Ezh2 Acts as a Tumor Suppressor in Kras-driven Lung Adenocarcinoma.
Previous studies have suggested that enhancer zeste homolog 2 (Ezh2), a histone methyltransferase subunit of polycomb repressive complex 2 (PRC2), acts as an oncogene in lung adenocarcinoma (ADC) development. However, we found that in human lung ADC samples, deletion and mutations of EZH2 were also frequently present, with 14% of patients harboring loss-of-function EZH2 alterations. To explore the effect of Ezh2 loss on lung tumor formation, lung epithelial Ezh2 gene was deleted in Kras-driven lung ADC mouse model. Unexpectedly, Ezh2 loss dramatically promoted Kras-driven ADC formation. KrasG12D/+;Ezh2fl/fl mice exhibited shorter lifespan, more tumor lesions and higher tumor burden than KrasG12D/+ mice, suggesting the tumor-suppressive role of Ezh2 in Kras-driven ADCs. Mechanistically, Ezh2 loss amplified Akt and ERK activation through de-repressing its target insulin-like growth factor 1 (Igf1). Additionally, Ezh2 loss cooperated with Kras mutation to exacerbate the inflammatory response, as shown by massive macrophage and neutrophil infiltrates, as well as a marked increase in tumor-associated cytokines such as IL-6 and TNF-α. Taken together, our findings revealed the tumor suppressive function of Ezh2 in Kras-driven ADCs, underlining the importance of revaluating the application of EZH2 inhibitors in a variety of cancers.


Mediterranean diet and health in the elderly.
The Mediterranean diet has probably been the most studied diet since the early 1950s. American physiologist Ancel Keys coined the term since it was based on the dietary habits of those populations bordering the Mediterranean basin, particularly the island of Crete and southern Italy. The motivation for the early studies lay in understanding why these populations had greater longevity and lower occurrence of chronic-degenerative diseases and forms of cancer when compared with the peoples of Northern Europe and North America. Traditionally, this dietary regimen was based on the seasonality of foods and the consumption of unrefined grains, legumes, fish, vegetables, fruits, little meat and use of olive oil as a condiment. The purpose of this paper is to understand, based on current scientific knowledge, how the different nutrients present in such a diet can play a preventive role in the onset of today's most frequent diseases.


Histogram analysis of MR imaging-derived cerebral blood volume maps: combined glioma grading and identification of low-grade oligodendroglial subtypes.
Inclusion of oligodendroglial tumors may confound the utility of MR based glioma grading. Our aim was, first, to assess retrospectively whether a histogram-analysis method of MR perfusion images may both grade gliomas and differentiate between low-grade oligodendroglial tumors with or without loss of heterozygosity (LOH) on 1p/19q and, second, to assess retrospectively whether low-grade oligodendroglial subtypes can be identified in a population of patients with high-grade and low-grade astrocytic and oligodendroglial tumors. Fifty-two patients (23 women, 29 men; mean age, 52 years; range, 19-78 years) with histologically confirmed gliomas were imaged by using dynamic susceptibility contrast MR imaging at 1.5T. Relative cerebral blood volume (rCBV) maps were created, and 4 neuroradiologists defined the glioma volumes independently. Averaged over the 4 observers, a histogram-analysis method was used to assess the normalized histogram peak height of the glioma rCBV distributions. Of the 52 patients, 22 had oligodendroglial tumors. The histogram method was able to differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) (Mann-Whitney U test, P < .001) and to identify low-grade oligodendroglial subtypes (P = .009). The corresponding intraclass correlation coefficients were 0.902 and 0.801, respectively. The sensitivity and specificity in terms of differentiating low-grade oligodendroglial tumors without LOH on 1p/19q from the other tumors was 100% (6/6) and 91% (42/46), respectively. With histology as a reference, our results suggest that histogram analysis of MR imaging-derived rCBV maps can differentiate HGGs from LGGs as well as low-grade oligodendroglial subtypes with high interobserver agreement. Also, the method was able to identify low-grade oligodendroglial tumors without LOH on 1p/19q in a population of patients with astrocytic and oligodendroglial tumors.


P-glycoprotein functions and substrates: possible roles of MDR1 gene in the kidney.
There is a renewed attention on the multidrug resistance genes and their products, P-glycoproteins, since recent molecular and functional studies revealed unexpected functions in normal tissues. There are two types of human P-glycoprotein: Type I, encoded by the MDR1 gene, present in excretory organs and in non-polarized cells; and Type II, encoded by MDR2, present in the canalicular membrane of hepatocytes. MDR1 Pgp transports xenobiotics, peptides, steroids, and phospholipids, and is also a regulator of swelling-activated chloride channels. MDR2 Pgp is exclusively a phosphatidylcholine translocase. In the kidney, the MDR1 gene and protein are expressed in mesangial, proximal tubule, thick loop of Henle, and collecting duct cells. In mesangial and proximal tubule cells Pgp transports xenobiotics. Concomitant exposure of kidney cells to two Pgp substrates results in increased cell toxicity. Extracts from supernatants of mesangial cell cultures inhibit Pgp-mediated transport, suggesting that a mesangial-cell metabolite could be a substrate of Pgp. Active vitamin D3 and platelet activating factor inhibit Pgp transport and are possible endogenous substrates in proximal tubule and mesangial cells, respectively. Pgp could be also a regulator of swelling-activated chloride channels present in the kidney.


Role of naturopathy and yoga treatment in the management of hypertension.
The primary aim was to study the effect of naturopathy and yoga interventions in treatment of mild to moderate hypertension. The variables of interest were measured at the beginning and end of the intervention using a pre-post design. The study was conducted by INYS medical research society in Jindal Nature Cure Institute, Bangalore. A total of 104 subjects, already diagnosed with mild to moderate hypertension and on treatment with antihypertensive medicines were included in study. The intervention consisted of various inpatient administration of different naturopathy treatments, yoga therapies, low calorie and low sodium diet for 21 days. Antihypertensive medicines were withdrawn for some patients in one week based upon response to the treatment. The outcome measures were values of diastolic and systolic blood pressure and body weight. Subjects were followed for a period of one year after every 3 months. After starting nonpharmacological approach of naturopathy and yoga, Systolic blood pressure came down from mean of 139.6 to 129.6 where as it came down from 91.2 to 86.1 for diastolic blood pressure. At the same time favorable effect was also seen in other variables like lipid profile and body weight. At the end of one year out of 57 patients who came for follow-up, 14 cases were found to have blood pressure within normal ranges without any medication over the previous 12 months. Naturopathy and yoga therapy can be considered as a valuable nonpharmacological approach in treatment of hypertension.


Diagnosis of B-cell non-hodgkin lymphomas with small-/intermediate-sized cells in cytopathology.
Fine needle sampling is a fast, safe, and potentially cost-effective method of obtaining tissue for cytomorphologic assessment aimed at both initial triage and, in some cases, complete diagnosis of patients that present clinically with lymphadenopathy. The cytologic diagnosis of B-cell non-Hodgkin lymphomas composed of small-/intermediate-sized cells, however, has been seen as an area of great difficulty even for experienced observers due to the morphologic overlap between lymphoma and reactive lymphadenopathies as well as between the lymphoma entities themselves. Although ancillary testing has improved diagnostic accuracy, the results from these tests must be interpreted within the morphological and clinical context to avoid misinterpretation. Importantly, the recognition of specific cytologic features is crucial in guiding the appropriate selection of ancillary tests which will either confirm or refute a tentative diagnosis. For these reasons, we here review the cytologic characteristics particular to five common B-cell non-Hodgkin lymphomas which typically cause the most diagnostic confusion based on cytological assessment alone: marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and lymphoplasmacytic lymphoma. We summarize the most pertinent cytomorphologic features for each entity as well as for reactive lymphoid hyperplasia, contrast them with each other to facilitate their recognition, and highlight common diagnostic pitfalls.


[Sexual dysfunctions in a group of psychiatric in-patients].
41 mentally ill patients with sexual dysfunctions were examined by means of a semistructured interview. In this interview we tried to assess quality, intensity and duration of the sexual dysfunctions. In addition to this we developed a self-rating-scale in order to assess the patients' possibilities to talk about their sexual problems with a therapist. These attitudes were related to the attitudes of the staff towards the same issue. We found out that the dysfunctions had lasted for 11.0 years on average and that 58.8 % of the patients hadn't made any attempts for specific therapeutic steps so far. Patients with sexual dysfunctions such as erectile impotence were more interested in having additional talks about their sexual problems than patients with sexual disturbances such as libido loss. They were also more inclined to see psychiatric medication as a cause for their sexual problems. In addition to this, the complete group of the examined patients considered as to be less important that the therapist was of the same sex than the staff, particularly if the interviewer was not of the same sex. Our results confirm the thesis, that it is worth paying more attention to sexual dysfunctions of mentally ill patients, necessary therapeutic steps should be taken if possible. A positive effect of this probably seems to be a better compliance.


A systematic review of the outcomes reported in the treatment of uncomplicated urinary tract infection clinical trials.
Uncomplicated urinary tract infections (UTIs) are amongst the most frequent infections presenting in the outpatient setting. A growing number of clinical trials are assessing the most effective treatment interventions for uncomplicated UTI. Due to the heterogeneity of the outcomes reported in these trials, however, comparing these outcomes is challenging. Identify the core outcomes that have been reported in trials and systematic reviews of interventions treating uncomplicated UTI in adults. We conducted a systematic search for core outcomes used to evaluate treatments of UTIs. We searched the Cochrane Database of Systematic Reviews, PubMed and Embase. One researcher independently screened each article for inclusion, and the Core Outcome Set for treatment of Urinary Tract Infections (COSUTI) team acted as second reviewers. All included articles were screened by two reviewers. All outcomes were extracted verbatim, and similar outcomes were grouped into domains and subdomains. In total, 334 outcomes were reported across 41 papers, the average number of outcomes reported being 8. Outcomes were categorized across 18 domains, the majority of which were related to clinical cure outcomes. Many outcomes varied in the timepoints within which the outcome was measured and reported. Comparing the outcomes of trials investigating uncomplicated UTI treatment remains challenging due to the difference in outcomes currently reported. Consistency of reporting of outcomes would be improved by developing a minimum number of consistent outcomes that should be reported in all trials.


