, the purchase of contact lenses and prescription glasses requires professional examination by a trained eye specialist. This peculiarity of the sector affects the shift toward omnichannel. This paper is novel in that it addresses a research gap by studying the distribution channels for regulated products and services such as health products that required a closer professional service. This paper addresses the transformation of companies toward an omnichannel model using a common scientific forecasting method (i.e., the Delphi method) to identify trends and problems. In this scenario of high complexity and uncertainty where there is insufficient relevant quantitative information for decision making, the Delphi method is applied to ensure a consensual decision-making process. Consensus was reached by a panel of 11 experts on the Spanish ophthalmology sector after three rounds of questioning. The final set of indicators involve 19 different criteria grouped into four categories (1) current situation of the distribution channel, (2) changes in distribution channels, (3) trends and near future of the distribution channel, and (4) consequences and adaptations for supply chain agents. The results from each round of consultation were then analyzed by means of statistical analysis with SPSS and discussed for each category. The results confirm that traditional intermediaries face difficulties to avoid being squeezed out of the sector because of shortening distribution channels and the entry of new online intermediaries with service integration models. We identify future scenarios and define actions that different agents can take to enhance their competitiveness in the short and long term. The arrival of omnichannel distribution is inevitable in the ophthalmology sector, entailing a major transformation from a rigid traditional distribution model to a more complex and flexible model following the entry of new online intermediaries.


General Burden of Adult Atopic Dermatitis: An Observational Study of Disease Perceptions among Patients and Dermatologists in France.
It is important to understand patients' and dermatologists' perceptions of various aspects of atopic dermatitis, but there is a lack of studies on quality of life and stakeholder viewpoints in this therapy area. The aim of this study was to compare patients' and dermatologists' viewpoints regarding the impact of atopic dermatitis that is uncontrolled by topical corticosteroids. Data were collected from 348 adult patients who responded to self-administered questionnaires, and 150 telephone interviews with the dermatologists who selected them. Patients and dermatologists reported both convergent and divergent assessments of the impact of atopic dermatitis and its treatment. Notable areas of agreement were regarding the safety of emollients, the time required and difficulty of applying topical corticosteroids, especially to certain parts of the body. Divergent views involved the perceived efficacy of available treatments and the impact of atopic dermatitis on professional life. A greater understanding of these differences would help dermatologists to optimize patient care.


Tetrahydro-β-carboline-3-carboxyl-thymopentin: a nano-conjugate for releasing pharmacophores to treat tumor and complications.
To improve the therapeutic efficacy of cancer patients a novel conjugate of thymopentin (TP5) and (1S,3S)-1-methyl-tetrahydro-β-carboline-3-carboxylic acid (MTC) was presented. In water and mouse plasma MTCTP5 forms the nanoparticles of 14-139 nm in diameter, the suitable size for delivery in blood circulation. In mouse plasma MTCTP5 releases MTC, while in the presence of trypsin MTCTP5 releases MTC and TP5. On mouse and rat models the MTCTP5 dose dependently slows down the tumor growth, inhibits inflammatory response and blocks thrombosis. The anti-tumor activity as well as the anti-inflammation activity and anti-thrombotic activity of MTCTP5 are 100 fold and 10 fold higher than those of MTC, respectively, which are attributed to the fact that it down-regulates the plasma levels of TNF-α and IL-8 of the treated animals. The immunology enhancing activities in vitro and in vivo of MTCTP5 are similar to those of TP5, which is attributed to the fact that MTCTP5 up-regulates the plasma levels of IL-2 and CD4 as well as down-regulates the plasma level of CD8 of the treated animals. The plasma alanine transaminase, aspartate transaminase and creatinine assays indicate that MTCTP5 therapy does not injure the liver and the kidney of the animals. The survival time of MTCTP5 treated mice is significantly longer than that of TP5 treated mice.


[Current therapeutic options for liver metastasis].
The liver is a common site of hematogenous metastasis, especially from gastrointestinal malignancies. Liver metastasis are generally classified as stage IV disease. Previously treatment in such patients was met with great skeptiscism. However, advances in surgical and medical therapies during the last two decades have provided effective therapeutic options for selected patients. Since major hepatic resections are now performed with acceptable morbidity and a mortality rate <3%, colorectal cancer metastasis to the liver are associated with 5-year survival rates of 30% or more. Meanwhile, a variety of new therapies have been developed, including hepatic artery infusion of chemotherapy; alcoholic, crio and radiofrequency ablation and novel strategies of systemic chemotherapy with the development of molecular targeted new products. These new therapeutic armamentarium have been used mostly in liver metastasis from colorectal cancer patients. However, liver metastasis of neuroendocrine tumors and selected cases of non colorectal cancer liver metastasis are benefited from the same strategies. This report summarizes the different therapeutic tools, their advantages and results mainly on colorectal cancer liver metastasis. These results are expected to improve even further with multimodality approaches.


A cognitive neuropsychological model of antidepressant drug action.
The psychological mechanisms by which antidepressant drugs act to improve mood remain underspecified. In this paper we consider the evidence to suggest that early changes in emotional processing underlie subsequent mood improvement following antidepressant treatment. Negative biases in information processing are consistently found in depression, and we argue that primary mode of action of antidepressant drugs may be to remediate these biases providing a more positive social environment in which the patient can relearn emotional associations fostering later improvement in mood. Evidence from behavioural and functional magnetic resonance imaging studies supports this hypothesis. Experimental medicine models developed under this premise have the potential to screen for new treatments, to predict individual treatment response and to consider the effects of pharmacological vs psychological treatments.


Clinicopathological characteristics and survival outcomes of male breast cancer according to race: A SEER population-based study.
To investigate the clinicopathological characteristics and survival outcomes of breast cancer in the male population, 8,607 cases of patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database, including white males (n = 7122), black males (n = 1111), and other males (American Indian/AK Native, Asian/Pacific Islander) (n = 374). Black male breast cancer patients were more likely to be in stages II-IV and have more advanced tumors. The rate of lymph node (LN) involvement at diagnosis was higher in black men than in whites and others. The ER- and PR-positive rates were lower in black men than in whites and others. The distant metastasis rate was higher in blacks than in whites and others. Furthermore, the overall survival (OR) rates and breast cancer-specific survival rates were significantly poorer in blacks than in whites and others (χ2 = 29.974, P < 0.001; χ2 = 7.285, P = 0.026, respectively). In a multivariate analysis, the results showed that race could also be a prognostic indicator (P < 0.001). Moreover, significant differences were also observed in OS among 1:1:1 matched white, black, and other groups (P < 0.001). Differences in outcomes may be partially explained by differences in tumor grades, LN status, and ER and PR status between the 3 groups. This study might provide insights into a better understanding of male breast cancer.


[Idiopathic fibrosing alveolitis and bronchioloalveolar cancer].
A case of bronchiolo-alveolar carcinoma (BAC) developing in the presence of idiopathic fibrosing alveolitis (IFA) in a man of 67 with a long history of pulmonary lesion is described. A honeycomb bung was found at the autopsy. Histologically, multiple foci of BAC of mixed-cell structure and those of mucus-producing cells against the background of fibrosing alveolitis at the stage of honeycomb lung were observed. An increased content of collagen type III, IV and V was found immunohistochemically. The role of sclerotic changes and defected immunological surveillance over the epithelial regeneration in the IFA-affected lung in relevant carcinoma genesis is suggested. The origin of the lung carcinoma in IFA is considered to be the regenerating epithelium of the low respiratory tract.


