Cytotoxic, proapoptotic and antioxidative potential of flavonoids isolated from propolis against colon (HCT-116) and breast (MDA-MB-231) cancer cell lines.
Isolated and structurally confirmed, eleven flavonoids from propolis were examined for their cytotoxicity toward human colon cancer and human breast cancer cells. Their effect on induction of apoptosis and their antioxidative activities were also evaluated. Six flavonoids induced cytotoxic effects in both cell lines. Luteolin had a marked effect on both cell lines, especially on HCT-116 cells (IC50 72h, 66.86μM). Also, luteolin was observed to have the highest apoptotic potential after 72h treatment of examined cell lines (27.13% and 37.09%, respectively). Myricetin exhibited selective inhibition of cell growth (IC50 114.75μM) and induced apoptosis in MDA-MB-231 cells only. Luteolin and galangin exhibited prooxidative properties 24h after the treatment in HCT-116 cells, while myricetin induced prooxidative effects in MDA-MB-231 cells. On the other hand, selected flavonoids exhibited antioxidative properties 72h after the treatment, decreasing superoxide anion radical and nitrite levels in both cell lines. Cytotoxic and proapoptotic effects on colon and breast cancer cell lines and the influence on their redox status make tested flavonoids good candidates for developing new anticancer drugs.


Swim with the tide: Tactics to maximize prey detection by a specialist predator, the greater sea snake (Hydrophis major).
The fitness of a predator depends upon its ability to locate and capture prey; and thus, increasing dietary specialization should favor the evolution of species-specific foraging tactics tuned to taxon-specific habitats and cues. Within marine environments, prey detectability (e.g., via visual or chemical cues) is affected by environmental conditions (e.g., water clarity and tidal flow), such that specialist predators would be expected to synchronize their foraging activity with cyclic variation in such conditions. In the present study, we combined behavioral-ecology experiments on captive sea snakes and their prey (catfish) with acoustic tracking of free-ranging sea snakes, to explore the use of waterborne chemical cues in this predator-prey interaction. In coral-reef ecosystems of New Caledonia, the greater sea snake (Hydrophis major) feeds only upon striped eel catfish (Plotosus lineatus). Captive snakes became more active after exposure to waterborne chemical cues from catfish, whereas catfish did not avoid chemical cues from snakes. Movement patterns of tracked snakes showed that individuals were most active on a rapidly falling tide, which is the time when chemical cues from hidden catfish are likely to be most readily available to a foraging predator. By synchronizing foraging effort with the tidal cycle, greater sea snakes may be able to exploit the availability of chemical cues during a rapidly falling tide to maximize efficiency in locating and capturing prey.


The effect of case management on childhood pneumonia mortality in developing countries.
With the aim of populating the Lives Saved Tool (LiST) with parameters of effectiveness of existing interventions, we conducted a systematic review of the literature assessing the effect of pneumonia case management on mortality from childhood pneumonia. This review covered the following interventions: community case management with antibiotic treatment, and hospital treatment with antibiotics, oxygen, zinc and vitamin A. Pneumonia mortality outcomes were sought where available but data were also recorded on secondary outcomes. We summarized results from randomized controlled trials (RCTs), cluster RCTs, quasi-experimental studies and observational studies across outcome measures using standard meta-analysis methods and used a set of standardized rules developed for the purpose of populating the LiST with required parameters, which dealt with the issues of comparability of the studies in a uniform way across a spectrum of childhood conditions. We estimate that community case management of pneumonia could result in a 70% reduction in mortality from pneumonia in 0-5-year-old children. In contrast treatment of pneumonia episodes with zinc and vitamin A is ineffective in reducing pneumonia mortality. There is insufficient evidence to make a quantitative estimate of the effect of hospital case management on pneumonia mortality based on the published data. The available evidence reinforces the effectiveness of community and hospital case management with World Health Organization-recommended antibiotics and the lack of effect of zinc and vitamin A supportive treatment for children with pneumonia. Evidence from one trial demonstrates the effectiveness of oxygen therapy but further research is required to give higher quality evidence so that an effect estimate can be incorporated into the LiST model. We identified no trials that separately evaluated the effectiveness of other supportive care interventions. The summary estimates of effect on pneumonia mortality will inform the LiST model.


Delayed-onset bleb-associated endophthalmitis: presentation and outcome by culture result.
To determine how culture results are associated with clinical presentations and outcomes in delayed-onset bleb-associated endophthalmitis (BAE). Retrospective consecutive case series of BAE at Bascom Palmer Eye Institute between January 1, 1996 and December 31, 2009. All patients had prior glaucoma filtering surgery. BAE was defined as intraocular infection with vitreous involvement receiving treatment with intravitreal antibiotics. Visual acuity (VA) outcomes and other clinical data were grouped by culture result and compared using the 2-sided Student's t-test. Mean logMAR change at 3 months after treatment (3-month logMARΔ). Eighty-six eyes of 85 patients were identified. Two eyes were primarily eviscerated. Fifty-three (63%) eyes were culture-positive with the following organisms: Streptococcus, 21 (25%); coagulase-negative Staphylococcus, 9 (11%); Enterococcus, 6 (7%); Gram-negative, 15 (18%); Moraxella, 8 (10%); Pseudomonas, 3 (4%); and Serratia, 3 (4%). Presenting logMAR VA: culture-positive worse than culture-negative cases (2.45 vs 2.19, P = 0.05). Presenting intraocular pressure (IOP): culture-positive higher than culture-negative cases (24 mmHg vs 14 mmHg, P = 0.002). Poor presenting view of the fundus: Streptococcus worse than coagulase-negative Staphylococcus cases (90% vs 44%, P = 0.006), Pseudomonas and Serratia worse than Moraxella cases (100% vs 50%, P = 0.04). Three month logMARΔ: culture-positive worse than culture-negative cases (1.03 vs 0.43, P = 0.02), Streptococcus worse than coagulase-negative Staphylococcus cases (1.44 vs 0.31, P = 0.004), Pseudomonas and Serratia worse than coagulase-negative Staphylococcus cases (2.41 vs 0.31, P = 0.001), Pseudomonas and Serratia worse than Moraxella cases (2.41 vs 0.04, P = 0.001). A culture result of Streptococcus or Serratia was present in 6 of 7 eyes that received an additional treatment of enucleation or evisceration (P = 0.01). Culture-positive cases were associated with worse presenting VA, higher presenting IOP, and worse VA outcomes than culture-negative cases. Streptococcus, Pseudomonas, and Serratia cases were associated with poor presenting view of the fundus and worse VA outcomes than coagulase-negative Staphylococcus and Moraxella cases.


The effect of progressive resistance training on oxidative stress and antioxidant enzyme activity in erythrocytes in untrained men.
This study was undertaken to investigate the effects of progressive resistance-training (PRT) on plasma oxidative stress and antioxidant enzyme activity in erythrocytes. Twenty male volunteers were randomly assigned to 2 groups: PRT and control. Blood samples were collected before and after 8 wk of PRT and analyzed for enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes, plasma total antioxidant capacity (TAC), and malondialdehyde concentration (MDA, an index of lipid per oxida- tion in plasma). Resistance training commenced with 8 exercises on nonconsecutive days for 8 wk at 50% of estimated 1-repetition maximum (E1RM) and reached 80% E1RM by Week 8. The results showed that PRT significantly increased erythrocyte SOD activity (1,323 ± 212.52 vs. 1,449.9 ± 173.8 U/g Hb, p = .014). Plasma concentration of MDA also decreased (5.39 ± 1.7 vs. 3.67.4 ± 0.7 nmol/ml, p = .030), although TAC (1.42 ± 0.21 vs. 1.61 ± 0.19 mmol/L, p = .1530) and GPx (39.87 ± 11.5 vs. 48.18 ± 14.48 U/g Hb, p = .883) activity did not undergo any considerable changes. Based on these data, the authors conclude that an 8-wk program of PRT strengthens the defensive system of erythrocytes against free-radical damage and therefore can be applied as a useful approach to alleviate oxidative stress.


Age and sex differences in the incorporation of EPA and DHA into plasma fractions, cells and adipose tissue in humans.
The aim of the present study was to determine whether age and sex influence both the status and incorporation of EPA and DHA into blood plasma, cells and tissues. The study was a double-blind, randomised, controlled intervention trial, providing EPA plus DHA equivalent to 0, 1, 2 or 4 portions of oily fish per week for 12 months. The participants were stratified by age and sex. A linear regression model was used to analyse baseline outcomes, with covariates for age or sex groups and by adjusting for BMI. The change in outcomes from baseline to 12 months was analysed with additional adjustment for treatment and average compliance. Fatty acid profiles in plasma phosphatidylcholine, cholesteryl esters, NEFA and TAG, mononuclear cells (MNC), erythrocyte membranes, platelets, buccal cells (BU) and adipose tissue (AT) were determined. At baseline, EPA concentrations in plasma NEFA and DHA concentrations in MNC, BU and AT were higher in females than in males (all P< 0·05). The concentrations of EPA in AT (P= 0·003) and those of DHA in plasma TAG (P< 0·01) and AT (P< 0·001) were higher with increasing age. Following 12-month supplementation with EPA plus DHA, adjusted mean difference for change in EPA concentrations in plasma TAG was significantly higher in females than in males (P< 0·05) and was greater with increasing age (P= 0·02). Adjusted mean difference for change in DHA concentrations in AT was significantly smaller with increasing age (P= 0·02). Although small differences in incorporation with age and sex were identified, these were not of sufficient magnitude to warrant a move away from population-level diet recommendations for n-3 PUFA.