[The long-term care insurance system and geriatric psychiatry].
The long-term care insurance system targets people who require support because of mental or physical disturbances due to aging. This overlaps in many areas with the field of geriatric psychiatry, which is expected to play a significant role in diagnosis and hospitalization in the long-term care insurance system. Representative of the former is the forgetfulness clinic, and representative of the latter is the "senile dementia disorder center". When a person at home or in a nursing facility becomes seriously demented or suffers serious physical illness, he is generally hospitalized. However, there is an ongoing project which allows group homes to care for the seriously demented or physically damaged elderly. Under the long-term care insurance system, there are many problems that should be dealt with by geriatric psychiatry. One essential issue is the lack of basic research on judgment abilities and mental competency, even though users are expected to select services and make their own decisions under this system. Once there is a social support system for the care-requiring elderly, it is necessary to assess the decision-making ability of individual elderly. If this ability is sufficiently maintained it should be respected to the utmost. If it is impaired, we must have a viewpoint on how to provide care through a social system. A consensus has yet to be reached on informed consent for the demented elderly, and this issue should be considered with a focus on geriatric psychiatry.


Amphicrine carcinoma of breast with giant granules: an immunohistochemical, histochemical and ultrastructural study.
A moderately differentiated grade 2 invasive ductal carcinoma was diagnosed in the right breast of an 81-year-old woman. The uniform nuclear profiles and moderately abundant granular cytoplasm suggested a neuroendocrine tumour and a Grimelius stain was positive. Neurone specific enolase, synaptophysin and somatostatin stained positively, and casein was interpreted as positive although with some background staining. By electron microscopy, tumour cells possessed desmosomes, tonofibrils, intercellular lumina, lamina and dense granules. Rounded dense granules 160-480 nm in diameter resembled neuroendocrine granules. They were found in both luminal and basal areas. Fewer and much larger ('giant') granules had a rounded profile and were up to 5 microm across. The smaller cytoplasmic granules were mostly Grimelius-positive while giant granules were negative. The smaller granules were also uranaffin-positive, but no uranaffin-positive cytoplasmic giant granules were encountered. Both small and giant granules were observed in lumina, and here both were uranaffin-positive. Intraluminal giant granules had a substructure of small pale lipid-like lacunae, and some had irregular profiles. The exceptional size of these exocrine granules is emphasised, and the nature of both the small and giant granules discussed in this amphicrine carcinoma.


Apparent and standardized ileal digestibility of amino acids in diverse barley cultivars fed to growing pigs.
The objectives of this study were to determine the chemical composition, ileal amino acid (AA) digestibility of barley varieties and to develop equations to predict the AA digestibility based on the chemical characteristics of individual barley. A wide selection of nine barley varieties in the main growing regions of China was used in the experiment. Ten crossbred pigs (30.9 ± 1.8 kg) were allotted to a 6 × 10 Youden Square. The treatments included a nitrogen-free diet and nine barley test diets. Considerable variation was observed in the content of neutral detergent fiber, acid detergent fiber, crude protein (CP) and all AAs among the barley samples. The standardized ileal digestibility (SID) of indispensable AAs with the exception of arginine, phenylalanine and threonine were different (P < 0.05) among the nine barley sources tested. With R2 values exceeding 0.50, significant linear regression equations for CP and threonine were obtained. In conclusion, significant differences existed in the ileal digestibility of CP and AAs among barley varieties. It is difficult to predict the SID of most of the amino acids in barely based upon chemical characteristics.


Multivalent Recognition at Fluid Surfaces: The Interplay of Receptor Clustering and Superselectivity.
The interaction between a biological membrane and its environment is a complex process, as it involves multivalent binding between ligand/receptor pairs, which can self-organize in patches. Any description of the specific binding of biomolecules to membranes must account for the key characteristics of multivalent binding, namely, its unique ability to discriminate sharply between high and low receptor densities (superselectivity), but also for the effect of the lateral mobility of membrane-bound receptors to cluster upon binding. Here we present an experimental model system that allows us to compare systematically the effects of multivalent interactions on fluid and immobile surfaces. A crucial feature of our model system is that it allows us to control the membrane surface chemistry, the properties of the multivalent binder, and the binding affinity. We find that multivalent probes retain their superselective binding behavior at fluid interfaces. Supported by numerical simulations, we demonstrate that, as a consequence of receptor clustering, superselective binding is enhanced and shifted to lower receptor densities at fluid interfaces. To translate our findings into a simple, predictive tool, we propose an analytical model that enables rapid predictions of how the superselective binding behavior is affected by the lateral receptor mobility as a function of the physicochemical characteristics of the multivalent probe. We believe that our model, which captures the key physical mechanisms underpinning multivalent binding to biological membranes, will greatly facilitate the rational design of nanoprobes for the superselective targeting of cells.


Research needs and strategies to establish best practices and cost effective models for chronic critical illness.
Past research in chronic critical illness has been effective in defining the population and identifying unique aspects of their outcomes and resource needs, but there has been little research focused on interventions to improve outcomes. This review discusses some research priorities that could have immediate impact on patient outcomes. General topics include prevention or limiting the incidence of chronic critical illness; specific topics related to patient management, such as interventions for weaning, rehabilitation, nutrition or infections; and methods to enhance communication and end-of-life care. In addition to specific patient management interventions, further comparative effectiveness research on care settings is indicated, considering the expected growth in the patient population and the substantial resource needs.


Duration of effects on clinical parameters and referred hyperalgesia in rats after abdominal surgery and multiple doses of analgesic.
This study evaluated the duration of clinical effects and referred hyperalgesia in rats (n = 10 per group) undergo ing abdominal surgery with analgesics (ketoprofen at 3 mg/kg and buprenorphine at 0.01 or 0.1 mg/kg) administered intramuscularly twice daily for 72 h beginning prior to surgery; no-surgery and no-analgesia control groups were included. Food and water consumption and body weight were monitored daily. As a measure of referred hyperalgesia, tail-flick latency was measured daily, before and 4 h after analgesia administration. Compared with those of the no-surgery controls, significant decreases in food consumption and body weight occurred 24 h after surgery without analgesics. There were nonsignificant reductions in these effects by analgesics, but the benefits were not significantly different than those of saline. These parameters continued to be decreased with variable significance in the buprenorphine groups at 48 and 72 h after surgery. In both buprenorphine-treated groups, water consumption was significantly increased at 24 h after surgery but not at 48 or 72 h. Tail-flick latency was not significantly different between the no-surgery and no-analgesia groups but was significantly increased 4 h after high-dose buprenorphine administration and declined nonsignificantly over time in the other groups. We conclude that painful effects from surgery are present primarily during the first 24 h after surgery. The analgesic regimens tested did not completely reduce these effects. Buprenorphine was associated with adverse effects for as long as 72 h after surgery. Referred hyperalgesia from this abdominal surgery could not be measured using the tail-flick assay.


The role of protein breakdown in growth, quiescence, and starvation of vascular smooth muscle cells.
Protein accumulation in growing cells may be due in part to a reduction in the rate of protein breakdown. Previous studies of the relation of cell proliferation to protein degradation often produced growth arrest by conditions that may involve nutritional deprivation. However, nutrient lack can itself accelerate proteolysis and produce negative protein balance. We therefore reexamined the relation between growth and protein breakdown using a more selective method for limiting cell growth. We produced quiescent cell cultures using a chemically defined, serum-free medium supplemented with hormones and nutrients. Such media can maintain viability and near neutral protein balance in cultured vascular smooth muscle cells, in part because of reduced breakdown of cellular protein. We then compared rates of protein degradation in these quiescent but not starving cells, to those of cultures stimulated to grow by addition of mitogenic substances. Platelet-derived growth factor, fibroblast growth factor, or fetuin added to insulin-containing medium stimulated growth of smooth muscle cells, but further reduced protein breakdown only slightly. Contrary to the implications of certain previous studies, our results show that proliferating cells can accumulate protein without an appreciable reduction in the rates of protein breakdown. Thus, while accelerated proteolysis appears to be an important adaptation to adverse nutritional conditions, growth of smooth muscle cells does not require changes in overall protein breakdown, but occurs primarily through an increase in protein synthesis.


An informativity-based account of negation complexity.
In sentence comprehension, negative sentences tend to elicit more processing cost than affirmative sentences. A growing body of work has shown that pragmatic context is an important factor that contributes to negation comprehension cost. The nature of this pragmatic effect, however, is yet to be determined. In 4 behavioral experiments, the current study assesses 2 possible pragmatic accounts: the expectation-based and the informativity-based accounts. Our findings suggest that informativity, instead of contextual expectation, is more directly responsible for negation comprehension. Contextual expectation only modulates negation comprehension cost if it facilitates the appropriate type of question under discussion. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


The relation between dimensions of normal and pathological personality and childhood maltreatment in incarcerated boys.
The relation between subtypes of maltreatment and dimensions of personality and personality pathology was investigated in a representative sample of 142 incarcerated Dutch male juveniles. Normal personality dimensions were assessed with the Big Five Inventory, the Dimensional Assessment of Personality Pathology-Basic Questionnaire for Adolescents was used to measure pathological personality dimensions, and the Childhood Trauma Questionnaire was used to assess childhood maltreatment. The five maltreatment subtypes were found to be differentially and uniquely related to the normal and pathological personality dimensions in juvenile delinquents. The association between the abusive subtypes and Emotional Dysregulation depended on the co-occurrence of neglect. It was concluded that subtypes of maltreatment are distinctively related to dimensions of personality and personality pathology, possibly due to specific gene-environment interactions. Further research on this interplay is needed to be able to recognize genetic vulnerability. Early identification of children at risk could aid to limit the long-term consequences of maltreatment.