Main left coronary artery disease. Clinical experience from 1964-1974.
Obstructive lesions of the main left coronary artery (LCA) were demonstrated angiographically in 73 patients, comprising 4.3% of the total population referred to us for diagnostic evaluation of chest pain. Although there were no specific historical or clinical features which could absolutely distinguish this subgroup from the larger population of coronary artery disease patients, 81% (34/42) of the double Master's exercise tests, in which the patient achieved a heart rate of at least 110 beats/min. demonstrated greater than or equal 2 mm R-ST segmental depression. Of the total group of 73, 32 were evaluated during the six-year period from 1964 to 1971 and a preliminary report made in 1972. The diagnosis in the remaining 41 patients was established in the 1/2 year period from 1971 to 1973. The initial 32 patients were seen before the significance of a main LCA lesion was appreciated. In this subgroup there were five deaths at the time of cardiac catheterization. However, in the more recent group improved recognition of patients with possible main LCA disease prior to catheterization has led to a much lower death rate related to diagnostic catheterization. Only one of the last 41 patients undergoing coronary angiography has died. Nineteen patients were managed medically. Of this group 17 were considered to be under the same risk of death as the surgical candidates. Their mortality rate, as high. The risk of hying was 43.6% after 24 months, 51.1% after 36 months, and 73.6% after 42 months of observation. Although the initial surgical experience, using internal mammary artery implants and saphenous venin bypass grafts, was associated with a high mortality, direct revascularization surgery over the last 2 1/2 years has been accomplished with a perioperative mortality of only 6.2%. All deaths in the group of 40 patients receiving elective revasularization with saphenous vein bypass grafts occurred in the first six months following surgery. The risk of dying was 12.5% after six months of observation and was unchanged for the remainder of the follow-up period. After 21 months the difference in survival between the two groups is statistically significant (P less than 0.05). The one late death among the surgical survivors occurred four months after the operative procedure and was related to noncardiovaxcular surgical complications. The surgical survivors have been followed for an average of 27 months. Thus revascularization surgery has improved the prognosis for patients with main LCA disease. We currently advise prompt evaluation for any patient suspected of having this type of obstruction and urgent idrect revascularization surgery if this lesion is demonstrated angiographically.


Advances in our understanding of vitamin E.
Vitamin E is an essential nutrient for animals and man since it is not synthesized in the body. The level of vitamin E in the lipoproteins of plasma and in the phospholipids of vital mitochondria, microsomes, and plasma membranes in humans depends (as in experimental animals) on the amount of biologically active vitamin E being consumed, the levels of dietary prooxidants and antioxidants, and the adequacy of dietary selenium. Studies with chicks have demonstrated an important mode of action of both vitamin E and selenium in metabolism, and provide a solution to the long-term enigma of the true role of vitamin E in the diet of all animals, including man. The biochemical actions of vitamin E and selenium are concerned with prevention of peroxidative damage to cells and subcellular elements, thereby aiding the body in maintaining its normal defense mechanisms against disease and environmental insult.


Role of DNA polymerases eta, iota and zeta in UV resistance and UV-induced mutagenesis in a human cell line.
Genes coding for DNA polymerases eta, iota and zeta, or for both Pol eta and Pol iota have been inactivated by homologous recombination in the Burkitt's lymphoma BL2 cell line, thus providing for the first time the total suppression of these enzymes in a human context. The UV sensitivities and UV-induced mutagenesis on an irradiated shuttle vector have been analyzed for these deficient cell lines. The double Pol eta/iota deficient cell line was more UV sensitive than the Pol eta-deficient cell line and mutation hotspots specific to the Pol eta-deficient context appeared to require the presence of Pol iota, thus strengthening the view that Pol iota is involved in UV damage translesion synthesis and UV-induced mutagenesis. A role for Pol zeta in a damage repair process at late replicative stages is reported, which may explain the drastic UV-sensitivity phenotype observed when this polymerase is absent. A specific mutation pattern was observed for the UV-irradiated shuttle vector transfected in Pol zeta-deficient cell lines, which, in contrast to mutagenesis at the HPRT locus previously reported, strikingly resembled mutations observed in UV-induced skin cancers in humans. Finally, a Pol eta PIP-box mutant (without its PCNA binding domain) could completely restore the UV resistance in a Pol eta deficient cell line, in the absence of UV-induced foci, suggesting, as observed for Pol iota in a Pol eta-deficient background, that TLS may occur without the accumulation of microscopically visible repair factories.


Correspondence between cluster-ion and bulk solution thermodynamic properties: on the validity of the cluster-pair-based approximation.
Since the single-ion thermodynamic properties of bulk solutions are not directly accessible from experiments, extrapolations have been devised to estimate them from experimental measurements on small-clusters. Extrapolations based on the cluster-pair-based approximation (CPA) technique (Tissandier et al. J. Phys. Chem. A 1998, 102, 7787-7794) and its variants are currently considered one of the most reliable source of single-ion hydration thermodynamic data and have been used as a benchmark for the development of molecular and continuum solvation models. Despite its importance, the CPA has not been thoroughly tested and recent studies have indicated inconsistencies with molecular simulations. The present work challenges the key CPA assumptions that the hydration properties of single cations and anions in growing clusters rapidly converge to each other following a monotonous trend. Using a combination of simulation techniques to study the transition between alkali halide ions in small clusters and bulk solution, we show that this convergence is rather slow and involves a surprising change in trends, which can result in significant errors in the original estimated single-ion properties. When these cluster-size-dependent effects are taken into account, the inconsistencies between molecular models and experimental predictions disappear, and the value of the proton hydration enthalpy based on the CPA aligns with estimates based on other principles.


A smoothing expectation and substitution algorithm for the semiparametric accelerated failure time frailty model.
This paper proposes an estimation procedure for the semiparametric accelerated failure time frailty model that combines smoothing with an Expectation and Maximization-like algorithm for estimating equations. The resulting algorithm permits simultaneous estimation of the regression parameter, the baseline cumulative hazard, and the parameter indexing a general frailty distribution. We develop novel moment-based estimators for the frailty parameter, including a generalized method of moments estimator. Standard error estimates for all parameters are easily obtained using a randomly weighted bootstrap procedure. For the commonly used gamma frailty distribution, the proposed algorithm is very easy to implement using widely available numerical methods. Simulation results demonstrate that the algorithm performs very well in this setting. We re-analyz several previously analyzed data sets for illustrative purposes.


Influence of cultural conditions on mitomycin C-mediated bacteriophage induction and release of Salmonella toxin.
Several isolates of Salmonella were examined for the capacity to synthesize and release a cholera toxin-like toxin that exerted a biological effect on Chinese hamster ovary cells. Measurements of this Salmonella toxin, which was contained in cell sonic extracts and culture filtrates, were expressed in cholera toxin equivalents (nanograms), since the Chinese hamster ovary cell responses of the cholera toxin and the Salmonella toxin were indistinguishable. Comparative titrations of Salmonella preparations were also performed by using an enzyme-linked immunosorbent assay specific for cholera toxin antigen. The amount of Salmonella toxin synthesized was low (nanogram levels), but the toxin was detectable in cell sonic extracts as early as 6 h after culture inoculation and reached maximal levels by 12 h. Salmonella toxin antigen was not detectable in control culture filtrates until 48 h, but the addition of mitomycin C at 8.5 h resulted in the sudden appearance of toxin antigen at 10 to 12 h, and the toxin antigen level reached a maximum at 14 h. A large peak of Chinese hamster ovary cell activity was observed at 48 h in the control culture, but significant Chinese hamster ovary cell activity was detected as early as 14 h. A larger amount of Chinese hamster ovary cell-reactive material was observed as early as 10 h in cultures grown with mitomycin C. The mechanism of the mitomycin-mediated phenomenon that yielded more toxin in culture filtrates was associated with bacteriophage induction. A bacteriophage plaque assay with a susceptible Salmonella strain revealed that there were free bacteriophage in mitomycin-treated culture filtrates (but not control culture filtrates) at 12 h. Toxin production was greatest when cultures were grown at 30 to 37 degrees C and lowest when cultures were grown at 25 degrees C. The inoculum size and degree of culture aeration (agitation) had little effect on synthesis of the toxin, and toxin production occurred during anaerobic growth.


Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion.
The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.


Analysis of an activatable promoter: sequences in the simian virus 40 late promoter required for T-antigen-mediated trans activation.
The late promoter of simian virus 40 (SV40) is activated in trans by the viral early gene product, T antigen. We inserted the wild-type late-promoter region, and deletion mutants of it, into chloramphenicol acetyltransferase transient expression vectors to identify promoter sequences which are active in the presence of T antigen. We defined two promoter activities. One activity was mediated by a promoter element within simian virus 40 nucleotides 200 to 270. The activity of this element was detectable only in the presence of an intact, functioning origin of replication and accounted for 25 to 35% of the wild-type late-promoter activity in the presence of T antigen. The other activity was mediated by an element located within a 33-base-pair sequence (simian virus nucleotides 168 to 200) which spans the junction of the 72-base-pair repeats. This element functioned in the absence of both the origin of replication and the T-antigen-binding sites and appeared to be responsible for trans-activated gene expression. When inserted into an essentially promoterless plasmid, the 33-base-pair element functioned in an orientation-dependent manner. Under wild-type conditions in the presence of T antigen, the activity of this element accounted for 65 to 75% of the late-promoter activity. The roles of the 33-base-pair element and T antigen in trans-activation are discussed.


Nasalised distribution of peripapillary retinal nerve fibre layers in large discs.
To describe the distribution pattern of the peripapillary retinal nerve fibre layer (RNFL) and major retinal vessel positions in patients with a large disc. The medical records of patients with a large disc and those of normal controls were reviewed retrospectively. Comprehensive ophthalmic examinations including Cirrus HD-optical coherence tomography (OCT) and Heidelberg Retinal Tomography III (HRT III) were performed. We divided patients into two groups (large disc group and control group) using an HRT-measured disc size of 2.5 mm2 as a reference point. We extracted RNFL thicknesses at 256 points with OCT, measured major retinal vessel positions and compared them between the two groups. In total, 97 eyes of 97 patients were included, with 60 patients in the large disc group and 37 patients in the control group. All patients were free of any glaucomatous change. We observed nasal shifting of the second superior and inferior peaks in the large disc group compared with the controls. The superior major temporal retinal arteries in patients with large disc also showed significant nasal displacement. We could observe nasalisation of the peripapillary RNFL and superior retinal artery in patients with a large disc. As this phenomenon may lead to false positive results in OCT-based RNFL thickness maps, results from our study may help prevent misdiagnosis of glaucoma and improve the sensitivity and specificity of glaucoma detection.


A three-dimensional (3D) printing approach to fabricate an isolation chip for high throughput in situ cultivation of environmental microbes.
The full plethora of environmental bacteria is often poorly represented in vitro as the majority remain difficult, if not impossible, to culture under standard laboratory settings. These bacteria often require native conditions for the formation of cell masses that collectively have higher chances of survival. With that, a 3D-printed version of the isolation chip (iChip) was used to cultivate bacteria from a tropical peat swamp in situ prior to growth and maintenance in vitro. Briefly, plates made from either acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), or epoxy resin were tested in terms of their usability and durability under acidic conditions similar to those of peat matter. The epoxy resin plates were then found to be most optimal for the sampling conditions. Peat soil samples were collected from the base of a Koompassia malaccensis tree and reconstituted in molten 10% (wt/vol) tryptone soy agar (TSA) prior to inoculation. The iChips were subsequently assembled and buried in the site of origin. As a comparison, bacteria from the same soil sample were cultivated directly on TSA and incubated at 28 °C for two weeks. Thereafter, agar plugs from the iChip were transferred to TSA plates to allow microcolonies within each plug to grow. Each pure isolate from both cultivation approaches that grew was then pooled and extracted for total DNA prior to 16S rRNA gene amplification and sequencing via Illumina MiSeq. Taxonomic abundance comparison revealed that the bacterial taxa at the level of order were significantly different between the two approaches, particularly in the orders, Burkholderiales, Xanthomonodales, Enterobacteriales, and Actinomycetales (differences of 12.0, 7.1, 8.0, and 4.2%, respectively). This indicated that the 3D-printed iChips present a possible low-cost tool for the isolation of bacterial genera that may not be able to grow on media directly in vitro.


Education in the practicum: a study of the ward learning climate in Hong Kong.
The major concern of this study was the quality of education in the practice setting in Hong Kong. Its purposes were to gain an understanding of how local Hong Kong student nurses perceive their practice experience, and to examine the quality of student nurses' practice experience in the light of an educational paradigm. A broad qualitative approach derived from some of the philosophical perspectives of phenomenology was adopted. The target population were those student nurses studying on hospital-based pre-registration programmes in Hong Kong. The total number of informants was 16, two from each of the eight schools of nursing. The semi-structured interview method using open-ended questions was used to collect data. All the interviews were conducted in Cantonese, being transcribed into Chinese and then into English. In order to provide some validity check on the adequacy of the translated interview transcripts, back-translation was carried out. Both structural analysis (latent content analysis) and content analysis (manifest content analysis) were used to analyse the interview data. The 11 themes identified indicated that the practice experience was not an educational experience because the learning methods did not advance student nurses' intellectual development. Students were only equipped with knowledge which enabled them to act as model operators who were expected to carry out routines in an unreflective fashion. The issues of developing an effective clinical curriculum and creating a supportive clinical learning environment are discussed. It is argued that the associated problems are likely to be repeated, if not exacerbated, as baccalaureate nursing programmes are developed if the profession fails to address the issues reported in the current study. The mere transfer of nursing preparation to tertiary education cannot itself solve the problems existing in nursing education in Hong Kong.


Fine-scale genetic structure in a free-living ungulate population.
The fine-scale genetic structure of wild animal populations has rarely been analysed, yet is potentially important as a confounding factor in quantitative genetic and allelic association studies, as well as having implications for population dynamics, inbreeding and kin selection. In this study, we examined the extent to which the three spatial subunits, or hefts, of the Village Bay population of Soay sheep (Ovis aries) on St Kilda, Scotland, are genetically structured using data from 20 microsatellite and protein loci. Allele frequencies differed significantly among three hefts in all the study years we considered (1987-2000 inclusive). Small but significantly positive F(ST) and negative F(IS) values were observed in most years, indicating that the hefts are genetically differentiated, and that within each heft there is more observed heterozygosity than would be expected if each were an isolated breeding population. Males showed less fidelity to their natal heft, and as a consequence higher levels of relatedness within hefts were observed among females than among males. There was a significant negative relationship between geographical proximity and relatedness in pairwise comparisons involving females, and on average pairs of females located within 50 m of each other were related at the equivalent level of second cousins. Structure is therefore largely driven by incomplete postnatal dispersal by females. Mating appears to be random with respect to the spatial-genetic substructure of the hefts, and therefore genetic structure does not contribute to the overall rate of inbreeding in the population. However, genetic substructure can lead to allelic associations and generate environmental effects within lineages that have the potential to confound heritability analyses and allelic association studies.