The importance of cyclic structure for Labaditin on its antimicrobial activity against Staphylococcus aureus.
Antimicrobial resistance has reached alarming levels in many countries, thus leading to a search for new classes of antibiotics, such as antimicrobial peptides whose activity is exerted by interacting specifically with the microorganism membrane. In this study, we investigate the molecular-level mechanism of action for Labaditin (Lo), a 10-amino acid residue cyclic peptide from Jatropha multifida with known bactericidal activity against Streptococcus mutans. We show that Lo is also effective against Staphylococcus aureus (S. aureus) but this does not apply to its linear analogue (L1). Using polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), we observed with that the secondary structure of Lo was preserved upon interacting with Langmuir monolayers from a phospholipid mixture mimicking S. aureus membrane, in contrast to L1. This structure preservation for the rigid, cyclic Lo is key for the self-assembly of peptide nanotubes that induce pore formation in large unilamellar vesicles (LUVs), according to permeability assays and dynamic light scattering measurements. In summary, the comparison between Labaditin (Lo) and its linear analogue L1 allowed us to infer that the bactericidal activity of Lo is more related to its interaction with the membrane. It does not require specific metabolic targets, which makes cyclic peptides promising for antibiotics without bacteria resistance.


Striatal resting-state connectivity after long-term diacetylmorphine treatment in opioid-dependent patients.
New treatment approaches for opioid-dependent patients include injectable opioid agonist treatment with diacetylmorphine. While evidence has shown beneficial clinical effects of diacetylmorphine, it is still not clear how long-term diacetylmorphine treatment affects the brain and whether functional brain changes are accompanied by clinical improvements. Therefore, this prospective case-control study focuses on long-term effects of diacetylmorphine on resting-state functional connectivity. We included opioid-dependent patients (N = 22, age range 33-58, 16 males) treated with diacetylmorphine and healthy controls (N = 9, age range 27-55, 5 males) that underwent two MRI assessments approximately nine years apart. For the patients, the assessments took part shortly after the diacetylmorphine intake to be able to explore changes in resting-state functional connectivity in brain regions related to the stage of binge and intoxication (caudate, putamen, nucleus accumbens). A cluster in the right superior frontal gyrus was detected, showing over nine years an increase in functional connectivity originating from the left caudate and the left accumbens in patients but not in healthy controls. These connectivity changes in patients were related to the duration of the diacetylmorphine treatment at the follow-up, indicating smaller increases in functional connectivity with longer treatment duration (r = 0.63, P < 0.01). These results suggest that long-term diacetylmorphine treatment in opioid-dependent patients increases fronto-striatal connections, an effect that is linked to the duration of the treatment duration. Future research needs to further address the wide-ranging effects of diacetylmorphine on brain functioning and deepen the understanding of their clinical relevance.


Self-administered acupressure reduces the symptoms that limit daily activities in bronchiectasis patients: pilot study findings.
To examine and compare the effects of acupressure on the perceived health-related quality of life of the participants with bronchiectasis. In an attempt to offer comfort, pain control and symptom management, nursing is becoming increasingly involved in offering complementary-alternative medicine as part of its caring-healing focus in comprehensive patient care. Acupressure is one such modality that is being increasingly used by both medical and nursing professionals. While acupressure has been reported to have beneficial effects in patients with respiratory disease, the benefits to bronchiectasis patients have remained uncertain. A randomized, partially blinded study consisting of three groups. Thirty-five out-patients of both genders, aged 59.46 SD 11.52 years, who were suffering from bronchiectasis, were randomly split into one of three groups: standard care with supplemental acupressure for eight weeks (11 participants); standard care with supplemental sham acupressure for eight weeks (11 participants); and standard care alone (13 participants). Outcomes were determined by changes in daily sputum amounts, sputum self-assessment, six-minute walking distance, breathing difficulty (measured on the dyspnea visual analogue scale) and health-related quality of life (measured by the Saint George Respiratory Questionnaire). The sputum self-assessment score improved over time for the sham acupressure participants (P = 0.03), when compared with the controls. For acupressure participants, the Saint George respiratory questionnaire activity component scores also improved over time, compared with controls (P = 0.01) after adjustment for covariates (treatment, time, age, sex and baseline values). Other variables did not differ between the standard care alone group and the other two groups. Eight weeks of self-administered acupressure could be useful in reducing the effects of bronchiectasis on a patient's daily activities. Acupressure may be regarded as a viable nursing intervention.


Neurochemical abnormalities in premanifest and early spinocerebellar ataxias.
To investigate whether early neurochemical abnormalities are detectable by high-field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. A cohort of 100 subjects (N = 18-21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA] <10 for all genotypes, and 22 matched controls) was scanned at 7 Tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multivariate approach (distance-weighted discrimination) was used to combine regional profiles into an "MRS score." MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1), and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early-manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3, and SCA6. Neurochemical abnormalities are detectable in individuals before manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality-of-life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. Ann Neurol 2018;83:816-829.


Prevalence of cardiovascular risk factors in a middle-income country and estimated cost of a treatment strategy.
We assessed the prevalence of risk factors for cardiovascular disease (CVD) in a middle-income country in rapid epidemiological transition and estimated direct costs for treating all individuals at increased cardiovascular risk, i.e. following the so-called "high risk strategy". Survey of risk factors using an age- and sex-stratified random sample of the population of Seychelles aged 25-64 in 2004. Assessment of CVD risk and treatment modalities were in line with international guidelines. Costs are expressed as USD per capita per year. 1255 persons took part in the survey (participation rate of 80.2%). Prevalence of main risk factors was: 39.6% for high blood pressure (> or =140/90 mmHg or treatment) of which 59% were under treatment; 24.2% for high cholesterol (> or =6.2 mmol/l); 20.8% for low HDL-cholesterol (<1.0 mmol/l); 9.3% for diabetes (fasting glucose > or =7.0 mmol/l); 17.5% for smoking; 25.1% for obesity (body mass index > or =30 kg/m2) and 22.1% for the metabolic syndrome. Overall, 43% had HBP, high cholesterol or diabetes and substantially increased CVD risk. The cost for medications needed to treat all high-risk individuals amounted to USD 45.6, i.e. 11.2 dollars for high blood pressure, 3.8 dollars for diabetes, and 30.6 dollars for dyslipidemia (using generic drugs except for hypercholesterolemia). Cost for minimal follow-up medical care and laboratory tests amounted to 22.6 dollars. High prevalence of major risk factors was found in a rapidly developing country and costs for treatment needed to reduce risk factors in all high-risk individuals exceeded resources generally available in low or middle income countries. Our findings emphasize the need for affordable cost-effective treatment strategies and the critical importance of population strategies aimed at reducing risk factors in the entire population.


The Arginine Pairs and C-Termini of the Sso7c4 from Sulfolobus solfataricus Participate in Binding and Bending DNA.
The Sso7c4 from Sulfolobus solfataricus forms a dimer, which is believed to function as a chromosomal protein involved in genomic DNA compaction and gene regulation. Here, we present the crystal structure of wild-type Sso7c4 at a high resolution of 1.63 Å, showing that the two basic C-termini are disordered. Based on the fluorescence polarization (FP) binding assay, two arginine pairs, R11/R22' and R11'/R22, on the top surface participate in binding DNA. As shown in electron microscopy (EM) images, wild-type Sso7c4 compacts DNA through bridging and bending interactions, whereas the binding of C-terminally truncated proteins rigidifies and opens DNA molecules, and no compaction of the DNA occurs. Moreover, the FP, EM and fluorescence resonance energy transfer (FRET) data indicated that the two basic and flexible C-terminal arms of the Sso7c4 dimer play a crucial role in binding and bending DNA. Sso7c4 has been classified as a repressor-like protein because of its similarity to Escherichia coli Ecrep 6.8 and Ecrep 7.3 as well as Agrobacterium tumefaciens ACCR in amino acid sequence. Based on these data, we proposed a model of the Sso7c4-DNA complex using a curved DNA molecule in the catabolite activator protein-DNA complex. The DNA end-to-end distance measured with FRET upon wild-type Sso7c4 binding is almost equal to the distance measured in the model, which supports the fidelity of the proposed model. The FRET data also confirm the EM observation showing that the binding of wild-type Sso7c4 reduces the DNA length while the C-terminal truncation does not. A functional role for Sso7c4 in the organization of chromosomal DNA and/or the regulation of gene expression through bridging and bending interactions is suggested.