Effect of abnormal thyroid function on the severity of Graves' ophthalmopathy.
Many clinicians have the impression that treatment of thyroid dysfunction ameliorates ophthalmopathy in Graves' disease. The aim of our study was to relate thyroid function to the severity of Graves' ophthalmopathy. We studied 90 patients with Graves' ophthalmopathy and Graves' hyperthyroidism in whom severity of Graves' ophthalmopathy and thyroid function (regardless of antithyroid treatment) were assessed when referred to our institution. Patients were assigned to four groups (A through D) with increasingly severe Graves' ophthalmopathy using Total Eye Score based on the NOSPECS classification. The percentage of dysthyroid patients in each group was determined: group A had 23% dysthyroid patient (5); group B, 32% (9); group C, 61% (14); and group D, 47% (8). More dysthyroid patients were in the groups with severe Graves' ophthalmopathy. We also compared the severity of Graves' ophthalmopathy between euthyroid (n = 54) and dysthyroid (n = 36) patients: euthyroid patients had less proptosis (19.9 +/- 3.5 vs 20.8 +/- 3.4 mm), better visual acuity (0.93 +/- 0.17 vs 0.88 +/- 0.18), and lower Total Eye Score (8.6 +/- 6.6 vs 10.6 +/- 6.6). We conclude that dysthyroidism is associated with more severe Graves' ophthalmopathy. Our findings suggest that meticulous control of thyroid function also during antithyroid treatment is important in the management of Graves' ophthalmopathy.


Natural phenols and diglycerides in virgin olive oil and their relation.
This work is to be included among an evaluation of analytical methods to be used for determination of olive oil quality. Studies on the diglycerides and phenols fraction have been conducted on some olive oils, obtained from cultivars grown in Calabria, during years 1997-2000. The analysis of obtained data indicates that there is a close relation between the content of phenols and diglycerides in virgin olive oil and that high content in phenols and 1,2-diglycerides is a characteristic of fresh olive oil.


Decreased lymphokine-activated killer cells in kidney transplant recipients. Correlation with a diminished number of CD3-/NKH1+ cells.
The activity of lymphokine-activated killer cells, measured either by a clonal or polyclonal technique, was assessed in 30 kidney transplant recipients (TX), in 13 hemodialyzed patients (HD-CRI), and in 18 normal (N) controls. A highly significant decrease of the LAK activity in TX in comparison with HD-CRI or N (P = 0.0001) was observed. Moreover, the percentage of CD3-/NKH1+ cells was decreased in TX in comparison with N (P = 0.01). LAK activity was strongly correlated (r = 0.72; P = 0.0001) with the percentage of CD3-/NKH1+ cells and not with that of double-positive CD3+/NKH1+ cells. Multivariate analysis showed that the sole independent variable that determined the LAK activity was the percentage of CD3-/NKH1+ cells: the pathological status (TX, HD-CRI, and N) variable was statistically not significant. On the other hand, two T cell-specific functions (IL-2 secretion and specific cytotoxic activity) were, on the whole, preserved in TX. Altogether, these results suggest that TX are LAK deficient predominantly because they have a decreased number of CD3-/NKH1+ cells. The normality of T cell functions suggests that the high rate of malignancies seen in TX is related to this LAK deficiency. Moreover, our study indicates that, in vivo, CD3+ cells do not significantly contribute to the LAK precursors.


Extracting time-frequency feature of single-channel vastus medialis EMG signals for knee exercise pattern recognition.
The EMG signal indicates the electrophysiological response to daily living of activities, particularly to lower-limb knee exercises. Literature reports have shown numerous benefits of the Wavelet analysis in EMG feature extraction for pattern recognition. However, its application to typical knee exercises when using only a single EMG channel is limited. In this study, three types of knee exercises, i.e., flexion of the leg up (standing), hip extension from a sitting position (sitting) and gait (walking) are investigated from 14 healthy untrained subjects, while EMG signals from the muscle group of vastus medialis and the goniometer on the knee joint of the detected leg are synchronously monitored and recorded. Four types of lower-limb motions including standing, sitting, stance phase of walking, and swing phase of walking, are segmented. The Wavelet Transform (WT) based Singular Value Decomposition (SVD) approach is proposed for the classification of four lower-limb motions using a single-channel EMG signal from the muscle group of vastus medialis. Based on lower-limb motions from all subjects, the combination of five-level wavelet decomposition and SVD is used to comprise the feature vector. The Support Vector Machine (SVM) is then configured to build a multiple-subject classifier for which the subject independent accuracy will be given across all subjects for the classification of four types of lower-limb motions. In order to effectively indicate the classification performance, EMG features from time-domain (e.g., Mean Absolute Value (MAV), Root-Mean-Square (RMS), integrated EMG (iEMG), Zero Crossing (ZC)) and frequency-domain (e.g., Mean Frequency (MNF) and Median Frequency (MDF)) are also used to classify lower-limb motions. The five-fold cross validation is performed and it repeats fifty times in order to acquire the robust subject independent accuracy. Results show that the proposed WT-based SVD approach has the classification accuracy of 91.85%±0.88% which outperforms other feature models.


Environmental Vibrio cholerae non O1/ non O139 from the Gangetic delta: a diarrhoeal disease purview.
Diarrhoea still remains an unsolved enigma in developing countries, a major concern for the health planners. We targeted the abundance and toxicity of Vibrio cholerae non-O1/non-O139 (NOVC) in Gangetic riverine-estuarine ecosystem. A total of 74 V. cholerae were isolated from 120 water samples (68 NOVC, 6 V. cholerae O1) from two sampling sites off river Ganges. V. cholerae showed distinct seasonality, with steady increase from summer to monsoon, steep ascent in post-monsoon and an abrupt decline in winter. Highest number of NOVC was isolated form Howrah, attributed to low salinity and high anthropogenic influence. Environmental NOVC harboured hlyA (94.0 %), rtxA (81.0 %) and toxR (28.0 %) genes. About 23.4 % of the hlyA harbouring NOVC showed haemolytic activity. Accessory toxin genes (tlcR, toxT, RJ and LJ and aldA), among 3-5 % of the NOVC carry significant health implications. Haemolytic activity and biofilm formation in NOVC, during unfavourable conditions, facilitates gene transfer and emphasises the role of environmental NOVC in diarrhoeal incidence in South Bengal, India.


Gastric metaplasia and Helicobacter pylori.
We investigated the relationships between gastric metaplasia occurring during the healing and scarring stages of duodenal ulcers and Helicobacter pylori by examining the course of gastric metaplasia in H. pylori-eradicated and non-eradicated patients. One hundred and six H. pylori-positive patients with active duodenal ulcers were assigned to either a non-eradication group or an eradication group. The non-eradication group received lansoprazole for 6 wk, followed by an H2-receptor antagonist. The eradication group also received amoxicillin and metronidazole for 1 wk, in addition to lansoprazole, after initial endoscopic examination. In both groups, biopsy specimens were obtained from the ulcer margin in the active stage and from the center of the scar in the scarring stage. Specimens were examined microscopically as well as by rapid urease test to assess the extent of gastric metaplasia and to detect the presence of H. pylori. The extent of gastric metaplasia increased as the ulcers healed. The extent of gastric metaplasia was of a lesser degree in the non-eradication group than in the eradication group at the time of healing, and this tendency became increasingly apparent in the course of follow-up, resulting in reduced defense mechanisms against acidity to promote the recurrence of ulcers. In the eradication group, among those in whom eradication was successful, gastric metaplasia presented a well-developed appearance with abundant intracellular mucus and remained in this condition for a prolonged period, resulting in adequate defense mechanisms against acidity to prevent the recurrence of ulcers. By the eradication of H. pylori, gastric metaplasia becomes well-developed and remains so for a prolonged period. Thus, the eradication of H. pylori appears to play a role in the prevention of ulcer recurrences by developing adequate defenses against acidity.


Adipokines and insulin resistance, predictors of response to therapy in Egyptian patients with chronic hepatitis C virus genotype 4.
Hepatitis C virus (HCV) infection has major health impact worldwide and is a significant cause of chronic liver disease. In Egypt, HCV is highly endemic (up to 15% of the population); 91% of the patients are infected with genotype 4. Searching for new predictors of response to therapy is mandatory to decrease the cost and the adverse effects of current therapy. The aim of this study was to clarify the usefulness of serum leptin, adiponectin, and insulin resistance (IR) as predictors of response to treatment in hepatitis C virus genotype 4 (HCVG4). One hundred patients with chronic HCVG4 who were candidates for treatment with pegylated interferon α and ribavirin were included in the study. Age, sex, and BMI were determined, and quantitative HCV PCR, assessment of serum leptin, adiponectin, IR, and pretreatment liver profile, and liver biopsy were performed. The male to female ratio was 68/32; the mean age of the patients was 40.9 ± 7.8 years and BMI was 28.3 ± 10 kg/m. Sustained virological response (SVR) was achieved by 56% of the patients. On performing logistic regression, BMI [odds ratio (OR) 6.5; P=0.004], serum leptin (OR 27.8; P ≤ 0.001), aspartate aminotransferase (OR 1.06; P ≤ 0.001), IR (OR 1.15; P ≤ 0.001), histological activity index (OR 1.77; P=0.006), and fibrosis (OR 2.93; P=0.001) were found to be independent negative predictors of SVR, whereas serum adiponectin (OR 0.74; P ≤ 0.001) was found to be an independent positive predictor of SVR. Pretreatment adiponectin (cutoff 13.75; sensitivity 92.86%; specificity 86.86%) shows area under the curve of 0.879 (95% confidence interval 0.802-0.956; P<0.001) and insignificant area under the curve for leptin or IR. BMI, pretreatment high leptin levels, and IR are negative predictors for SVR and pretreatment low adiponectin levels are an independent positive predictor for SVR in HCVG4.


The type III secretion system of Proteus mirabilis HI4320 does not contribute to virulence in the mouse model of ascending urinary tract infection.
The Gram-negative enteric bacterium Proteus mirabilis is a frequent cause of urinary tract infections (UTIs) in individuals with long-term indwelling catheters or with complicated urinary tracts. The recent release of the P. mirabilis strain HI4320 genome sequence has facilitated identification of potential virulence factors in this organism. Genes appearing to encode a type III secretion system (TTSS) were found in a low GC-content pathogenicity island in the P. mirabilis chromosome. This island contains 24 intact genes that appear to encode all components necessary to assemble a TTSS needle complex, plus at least two putative secreted effector proteins and their chaperones. The genetic organization of the TTSS genes is very similar to that of the TTSS of Shigella flexneri. RT-PCR analysis indicated that these genes are expressed at low levels in vitro. However, insertional mutation of two putative TTSS genes, encoding the requisite ATPase and a possible negative regulator, resulted in no change in either the growth rate of the mutant or the secreted protein profile compared to wild-type. Furthermore, there was no difference in quantitative cultures of urine, bladder and kidney between the ATPase mutant and the wild-type strain in the mouse model of ascending UTI in either independent challenge or co-challenge experiments. The role of the P. mirabilis TTSS, if any, is yet to be determined.