[Effect of the curriculum including the computer use on work capacity and health status of older schoolchildren].
Formation of computer skills + of pupils is one of the most acute tasks for school today. The relationship between the functional state of the central nervous system, visual analyser and efficiency of pupils with age, have been established. Motivation for work with the computer and quality of the computer video-terminal has been established. Questionnaires given to about 500 pupils have shown that the majority of pupils show an interest to working with computers: 82.5% of 13-14-year old and 70% of 16-17-year old adolescents. Efficiency of pupils becomes more stable with age. The highest number of astheno-neurotic tic symptoms and fatigue complaints are registered in pupils with a low interest to working with computers, as well as in pupils dealing with computers of low quality (of the type Personal Computer 0010). Duration of pupils' work with computers should be no longer than 30 minutes.


The Impact of Automated Brief Messages Promoting Lifestyle Changes Delivered Via Mobile Devices to People with Type 2 Diabetes: A Systematic Literature Review and Meta-Analysis of Controlled Trials.
Brief automated messages have the potential to support self-management in people with type 2 diabetes, but their effect compared with usual care is unclear. To examine the effectiveness of interventions to change lifestyle behavior delivered via automated brief messaging in patients with type 2 diabetes. A systematic literature review of controlled trials examined the impact of interventions, delivered by brief messaging, and intended to promote lifestyle change in people with type 2 diabetes, on behavioral and clinical outcomes. Bibliographic databases searched included Medline, Embase, CINAHL, PsycINFO, and ISI WoK. Two reviewers independently screened citations. We extracted information on study risk of bias, setting (high versus low- and middle-income countries) and intervention characteristics (including use of theory and behavior-change techniques). Outcome measures included acceptability of the interventions and their impact on 1) determinants of lifestyle behavior (knowledge about diabetes, self-efficacy, attitudes towards self-management), 2) lifestyle behavior (diet, physical activity), and 3) clinical and patient-reported outcomes. Where possible, we pooled data using random-effects meta-analyses to obtain estimates of effect size of intervention compared to usual care. We identified 15 trials (15 interventions) meeting our inclusion criteria. Most interventions were delivered via short message service text messaging (n=12) and simultaneously targeted diet and physical activity (n=11). Nine interventions consisted of unidirectional messages, whereas six consisted of bidirectional messages, with patients receiving automated tailored feedback based on self-reported data. The acceptability of the interventions, and their impact on lifestyle behavior and its determinants, were examined in a low proportion of trials, with heterogeneous results being observed. In 13 trials (1155 patients) where data were available, there was a difference in glycated hemoglobin of -0.53% (95% CI -0.59% to -0.47%) between intervention groups compared to usual care. In five trials (406 patients) there was a non-significant difference in body mass index of -0.25 kg/m2 (95% CI -1.02 to 0.52). Interventions based on unidirectional messages produced similar effects in the outcomes examined, compared to those based on bidirectional messages. Interventions conducted in low- and middle-income countries showed a greater impact than those conducted in high-income countries. In general, trials were not free of bias and did not use explicit theory. Automated brief messages strategies can improve health outcomes in people with type 2 diabetes. Larger, methodologically robust trials are needed to confirm these positive results.


IgE levels, atopy markers and hay fever in relation to age, sex and smoking status in a normal adult Swiss population. SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) Team.
Within the framework of the SAPALDIA survey (Swiss study on Air Pollution and Lung Diseases in Adults), we studied the influence of sex, age and smoking habits on total serum IgE and allergen-specific IgE antibody concentrations (assessed by means of the Phadiatop test) and on the prevalence of hay fever. A total of 8,344 subjects aged 18-60 years, comprising 2,776 current smokers, 1,888 former smokers and 3,680 nonsmokers, were included in the study. Smokers had both a statistically significant (p<0.001) higher mean serum IgE concentration (geometric mean 39.7 kU/l), and a higher percentage (27.5%) of persons with elevated serum IgE (> 100 kU/l) than nonsmokers (27.2 kU/l; respectively 20.5%). The IgE level was significantly lower in women than men (p<0.001) in all smoking categories. The percentage of persons with positive atopic markers (positive Phadiatop test, positive skin prick tests to common inhalant allergens) and self-reported hay fever was significantly higher in nonsmokers than in smokers or former smokers. In Phadiatop positive (atopic) subjects, the IgE levels were highest, with a mean of 104.3 kU/l (99.0-109.8), and lowest in Phadiatop-negative nonsmokers at 27.2 kU/L (25.9-28.6). These findings correlate well with the current interpretation of total serum IgE values in screening for atopic diseases in adults (IgE < 20 kU/l: atopy improbable; IgE > 100 kU/l: atopy probable). In multivariate logistic regression models, the prevalence of positive Phadiatop tests, positive skin tests, and atopy decreased significantly with age. The odds of having a positive Phadiatop and skin test, or being atopic were found to decrease on average by 23.0, 21.1 and 21.0%, respectively, with every 10-year increase in age. With respect to smoking status, the odds ratios for the three atopic markers were significantly lower in current and former smokers than in nonsmokers. The prevalence of (self-reported) hay fever was highest in nonsmokers, intermediate in former smokers (odds ratio = 0.81, p<0.05) and lowest in current smokers (odds ratio = 0.76 in comparison to former smokers, p<0.01). The odds ratio of self-reported current hay fever decreased with age at an estimated average of 23% every 10 years. The decrease in former smokers might be slightly faster than in the other two categories. In conclusion, the present results demonstrated that tobacco smoking is associated with increased IgE levels and negatively related to atopy and hay fever. In addition, it is shown that atopy prevalence decreases with age.


Prolonged exposure for the treatment of Spanish-speaking Puerto Ricans with posttraumatic stress disorder: a feasibility study.
Most of the empirical studies that support the efficacy of prolonged exposure (PE) for treating posttraumatic stress disorder (PTSD) have been conducted on white mainstream English-speaking populations. Although high PTSD rates have been reported for Puerto Ricans, the appropriateness of PE for this population remains unclear. The purpose of this study was to examine the feasibility of providing PE to Spanish speaking Puerto Ricans with PTSD. Particular attention was also focused on identifying challenges faced by clinicians with limited experience in PE. This information is relevant to help inform practice implications for training Spanish-speaking clinicians in PE. Fourteen patients with PTSD were randomly assigned to receive PE (n = 7) or usual care (UC) (n = 7). PE therapy consisted of 15 weekly sessions focused on gradually confronting and emotionally processing distressing trauma-related memories and reminders. Five patients completed PE treatment; all patients attended the 15 sessions available to them. In UC, patients received mental health services available within the health care setting where they were recruited. They also had the option of self-referring to a mental health provider outside the study setting. The Clinician-Administered PTSD Scale (CAPS) was administered at baseline, mid-treatment, and post-treatment to assess PTSD symptom severity. Treatment completers in the PE group demonstrated significantly greater reductions in PTSD symptoms than the UC group. Forty percent of the PE patients showed clinically meaningful reductions in PTSD symptoms from pre- to post-treatment. PE appears to be viable for treating Puerto Rican Spanish-speaking patients with PTSD. This therapy had good patient acceptability and led to improvements in PTSD symptoms. Attention to the clinicians' training process contributed strongly to helping them overcome the challenges posed by the intervention and increased their acceptance of PE.