Paternally derived H19 is differentially expressed in malignant and nonmalignant trophoblast.
The paternal allele of the H19 gene has been shown to be transcriptionally inactive in the developing human embryo. Using reverse transcription PCR and RNase protection assays, we demonstrate that expression of H19 is predominantly, but not exclusively, from the maternal allele in the human placenta. In situ hybridization analysis shows strong expression of the H19 gene in eight complete hydatidiform moles, hyperplastic tissues consisting of trophoblasts which contain only paternally derived genetic material, indicating that H19 is not functionally imprinted in this tissue. H19, a putative growth suppressor, is oppositely imprinted to the neighboring insulin-like growth factor II (IGF2) gene and an up-regulation of IGF2 expression has been linked previously to a down-regulation of H19 expression in the progression to Wilms' tumor. Two cases of complete hydatidiform mole which progressed to choriocarcinoma show high levels of expression of both H19 and IGF2. The choriocarcinomas which developed from these complete hydatidiform moles showed similar expression of IGF2 but a decreased number of H19-positive cells, which may reflect selection for cells expressing IGF2 and against those expressing H19 in this tissue.


A study of chromium induced allergic contact dermatitis with 54 volunteers: implications for environmental risk assessment.
Over the past 60 years, dose-response patch test studies by various methods have been conducted in an attempt to identify the minimum elicitation threshold (MET) concentration of hexavalent chromium (Cr(VI)) that produces an allergic response in Cr(VI) sensitive subjects. These data are not adequate, however, to provide an accurate estimate of the MET because of the variability in the patch testing techniques and the variability in diagnostic criteria used. Furthermore, the data were not reported in terms of mass of allergen per surface area of skin (mg Cr/cm2-skin), which is necessary for conducting occupational or environmental health risk assessments. Thus the purpose of this study was to determine the MET (mg allergen/cm2) for Cr(VI) and trivalent chromium (Cr(III)) by patch testing techniques. A patch test method that delivers a controlled amount of allergen per surface area of skin was used. A group of 54 Cr(VI) sensitised volunteers were patch tested with serial dilutions of Cr(VI) and Cr(III) to determine the cumulative response rate at several concentrations. The results indicate that the 10% MET for Cr(VI) based on the cumulative response was 0.089 micrograms Cr(VI)/cm2-skin. Only one of the 54 volunteers may have responded to 33 micrograms Cr(III)/cm2-skin, otherwise Cr(III) was unable to produce allergic contact dermatitis in these highly sensitive volunteers. Two supplemental studies were also conducted to assess whether the surface area of the patch and the concentration of Cr(VI) in the patch (related to patch thickness) were likely to influence the results. The data from these studies were used to assess the risk of developing allergic contact dermatitis due to contact with Cr(VI) and Cr(III) in soil. The findings indicated that soil concentrations at least as high as 450 ppm Cr(VI) and 165,000 ppm Cr(III) should not pose an allergic contact dermatitis hazard for at least 99.99% of the people in the community who might be exposed.


Non-response to a life course socioeconomic position indicator in surveillance: comparison of telephone and face-to-face modes.
Measurement of socioeconomic position (SEP) over the life course in population health surveillance systems is important for examining differences in health and illness between different population groups and for monitoring the impact of policies and interventions aimed at reducing health inequities and intergenerational disadvantage over time. While face-to-face surveys are considered the gold standard of interviewing techniques, computer-assisted telephone interviewing is often preferred for cost and convenience. This study compared recall of parents' highest level of education in telephone and face-to-face surveys. Questions about father's and mother's highest education level were included in two representative population health surveys of South Australians aged 18 years and over in Spring 2004. A random sample selected from the electronic white pages (EWP) responded to a computer-assisted telephone interview (n = 2999), and a multistage clustered area sample responded to a face-to-face interview (n = 2893). A subsample of respondents in the face-to-face sample who owned a telephone that was listed in the EWP (n = 2206) was also compared to the telephone interview sample. The proportion of respondents who provided information about their father's and mother's highest education level was significantly higher in the face-to-face interview (86.3% and 87.8%, respectively) than in the telephone interview (80.4% and 79.9%, respectively). Recall was also significantly higher in the subsample of respondents in the face-to-face interview who had a telephone that was listed in the EWP. Those with missing data for parents' education were more likely to be socioeconomically disadvantaged regardless of the survey mode. While face-to-face interviewing obtained higher item response rates for questions about parents' education, survey mode did not appear to influence the factors associated with having missing data on father's or mother's highest education level.


Herpesvirus saimiri DNA in tumor cells--deleted sequences and sequence rearrangements.
Herpesvirus saimiri DNA in continuous lymphoblastoid cell lines obtained from viral induced tumors in marmosets has been analyzed by gel electrophoresis of restricted DNA. Southern transfer to nitrocellulose filters, and hybridization to 32P-labeled viral DNA or DNA fragments. The viral DNA fragments EcoRI-G, -H, -D, and -I, KpnI-A, and BamHI-D and -E were not detected in Southern transfers of DNA from the nonproducing 1670 cell line. For each restriction endonuclease, a new fragment appeared, consistent with a 13.0-megadalton deletion of viral DNA sequences. This deletion encompassed 35 to 48 +/- 0.6 megadaltons from the left end of the unique DNA region. A sequence arrangement map is presented for the major population of H. saimiri DNA sequences in the 1670 cell line. Although H. saimiri DNA in the nonproducing 70N2 cell line can be distinguished from viral DNA in the 1670 cell line by several criteria, the same sequences were found to be deleted in the major population of viral DNA molecules. Unlike 1670 and 70N2 cells, restricted DNA from the virus-producing cell lines 77/5 and 1926 contained all of the DNA fragments present in the parental virion DNA. DNA from 1670, 70N2, and 77/5 cells contained additional viral DNA fragments that did not comigrate with any virion DNA fragments. Most of these unexplained fragments were confined to or highly enriched in partially purified circular or linear DNA fractions. DNA from tumor cells taken directly from a tumor-bearing animal contained viral DNA indistinguishable from the parental virion DNA by the assay conditions used. These results indicate that viral DNA sequence rearrangements can occur upon cultivation of tumor cells in vitro and that excision of DNA sequences from the viral genome may play a role in establishing the nonproducing state of some tumor cell lines.


Ablation of Hepatic Production of the Acid-Labile Subunit in Bovine-GH Transgenic Mice: Effects on Organ and Skeletal Growth.
Growth hormone (GH) and insulinlike growth factor 1 (IGF-1) are anabolic hormones that facilitate somatic and skeletal growth and regulate metabolism via endocrine and autocrine/paracrine mechanisms. We hypothesized that excess tissue production of GH would protect skeletal growth and integrity in states of reduction in serum IGF-1 levels. To test our hypothesis, we used bovine GH (bGH) transgenic mice as a model of GH hypersecretion and ablated the liver-derived acid-labile subunit, which stabilizes IGF-1 complexes with IGF-binding protein-3 and -5 in circulation. We used a genetic approach to create bGH/als gene knockout (ALSKO) mice and small interfering RNA (siRNA) gene-silencing approach to reduce als or igf-1 gene expression. We found that in both models, decreased IGF-1 levels in serum were associated with decreased body and skeletal size of the bGH mice. Excess GH produced more robust bones but compromised mechanical properties in male mice. Excess GH production in tissues did not protect from trabecular bone loss in response to reductions in serum IGF-1 (in bGH/ALSKO or bGH mice treated with siRNAs). Reduced serum IGF-1 levels in the bGH mice did not alleviate the hyperinsulinemia and did not resolve liver or kidney pathologies that resulted from GH hypersecretion. We concluded that reduced serum IGF-1 levels decrease somatic and skeletal growth even in states of excess GH.


Multimodal Intraoperative Neurophysiological Monitoring in Neurosurgical Oncology.
Neurosurgical oncology that is performed for lesions located in critical areas like the sensorimotor area has additional risk because it may cause serious neurological deficiencies. Some intraoperative neuromonitoring (IONM) modalities can effectively help the surgeons to maximize resections of this kind of lesions with or without an acceptable neurological deficiency. Our aim was to share our IONM experiences with patients who underwent intracranial lesion surgery in critical areas between September 2013 and January 2015. This retrospective study was performed on 31 patients who underwent brain surgery for the resection of lesions located in eloquent areas. Demographic characteristics, lesion localizations, lesion pathologies, surgery, IONM recordings, and pre- and postoperative neurological examinations were reviewed. Five of the 31 patients had lesions in the cerebellopontine angle and 26 patients had lesions close to critical locations. Transcranial motor evoked potentials and somatosensory evoked potentials were performed in 27, electroencephalography in 31, auditory evoked potentials in 8, visual evoked potentials in 2, triggered electromyography in 8, and central sulcus determination and brain mapping in 17 patients. Motor evoked potential changes occurred in 2 patients intraoperatively. One had right hemiparesia lasting 3 days while the other had monoparesia which improved within 2 months. Permanent neurological deficit was not observed. Intraoperative neuromonitoring helps the surgeons to maximize resection of lesions in or close to eloquent areas of the brain. Using only one modality is not sufficient, whereas a combination of modalities is required to obtain a better outcome.