Herpes simplex virus 1 protein kinase is encoded by open reading frame US3 which is not essential for virus growth in cell culture.
Earlier reports have described a novel protein kinase in cells infected with herpes simplex or pseudorabies viruses. These novel enzymes were characterized by their acceptance of protamine as a substrate and by their differential chromatographic behavior in anion-exchange chromatography. We report that this activity was not present in extracts of uninfected cells or of cells infected with a mutant constructed so as to contain a deletion in the US3 open reading frame mapping in the small component of herpes simplex virus 1 DNA. The activity was present in extracts of cells infected with wild-type virus and with a recombinant in which the US3 open reading frame had been rescued. Our results are consistent with the observation reported earlier that the coding sequences predict an amino acid motif common to protein kinases and lead to the conclusion that the US3 open reading frame encodes a virus-specific protein kinase that is not required for virus growth in cells in culture.


Cell-wall lipopolysaccharide from Escherichia coli B.
The lipopolysaccharide of Escherichia coli BB and a number of R-phage selected (e.g. T3, T4) cell-wall-defective mutants were analyzed. From their lipopolysaccharides the respective core oligosaccharides were obtained. Following dephosphorylation, the oligosaccharides were methylated and analyzed by gas chromatography/mass spectrometry. This revealed the sugar sequence in the hexose-heptose region of the core. The linkage of heptose (Hep) to 2-keto-3-deoxyoctonate (KDO) was established as ... Hep 1,5 leads to KDO ... by methylation analysis. The substituted derivative of KDO was identified by gas chromatography and mass spectrometry. The KDO region contains three KDO units. Its structure was elaborated by (a) selective removal and identification of 7-phosphoryl ethanolamine-KDO (KDO-PN), (b) periodate oxidation and thiobarbituric acid reaction in conjunction with mild hydrolysis, (c) a modified methylation analysis. Phosphate substitution of E. coli BB core was studied by beta-elimination and using the information obtained with KDO-PN. The structures of the cell wall lipopolysaccharides from E. coli BB and cell-wall-defective mutants are given.


A NEW DOSE DETERMINATION METHOD FOR HP(3) AND DP LENS FOR BETA REFERENCE RADIATION QUALITIES.
For the purpose of obtaining the smaller uncertainties for Hp(3) and Dp lens in 90Sr/90Y beta reference fields, a new dose determination method based on the Monte-Carlo simulation was proposed. The conversion coefficients from the absorbed dose in air, at the reference point of the extrapolation ionisation chamber, Dair, det to Hp(3; α) and the conversion factors from Dair, det to Dp lens(α) were calculated with EGSnrc, respectively, for the irradiation angles from 0° to 60°. Compared with the dose determination method in International Organization for Standardization (ISO) 6980 standard, the uncertainty reductions of 7.7-52.8% for Hp(3; α) and 7.9-55.0% for Dp lens(α) were achieved, respectively. In addition, for the conversion coefficients from the reference absorbed dose DR to Hp(3; α), the calculations were performed for more irradiation conditions, which are not included in the current ISO 6980 standard. For the calculations of the conversion factors from DR to Dp lens(α), the eye and head phantoms with Chinese characteristics were utilised, which makes the conversion factors more suitable for use in China.


Gas-liquid chromatographic determination of technical chlordane residues in food crops: interpretation of analytical data.
An interlaboratory investigation of technical chlordane residues in food crops was carried out to determine the most practical and consistent method of reporting results. Using a technical chlordane reference standard, 8 gas chromatographic stationary phases were studied for their resolution capabilities. The best separations were obtained with SE-30 and its OV-1 equivalent. Using these columns and electron capture detection, potatoes and carrots from supervised field experiments were analyzed in duplicate and quantitated by using 4 methods of calculation. The data were statistically treated to determine the precision and bias for each method. Also, 1 sample was analyzed in duplicate on 2 different occasions by 6 laboratories to substantiate the initial conclusions. Based on the criterion of high precision it is suggested that a comparison of total area under the chromatogram of the sample with total area of standard technical chlordane be the method of quantitation. Only peaks which are common to both standard and sample have any significance in this type of calculation.


[The dominant medical thought against the epidemic: the interpretation of the cholera at its first appearance in Italy (1835-37)].
For the present study in the history of Italian medical thought original texts published during the first cholera epidemic in Italy (1835-37) by Tommasini, Giacomini, Pirondi, Bufalini, are analyzed. Tommasini, Giacomini and Pirondi, belonging to the Rasorian School, nonetheless develope different positions: Pirondi is a strict Rasorian, Giacomini defines a neuro-vascular theory including a symptomatic analysis, Tommasini syncretizes the Italian irritation theses, expanding Rasorian thought to include qualitative variations. Bufalini, by contrast, develops an epidemiological-materialistic theory.


1H NMR (500 MHz) of gene 32 protein--oligonucleotide complexes.
In concentrated solutions, gene 32 single-stranded DNA binding protein from bacteriophage T4 (gene 32P) forms oligomers with long rotational correlation times, rendering 1H NMR signals from most of the protons too broad to be detected. Small flexible N- and C-terminal domains are present, however, the protons of which give rise to sharp resonances. If the C-terminal A domain (48 residues) and the N-terminal B domain (21 residues) are removed, the resultant core protein of 232 residues (gene 32P) retains high affinity for ssDNA and remains a monomer in concentrated solution, and most of the proton resonances of the core protein can now be observed. Proton NMR spectra (500 MHz) of gene 32P and its complexes with ApA, d(pA)n (n = 2, 4, 6, 8, and 10), and d(pT)8 show that the resonances of a group of aromatic protons shift upfield upon oligonucleotide binding. Proton difference spectra show that the 1H resonances of at least one Phe, one Trp, and five Tyr residues are involved in the chemical shift changes observed with nucleotide binding. The number of aromatic protons involved and the magnitude of the shifts change with the length of the oligonucleotide until the shifts are only slightly different between the complexes with d(pA)8 and d(pA)10, suggesting that the binding groove accommodates approximately eight nucleotide bases. Many of the aromatic proton NMR shifts observed on oligonucleotide complex formation are similar to those observed for oligonucleotide complex formation with gene 5P of bacteriophage fd, although more aromatic residues are involved in the case of gene 32P.(ABSTRACT TRUNCATED AT 250 WORDS)


Recurring Necrotic Enteritis Outbreaks in Commercial Broiler Chicken Flocks Strongly Influence Toxin Gene Carriage and Species Richness in the Resident Clostridium perfringens Population.
Extensive use of antibiotic growth promoters (AGPs) in food animals has been questioned due to the globally increasing problem of antibiotic resistance. For the poultry industry, digestive health management following AGP withdrawal in Europe has been a challenge, especially the control of necrotic enteritis. Much research work has focused on gut health in commercial broiler chicken husbandry. Understanding the behavior of Clostridium perfringens in its ecological niche, the poultry barn, is key to a sustainable and cost-effective production in the absence of AGPs. Using polymerase chain reaction and pulsed-field gel electrophoresis, we evaluated how the C. perfringens population evolved in drug-free commercial broiler chicken farms, either healthy or affected with recurring clinical necrotic enteritis outbreaks, over a 14-month period. We show that a high genotypic richness was associated with an increased risk of clinical necrotic enteritis. Also, necrotic enteritis-affected farms had a significant reduction of C. perfringens genotypic richness over time, an increase in the proportion of C. perfringens strains harboring the cpb2 gene, the netB gene, or both. Thus, necrotic enteritis occurrence is correlated with the presence of an initial highly diverse C. perfringens population, increasing the opportunity for the selective sweep of particularly virulent genotypes. Disease outbreaks also appear to largely influence the evolution of this bacterial species in poultry farms over time.


Icotinib hydrochloride enhances chemo- and radiosensitivity by inhibiting EGFR signaling and attenuating RAD51 expression and function in Hela S3 cells.
Radiotherapy and cisplatin-based chemotherapy are currently considered as standard treatments employed for advanced cervical cancer (CC). However, patients with local recurrence or distant metastasis continue to have poor outcomes. EGFR overexpression correlated with chemo/radioresistance, and disease failure has been well proved in the previous studies. Hence, the aim of this study was to explore the therapeutic efficacy and underlying mechanism of the sensitization to radiation or cisplatin of icotinib hydrochloride (IH), a high-selective EGFR tyrosine kinase inhibitor (TKI), in the Hela S3 human CC cell line. Cell proliferation was measured with cell counting kit-8 (CCK-8) assay. Flow cytometry analysis was performed to examine cell cycle distribution and apoptosis. The phosphorylation of EGFR and its downstream signaling molecules were measured by Western blot analysis. γ-H2AX foci and RAD51 foci in the cellular nucleus were visualized using immunofluoresence staining. Expression levels of RAD51 in the whole cells and subceullar fractions were detected to demonstrate the impact of IH on DNA repair. IH can significantly inhibit cell proliferation, redistribute cell cycle, enhance apoptosis and impair DNA damage response of Hela S3 cells following radiation or cisplatin treatment through suppressing the activation of the EGFR signaling pathway and attenuating the expression and function of homologous recombination (HR) protein RAD51. This study suggests that IH is a potential sensitizer in radiotherapy and cisplatin-based chemotherapy for CC and RAD51 may serve as a prognosis biomarker for this combination treatment.