The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3β Signaling Pathway in MK801-Induced Amnesia in Mice.
The role of histamine H3 receptors (H3Rs) in memory and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer's disease (AD), is well-accepted. Therefore, the procognitive effects of acute systemic administration of H3R antagonist E169 (2.5-10 mg/kg, i.p.) on MK801-induced amnesia in C57BL/6J mice using the novel object recognition test (NORT) were evaluated. E169 (5 mg) provided a significant memory-improving effect on MK801-induced short- and long-term memory impairments in NORT. The E169 (5 mg)-provided effects were comparable to those observed with the reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and were abrogated with the H3R agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that E169 ameliorated MK801-induced memory deficits by antagonism of H3Rs and by modulation of the level of disturbance in the expression of PI3K, Akt, and GSK-3β proteins, signifying that E169 mitigated the Akt-mTOR signaling pathway in the hippocampus of tested mice. Moreover, the results observed revealed that E169 (2.5-10 mg/kg, i.p.) did not alter anxiety levels and locomotor activity of animals in open field tests, demonstrating that performances improved following acute systemic administration with E169 in NORT are unrelated to changes in emotional response or in spontaneous locomotor activity. In summary, these obtained results suggest the potential of H3R antagonists such as E169, with good in silico physicochemical properties and stable retained key interactions in docking studies at H3R, in simultaneously modulating disturbed brain neurotransmitters and the imbalanced Akt-mTOR signaling pathway related to neurodegenerative disorders, e.g., AD.


Topical minoxidil dose-response effect in alopecia areata.
Topical 5% minoxidil solution was used to treat 47 patients with severe alopecia areata. Forty patients (85%) had terminal hair regrowth after 48 to 60 weeks of treatment. In the majority of patients, hair regrowth was not cosmetically acceptable. Data were compared with those from a previous study with topical 1% minoxidil solution. Both the percentage of responders and the quality of their hair regrowth were significantly greater with 5% than with 1% topical minoxidil solution. One patient developed an allergic contact dermatitis to minoxidil, but no systemic side effects were detected. The results strongly suggest a dose-response effect for topical minoxidil treatment of alopecia areata and the importance of exploring modifications in dosing and delivery systems to enhance therapeutic efficacy.


Specific expression of an elastase-human growth hormone fusion gene in pancreatic acinar cells of transgenic mice.
Transfection of genes into tissue culture cell lines has demonstrated that relatively short DNA sequences can allow expression of immunoglobulin, insulin and chymotrypsin genes in their appropriate cell types. A definitive test of cell-specific gene expression, however, requires testing genes in every possible cell type, an experiment performed easily by introducing the gene in question into the germ line of an animal. Transfer of intact genes into mice has demonstrated that a mouse immunoglobulin kappa gene is expressed specifically in B lymphocytes, a rat elastase I gene is expressed specifically in pancreas and a chicken transferrin gene is expressed preferentially in liver. Mouse metallothionein-growth hormone fusion genes introduced into mice are preferentially expressed in the liver, consistent with the expression of endogenous metallothionein genes, but initial experiments with beta-globin genes have not revealed proper regulation. To identify the DNA elements required for pancreas-specific expression of the rat elastase I gene, we joined the 5'-flanking region of this gene to the human growth hormone (hGH) structural gene and introduced the fusion gene into mice. Here we demonstrate that a fusion gene containing only 213 base pairs (bp) of elastase I gene sequence directs expression of hGH in pancreatic acinar cells.


Ecological risks and community perceptions of fairness and justice: a cross-cultural model.
Intergenerational justice is implicit in international commitments to sustainability. If ecological, economic, and social components of sustainability are to be achieved, there is a necessity for intergenerational justice considerations to be included in decision making. The present generation's risk judgments should include consideration of the possible outcomes for their children. But intergenerational issues cannot be considered in isolation from other current risk and fairness concerns. This article reports on a community-based integrative model that describes justice and other attitudes and motivations that determine community and individual proenvironmental behavior in two nations: Germany and Australia. This model can account for a considerable amount of the variance in political compliance as well as various proenvironmental behaviors. Group or individual self-interests have nearly no effects on global protective behavior. It is shown that universal as well as contextual principles, including distributive (within or between generations), procedural, and interactive justice, play a crucial role in fairness judgments. Other principles are also taken into account, such as efficiency, environmental rights, and rights to economic welfare. The results are discussed in relation to the importance of complex community fairness judgments in predicting and evaluating acceptance of political decisions, and for promoting proenvironmental behavior.


Fetal calf ligament fibroblasts in culture secrete a low molecular weight collagen with a unique resistance to proteolytic degradation.
A highly unusual collagen was secreted by fibroblasts cultured from 150- and 270-d-old fetal calf nuchal ligaments. Purification revealed that this protein (which may be synthesized in a higher molecular weight form) was precipitated at unusually high concentrations of ammonium sulfate and was also eluted from DEAE-cellulose at greater salt concentrations than were types I and III procollagens. On SDS PAGE, the collagenous protein exhibited an Mr of approximately 12,750 that was not altered in the presence of reducing agent. The low molecular weight collagen (FCL-1) was sensitive to bacterial collagenase and had a [3H]glycine content comparable to that found in type I procollagen, although the [3H]Hyp to [3H]Pro ratio was 0.43. FCL-1 was not cleaved by human skin collagenase, mast cell protease, trypsin, Staphylococcal V8 protease, or proteinase K at 37 degrees C. The collagen was susceptible to trypsin, but not to V8 protease, only after heating at 80 degrees C for 30 min. Preliminary structural studies indicate that FCL-1 was resistant to cleavage by CNBr but exhibited limited proteolysis with pepsin. Both 150- and 270-d-old fibroblasts produced comparable levels of interstitial (types I and III) procollagens, which comprised approximately 70% of the total protein secreted into the culture medium. However, 270-d-old (term) fibroblasts secreted approximately 50% more FCL-1, as percent of total culture medium protein, in comparison to the cells from the earlier gestational stage. This collagen may therefore play a role in the development of the nuchal ligament.


Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy.
The delivery of drugs to tumors by nanoparticles is a rapidly growing field. However, the complex tumor microenvironment (TME) barriers greatly hinder drug delivery to tumors. In this study, we first summarized the barriers in TME, including anomalous vasculature, rigid extracellular matrix, hypoxia, acidic pH, irregular enzyme level, altered metabolism pathway and immunosuppressive conditions. To overcome these barriers, many strategies have been developed, such as modulating TME, active targeting by ligand modification and biomimetic strategies, and TME-responsive drug delivery strategies to improve nanoparticle penetration, cellular uptake and drug release. Although extensive progress has been achieved, there are still many challenges, which are discussed in the last section. Overall, we carefully discuss the landscape of TME, development for improving drug delivery, and challenges that need to be further addressed.


Amplifying the role of knowledge translation platforms in the COVID-19 pandemic response.
The COVID-19 pandemic presents the worst public health crisis in recent history. The response to the COVID-19 pandemic has been challenged by many factors, including scientific uncertainties, scarcity of relevant research, proliferation of misinformation and fake news, poor access to actionable evidence, time constraints, and weak collaborations among relevant stakeholders. Knowledge translation (KT) platforms, composed of organisations, initiatives and networks supporting evidence-informed policy-making, can play an important role in providing relevant and timely evidence to inform pandemic responses and bridge the gap between science, policy, practice and politics. In this Commentary, we highlight the emerging roles of KT platforms in light of the COVID-19 pandemic. We also reflect on the lessons learned from the efforts of a KT platform in a middle-income country to inform decision-making and practice during the COVID-19 pandemic. The lessons learned can be integrated into strengthening the role, structures and mandates of KT platforms as hubs for trustworthy evidence that can inform policies and practice during public health crises and in promoting their integration and institutionalisation within the policy-making processes.