Prevention for better health among older persons: are primary healthcare clinics in Jamaica meeting the challenge?
The study sought to determine the level and type of preventive care offered to older persons (persons 50 years and over) in the primary healthcare system and to identify the barriers to prevention-related activities. The study was carried out in three phases utilizing quantitative and qualitative methods. Quantitative data were collected over a six-week period from 738 older patients accessing health centre curative services and from 86 health centre staff Focus group discussions were used to obtain information from non-users of health centres. The findings showed that while clinical practice was good, there were relatively inadequate levels of prevention care practices and there were barriers to prevention-related activities for older persons in the primary healthcare system. Only 5.1%, 24.5% and 9.6% of older persons reported being advised about smoking, physical activity and alcohol consumption respectively by health centre staff A higher proportion (56.5%) reported being advised about diet. Older persons did not appear to understand the role of prevention in maintaining health status. Barriers identified include inadequate numbers of staff overcrowded clinics, rapid staffturnover; high costs of investigations and medications, and poor staff perception of older persons 'abilities to care for themselves. Health promotion and secondary prevention for older persons in the primary healthcare clinics need strengthening. Training and facilitation of health workers in age-related age-specific prevention activities are recommended. The provision of appropriate resources for prevention activities among older persons in primary healthcare settings should be addressed.


Determination of metals in composite diet samples by inductively coupled plasma-mass spectrometry.
A study was conducted to evaluate the applicability of inductively coupled plasma-mass spectrometry (ICP-MS) techniques for determination of metals in composite diets. Aluminum, cadmium, chromium, copper, lead, manganese, nickel, vanadium, and zinc were determined by this method. Atmospheric pressure microwave digestion was used to solubilize analytes in homogenized composite diet samples, and this procedure was followed by ICP-MS analysis. Recovery of certified elements from standard reference materials ranged from 92 to 119% with relative standard deviations (RSDs) of 0.4-1.9%. Recovery of elements from fortified composite diet samples ranged from 75 to 129% with RSDs of 0-11.3%. Limits of detection ranged from 1 to 1700 ng/g; high values were due to significant amounts of certain elements naturally present in composite diets. Results of this study demonstrate that low-resolution quadrupole-based ICP-MS provides precise and accurate measurements of the elements tested in composite diet samples.


Derivation of transfer parameters for use within the ERICA Tool and the default concentration ratios for terrestrial biota.
An ability to predict radionuclide activity concentrations in biota is a requirement of any method assessing the exposure of biota to ionising radiation. Within the ERICA Tool fresh weight whole-body activity concentrations in organisms are estimated using concentration ratios (the ratio of the activity concentration in the organism to the activity concentration in an environmental media). This paper describes the methodology used to derive the default terrestrial ecosystem concentration ratio database available within the ERICA Tool and provides details of the provenance of each value for terrestrial reference organisms. As the ERICA Tool considers 13 terrestrial reference organisms and the radioisotopes of 31 elements, a total of 403 concentration ratios were required for terrestrial reference organisms. Of these, 129 could be derived from literature review. The approaches taken for selecting the remaining values are described. These included, for example, assuming values for similar reference organisms and/or biogeochemically similar elements, and various simple modelling approaches.


The accountability for reasonableness approach to guide priority setting in health systems within limited resources--findings from action research at district level in Kenya, Tanzania, and Zambia.
Priority-setting decisions are based on an important, but not sufficient set of values and thus lead to disagreement on priorities. Accountability for Reasonableness (AFR) is an ethics-based approach to a legitimate and fair priority-setting process that builds upon four conditions: relevance, publicity, appeals, and enforcement, which facilitate agreement on priority-setting decisions and gain support for their implementation. This paper focuses on the assessment of AFR within the project REsponse to ACcountable priority setting for Trust in health systems (REACT). This intervention study applied an action research methodology to assess implementation of AFR in one district in Kenya, Tanzania, and Zambia, respectively. The assessments focused on selected disease, program, and managerial areas. An implementing action research team of core health team members and supporting researchers was formed to implement, and continually assess and improve the application of the four conditions. Researchers evaluated the intervention using qualitative and quantitative data collection and analysis methods. The values underlying the AFR approach were in all three districts well-aligned with general values expressed by both service providers and community representatives. There was some variation in the interpretations and actual use of the AFR in the decision-making processes in the three districts, and its effect ranged from an increase in awareness of the importance of fairness to a broadened engagement of health team members and other stakeholders in priority setting and other decision-making processes. District stakeholders were able to take greater charge of closing the gap between nationally set planning and the local realities and demands of the served communities within the limited resources at hand. This study thus indicates that the operationalization of the four broadly defined and linked conditions is both possible and seems to be responding to an actual demand. This provides arguments for the continued application and further assessment of the potential of AFR in supporting priority-setting and other decision-making processes in health systems to achieve better agreed and more sustainable health improvements linked to a mutual democratic learning with potential wider implications.


Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans.
We propose guidelines to evaluate the cumulative evidence of gene-environment (G × E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G × E interactions, discovery and modelling methods for G × E interactions, and issues in systematic reviews of evidence for G × E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.


The cognitive and neural basis of option generation and subsequent choice.
Decision-making research has thoroughly investigated how people choose from a set of externally provided options. However, in ill-structured real-world environments, possible options for action are not defined by the situation but have to be generated by the agent. Here, we apply behavioral analysis (Study 1) and functional magnetic resonance imaging (Study 2) to investigate option generation and subsequent choice. For this purpose, we employ a new experimental task that requires participants to generate options for simple real-world scenarios and to subsequently decide among the generated options. Correlational analysis with a cognitive test battery suggests that retrieval of options from long-term memory is a relevant process during option generation. The results of the fMRI study demonstrate that option generation in simple real-world scenarios recruits the anterior prefrontal cortex. Furthermore, we show that choice behavior and its neural correlates differ between self-generated and externally provided options. Specifically, choice between self-generated options is associated with stronger recruitment of the dorsal anterior cingulate cortex. This impact of option generation on subsequent choice underlines the need for an expanded model of decision making to accommodate choice between self-generated options.


A rare indication for stenting: persistent coronary artery spasm.
A 34-year-old man presenting with angina both at rest and on exertion was investigated. He developed severe ST segment elevation and a brief period of ventricular tachycardia during an exercise tolerance test. On coronary angiography, 60% fixed luminal narrowing was observed in the proximal left anterior descending coronary artery and a severe spasm developed at this site, leading to temporary total occlusion of the vessel. Successful coronary angioplasty (PTCA) was performed on this lesion, with a residual 15% narrowing. However, the patient had a recurrence of angina 3 weeks later, despite being administered high doses of nitrate and calcium antagonist. During control angiography, the lesion severity was unchanged, but spasm developed again following contrast injection. At this time, a Palmaz-Schatz stent was implanted. Calcium antagonist, nitrate, Ticlopidine and low molecular weight heparin therapy was started. There was no recurrence of symptoms during a 3-month follow-up. The exercise tolerance test, and myocardial perfusion scintigraphy findings were normal and the stent was patent without restenosis at the end of the 3-month follow-up. Intracoronary stent implantation for persistent coronary spasm refractory to conventional medical therapy can be considered a feasible and attractive treatment modality for the control of symptoms.


Giant photovoltaic effect of ferroelectric domain walls in perovskite single crystals.
The photovoltaic (PV) effect in polar materials offers great potential for light-energy conversion that generates a voltage beyond the bandgap limit of present semiconductor-based solar cells. Ferroelectrics have received renewed attention because of the ability to deliver a high voltage in the presence of ferroelastic domain walls (DWs). In recent years, there has been considerable debate over the impact of the DWs on the PV effects, owing to lack of information on the bulk PV tensor of host ferroelectrics. In this article, we provide the first direct evidence of an unusually large PV response induced by ferroelastic DWs-termed 'DW'-PV effect. The precise estimation of the bulk PV tensor in single crystals of barium titanate enables us to quantify the giant PV effect driven by 90° DWs. We show that the DW-PV effect arises from an effective electric field consisting of a potential step and a local PV component in the 90° DW region. This work offers a starting point for further investigation into the DW-PV effect of alternative systems and opens a reliable route for enhancing the PV properties in ferroelectrics based on the engineering of domain structures in either bulk or thin-film form.


Seatone in rheumatoid arthritis: a six-month placebo-controlled study.
Thirty-five patients with rheumatoid arthritis were randomly allocated to either Seatone (green-lipped mussel extract) or placebo in order to assess the former's claimed effectiveness in rheumatoid disease. After six months there was no significant improvement in any laboratory or clinical measurement of disease activity in the Seatone group. The patients on active drug fared no better than those on placebo. These results suggest that Seatone is not effective in rheumatoid arthritis.