[Effect of glutamic acid content of the diet on the catabolic rate of isotope-labeled glutamic acid in rats. 3. Determination of 14CO2 and 15N excretion following intragastric infusion of 14C- and 15N-glutamic acid].
Male rats (body weight 100 g) received during a 8 days experimental feeding period diets with different contents in glutamic acid. The daily feed intake was restricted to the energy maintenance level of 460 kJ/kg0.75. The diet contained a mixture of L-amino acids corresponding to the pattern of egg protein except glutamic acid. Glutamic acid was added successively at 10 levels (0 to 14,8% of dry matter) and the resulting diets were fed to groups of 4 animals each. At the end of the experimental feeding period 14C- and 15N-labelled glutamic acid were applied by intragastric infusion. CO2- and 14CO2-excretion was measured during the following 4 hours and the urinary N- and 15N-excretion during the following 24 hours. The CO2-excretion decreased from 53 to 44 mmol CO2/100 g body weight with increasing levels of dietary glutamic acid. This change seems to result from the increasing proportion of amino acids as an energetic fuel. While the amount of oxidized glutamic acid increased with increasing supplements of glutamic acid the relative 14CO2-excretion decreased from 57 to 48% of the applied radioactivity. The urinary 15N-excretion during 24 hours was 31% of the given amount of 15N if no glutamic acid was included in the diet. This proportion increased successively up to 52% in the case of the highest supply of glutamic acid. Because the total N-excretion increased at the same extent as the 15N-excretion a complete mixing of the NH2-groups resulting from glutamic acid due to desamination with the ammonia pool was assumed. No correlation between glutamic acid content of the diet and specific radioactivity of CO2 or atom-% 15N excess of urinary N was observed.


Peristomal varices--life threatening or luminal?
Bleeding from the edge of an ileostomy site is a common problem. In those who have undergone a proctocolectomy with ileostomy formation in conjunction with a risk of chronic liver disease (even with normal liver function tests), this may be due to peristomal varices. If this is the case, significant, difficult-to-control and potentially life-threatening bleeding is likely in the future and may require transfusion. Improvements in radiological imaging techniques can give quick, sensitive and specific information to diagnose and guide management in this group. In those patients with major bleeding episodes, an initial conservative management policy should be adopted with the knowledge that, if bleeding persists, propanolol therapy, portosystemic shunt insertion or even liver transplantation may be indicated.


The Arched Rainbow Brow in Thyroid Eye Disease.
To morphologically describe and mathematically quantify a novel clinical feature of thyroid eye disease (TED). A retrospective study was conducted of TED patients and age-sex-matched normal controls. The arched Rainbow Brow appearance in TED patients was determined by unanimous agreement of 3 oculoplastic surgeons. Eyebrow curvature was assessed by plotting 15 points along the eyebrow in ImageJ. The fourth-degree polynomial ( y = ax4 + bx3 + cx2 + dx + e ) was fitted to each eyebrow. Two hundred seventy-one eyes were analyzed (200 TED and 71 age-sex-matched normal controls). A Rainbow Brow was identified in 42% of TED patients. A unilateral Rainbow Brow was seen in 15% of patients. The fourth-degree polynomial coefficients yielded significant differences between Rainbow Brow patients and age-sex-matched normal controls for the coefficients a, b, c , and d . Similar analysis of TED patients with and without a Rainbow Brow showed differences in coefficients a and b . Age >50 years ( p = 0.009) and the presence of brow fat expansion ( p < 0.001) were associated with the presence of a Rainbow Brow. Proptosis >24 mm showed a trend toward association with the presence of a Rainbow Brow ( p = 0.057). When considering the contribution of these features in a multivariable analysis, only brow fat expansion was a significant contributing factor ( p = 0.009). The Rainbow Brow is a distinct entity in TED and is likely consequent to brow fat pad expansion. Patients with a Rainbow Brow have different eyebrow curvature as compared to both normal age-sex-matched controls and TED patients without a Rainbow Brow.


Changes in arterial oxygen tension after gastric lavage for drug overdose.
1. Changes in arterial oxygen tension after gastric lavage were investigated in a prospective study of 55 patients admitted for drug overdose. 2. A significantly greater decrease was observed in smokers compared to non-smokers. 3. A correlation was found between the tricyclic antidepressant serum level and the observed oxygen tension decrease. 4. The usefulness, as well as the safety of the lavage procedure, in managing tricyclic antidepressants overdoses is controversial.


Renin-angiotensin system inhibition after surgical aortic valve replacement for aortic stenosis.
The optimal medical therapy after surgical aortic valve replacement (SAVR) for aortic stenosis remains unknown. Renin-angiotensin system (RAS) inhibitors could potentially improve cardiac remodelling and clinical outcomes after SAVR. All patients undergoing SAVR due to aortic stenosis in Sweden 2006-2020 and surviving 6 months after surgery were included. The primary outcome was major adverse cardiovascular events (MACEs; all-cause mortality, stroke or myocardial infarction). Secondary endpoints included the individual components of MACE and cardiovascular mortality. Time-updated adjusted Cox regression models were used to compare patients with and without RAS inhibitors. Subgroup analyses were performed, as well as a comparison between angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). A total of 11 894 patients (mean age, 69.5 years, 40.4% women) were included. Median follow-up time was 5.4 (2.7-8.5) years. At baseline, 53.6% of patients were dispensed RAS inhibitors, this proportion remained stable during follow-up. RAS inhibition was associated with a lower risk of MACE (adjusted hazard ratio (aHR) 0.87 (95% CI 0.81 to 0.93), p<0.001), mainly driven by a lower risk of all-cause death (aHR 0.79 (0.73 to 0.86), p<0.001). The lower MACE risk was consistent in all subgroups except for those with mechanical prostheses (aHR 1.07 (0.84 to 1.37), p for interaction=0.040). Both treatment with ACE inhibitors (aHR 0.89 (95% CI 0.82 to 0.97)) and ARBs (0.87 (0.81 to 0.93)) were associated with lower risk of MACE. The results of this study suggest that medical therapy with an RAS inhibitor after SAVR is associated with a 13% lower risk of MACE and a 21% lower risk of all-cause death.


Rapid and flexible synthesis of 1-deoxy-D-xylulose-5-phosphate, the substrate for 1-deoxy-D-xylulose-5-phosphate reductoisomerase.
1-Deoxy-D-xylulose-5-phosphate (DXP) is a key intermediate in the non-mevalonate pathway to terpenoids in bacteria, and it is the substrate for the enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXP-R). In order to study the mechanism of DXP-R, we required a flexible synthesis of the substrate which would allow the incorporation of isotopic labels, and the variation of the two stereocentres. Thus 1,4-dihydroxypent-2-yne was selectively reduced to give the E-olefin, and selective phosphorylation of the primary alcohol followed by oxidation of the secondary alcohol gave a substrate suitable for dihydroxylation. Dihydroxylation using stoichiometric OsO4 in the presence of chiral ligands gave protected DXP in high ee. Final hydrogenolysis gave DXP in quantitative yield and high purity. DXP-R was produced by rapid cloning of the dxr gene from Escherichia coli through controlled expression and ion exchange chromatography. The synthetic DXP was fully active in enzyme assays catalysed by recombinant DXP-R.


[Skin to skin contact and breast-feeding after birth: not always without risk!].
Skin-to-skin contact after birth is propagated to facilitate breast-feeding and mother-child bonding. We describe two term infants with sudden unexpected postnatal collapse (SUPC) during skin-to-skin contact. The infants were found with abnormal colour, hypotonia and apnoea, in a prone position on the chest of their mothers, both of whom were primipara with a high BMI. After stimulation, both infants recovered completely. No specific potential cause, other than the position, could be found. These cases illustrate that skin-to-skin contact after birth is not without risk. In available literature, risk factors for SUPC include primiparity and infant orientation such as prone and lateral positions. These positions are also risk factors for sudden infant death syndrome (SIDS). To improve safety, a primipara should be supervised during skin-to-skin contact and not be left alone in the first hours after delivery; the infant should be guaranteed a free airway, especially when the mother has a high BMI.


[A case of adrenal black adenoma associated with Cushing's syndrome].
A 36-year-old female was admitted to Asahi General Hospital because of hypertension. Laboratory findings showed elevated levels of urine 17 (11)-hydroxycorticosteroid and blood cortisol. Computerized tomography and ultrasound sonography demonstrated a round tumor at the suprarenal region. The black tumor, 5 X 3 X 2 cm, was removed by left adrenalectomy. Microscopic findings revealed adrenal adenoma consisting of compact cells containing numerous pigmented granules. Postoperative course was uneventful. Hormonal condition was recovered 11 months after operation.


Understanding Associations of Personal Values With Support for Tobacco and Alcohol Control Policies.
This cross-sectional analysis of the 2020 Health Information National Trends Survey (N=3,604) examines the associations of personal values with tobacco and alcohol control policy support, which may inform policy-related communication efforts. Respondents selected which of 7 value options they considered most important in their daily life and rated their support for 8 proposed tobacco and alcohol control policies (1=strongly oppose, 5=strongly support). Weighted proportions for each value were described across sociodemographic characteristics, smoking status, and alcohol use. Weighted bivariate and multivariable regressions tested the associations of values with mean policy support (alpha=0.89). Analyses occurred from 2021 to 2022. The most frequently selected values were assuring my family is safe and secure (30.2%), being happy (21.1%), and making my own decisions (13.6%). Selected values varied across sociodemographic and behavioral characteristics. For example, people with lower education and incomes were overrepresented among those selecting making my own decisions and keeping myself in good health. After adjusting for sociodemographics, smoking, and alcohol use, people selecting family safety (β=0.20, 95% CI=0.06, 0.33) or religious connection (β=0.34, 95% CI=0.14, 0.54) as most important reported higher policy support than those selecting making their own decisions, the value associated with the lowest mean policy support. Mean policy support did not significantly differ across any other value comparisons. Personal values are associated with support for alcohol and tobacco control policies, with making my own decisions associated with the lowest policy support. Future research and communication efforts may consider aligning tobacco and alcohol control policies with the idea of supporting autonomy.


Genetic evolutionary taboo search for optimal marker placement in infrared patient setup.
In infrared patient setup adequate selection of the external fiducial configuration is required for compensating inner target displacements (target registration error, TRE). Genetic algorithms (GA) and taboo search (TS) were applied in a newly designed approach to optimal marker placement: the genetic evolutionary taboo search (GETS) algorithm. In the GETS paradigm, multiple solutions are simultaneously tested in a stochastic evolutionary scheme, where taboo-based decision making and adaptive memory guide the optimization process. The GETS algorithm was tested on a group of ten prostate patients, to be compared to standard optimization and to randomly selected configurations. The changes in the optimal marker configuration, when TRE is minimized for OARs, were specifically examined. Optimal GETS configurations ensured a 26.5% mean decrease in the TRE value, versus 19.4% for conventional quasi-Newton optimization. Common features in GETS marker configurations were highlighted in the dataset of ten patients, even when multiple runs of the stochastic algorithm were performed. Including OARs in TRE minimization did not considerably affect the spatial distribution of GETS marker configurations. In conclusion, the GETS algorithm proved to be highly effective in solving the optimal marker placement problem. Further work is needed to embed site-specific deformation models in the optimization process.