[Prenatal and childbirth care equity in an area in Greater Metropolitan São Paulo, 1996].
A cross-sectional study was conducted to evaluate prenatal and childbirth care interviewing mothers of infants in the municipality of Embu (Greater Metropolitan São Paulo) in 1996, according to four socioeconomic strata. A door-to-door survey included a probabilistic sample consisting of 483 infants. In all strata more than 90% of the mothers had received prenatal care, but with late access in stratum 4 (residents of favelas, or slums). Breast examination during prenatal care, reported by only 60.8% of the mothers, was the worst single indicator of quality of prenatal care in the municipality. The outcome indicator - first prenatal consultation after the first trimester and total number of consultations less than six - was associated with maternal age (less than 20 years), low per capita family income (less than one minimum wage), and lack of private health plan. As for deliveries, 97.7% occurred in hospital, of which 32.5% by cesarean section, with the latter more frequent in private health care facilities (63.2%). No population segments were identified as being excluded from the health care system, but some indicators suggest greater deficiencies in socioeconomic stratum 4. These results have supported local health system managers in redefining health measures for the municipality.


Should All Massively Transfused Patients Be Treated Equally? An Analysis of Massive Transfusion Ratios in the Nontrauma Setting.
Although balanced resuscitation has become integrated into massive transfusion practice, there is a paucity of evidence supporting the delivery of high ratios of plasma and platelet to RBCs in the nontrauma setting. This study investigated the administration of blood component ratios in the massively transfused nontrauma demographic. Retrospective analysis of a prospective, observational cohort of massively bleeding patients. Surgical and critically ill patients at a tertiary medical center between 2011 and 2015. Massively transfused nontrauma patients. Patients receiving plasma, platelet, and RBC transfusions were categorized into high and low ratio groups and analyzed for differences in characteristics and clinical outcomes. The primary outcome was 30-day mortality. Secondary outcomes included 48-hour mortality, hospital length of stay, ICU length of stay, and ventilator-free days. Among 601 massively transfused nontrauma patients, cardiothoracic surgery and gastrointestinal or hepato-pancreatico-biliary bleeds were the most common indications for massive transfusion. Higher fresh frozen plasma ratios (> 1:2) were not associated with increased 30-day mortality. A high platelets-to-packed RBCs ratio (> 1:2) was associated with decreased 48-hour mortality (10.5% vs 19.3%; p = 0.032), but not 30-day mortality. Fresh frozen plasma-to-packed RBCs and platelets-to-packed RBCs ratios were not associated with 30-day mortality hazard ratios after controlling for baseline characteristics and disease severity. The benefits of higher ratios of fresh frozen plasma-to-packed RBCs and platelets-to-packed RBCs described in trials of trauma patients were not observed in this analysis of a nontrauma, massively transfused population. These data suggest that greater than 1:2 ratio transfusion in the setting of massive hemorrhage may not be appropriate for all patients, and that further research to guide appropriate resuscitation strategies in nontrauma patients is warranted.


[Low-Molecular Thiols as a Factor Improving the Sensitivity of Escherichia coli Mutants with Impaired ADP-Heptose Synthesis to Antibiotics].
Low molecular-weight thiols as glutathione and cysteine are an important part of the cell's redox regulation system. Previously, we have shown that inactivation of ADP-heptose synthesis in Escherichia coli with a gmhA deletion induces the oxidative stress. It is accompanied by rearrangement of thiol homeostasis and increased sensitivity to antibiotics. In our study, we found that restriction of cysteine metabolism (ΔcysB and ΔcysE) and inhibition of glutathione synthesis (ΔgshAB) lead to a decrease in the sensitivity of the ΔgmhA mutant to antibiotics but not to its expected increase. At the same time, blocking of the export of cysteine (ΔeamA) or increasing import (Ptet-tcyP) into cells of the oxidized form of cysteine-cystine leads to an even greater increase in the sensitivity of gmhA-deleted cells to antibiotics. In addition, there is no correlation between the cytotoxic effect of antibiotics and the level of reactive oxygen species (ROS), the total pool of thiols, or the viability of the initial cell population. However, a correlation between the sensitivity to antibiotics and the level of oxidized glutathione in cells was found in our study. Apparently, a decrease in the content of low-molecular-weight thiols saves NADPH equivalents and limits the processes of protein redox modification. This leads to increasing of resistance of the ΔgmhA strain to antibiotics. An increase in low-molecular-weight thiols levels requires a greater expenditure of cell resources, leads to an increase in oxidized glutathione and induces to greater increase in sensitivity of the ΔgmhA strain to antibiotics.


Effects of CO2 and seawater acidification on the early stages of Saccharina japonica development.
In this paper, we demonstrated that ocean acidification (OA) had significant negative effects on the microscopic development of Saccharina japonica in a short-term exposure experiment under a range of light conditions. Under elevated CO2, the alga showed a significant reduction in meiospore germination, fecundity, and reproductive success. Larger female and male gametophytes were noted to occur under high CO2 conditions and high light magnified these positive effects. Under conditions of low light combined with high PCO2, the differentiation of gametophytes was delayed until the end of the experiment. In contrast, gametophytes were able to survive after having been subjected to a long-term acclimation period, of 105 days. Although the elevated PCO2 resulted in a significant increase in sporophyte length, the biomass abundance (expressed as individual density attached to the seed fiber) was reduced significantly. Further stress resistance experiments showed that, although the acidified samples had lower resistance to high light and high temperature conditions, they displayed higher acclimation to CO2-saturated seawater conditions compared with the control groups. These combined results indicate that OA has a severe negative effect on S. japonica, which may result in future shifts in species dominance and community structure.


Glyphosate ban in Mexico: potential impacts on agriculture and weed management.
Since glyphosate was classified as potentially carcinogenic by the International Agency for Research on Cancer, public debate regarding the environmental impact and health risks from its use has intensified. Almost all regulatory agencies throughout the world have concluded that the judicious use of glyphosate does not pose risks to the environment and human health. However, on the last day of 2020 the Mexican government decreed a ban of this herbicide beginning January, 2024. In current Mexican agriculture there are no safer chemical and/or other weed management technologies that allow for the economical substitution of glyphosate for weed control. Many Mexican weed scientists agree that glyphosate use should be reduced, but not banned outright. This decree could have more negative economic and social consequences as well as environmental and human health risks than benefits, which could compromise the country's food and public security. Crop yields are projected by some to decline by up to 40% with this ban, increasing food prices, making food less accessible to low-income consumers. In addition, a black market for the smuggling and illegal sale of glyphosate is possible. The possible environmental, economic and social impacts caused by the glyphosate ban in Mexico are discussed, emphasizing the impact on weed management. © 2021 Society of Chemical Industry.


Controlling variation in health care: a consultation from Walter Shewhart.
The control of unintended variation is an objective central to modern industrial quality management methods, based largely on the theoretical work of Walter A. Shewhart. As industrial quality management techniques find their place in health care, professionals may feel threatened by the effort to reduce variation. Understanding may reduce this fear. Variation of the types addressed in quality control efforts erodes quality and reliability, and adds unnecessarily to costs. Such undesirable variation derives, for example, from misinterpretation of random noise in clinical data, from unreliability in the performance of clinical and support systems intended to support care, from habitual differences in practice style that are not grounded in knowledge or reason, and from the failure to integrate care across the boundaries of components of the health care system. Quality management efforts can successfully reduce each of these forms of variation without insult to the professional autonomy, dignity, or purpose of health care professionals. Professionals need to embrace the scientific control of variation in the service of their patients and themselves.