Hypotension and cardiac stimulation due to the parathyroid hormone-related protein, humoral hypercalcemia of malignancy factor.
Patients with humoral hypercalcemia of malignancy display markedly increased serum calcium levels, reduced blood pressure, and tachycardia. The causative agent, humoral hypercalcemia of malignancy factor [also called PTH-related protein (PTHrp)] has been shown to interact with PTH receptors in bone and kidney. We compared human PTHrp-(1-34) with rat PTH-(1-34) for the effects of each peptide on cardiovascular function in unrestrained conscious rats. Both PTHrp and PTH decreased blood pressure in a dose-dependent manner over the concentration range of 0.3-30 micrograms/kg. PTHrp was approximately 3-fold more potent than PTH, producing up to a 50 mm Hg decrease in pressure within 2 min at 10 micrograms/kg. Both peptides increased heart rate more than 70 beats/min at this dose. However, PTH appeared to exert greater efficacy and potency than PTHrp in increasing heart rate in vivo. In the isolated and perfused rat heart, PTHrp and PTH produced positive chronotropic and positive inotropic effects as well as increased coronary flow. PTHrp was more potent and more effective than PTH. The time courses of these effects in the perfused heart preparations indicated that both peptides produced maximal effects within 1 min, with all responses returning to baseline within 10 min. In isolated helical strips of rat aorta, PTHrp and PTH relaxed norepinephrine-contracted tissues in a concentration-dependent fashion. A functional endothelium was not required for the relaxing effects of either peptide. These studies indicate that PTHrp and PTH decrease blood pressure by relaxing vascular tissue in an endothelium-independent manner. Also, these peptides directly increased heart rate, contractility, and coronary flow. Since PTHrp has recently been found in normal human cells, these studies suggest the possibility of PTHrp as a regulator or modulator of cardiovascular function.


Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics.
The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies.


Hyperthermia, tissue microcirculation, and temporarily increased thermosensitivity in VX2 carcinoma in rabbit liver.
The role of microcirculatory factors within and around liver tumors after heat treatment was investigated in a rabbit model of liver cancer (VX2 carcinoma). As a physiological factor of the microenvironment, regional blood flow (RBF) was measured by the hydrogen clearance method, and a histopathological study was done. Local hyperthermia was administered directly to the liver tumor via a 915-MHz microwave. Hyperthermia produced a temporary reduction of RBF in both the tumor and the surrounding normal liver tissues, and the histopathology revealed congestion, petechiae, and thrombosis. After hyperthermia at 43.0 degrees C for 20 min, RBF in the tumor rapidly decreased to a minimum of 40% of the control level during 0-12 h after the treatment and increased gradually to the pretreatment level at 2 days. RBF in the normal liver also decreased rapidly after hyperthermia, to a minimum of 30% of the pretreatment level, 1-12 h after treatment. In the case of treatment at 42.5 degrees C for 20 min, RBF in the tumor also rapidly decreased to a minimum of 40% of the control level, at 4 h after the treatment, and recovery was within 2 days. However, RBF in the surrounding normal liver decreased to 80% of the control level, at 2 h after the treatment, and then increased more rapidly to reach levels seen in the controls. Thus, the latter condition of heat treatment was considered to be favorable for therapeutic gain. Based on the results of these sequential microcirculatory changes, the effects of continuous and intermittent hyperthermia were studied in groups given various treatments. In a group treated with intermittent hyperthermia at 4-h intervals, the antitumor effects determined by tumor growth retardation were significantly greater, as compared with findings in the group given treatment without an interval and that given at a 24-h interval (P less than 0.001). In the tumor at 4 h after hyperthermia, the increased thermosensitivity was considered to surpass the developing thermotolerance. Thus, the antitumor effect of hyperthermia in vivo greatly depends on the microcirculation. The most efficacious mode for application of hyperthermia must be vigorously examined if a clinical relevance is to be gained.


Increased association between endometriosis and endometrial cancer: a nationwide population-based retrospective cohort study.
Association between endometriosis and ovarian cancer has been well established. Nonetheless, endometriosis may also be associated with endometrial cancer because of shared etiological mechanisms of both estrogen stimulation and chronic inflammation; however, the association between these 2 disorders has rarely been investigated. The National Health Insurance Research Databases in Taiwan were retrieved and analyzed. The case cohort consisted of patients with a diagnosis of endometriosis between January 1997 and December 2000 (N = 15,488). For the construction of control cohort, 8 age- and sex-matched control patients for every patient in the case cohort were selected using a random sampling method (n = 123,904). All subjects were tracked for 10 years from the date of entry to identify whether they had developed endometrial cancer. The Cox proportional hazards regression model was used to evaluate 10-year event occurrence of endometrial cancer. During the 10-year follow-up period, 392 participants developed endometrial cancer, with 104 (0.7%) distributed in the case cohort and 288 (0.2%) in the control cohort. Multivariable Cox regression modeling demonstrates a higher risk for developing endometrial cancer in the case cohort than in the control cohort (adjusted hazard ratio [aHR], 2.83; 95% confidence interval [CI], 1.495.35; P < 0.01). Age at diagnosis of endometriosis shows a moderator effect: when 40 years or younger, the risk for developing endometrial cancer was comparable between the case cohort and the control cohort (aHR, 1.42; 95% CI, 0.55-3.70; P = 0.226), whereas when older than 40 years, the risk for developing endometrial cancer was higher in the former group than in the latter group (aHR, 7.08; 95% CI, 2.33-21.55; P = 0.007). Patients diagnosed with endometriosis may harbor an increased risk for developing endometrial cancer in their later life. Closer monitoring is advised for this patient population.


A Simulation Study to Evaluate Improvements in Anesthesia Work Environment Contamination After Implementation of an Infection Prevention Bundle.
Microbiological contamination of the anesthesia work environment (AWE) is a potential source of health care-associated infections. Medication syringes, stopcocks, and many other areas are routinely contaminated during anesthetic care, and adherence to hand hygiene recommendations is poor. Using a simulation model, we investigated whether AWE contamination could be reduced by implementing an intervention bundle focused on infection prevention. Twenty-five anesthesia providers were enrolled in this nonrandomized simulation scenario crossover design study. Subjects were asked to complete 2 general anesthesia scenarios in a mock operating room: a baseline scenario and an intervention scenario in which the bundle was implemented. The bundle included: double gloving before intubation, confining all airway equipment to 1 area, and performing hand hygiene before touching the anesthesia cart. Before each scenario, a manikin's oropharynx and face were marked with ultraviolet fluorescent tracers. After each scenario, the AWE was inspected with a ultraviolet light source to detect contaminant, and all sites were photographed. A blinded observer scored the images for the presence or absence of tracer at 20 sites. Videos of the scenarios were analyzed for duration and number of hand hygiene and glove removal events. Data were analyzed using a mixed effects model. Subjects completed a survey about their experience and the value of the scenarios. The intervention was associated with a decreased subject contamination score of 4.0 (95% confidence interval, 2.2-5.6; P < .001), a 27% reduction in score between baseline and intervention scenarios. Some sites were universally contaminated despite the intervention (eg, laryngoscope handles). The intervention had a statistically significant impact on reducing contamination on medication syringes and the anesthesia cart. There was no significant difference in time needed to complete baseline and intervention scenarios. The majority of subjects felt that the simulations had significant value and would affect their future clinical behavior. Our results support the concept of an infection prevention bundle in reducing AWE contamination. Anesthesia providers deliver care in a unique environment in which "clean" and "contaminated" tasks are performed rapidly and often in parallel. Linking hand hygiene to specific high-impact tasks such as administering medications, designating areas for contaminated equipment, and double gloving before airway management are simple steps that can be implemented rapidly and are compatible with timely patient care. Our study has improved awareness of infection prevention issues in our department, and has highlighted simple and achievable actions that have the potential to reduce health care-associated infections.


Bioaccumulation and Metabolic Effects of the Endocrine Disruptor Methoprene in the Lobster, Homarus americanus.
Methoprene is a pesticide that acts as a juvenile hormone agonist. Although developed initially against insects, it has since been shown to have toxic effects on larval and adult crustaceans. Methoprene was one of several pesticides applied to the Western Long Island Sound (WLIS) watershed area during the summer of 1999; the other pesticides were malathion, resmethrin, and sumethrin. These pesticides were applied as part of a county-by-county effort to control the mosquito vector of West Nile Virus. Subsequently, the seasonal lobster catches from the WLIS have decreased dramatically. The lethality of the pesticides to lobsters had been unknown. We studied the effects of methoprene while other investigators studied effects of the other pesticides. We questioned whether methoprene, through its effects on larvae, adults or both, could have contributed to this decline. We found that low levels of methoprene had adverse effects on lobster larvae. It was toxic to stage II larvae at 1 ppb. Stage IV larvae were more resistant, but did exhibit significant increases in molt frequency beginning at exposures of 5 ppb. Juvenile lobsters exhibited variations in tissue susceptibility to methoprene: hepatopancreas appeared to be the most vulnerable, reflected by environmental concentrations of methoprene inhibiting almost all protein synthesis in this organ.Our results indicated that methoprene concentrates in the hepatopancreas, nervous tissue and epidermal cells of the adult lobster. Methoprene altered the synthesis and incorporation of chitoproteins (cuticle proteins) into adult postmolt lobster explant shells. SDS PAGE analyses of adult post-molt shell extracts revealed changes in the synthesis of chitoproteins in the methoprene-treated specimens, suggesting that methoprene affects the normal pathway of lobster cuticle synthesis and the quality of the post-molt shell. Although it is likely that a combination of factors led to the reduced lobster population in WLIS, methoprene may have contributed both by direct toxic effects and by disrupting homeostatic events under endocrine control.