Mutagenicity and oxidative damage induced by an organic extract of the particulate emissions from a simulation of the deepwater horizon surface oil burns.
Emissions from oil fires associated with the "Deepwater Horizon" explosion and oil discharge that began on April 20, 2010 in the Gulf of Mexico were analyzed chemically to only a limited extent at the time but were shown to induce oxidative damage in vitro and in mice. To extend this work, we burned oil floating on sea water and performed extensive chemical analyses of the emissions (Gullett et al., Marine Pollut Bull, in press, ). Here, we examine the ability of a dichloromethane extract of the particulate material with an aerodynamic size ≤ 2.5 µm (PM2.5 ) from those emissions to induce oxidative damage in human lung cells in vitro and mutagenicity in 6 strains of Salmonella. The extract had a percentage of extractable organic material (EOM) of 7.0% and increased expression of the heme oxygenase (HMOX1) gene in BEAS-2B cells after exposure for 4 hr at 20 µg of EOM/ml. However, the extract did not alter mitochondrial respiration rate as measured by extracellular flux analysis. The extract was most mutagenic in TA100 +S9, indicative of a role for polycyclic aromatic hydrocarbons (PAHs), reflective of the high concentrations of PAHs in the emissions (1 g/kg of oil consumed). The extract had a mutagenicity emission factor of 1.8 ± 0.1 × 105 revertants/megajoulethermal in TA98 +S9, which was greater than that of diesel exhaust and within an order of magnitude of open burning of wood and plastic. Thus, organics from PM2.5 of burning oil can induce oxidative responses in human airway epithelial cells and are highly mutagenic. Environ. Mol. Mutagen. 58:162-171, 2017. © 2017 Wiley Periodicals, Inc.


Introduction to the Special Issue: Bullying and Its Linkage to Other Forms of Violence.
As studies have documented, children and adolescents who are identified as bullies, bully victims, or both are at an elevated risk of being involved in other forms of violence, for example, dating violence and sexual violence. Moreover, those who are exposed to violence (e.g., exposure to community violence) have increased odds of being involved in bullying. This special issue brings together scholars from a variety of disciplines (e.g., psychology, criminology/criminal justice, and social work) to investigate how involvement in bullying and other forms of violence are interrelated.


A single dose of trichloroethylene given during development does not substantially alter markers of neuroinflammation in brains of adult mice.
Trichloroethylene (TCE) is a widespread environmental contaminant associated with developmental immunotoxicity and neurotoxicity. Previous studies have shown that MRL+/+ mice exposed to TCE from gestation through early-life demonstrate robust increases in inflammatory markers in peripheral CD4+ T-cells, as well as glutathione depletion and increased oxidative stress in cerebellum-associated with alterations in behavior. Since increased oxidative stress is associated with neuroinflammation, we hypothesized that neuroinflammatory markers could be altered relative to unexposed mice. MRL+/+ mice were given 0.5 mg/ml of TCE in vehicle or vehicle (water with 1% Alkamuls EL-620) from conception through early adulthood via drinking water to dams and then directly to post-weaning offspring. Animals were euthanized at 49 days of age and levels of pro- and anti-inflammatory cytokines, density of T-cell staining, and micro-glial morphology were evaluated in brains to begin to ascertain a neuroinflammatory profile. Levels of IL-6 were decreased in female animals and while not statistically significant, and levels of IL-10 were higher in brains of exposed male and female animals. Supportive of this observation, although not statistically significant, the number of ameboid microglia was higher in exposed relative to unexposed animals. This overall profile suggests the emergence of an anti-inflammatory/neuroprotective phenotype in exposed animals, possibly as a compensatory response to neuroinflammation that is known to be induced by developmental exposure to TCE.


Studies on the microheterogeneity of chorionic gonadotrophin secreted by the human cytotrophoblast in culture.
In the present study, we investigated the biological characteristics of different molecular forms of chorionic gonadotrophin (HCG) secreted by the human cytotrophoblast during its morphological and functional differentiation in culture. Highly purified cytotrophoblasts were prepared from term placentae and cultured for 24 to 96 h in the absence or presence of 8-bromo-3',5'-cAMP. Media were collected at 24 h intervals and the secreted isoforms of HCG were then separated by polyacrylamide gel isoelectric focusing (pH range 8.0-3.0) and quantified by radioimmunoassay. The secretion of HCG was significantly increased by 8-bromo-cAMP (from 23.5 +/- 6.3 ng/ml at 24 h to 1619 +/- 835.8 ng/ml at 96 h; controls, 9.3 +/- 0.1 ng/ml at 24 h and 26.6 +/- 3.5 ng/ml at 96 h, mean +/- SD). Analysis of media concentrates from cAMP-stimulated cultures by isoelectric focusing revealed the presence of several distinct peaks of HCG within the pH range of 7.3-4.8; major peaks consistently exhibited isoelectric points (pI) of 7.3-7.0 (peak 1), 5.6-5.4 (peak 2) and 5.1-4.8 (peak 3). The relative HCG content of the most acidic peak (as % of total on gel) progressively increased with time of exposure to the cAMP analogue (from 19.8 +/- 1.6% at 24 h to 34.4 +/- 4.3% at 96 h, mean +/- SEM, P less than 0.01). HCG recovered from peak 1 exhibited the highest receptor-binding capacity and in-vitro biological potency.(ABSTRACT TRUNCATED AT 250 WORDS)


Orthonormal polynomials in wavefront analysis: error analysis.
Zernike circle polynomials are in widespread use for wavefront analysis because of their orthogonality over a circular pupil and their representation of balanced classical aberrations. However, they are not appropriate for noncircular pupils, such as annular, hexagonal, elliptical, rectangular, and square pupils, due to their lack of orthogonality over such pupils. We emphasize the use of orthonormal polynomials for such pupils, but we show how to obtain the Zernike coefficients correctly. We illustrate that the wavefront fitting with a set of orthonormal polynomials is identical to the fitting with a corresponding set of Zernike polynomials. This is a consequence of the fact that each orthonormal polynomial is a linear combination of the Zernike polynomials. However, since the Zernike polynomials do not represent balanced aberrations for a noncircular pupil, the Zernike coefficients lack the physical significance that the orthonormal coefficients provide. We also analyze the error that arises if Zernike polynomials are used for noncircular pupils by treating them as circular pupils and illustrate it with numerical examples.


Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for treating uncomplicated malaria.
Chloroquine (CQ), amodiaquine (AQ), and sulfadoxine-pyrimethamine (SP) are inexpensive drugs, but treatment failure is a problem. Combination therapy may reduce treatment failure. CQ or AQ plus SP are affordable options of combination treatment, but there is debate about their effectiveness. To assess the combination of CQ or AQ plus SP compared with SP alone for first-line treatment of uncomplicated falciparum malaria. We searched the Cochrane Infectious Diseases Group Specialized Register (April 2005), CENTRAL (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to April 2005), EMBASE (1974 to April 2005), LILACS (1982 to April 2005), Science Citation Index (1981 to April 2005), African Index Medicus (1993 to 1998), and reference lists. We also contacted researchers at relevant organizations and a pharmaceutical company. Randomized controlled trials in adults or children with uncomplicated Plasmodium falciparum malaria were eligible for inclusion. The main outcomes of interest were total and clinical failure at day 28 follow up and serious adverse events. Two people independently applied the inclusion criteria. One author extracted data and another checked them independently. We used relative risk (RR) and 95% confidence intervals (CI). Twelve trials (2107 participants) met the inclusion criteria. A meta-analysis of five AQ trials (461 participants) showed a statistically significant reduction in total failure at day 28 with the combination therapy (RR 0.64, 95% CI 0.46 to 0.91), and meta-analysis of three trials (384 participants) showed a significant reduction in clinical failure at day 28 (RR 0.23, 95% CI 0.11 to 0.49). The statistical significance in the total failure analysis was sensitive to losses to follow up. Data from two CQ trials showed no advantage for total failure with combination therapy at day 28. There was no evidence from the included trials of serious adverse events. The evidence base is not strong enough to support firm conclusions. The available evidence suggests that AQ plus SP can achieve less treatment failure than SP, but this might depend on existing levels of parasite resistance to the individual drugs.


Pharmacists' acceptability of a men's mental health promotion program using the Theoretical Framework of Acceptability.
Community pharmacists are accessible, knowledgeable, and capable of providing mental health promotion and care in communities. This may not be a role that is recognized by the public, and men in particular. Differences between men and women exist in help seeking practices. Headstrong-Taking Things Head-On is a men's mental health promotion program for community pharmacies that was designed to increase the capacity of community pharmacists in caring for men with lived experience of mental illness and addictions. The program's core components included signage in pharmacies, education and training for pharmacists, and a website for use with patients. We applied the Theoretical Framework of Acceptability as the coding scheme to pharmacists' qualitative interviews to examine the acceptability of Headstrong for pharmacists. Nine pharmacists consented to participate and all chose telephone interviews. With the exceptions of ethicality, affective attitude, and opportunity costs, all components from the TFA were coded in each of the nine transcripts. The most frequently coded constructs were perceived effectiveness of the intervention, burden, and self-efficacy. These were coded at least 20 times. The remaining categories ethicality, intervention coherence, affective attitude, and opportunity costs were coded between 11 to 17 times. Pharmacists' perceptions of the effectiveness of the program was mixed. The overall burden was perceived to be low, but opportunity costs appear to have limited the participation of some pharmacists in the program. Use of the Theoretical Framework of Acceptability as a coding scheme for qualitative data from community pharmacists in a men's mental health program was helpful for identifying issues with the program that may require redesign (e.g., signage). Program design should consider how services are advertised in the pharmacy setting, how personal values of pharmacists influence intervention coherence, and whether minimizing the burden of an intervention negates issues related to opportunity costs.