[Role Ofhydrogen Sulfide on Inflammatory Immune Disorders in Cardiovascular Diseases].
Hydrogen sulfide (H2S),a colorless gas with a characteristic rotten-egg odor, has traditionally been considered to be a toxic environmental pollutant. Recently, a multitude of works have demonstrated that H2S was identified as the third gaseous signaling molecule alongside nitric oxide and carbon monoxide. Similar to other gaseous signaling molecules,H2S playeda pivotal role in the pathophysiological processes of cardiovascular disease due to its various biological activities, including anti-oxidative, antiapoptotic, proangiogenic, vasodilating capacities, modulating endothelial nitric oxide synthase activity, and so on. However, the mechanisms of H2S underlying the process remained unclear. In the present review, we summarized the current knowledge on the regulatory effects of H2S on disorders of immune inflammation in cardiovascular disease and underlying molecular mechanisms. A better understanding of the biochemical function of H2S might provide a new therapeutic strategy for cardiovascular diseases.


Comparison of the effect of two different types of dry-needling techniques on subacromial impingement syndrome.
Infraspinatus is one of the main muscles that is involved in the subacromial impingement syndrome. Dry needling and routine physical therapy can improve this syndrome. However, the dry needling technique is not well defined. randomized controlled clinical trial, single-blind study. Sixty-six patients diagnosed with shoulder impingement syndrome were recruited and randomly divided into three groups. In 1st group; patients received deep dry needling technique in addition to routine physical therapy, in Hong's group; patients received Hong's dry needling technique in addition to routine physiotherapy and in third group; patient just received routine physical therapy. Before, immediately after and 4 weeks after the intervention, pain, disability and the pressure pain threshold were measured. The findings of this study indicated that in DDN group, pain and disability reduction was significantly more than two other groups. Although, the pressure pain tolerance increased in all three groups after treatment, but the increase between groups was not significantly different. All study groups showed reduction in pain, while there was no significant difference between the three groups. Pain and disability reduction in the DDN group compared to the other two groups may reveal the treatment with deep dry needling technique along with routine physiotherapy is more effective than receiving dry needling with Hong's technique or routine physiotherapy alone. However, there was no significant difference between the three groups in pressure pain tolerance threshold and pain reduction.


Use of hypertonic saline in the treatment of severe refractory posttraumatic intracranial hypertension in pediatric traumatic brain injury.
To evaluate the effect of prolonged infusion of 3% hypertonic saline (514 mEq/L) and sustained hypernatremia on refractory intracranial hypertension in pediatric traumatic brain injury patients. A prospective study. A 24-bed Pediatric Intensive Care Unit (Level III) at Children's Hospital. We present ten children with increased intracranial pressure (ICP) resistant to conventional therapy (head elevation at 30 degrees, normothermia, sedation, paralysis and analgesia, osmolar therapy with mannitol, loop diuretic, external ventricular drainage in five patients), controlled hyperventilation (Pco2, 28-35 mm Hg), and barbiturate coma. We continuously monitored ICP, cerebral perfusion pressure (CPP), mean arterial pressure, central venous pressure, serum sodium concentrations, serum osmolarity, and serum creatinine. A continuous infusion of 3% saline on a sliding scale was used to achieve a target serum sodium level that would maintain ICP <20 mm Hg once the conventional therapy and barbiturate coma as outlined above failed to control intracranial hypertension. The mean duration of treatment with 3% saline was 7.6 days (range, 4-18 days). The mean highest serum sodium was 170.7 mEq/L (range, 157-187 mEq/L). The mean highest serum osmolarity was 364.8 mosm/L (range, 330-431 mosm/L). The mean highest serum creatinine was 1.31 mg/dL (range, 0.4-5.0 mg/dL). There was a steady increase in serum sodium versus time zero that reached statistical significance at 24, 48, and 72 hrs (p < .01). There was a statistically significant decrease in ICP spike frequency at 6, 12, 24, 48, and 72 hrs (p < .01). There was a statistically significant increase in CPP versus time zero at 6, 12, 24, 48, and 72 hrs (p < .01). There was a statistically significant increase in serum osmolarity versus time zero at 12 hrs (p < .05) and at 24, 48, and 72 hrs (p < .01). Two patients developed acute renal failure and required continuous veno-venous hemodialysis; these were concurrent with an episode of sepsis and multisystem organ dysfunction. Both recovered full renal function with no electrolyte abnormalities at the time of discharge. An increase in serum sodium concentration significantly decreases ICP and increases CPP. Hypertonic saline is an effective agent to increase serum sodium concentrations. Sustained hypernatremia and hyperosmolarity are safely tolerated in pediatric patients with traumatic brain injury. Controlled trials are needed before recommendation of widespread use.


Peak compression and resolution for electrophoretic separations in diverging microchannels.
We report the results of experiments and simulations on electrokinetic flow in diverging microchannels (with cross-sectional area that increases with distance along the channel). Because of conservation of mass and charge, the velocity of an analyte in the channel decreases as the channel cross-section increases. Consequently, the leading edge of a band of sample moves more slowly than the trailing edge and the sample band is compressed. Sample peak widths, rather than increasing diffusively with time, can then be controlled by the geometry of the channel and can even be made to decrease with time. We consider the possibility of using this peak compression effect to improve the resolution of electrophoretic separations. Our results indicate that for typical separations that are dispersion limited, this peak compression effect is more than offset by the decreased distance between peaks, and the separation resolution in diverging channels is worse than that found for straight channels at the same applied voltage. For separations in very short channels or at very high field strengths, however, when the separation efficiency is injection limited, the peak compression effect is dominant and diverging channels can then be used to achieve improved separation resolution.


Biotechnology research on cestodes in the Philippines, Malaysia, and Indonesia.
There are essentially no reports on the use of modern biotechnological methods on the study of cestode parasites in the Philippines, Indonesia or Malaysia. The only recent reports of cestode studies in these countries have been on reports of new species in animals and on prevalence rates of cestode parasites in humans; Taenia solium and cysticercosis, Taenia saginata and Hymenolepis nana, etc. Reports on the use of biotechnology has emanated from outside the area on cestodes of humans and animals, and some of these methods could be used to study cestodes in this part of the world.


Chemical composition and insecticidal activities of Blumea balsamifera (sambong) essential oil against three stored product insects.
Blumea balsamifera (L.) DC. (Asteraceae), also known as sambong, is a perennial herb used in China for medicinal purposes. The essential oil (EO) of B. balsamifera was extracted by hydrodistillation. Thirty-three chemical components of the EO were analysed by gas chromatography-mass spectrometry (GC-MS) and GC, accounting for 90.2% (w/w) of the total oil. The EO of B. balsamifera was mainly composed of monoterpenes and sesquiterpenes, in which borneol (23.3%), β-caryophyllene (20.9%) and camphor (11.8%) were the major components. The insecticidal activities of the EO and its three main compounds against Tribolium castaneum, Lasioderma serricorne and Sitophilus oryzae were evaluated. The results of bioassays displayed that the EO of B. balsamifera did not have fumigant toxicity to the three target insects, but exhibited significant contact activity against L. serricorne (LD50 = 12.4 μg/adult) and S. oryzae (LD50 = 44.4 μg/adult). Meanwhile, the EO showed a notable repellent effect on T. castaneum at all testing concentrations and a general repellent effect on S. oryzae at high concentrations (78.63 nL/cm2). β-Caryophyllene showed the best performance in the contact toxicity bioassays against the three insects. The results indicated that B. balsamifera has the potential to be used as a source of botanical insecticides for the control of stored-product insects.