Efficacy of an exercise program combined with lifestyle education in patients with knee osteoarthritis.
Therapeutic exercise and lifestyle changes (LS) are usually recommended for the treatment of knee osteoarthritis (OA). to compare the impact of an exercise program vs. exercise program plus LS education in individuals with knee OA. Single-blind randomized clinical trial with individuals of both sexes with clinical and radiological diagnosis of knee OA. Participants received the treatment 2 times/week for 8 weeks. Therapeutic exercise involved warm-up, flexibility, muscle strengthening, balance and proprioception. The exercise plus lifestyle education group (ELG) also participated in 8 sessions of lectures and discussion on disease self-management and healthy LS. Participants were assessed for pain intensity (visual analog scale), lifestyle, symptoms and physical disability (WOMAC) and pressure pain tolerance threshold (PPT). Sample consisted of 39 participants, divided into exercise group (EG, n=17) and ELG (n=22). Groups were homogeneous regarding regarding age, weight, height, initial pain perception (VAS) and gender predominance age and body mass index. After the interventions, reduction in pain perception and increase in PPT was observed in both groups. Despite the improvement in LS of both groups, only ELG exhibited a significant reduction in pain assessed by WOMAC. Therapeutic exercise programs may produce pain relief, but no improvements were observed in joint stiffness and funcionality.


Evaluation and treatment of older patients with hypercholesterolemia: a clinical review.
Hypercholesterolemia is common among people older than 80 years. Substantial functional heterogeneity exists among older patients, and decision making for statin use differs in older patients relative to younger ones. To discuss the presentation, modifying factors, and treatment of hypercholesterolemia (usually with statins) among persons older than 80 years. MEDLINE and other sources were searched from January 1990 to June 2014. Personal libraries and a hand search of reference lists from guidelines and reviews from January 2000 to June 2014 were also used. No randomized clinical trials (RCTs) of statin or any other hypocholesterolemic medication included persons older than 80 years at baseline. Findings from 75- to 80-year-old patients enrolled in RCTs and information from observational studies support statin treatment for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) and probably in patients with diabetes without ASCVD. Harms from statin drugs are not increased in older patients, so the use of these agents for primary prevention is possible. Because people older than 80 years are biologically heterogeneous with varying life expectancy, may have frailty or comorbid conditions, and may take multiple medications, the decision to treat with statins must be individualized. Ideally, treatment of hypercholesterolemia for patients at risk of ASCVD should start before they turn 80 years old. No RCT evidence exists to guide statin initiation after age 80 years. Decisions to use statins in older individuals are made individually and are not supported by high-quality evidence.


Pedobacterlycopersici sp. nov., isolated from the rhizosphere of tomato plant (Solanum lycopersicum L.).
A Gram-stain-negative, rod-shaped, white bacterium, designated strain T16R-88T, was isolated from a rhizosphere soil sample collected in Buyeo-gun of Chungcheongnam-do, South Korea. A phylogenetic tree based on 16S rRNA gene sequences showed that strain T16R-88T formed a lineage within the genus Pedobacter. It showed highest sequence similarities to Pedobacter ginsengisoli Gsoil 104T (97.4 %), Pedobacter nutrimenti J22T (97.2 %), Pedobacter nyackensis NWG-II14T (97.1 %), Pedobacter seoulensis THG-G12T (97.1 %) and Pedobacter panaciterrae Gsoil 042T (97.0 %). The predominant respiratory quinone was menaquinone MK-7. The major cellular fatty acids (>10 % of the total fatty acids) were summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1ω7c), iso-C17 : 0 3-OH and iso-C15 : 0. The polar lipids consisted of phosphatidylethanolamine, sphingolipid, one unidentified aminophospholipid, three unidentified aminolipids, three unidentified lipids and one unidentified phospholipid. DNA-DNA hybridization values between strain T16R-88T and its most closely related species were below 70 %. The DNA G+C content was 35.6 mol%. On the basis of the evidence presented in this study, strain T16R-88T represents a novel species of the genus Pedobacter, for which the name Pedobacter lycopersici sp. nov. is proposed. The type strain is T16R-88T (=KACC 18652T=NBRC 111984T).


Spectroscopy and dynamics of the predissociated, quasi-linear S2 state of chlorocarbene.
In this work, we report on the spectroscopy and dynamics of the quasi-linear S(2) state of chlorocarbene, CHCl, and its deuterated isotopologue using optical-optical double resonance (OODR) spectroscopy through selected rovibronic levels of the S(1) state. This study, which represents the first observation of the S(2) state in CHCl, builds upon our recent examination of the corresponding state in CHF, where pronounced mode specificity was observed in the dynamics, with predissociation rates larger for levels containing bending excitation. In the present work, a total of 14 S(2) state vibrational levels with angular momentum l = 1 were observed for CHCl, and 34 levels for CDCl. The range of l in this case was restricted by the pronounced Renner-Teller effect in the low-lying S(1) levels, which severely reduces the fluorescence lifetime for levels with K(a) > 0. Nonetheless, by exploiting different intermediate S(1) levels, we observed progressions involving all three fundamental vibrations. For levels with long predissociation lifetimes, rotational constants were determined by measuring spectra through different intermediate J levels of the S(1) state. Plots of the predissociation linewidth (lifetime) vs. energy for various S(2) levels show an abrupt onset, which lies near the calculated threshold for elimination to form C((3)P) + HCl on the triplet surface. Our experimental results are compared with a series of high level ab initio calculations, which included the use of a dynamically weighted full-valence CASSCF procedure, focusing maximum weight on the state of interest (the singlet and triplet states were computed separately). This was used as the reference for subsequent Davidson-corrected MRCI(+Q) calculations. These calculations reveal the presence of multiple conical intersections in the singlet manifold.


Review of the Palaearctic (and Oriental) Allurus (Braconidae, Euphorinae) based on material from Sweden.
The tribe Centistini includes three genera, Allurus, Centistes and Centistoides (Stigenberg et al. 2015). They are solitary endoparasitoids of adults and final instar larvae of beetles from the family Curculionidae (Jackson 1920, Aeschlimann 1980, Tobias 1986). In this paper we present a key, molecular data (standard DNA barcode, CO1) and images of the two species of Allurus occurring in the Western Palaearctic. A third Oriental species described from China (Taiwan) is also included in the key. Allurus is a Holarctic genus with three known species (A. choui, A. lituratus, A. muricatus). Our sequence data confirms that A. muricatus and A. lituratus are two distinct and separate species and this paper points out good and easy characters to separate them.


Use of theoretical waste inventories in planning and monitoring of hazardous waste management systems.
Hazardous waste (HW) generation information is an absolute necessity for ensuring the proper planning, implementation, and monitoring of any waste management system. Unfortunately, environmental agencies in developing countries face difficulties in gathering data directly from the creators of such wastes. It is possible, however, to construct theoretical HW inventories using the waste generation factors (WGFs). The objective of this study was to develop a complete nationwide HW inventory of Turkey that relies on nation-specific WGFs to support management activities of the Turkish Ministry of Environment and Urbanization (MoEU). Inventory studies relied on WGFs from: (a) the literature and (b) field studies and analysis of waste declarations reflecting country-specific industrial practices. Moreover, new tools were introduced to the monitoring infrastructure of MoEU to obtain a comprehensive waste generation data set. Through field studies and a consideration of country specific conditions, it was possible to more thoroughly elucidate HW generation trends in Turkey, a method that was deemed superior to other alternatives. Declaration and literature based WGFs also proved most helpful in supplementing field observations that could not always be conducted. It was determined that these theoretical inventories could become valuable assets in supporting regulating agencies in developing countries for a more thorough implementation of HW management systems.


Gene expression analysis supports tumor threshold over 2.0 cm for T-category breast cancer.
Tumor size, as indicated by the T-category, is known as a strong prognostic indicator for breast cancer. It is common practice to distinguish the T1 and T2 groups at a tumor size of 2.0 cm. We investigated the 2.0-cm rule from a new point of view. Here, we try to find the optimal threshold based on the differences between the gene expression profiles of the T1 and T2 groups (as defined by the threshold). We developed a numerical algorithm to measure the overall differential gene expression between patients with smaller tumors and those with larger tumors among multiple expression datasets from different studies. We confirmed the performance of the proposed algorithm by a simulation study and then applied it to three different studies conducted at two Norwegian hospitals. We found that the maximum difference in gene expression is obtained at a threshold of 2.2-2.4 cm, and we confirmed that the optimum threshold was over 2.0 cm, as indicated by a validation study using five publicly available expression datasets. Furthermore, we observed a significant differentiation between the two threshold groups in terms of time to local recurrence for the Norwegian datasets. In addition, we performed an associated network and canonical pathway analyses for the genes differentially expressed between tumors below and above the given thresholds, 2.0 and 2.4 cm, using the Norwegian datasets. The associated network function illustrated a cellular assembly of the genes for the 2.0-cm threshold: an energy production for the 2.4-cm threshold and an enrichment in lipid metabolism based on the genes in the intersection for the 2.0- and 2.4-cm thresholds.