Misclassification problems in diagnosis-related groups. Cystic fibrosis as an example.
Under the Medicare prospective payment system, which is based on diagnosis-related groups, patients with certain diseases may be inappropriately classified. To study this problem using cystic fibrosis as an example, we examined discharge-abstract data from 14 cystic fibrosis centers in a comparison of resource-use requirements by patients with cystic fibrosis and other patients in the same diagnosis-related group. There were 1763 patients with cystic fibrosis and 25,628 other patients in the 87 diagnosis-related groups that contained at least one patient with cystic fibrosis. For the eight diagnosis-related groups in which patients with cystic fibrosis were classified most often, the average length of stay of patients with cystic fibrosis was 14.9 days, as compared with an average of 8.3 days for the other patients (P less than 0.001). For three hospitals, we were able to convert charges to costs. The average cost of treating patients with cystic fibrosis was $7,262, as compared with $2,908 for all other patients in the same diagnosis-related group (P less than 0.001). The ratio between the costs of treating patients with cystic fibrosis and other patients (2.5) was greater than the ratio between the lengths of stay for the two groups (1.8), reflecting the more intense use of resources by the patients with cystic fibrosis. A possible solution to the problem of misclassification is to define one or more new diagnosis-related groups for cases of cystic fibrosis or determine a new location within the diagnosis-related group system so that patients with cystic fibrosis can be classified with patients who use similar amounts of resources.


The incidence of cleft lip, cleft palate, hydrocephalus and spina bifida at Queen Elizabeth Central Hospital, Blantyre, Malawi.
To determine the incidence of cleft lip, cleft palate, spina bifida and hydrocephalus; and to compare these with those of Asian and European subjects. A retrospective study. The Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. Delivery and nursery records compiled between January 1998 and December 1999 were studied. To measure the incidence of cleft lip, cleft palate, spina bifida and hydrocephalus. Of the total 25562 births, 39 (0.2%) had defects; eight boys and 31 girls. Clefts (all types) comprised the largest group, 43.6%, with an incidence of 0.67/1 000; spina bifida, 30.8% with an incidence of 0.47/1000; hydrocephalus, 15.4%, and an incidence of 0.23/1000; and spina bifida with hydrocephalus, 10.3%, with 0.16/1000 incidence. The respective mean (SD) birth weights for clefts (all types), spina bifida, hydrocephalus and spina bifida with hydrocephalus were 2806.47 (569.07) g, 2650.00 (360.55) g 2610.00 (720.97) g and 3362.50 (696.87) g respectively. Our findings show a higher incidence of spina bifida in Malawians than in Caucasians and Orientals, but the incidence was lower than Omani subjects. The incidence of clefts and hydrocephalus in black Malawians, however, was lower than previously reported in other population groups, and hydrocephalus probably showed the lowest incidence among blacks in the continent. Furthermore, congenital malformations affected more girls than boys 4:1, but the infants had normal birth weight.


Caudal Septal Support Versus Strut Graft in Achieving the Desired Lateral Profile in Rhinoplasty.
Nasal tip support is critical to achieve a lasting result in rhinoplasty. In this article, the authors compared the effects of strut grafts (SG) and caudal septum-based nasal tip supporting techniques (CSB-T) in terms of reaching the desired tip projection.Included in this study were 40 patients (24 women and 16 men) who underwent primary open rhinoplasty via transcolumellar incision between January and June 2012. To achieve a good nasal projection, SG and CSB-T were used for 15 and 25 of these patients, respectively.Certain anatomic landmarks were identified on preoperative, simulative, and 1-year follow-up photos. With these landmarks, certain angular and proportional values were calculated.In the SG, the authors found no statistically significant difference in between simulative goals and postoperative results regarding bending angle. Postoperative nasolabial angle (NLA), tip angle, subnasal-tip/subnasal-radix (SnT/SnR) ratios were significantly lower than the simulation values; radix angle and supratip index values were significantly higher.In the CSB-T group, the authors found no statistically significant difference in between preoperative values and postoperative results regarding NLA, tip angle, bending angle, (SnT/SnR) ratio values. Postoperative supratip index and radix angle measurements were found to be significantly higher than the simulation values.With these findings, the authors concluded that CSB-T support is superior than the SG for supporting the nasal tip in noses that also need shortening in caudal length. In noses that do not need caudal shortening, nasal tip projection can again be supported by the caudal septum by just forming a bridge between lower lateral cartilage and quadrangular septum using a wider SG that mimics septal extension grafts.


Preparation of Pt/polypyrrole-para toluene sulfonate hydrogen peroxide sensitive electrode for the utilizing as a biosensor.
A film electrode with electropolymerization of pyrrole (Py) and para-toluene sulfonate (pTS) as a anionic dopant is prepared and its sensitivity to hydrogen peroxide is investigated. The polypyrrole is deposited on a 0.5 cm(2) Pt plate an electrochemically prepared pTS ion-doped polypyrrole film by scanning the electrode potential between - 0.8 and + 0.8 V at a scan rate of 20 mV/s. The electrode's sensitivity to hydrogen peroxide is investigated at room temperature using 0.1 M phosphate buffer at pH 7.5. The working potential is found as a 0.3 V. The concentrations of pyrrole and pTS are 50mM M and 25 mM. Polypyrrole was coated on the electrode surface within 10 cycles. İmmobilization of glucose oxidase carried out on Pt/polypyrrole-para toluene sulfonate (Pt/PPy-pTS) film by cross-linking with glutaraldehyde. The morphology of electrodes was characterized by SEM and AFM. Moreover, contact angle measurements were made with 1 μL water of polymer film and enzyme electrode. It has shown that enzyme electrode is very sensitive against to glucose.


Graphitized Carbon Fibers as Multifunctional 3D Current Collectors for High Areal Capacity Li Anodes.
The Li metal anode has long been considered as one of the most ideal anodes due to its high energy density. However, safety concerns, low efficiency, and huge volume change are severe hurdles to the practical application of Li metal anodes, especially in the case of high areal capacity. Here it is shown that that graphitized carbon fibers (GCF) electrode can serve as a multifunctional 3D current collector to enhance the Li storage capacity. The GCF electrode can store a huge amount of Li via intercalation and electrodeposition reactions. The as-obtained anode can deliver an areal capacity as high as 8 mA h cm-2 and exhibits no obvious dendritic formation. In addition, the enlarged surface area and porous framework of the GCF electrode result in lower local current density and mitigate high volume change during cycling. Thus, the Li composite anode displays low voltage hysteresis, high plating/stripping efficiency, and long lifespan. The multifunctional 3D current collector promisingly provides a new strategy for promoting the cycling lifespan of high areal capacity Li anodes.


Effects of inflammation on the ultrastructural localization of spinal cord dorsal horn group I metabotropic glutamate receptors.
Inflammatory pain is thought to induce functional plasticity of spinal dorsal horn neurons and may produce changes in glutamate receptor expression. Plasticity of group I metabotropic glutamate receptors (mGluR1 and mGluR5) is important in various neuronal systems, and these receptors are also known to modulate nociceptive neurotransmission in the spinal dorsal horn. The present study aimed at determining whether persistent inflammatory pain produces alterations in intracellular and plasma membrane-associated mGluR1alpha and mGluR5 in spinal cord dorsal horn. Persistent inflammation was induced in male Long Evans rats by a unilateral intraplantar injection of 100 muL of complete Freund's adjuvant (CFA). Three days after the CFA injection thermal withdrawal latencies were obtained prior to processing of transverse spinal cord sections for preembedding immunogold labeling after incubation in primary antibody for mGluR1alpha or mGluR5. Using electron microscopy, we quantified immunogold-labeled mGluR1alpha and mGluR5 profiles, located in lamina V and I-II, respectively, of both CFA-treated rats and untreated control rats. Compared to untreated rats, CFA-treated rats had a significant increase in the number of plasma membrane-associated mGluR5 immunogold-labeled particles in lamina I-II neurons of the spinal cord. Although no changes to mGluR1alpha expression were found in CFA-treated rats, plasma membrane-associated mGluR1alpha was significantly closer to the synapse. Therefore, in CFA-treated rats there was a specific increase in the ratio of plasma membrane-associated versus intracellular immunogold-labeled particles for mGluR5, and lateral movement of mGluR1alpha toward the synapse, indicating that peripheral inflammation-induced trafficking of group I mGluRs in spinal dorsal horn neurons may be an important factor in the development of plastic changes associated with inflammation-induced chronic pain.


Placenta growth factor stimulates the growth of Philadelphia chromosome positive acute lymphoblastic leukemia cells by both autocrine and paracrine pathways.
Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases. On the other hand, expression level of VEGF was not different between Ph(+) and Ph(-) cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph(+)), and Nalm6 (Ph(-)). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph(+) ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph(+) ALL.


An update on malignant tumor-related stiff person syndrome spectrum disorders: clinical mechanism, treatment, and outcomes.
Stiff person syndrome (SPS) is a rare central nervous system disorder associated with malignancies. In this review, we retrieved information from PubMed, up until August 2023, using various search terms and their combinations, including SPS, stiff person syndrome spectrum disorders (SPSSDs), paraneoplastic, cancer, and malignant tumor. Data from peer-reviewed journals printed in English were organized to explain the possible relationships between different carcinomas and SPSSD subtypes, as well as related autoantigens. From literature searching, it was revealed that breast cancer was the most prevalent carcinoma linked to SPSSDs, followed by lung cancer and lymphoma. Furthermore, classic SPS was the most common SPSSD subtype, followed by stiff limb syndrome and progressive encephalomyelitis with rigidity and myoclonus. GAD65 was the most common autoantigen in patients with cancer and SPSSDs, followed by amphiphysin and GlyR. Patients with cancer subtypes might have multiple SPSSD subtypes, and conversely, patients with SPSSD subtypes might have multiple carcinoma subtypes. The first aim of this review was to highlight the complex nature of the relationships among cancers, autoantigens, and SPSSDs as new information in this field continues to be generated globally. The adoption of an open-minded approach to updating information on new cancer subtypes, autoantigens, and SPSSDs is recommended to renew our database. The second aim of this review was to discuss SPS animal models, which will help us to understand the mechanisms underlying the pathogenesis of SPS. In future, elucidating the relationship among cancers, autoantigens, and SPSSDs is critical for the early prediction of cancer and discovery of new therapeutic modalities.