The treatment of mild to moderate hypertension with ACE inhibitors.
The efficacy and safety of quinapril were evaluated in patients with mild to moderate hypertension [sitting diastolic blood pressure (DBP) of 95-115 mm Hg] in seven large, multicenter studies and in one large, single-center study. In double-blind trials, 1,367 patients were treated with quinapril and 820 patients were treated with comparative therapies (enalapril, captopril, chlorthalidone, or placebo). The usual effective dosage of quinapril was 10-40 mg/day, with some patients receiving up to 80 mg/day. Diuretics were added optionally for nonresponders in some studies. Quinapril was equally safe and effective administered either once daily (o.d.) or twice daily and was significantly more effective in lowering blood pressure than was placebo. Quinapril and enalapril administered o.d. were similarly effective in producing clinically and statistically significant reductions in resting blood pressure 24 h after dosing. Quinapril in o.d. doses was as effective as captopril administered two or three times daily. Quinapril was well tolerated; the incidence of adverse events was similar to that for placebo and was comparable to or less than that reported for captopril or enalapril. Quinapril in o.d. doses (10-40 mg/day) is safe and effective as first-line therapy for the treatment of mild to moderate hypertension. Diuretics can be safely added for patients who are not controlled by quinapril alone.


Alterations in adaptive immunity persist during long-duration spaceflight.
It is currently unknown whether immune system alterations persist during long-duration spaceflight. In this study various adaptive immune parameters were assessed in astronauts at three intervals during 6-month spaceflight on board the International Space Station (ISS). To assess phenotypic and functional immune system alterations in astronauts participating in 6-month orbital spaceflight. Blood was collected before, during, and after flight from 23 astronauts participating in 6-month ISS expeditions. In-flight samples were returned to Earth within 48 h of collection for immediate analysis. Assays included peripheral leukocyte distribution, T-cell function, virus-specific immunity, and mitogen-stimulated cytokine production profiles. Redistribution of leukocyte subsets occurred during flight, including an elevated white blood cell (WBC) count and alterations in CD8+ T-cell maturation. A reduction in general T-cell function (both CD4+ and CD8+) persisted for the duration of the 6-month spaceflights, with differential responses between mitogens suggesting an activation threshold shift. The percentage of CD4+ T cells capable of producing IL-2 was depressed after landing. Significant reductions in mitogen-stimulated production of IFNγ, IL-10, IL-5, TNFα, and IL-6 persisted during spaceflight. Following lipopolysaccharide (LPS) stimulation, production of IL-10 was reduced, whereas IL-8 production was increased during flight. The data indicated that immune alterations persist during long-duration spaceflight. This phenomenon, in the absence of appropriate countermeasures, has the potential to increase specific clinical risks for crewmembers during exploration-class deep space missions.


Does the risk of childhood diabetes mellitus require revision of the guideline values for nitrate in drinking water?
In recent years, several studies have addressed a possible relationship between nitrate exposure and childhood type 1 insulin-dependent diabetes mellitus. The present ecologic study describes a possible relation between the incidence of type 1 diabetes and nitrate levels in drinking water in The Netherlands, and evaluates whether the World Health Organization and the European Commission standard for nitrate in drinking water (50 mg/L) is adequate to prevent risk of this disease. During 1993-1995 in The Netherlands, 1,104 cases of type 1 diabetes were diagnosed in children 0-14 years of age. We were able to use 1,064 of these cases in a total of 2,829,020 children in this analysis. We classified mean nitrate levels in drinking water in 3,932 postal code areas in The Netherlands in 1991-1995 into two exposure categories. One category was based on equal numbers of children exposed to different nitrate levels (0.25-2.08, 2.10-6.42, and 6.44-41.19 mg/L nitrate); the other was based on cut-off values of 10 and 25 mg/L nitrate. We determined standardized incidence ratios (SIRs) for type 1 diabetes in subgroups of the 2,829,020 children with respect to both nitrate exposure categories, sex, and age and as compared in univariate analysis using the chi-square test for trend. We compared the incidence rate ratios (IRRs) by multivariate analysis in a Poisson regression model. We found an effect of increasing age of the children on incidence of type 1 diabetes, but we did not find an effect of sex or of nitrate concentration in drinking water using the two exposure categories. For nitrate levels > 25 mg/L, an increased SIR and an increased IRR of 1.46 were observed; however, this increase was not statistically significant, probably because of the small number of cases (15 of 1,064). We concluded that there is no convincing evidence that nitrate in drinking water at current exposure levels is a risk factor for childhood type 1 diabetes mellitus in The Netherlands, although a threshold value > 25 mg/L for the occurrence of this disease can not be excluded.


Cigarette smoking and random serum cholesterol levels in a Northern Ireland general practice population of 18- to 20-year-old students and non-students.
Coronary heart disease is the commonest cause of death in Northern Ireland, but few data exist on the incidence of risk factors in young adult students and non-students. To gather data on the prevalence of cigarette smoking and raised serum total cholesterol in a population of 18- to 20-year-old students and non-students. Subjects were patients are Mountsandel Surgery, Coleraine on 1 January 1989 and were 18-20 years of age inclusive on that date. Subjects were interviewed by a research nurse who recorded socio-demographic data, tobacco consumption and random serum total cholesterol. Smoking status validation was by serum thiocyanate and expired air carbonmonoxide estimations. Out of the 832 subjects surveyed, 570 were students and 262 were non-students. Cigarettes were smoked by 239 (28.7%) subjects, and a significantly greater proportion of non-students compared with students were smokers (36.6% and 25.1%, respectively; P < 0.001). The proportion of males compared with females who smoked cigarettes was not significantly different, but males smoked significantly more cigarettes per day than females (14 and 11 cigarettes, respectively; P = 0.005). The average age for commencing regular cigarette smoking was 15.3 years, and 49.9% of smokers had started regular smoking by the age of 16 years. A greater proportion of non-students (65.7%) compared with students (39.2%) had started smoking before the age of 16 years. Out of those sampled, 156 (19.2%) had random serum cholesterol levels above 5.2 mmol l-1. Mean total cholesterol for non-students was significantly higher than for students (4.61 and 4.45 mmol l-1, respectively; P = 0.01) and increased significantly with increasing age (P = 0.03). Three subjects recorded cholesterol levels above 7.8 mmol l-1. Cigarette smoking and raised serum total cholesterol were prevalent among an apparently healthy population of students and non-students. These young adults may be significantly more at risk from subsequent coronary heart disease than was previously suspected.


Effect of a combination of clevudine and emtricitabine with adenovirus-mediated delivery of gamma interferon in the woodchuck model of hepatitis B virus infection.
Our aim was to evaluate the antiviral effect of a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and clevudine (L-FMAU), with the addition of an adenovirus-driven delivery of recombinant gamma interferon (IFN-gamma) in the woodchuck model of hepatitis B virus infection. Six woodchuck hepatitis virus (WHV)-infected woodchucks received L-FMAU (10 mg/kg) plus FTC (30 mg/kg) intraperitoneally for 8 weeks; six other animals received in addition an intravenous injection of a recombinant adenovirus vector expressing woodchuck IFN-gamma (Ad-IFN) at weeks 4 and 8. In the control group, two animals received Ad-IFN alone, two received adenovirus vector expressing the green fluorescent protein reporter gene, and one remained untreated. In less than 2 weeks, all woodchucks that received L-FMAU plus FTC showed a rapid and marked inhibition of viral replication, with a 4-log(10) drop in serum WHV DNA. In two animals, viremia remained suppressed for several months after the end of treatment. Similarly, a dramatic decrease in intrahepatic replicative intermediates of viral DNA was observed in the L-FMAU/FTC-treated groups. The additional administration of Ad-IFN led to increased inflammation in the liver but did not enhance the antiviral effect of the L-FMAU/FTC combination. In conclusion, therapies combining L-FMAU and FTC in WHV-infected woodchucks resulted in a potent and sustained antihepadnaviral effect both in the liver and in the blood circulation. However, no extra benefit of adding IFN-gamma gene transduction to the L-FMAU/FTC combination could be detected.