EUROmediCAT signal detection: a systematic method for identifying potential teratogenic medication.
Information about medication safety in pregnancy is inadequate. We aimed to develop a signal detection methodology to routinely identify unusual associations between medications and congenital anomalies using data collected by 15 European congenital anomaly registries. EUROmediCAT database data for 14 950 malformed foetuses/babies with first trimester medication exposures in 1995-2011 were analyzed. The odds of a specific medication exposure (coded according to chemical substance or subgroup) for a specific anomaly were compared with the odds of that exposure for all other anomalies for 40 385 medication anomaly combinations in the data. Simes multiple testing procedure with a 50% false discovery rate (FDR) identified associations least likely to be due to chance and those associations with more than two cases with the exposure and the anomaly were selected for further investigation. The methodology was evaluated by considering the detection of well-known teratogens. The most common exposures were genitourinary system medications and sex hormones (35.2%), nervous system medications (28.0%) and anti-infectives for systemic use (25.7%). Fifty-two specific medication anomaly associations were identified. After discarding 10 overlapping and three protective associations, 39 associations were selected for further investigation. These associations included 16 which concerned well established teratogens, valproic acid (2) and maternal diabetes represented by use of insulin (14). Medication exposure data in the EUROmediCAT central database can be analyzed systematically to determine a manageable set of associations for validation and then testing in independent datasets. Detection of teratogens depends on frequency of exposure, level of risk and teratogenic specificity.


Rapid synthesis of oligomannosides with orthogonally protected monosaccharides.
We developed a facile synthesis to yield orthogonally protected mannose building blocks with high overall yields. The protection/glycosylation steps can be carried out in a successive manner without purification of intermediate products. This developed synthesis led to formation of linear/branched tri-, penta- and heptasaccharides.


Cerebrospinal Fluid MicroRNA Signatures as Diagnostic Biomarkers in Brain Tumors.
Central nervous system (CNS) malignancies include primary tumors that originate within the CNS as well as secondary tumors that develop as a result of metastatic spread. Circulating microRNAs (miRNAs) were found in almost all human body fluids including cerebrospinal fluid (CSF), and they seem to be highly stable and resistant to even extreme conditions. The overall aim of our study was to identify specific CSF miRNA patterns that could differentiate among brain tumors. These new biomarkers could potentially aid borderline or uncertain imaging results onto diagnosis of CNS malignancies, avoiding most invasive procedures such as stereotactic biopsy or biopsy. In total, 175 brain tumor patients (glioblastomas, low-grade gliomas, meningiomas and brain metastases), and 40 non-tumor patients with hydrocephalus as controls were included in this prospective monocentric study. Firstly, we performed high-throughput miRNA profiling (Illumina small RNA sequencing) on a discovery cohort of 70 patients and 19 controls and identified specific miRNA signatures of all brain tumor types tested. Secondly, validation of 9 candidate miRNAs was carried out on an independent cohort of 105 brain tumor patients and 21 controls using qRT-PCR. Based on the successful results of validation and various combination patterns of only 5 miRNA levels (miR-30e, miR-140, let-7b, mR-10a and miR-21-3p) we proposed CSF-diagnostic scores for each tumor type which enabled to distinguish them from healthy donors and other tumor types tested. In addition to this primary diagnostic tool, we described the prognostic potential of the combination of miR-10b and miR-196b levels in CSF of glioblastoma patients. In conclusion, we performed the largest study so far focused on CSF miRNA profiling in patients with brain tumors, and we believe that this new class of biomarkers have a strong potential as a diagnostic and prognostic tool in these patients.


White matter alterations in social anxiety disorder.
White matter architecture in patients with social anxiety disorder (SAD) has rarely been investigated, but may yield insights with respect to altered structural brain connectivity. Initial evidence points to alterations in the uncinate fasciculus (UF). We applied diffusion tensor imaging in 25 patients with SAD and 25 matched healthy subjects. Whole-brain fractional anisotropy (FA) maps were used for group comparison and voxel-wise correlation with psychometric and clinical measures. Additionally, a region-of-interest analysis of the UF was performed. Patients with SAD had reduced FA compared to healthy subjects in or near the left UF and the left superior longitudinal fasciculus. There were no regions with increased FA in SAD. In the region-of-interest analysis, a negative correlation between FA and trait anxiety was identified in the left and right UF in patients, but not in healthy subjects. No correlations with social anxiety scores were observed. The present study partially confirms previous results pointing to frontal WM alterations in or near the UF in patients with SAD. SAD-specific dimensional associations of FA with trait anxiety might reflect general pathological and/or compensatory mechanisms as a function of symptom severity in patients. Future studies should disentangle in which way the identified WM alterations match functional alterations.


Colloidal Silver Ingestion Associated with Leukocytoclastic Vasculitis in an Adolescent Female.
BACKGROUND Leukocytoclastic vasculitis is a disease of the small vessels and is uncommon in children. In this case report, we present an adolescent case of leukocytoclastic vasculitis associated with the ingestion of colloidal silver, a naturopathic drug. This report highlights the rarity of the patient's presentation and inducing agent. CASE REPORT A 19-year-old female presented in the Emergency Department with severe rash on the face, and neck, and then continued to spread in a craniocaudal fashion during the day of presentation to involve trunk, back, upper and lower extremities. There was no recent travel, no pets and a negative family history for rheumatologic or autoimmune diseases. Her home medications included colloidal silver for "internal cleansing" for 4 weeks prior to Emergency Department presentation. Once the clinicians were aware of the continued ingestion of colloidal silver, the patient was advised to discontinue the drug. The patient was started on methylprednisolone with preliminary diagnosis of vasculitis, as well as concurrent therapy with colchicine. The rash was noted to be receding from the face within 24 hours. Over a hospital course of 5 days, the patient's rash and pruritus continued to slowly improve. CONCLUSIONS The ingestion of a naturopathic drug, colloidal silver, caused vast leukocytoclastic vasculitis in our patient warranting hospitalization due to the extent of the disease. The symptoms resolved after discontinuation of colloidal silver ingestion. Due to unknown safe ingestion concentrations and potential side effects, use of colloidal silver should be discouraged.


Health-related quality of life and functioning of middle-aged and elderly adults with bipolar disorder.
Data characterizing bipolar disorder in older people are scarce, particularly on functional status. We evaluated health-related quality of life and functioning (HRQoLF) among older outpatients with bipolar disorder as well as the relationship of HRQoLF to bipolar illness characteristics. We compared community-dwelling middle-aged and older adults (age range, 45 to 85 years) with bipolar disorder (N=54; mean age=57.6 years), schizophrenia (N=55; mean age=58.5 years), or no psychiatric illnesses (N=38; mean age=64.7 years) on indicators of objective functioning (e.g., education, occupational attainment, medical comorbidity) and health status (e.g., Quality of Well-Being scale [QWB] and the Medical Outcomes Study-Short Form Health Survey [SF-36]). Within the group with bipolar disorder, we examined the relationship between HRQoLF and clinical variables (e.g., phase and duration of illness, psychotic symptoms, cognitive functioning). Patients with bipolar disorder were similar in educational and occupational attainment to the normal comparison group, but they obtained lower scores on the QWB and SF-36 (with large effect sizes). Compared with schizophrenia, bipolar disorder was associated with better educational and work histories but similar QWB and SF-36 scores and more medical comorbidity. Patients in remission from bipolar disorder had QWB scores that were worse than those of normal comparison subjects. Greater severity of psychotic and depressive symptoms and cognitive impairment were associated with lower HRQoLF. Bipolar disorder was associated with substantial disability in this sample of older adults, similar in severity to schizophrenia. Remission of bipolar disorder was associated with significant but incomplete improvement in functioning, whereas psychotic and depressive symptoms and cognitive impairment seemed to contribute to lower HRQoLF.


Acromegaly.
Acromegaly is an acquired disorder related to excessive production of growth hormone (GH) and characterized by progressive somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The prevalence is estimated at 1:140,000-250,000. It is most often diagnosed in middle-aged adults (average age 40 years, men and women equally affected). Due to insidious onset and slow progression, acromegaly is often diagnosed four to more than ten years after its onset. The main clinical features are broadened extremities (hands and feet), widened thickened and stubby fingers, and thickened soft tissue. The facial aspect is characteristic and includes a widened and thickened nose, prominent cheekbones, forehead bulges, thick lips and marked facial lines. The forehead and overlying skin is thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, tooth separation and jaw malocclusion. The disease also has rheumatologic, cardiovascular, respiratory and metabolic consequences which determine its prognosis. In the majority of cases, acromegaly is related to a pituitary adenoma, either purely GH-secreting (60%) or mixed. In very rare cases, acromegaly is due to ectopic secretion of growth-hormone-releasing hormone (GHRH) responsible for pituitary hyperplasia. The clinical diagnosis is confirmed biochemically by an increased serum GH concentration following an oral glucose tolerance test (OGTT) and by detection of increased levels of insulin-like growth factor-I (IGF-I). Assessment of tumor volume and extension is based on imaging studies. Echocardiography and sleep apnea testing are used to determine the clinical impact of acromegaly. Treatment is aimed at correcting (or preventing) tumor compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. Transsphenoidal surgery is often the first-line treatment. When surgery fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogs and/or radiotherapy can be used. The GH antagonist (pegvisomant) is used in patients that are resistant to somatostatin analogs. Adequate hormonal disease control is achieved in most cases, allowing a life expectancy similar to that of the general population. However, even if patients are cured or well-controlled, sequelae (joint pain, deformities and altered quality of life) often remain.