Long term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid arthritis: a three year study of radiographic progression, renal function, and arterial hypertension.
To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment. The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure. Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%. Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.


Alphavirus budding is dependent on the interaction between the nucleocapsid and hydrophobic amino acids on the cytoplasmic domain of the E2 envelope glycoprotein.
The interaction between the nucleocapsid core and the glycoprotein spikes is a critical component in the budding process of alphaviruses. A molecular model was previously proposed which suggested that this interaction was mediated by the binding of the cytoplasmic domain of glycoprotein E2 into a hydrophobic pocket found on the surface of the nucleocapsid protein [S. Lee, K. E. Owen, H.-K. Choi, H. Lee, G. Lu, G. Wengler, D. T. Brown, M. G. Rossmann, and R. J. Kuhn (1996) Structure 4, 531-541; U. Skoging, M. Vihinen, L. Nilsson, and P. Liljeström (1996) Structure 4, 519-529]. Two hydrophobic amino acids in the cytoplasmic domain of E2 were predicted to be important in the contact between the proteins. One of the residues, Y400 (Sindbis virus numbering), had previously been shown by mutational studies to be important in the budding of Semliki Forest virus [H. Zhao, B. Lindqvist, H. Garoff, C. H. von Bonsdorf, and P. Liljeström (1994) EMBO J. 13, 4204-4211]. The role of the second residue, L402, had not been examined. By creating a panel of amino acid substitutions at this residue, followed by phenotypic analysis of rescued mutant viruses, we now show that L402 is critical for the production of Sindbis virus. Substitutions at this amino acid inhibit budding, and the data suggest the L402 plays an important role in the interaction, between the glycoprotein and the nucleocapsid core. These data support the model and suggest that the proposed molecular interactions are important for the budding of alphaviruses from the cell.


The metal-insulator transition in dimerized Hückel chains.
The metal-insulator transition is investigated in the case of linear chains described by a one-electron Hückel Hamiltonian. In these systems, the transition is a consequence of a dimerization of the chain bond length, which induces a similar dimerization of the hopping integral. Three indicators of the chain character are considered: The highest occupied molecular orbital-lowest unoccupied molecular orbital gap, the polarizability, and the localization tensor. In the case of even open chains, the behavior of the large chains depends in a crucial way on the alternating structure of the hopping integrals. If the ending atoms of the chain are weakly bonded to their neighbors, the energy spectrum of the Hamiltonian shows two quasidegenerated eigenvalues, and all the indicators would predict a (spurious) metallic behavior. It is shown that if the corresponding eigenvectors are removed from the Hamiltonian, the ordinary insulating behavior of alternating chains is recovered.


Perflubron reduces lung inflammation in respiratory syncytial virus infection by inhibiting chemokine expression and nuclear factor-kappa B activation.
Airway mucosa inflammation plays a critical role in the pathogenesis of lower respiratory tract infections caused by respiratory syncytial virus (RSV), the major etiologic agent of bronchiolitis in infancy. Type and intensity of cellular infiltration are dictated by inflammatory chemokines, which are rapidly and abundantly induced in lung tissue by RSV. This process is, to a large extent, transcriptionally regulated by RSV-mediated activation of the nuclear factor-kappa B. The administration of a perfluorocarbon (PFC) liquid, such as perflubron, during partial liquid ventilation improves lung function and also reduces inflammation. In this study we demonstrate that treatment of BALB/c mice with perflubron intranasally 6 hours after RSV infection significantly inhibited lung cellular inflammation as well as the expression of the chemokines RANTES, MIP-1 alpha, MIP-1 beta, and MIP-2, compared with phosphate-buffered saline-treated control mice. However, perflubron treatment did not affect RSV replication. Strikingly, treatment with perflubron abrogated nuclear factor-kappa B activation in lung of RSV-infected mice. These results demonstrate a novel mechanism by which PFC may exert antiinflammatory activity and suggest that partial liquid ventilation with PFC may be considered in future clinical trials for infants with severe RSV infections requiring mechanical ventilation.


Perspectives of Decision-Making for Corneal Donation: A Qualitative Research Among Cancer Patients.
This study investigates the subjective experiences of terminal cancer patients who expedite their corneal donation decisions. The percentage of cancer patients who donate their corneas postmortem is low in Taiwan. The reasons are complex and needs further exploration. A qualitative design using content analysis was used. A semistructured interview approach was adopted to interview cancer patients recruited from a cancer ward in northern Taiwan. The study findings show that the factors contributing to an aversive preference of cancer patients included the necessity to consider the emotions of family members, traditional perceptions, religious reasons, disease, and no reason at all. Most cancer patients maintain a negative stance toward corneal donation. The results obtained in the present study can be used as a reference for future in-service education and promotional efforts regarding corneal donation. Discussing cornea donation needs to become a routine end-of-life care discussion.


Efficacy and tolerability of various bowel preparations in diabetic patients: a randomized controlled trial.
Background and study aims Diabetes mellitus (DM) is an independent risk factor for poor bowel preparation prior to colonoscopy. Bisacodyl is a stimulant laxative that may mitigate colonic dysmotility associated with diabetes. We hypothesized that adding bisacodyl to split-dose bowel preparation (SDBP) would improve the quality of bowel preparation among patients with diabetes. Patients and methods Adult outpatients aged 18 to 80 years undergoing colonoscopy were recruited. One hundred and eighty-six patients with diabetes were randomly assigned to 1 of 3 treatment arms: 1) conventional 4 L of polyethylene glycol electrolyte lavage solution (PEG-ELS; conventional bowel preparation [CBP]); 2) split-dose of 4 L PEG-ELS (split-dose bowel preparation [SDBP]); or 3) split-dose of 4 L PEG-ELS preceded by 10 mg of oral bisacodyl 10 (SDBP-B). The primary outcome measure was bowel cleansing as indicated by Boston Bowel Preparation Scale (BBPS) score. Endoscopists were blinded to the preparation used. Secondary outcome measures were safety and patient tolerability. Results Of the 212 patients randomized, only 186 received assigned bowel preparation. There were no differences among the three study groups with regard to age, indication, duration of DM, insulin use, narcotic use, or presence of end-organ diabetic complications. There was a trend toward better bowel preparation quality among those receiving SDBP and SDBP-B compared to those receiving CBP, but the trend was not statistically significant ≥ 6 BBPS; 67 % vs. 83 % vs. 75 %, P = 0.1). In terms of safety and tolerability, there were no differences among the three groups. Conclusion Adding bisacodyl to SDBP does not improve the quality of bowel preparation in patients with DM. Further efforts are needed to optimize colonoscopy bowel preparation in this population.


Low-density lipoproteins of the postprandial state induce cellular cholesteryl ester accumulation in macrophages.
Chemically or biologically modified low-density lipoproteins (LDL) but not native unmodified LDL lead to foam cell formation in monocyte-derived macrophages. Since the magnitude of postprandial lipemia after a challenge test seems to be associated with coronary artery disease, we tested the hypothesis that in the course of postprandial lipemia, LDL appear in plasma that are capable of leading to foam cell formation even without prior modification. We incubated the macrophage-like cell line P388 with unmodified postabsorptive and postprandial LDL from 17 healthy donors and measured the cellular cholesterol and triglyceride contents and amounts of exogenous [14C]oleic acid incorporated into the cholesteryl ester fraction. Postprandial LDL induced a significantly more pronounced cholesteryl ester accumulation than did postabsorptive LDL (477 +/- 286% versus 212 +/- 173%, respectively; P < .003). The increase in cellular total cholesterol was significantly higher as a result of cell incubation with postprandial LDL (107 +/- 61%) than with postabsorptive LDL (54 +/- 40%, P < .003), whereas no increase in triglyceride content was observed (P < .589) in either case. After CuSO4 incubation and incubation with P388 cells, postprandial LDL revealed more thiobarbituric acid-reacting substances than did postabsorptive LDL (55 +/- 10 versus 28 +/- 9 nmol/mg protein, P < .018; 28 +/- 4 versus 20 +/- 3 nmol/mg protein). The increase in cellular cholesteryl ester synthesis caused by postprandial LDL was reduced by more than 50% when lipoproteins and cells were incubated in the presence of ascorbic acid (P < .007).(ABSTRACT TRUNCATED AT 250 WORDS)


Physical activity domains and risk of gastric adenocarcinoma in the MCC-Spain case-control study.
Evidence for a protective role of physical activity against development of stomach cancer is yet inconclusive. We studied the association of domain-specific physical activity and the risk of gastric adenocarcinoma (GAC), by site and histology, in the MCC-Spain case-control study. 428 histologically confirmed GAC cases (67% men) including the gastro-esophageal region and 3225 controls were included. Cases were recruited in hospitals from 10 different Spanish regions, whereas population controls were randomly selected within the respective hospitals' catchment areas. A physical activity (PA) questionnaire was used to gather information on household and recreational activities, allowing estimation of PA volume (in metabolic equivalents (MET)-min/week). Participants also reported the intensity of working PA and daily sitting time. Questionnaire data on diet, lifestyles and clinical variables including Helicobacter pylori serology were available. Adjusted odds ratios (OR) of GAC were estimated for domains of physical activity, stratifying by sex, site (cardia vs. non-cardia), and Lauren classification (intestinal vs. diffuse). Household physical activity (HPA) showed a strong inverse association with GAC, observed for both cardia and non-cardia tumours. Risk of overall gastric cancer was 50% lower risk among participants in the highest HPA category (OR = 0.50, 95%CI: 0.38, 0.66). Recreational physical activity (RPA) was also associated with lower overall GAC risk (OR = 0.68, 95% CI: 0.52, 0.88), particularly at moderate levels of intensity such as walking (OR = 0.61, 95% CI: 0.46, 0.79). The protective effect of RPA was strongest for non-cardia tumours. Sedentary time was not related to GAC risk (p-trend = 0.392), but the potential protective effect of RPA was restricted to non-sedentary participants. Both household and recreational physical activities were independently related to lower GAC risk in the MCC-Spain study.