Human natural killer cell adhesion molecules. Differential expression after activation and participation in cytolysis.
Cell adhesion molecules (CAM) participate in interactions between lymphocytes, accessory cells, and target cells that are critical in the generation of effective immune responses. To characterize the involvement of CAM in NK and lymphokine activated killer (LAK) activities, we examined the expression of several CAM by freshly isolated human NK cells and by NK cells activated in vitro with IL-2, and compared this to CAM expression by T lymphocytes under similar conditions. Freshly isolated human NK cells were uniformly LFA-3 (CD58)+ and expressed two to three-fold higher surface levels of LFA-1 (CD11a/CD18) than resting T lymphocytes. More NK cells than T cells also expressed phenotypically detectable levels of intercellular adhesion molecule-1 (CD54). After in vitro incubation with IL-2, human NK cells demonstrated four- to sixfold increases in surface levels of CD11a/CD18, CD2, CD54, CD58, and the NK cell-associated Ag NKH-1 (CD56). Furthermore, essentially all NK cells became CD54+ within 3 days of exposure to IL-2. T cells did not demonstrate comparable up-regulation of CAM after incubation with IL-2. Increases in NK cell CAM expression were associated with enhanced formation of E:T cell conjugates, enhanced killing of NK-sensitive targets, and the induction of cytotoxicity for previously NK-resistant targets (LAK activity). The LAK activity induced by exogenous IL-2 could be partially inhibited by anti-CD2, anti-CD11a, or anti-CD54 antibodies and almost completely abrogated by anti-CD2 and anti-CD11a in combination. These studies suggest that CAM play a central role in the regulation of NK cytolysis, and that changes in CAM expression may alter the target cell specificity of activated NK effectors.


[Managing epilepsy in the primary care network in Brazil: are health professionals prepared?].
To assess attitudes and beliefs concerning epilepsy held by physicians and allied health professionals who work in the primary care network in Brazil. The data were collected during a national family and community medicine conference held in Rio de Janeiro in 2004, which was attended by 1,200 health professionals from throughout the country. Two questionnaires were used, one for physicians and another for nonphysician health workers. A total of 598 conference participants (345 physicians and 253 nonphysician health professionals) completed a questionnaire. Both the physicians and the nonphysician health professionals had acceptable personal attitudes towards persons with epilepsy. According to data from 286 physicians who provided information, the estimated mean percentage of individuals with epilepsy in the populations cared for by the physicians' health care systems in the preceding year was 0.78% (range, 0 to 8%; median = 0.37%). The estimated mean percentage of seizure-free patients was 60%. The estimated mean percentage of persons on monotherapy was 55%. The estimated mean percentage of referrals to a neurologist was 59%. The estimated mean percentage of patients who were working or studying was 56%. Of the 345 physicians, 252 of them (73%) reported not feeling confident about managing individuals with epilepsy, whereas 84 (24%) felt confident, and 9 (3%) were not sure. Of the 252 physicians who did not feel confident, 226 (90%) said that they would participate in a training program to improve the quality of the care provided to individuals with epilepsy. The professionals participating in the study indicated that the primary care system has the essential elements needed to provide comprehensive epilepsy care, including professional personnel who want to improve their skills. However, establishing an efficient, effective program of epilepsy management in the primary care network will require an effective referral network, regular distribution of antiepileptic drugs, the close monitoring of epilepsy management by using the federal primary health information system, and the ongoing education of health professionals, with emphasis on psychological support and the inclusion in society of individuals with epilepsy.


Comparative metabolism of fenclorac in rat, dog, monkey, and man.
Fenclorac (alpha,m-dichloro-p-cyclohexylphenylacetic acid, diethylammonium salt), a new nonsteroidal anti-inflammatory agent, was rapidly and quantitatively absorbed from the gastrointestinal tract of rat, dog, monkey, and man following oral administration of a solution of 14C-labeled compound. Radiochromatography and mass spectrometry indicated that fenclorac was the principal component in plasma during both the absorption and elimination phases in all species. Small quantities of m-chloro-p-cyclohexylphenylglycolic acid metabolite were also present. Fenclorac and metabolite were confined primarily to the plasma phase of whole blood and were extensively bound to serum albumin. The plasma elimination half-time was species-dependent and varied from 1.6 hr in the rat to 6.5 hr in the dog. The principal tissues of distribution were liver, kidney, and small intestine. There was no significant accumulation or retention of drug or metabolites in any tissue compartment. Fenclorac was completely biotransformed prior to elimination in urine and bile. The major route of elimination was renal in man and monkey, and biliary in the dog. Enterohepatic recirculation of fenclorac metabolites was shown to occur in the rat. The major urinary metabolites were hydroxycyclohexyl analogs of fenclorac and m-chloro-p-cyclohexylphenylglycolic acid. There was no difference in metabolism and biological disposition of fenclorac in normal rats and rats with adjuvant-induced polyarthritis.


The Effect of Excessive Crying on the Development of Emotion Regulation.
The goal of this study was to examine the effect of excessive crying in early infancy on the development of emotion self-regulation. Cry diaries were used to categorize excessive criers and typical criers at 6 weeks of age. At 5 and 10 months of age, infants and mothers participated in procedures to elicit infant reactivity and regulation during a frustration task and maternal sensitivity and intrusiveness during a free-play session. Last, maternal ratings of temperament were obtained. Results revealed excessive criers to show higher levels of negative reactivity than typical criers. Excessive criers also demonstrated lower regulation, but this finding was only significant for male infants. Boys in the excessive criers group exhibited the lowest level of emotion self-regulation. Maternal behavior and ratings of temperament at 5 and 10 months failed to distinguish the 2 cry groups. The findings suggest that excessive crying may influence the developmental trajectory of the ability of boys to self-regulate emotion. The hypothesized processes involved in this outcome are discussed.


Is Asacol as effective as sulphasalazine in maintaining remission of Crohn's disease and ulcerative colitis?
To compare the efficacy of Asacol (mesalazine coated with Eudraget-S) as a maintenance therapy with that of sulphasalazine, relapse rates of patients with ulcerative colitis and Crohn's disease, treated with sulphasalazine or Asacol were assessed in a retrospective study. A total of 164 patients were investigated, 127 on sulphasalazine and 37 on Asacol. None of the patients on Asacol was changed from sulphasalazine because of lack of efficacy to sulphasalazine. Relapse rates were measured over a 4 year period. In ulcerative colitis these were sulphasalazine 10/77 (13.0%), Asacol 5/20 (25.0%), NS; in all Crohn's disease patients, sulphasalazine 12/50 (24.0%), Asacol 11/17 (64.7%); P less than 0.0025. In patients with Crohn's disease with ileal involvement, relapse rates were sulphasalazine 9/28 (32.1%), Asacol 9/11 (81.6%), P less than 0.0125; without ileal involvement, sulphasalazine 3/22 (13.6%), Asacol 2/6 (33.4%), NS. This study suggests that Asacol is as effective as sulphasalazine in maintaining remission in ulcerative colitis and in patients with Crohn's disease without ileal involvement. Sulphasalazine seems to be more effective than Asacol in maintaining remission in patients with Crohn's disease with terminal ileal involvement.


Vasohibin-2 expressed in human serous ovarian adenocarcinoma accelerates tumor growth by promoting angiogenesis.
Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor and VASH2 is its homolog. Our previous analysis revealed that VASH1 is expressed in endothelial cells to terminate angiogenesis, whereas VASH2 is expressed in infiltrating mononuclear cells mobilized from bone marrow to promote angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis. To test the possible involvement of VASH2 in the tumor, we examined human ovarian cancer cells for the presence of VASH2. Immunohistochemical analysis revealed that VASH2 protein was preferentially detected in cancer cells of serous ovarian adenocarcinoma. We then used SKOV-3 and DISS, two representative human serous adenocarcinoma cell lines, and examined the role of VASH2 in the tumor. The knockdown of VASH2 showed little effect on the proliferation of cancer cells in vitro but notably inhibited tumor growth, peritoneal dissemination, and tumor angiogenesis in a murine xenograft model. Next, we stably transfected the human VASH2 gene into two types of murine tumor cells, EL-4 and MLTC-1, in which endogenous VASH2 was absent. When either EL-4 or MLTC-1 cells were inoculated into VASH2 (-/-) mice, the VASH2 transfectants formed bigger tumors when compared with the controls, and the tumor microvessel density was significantly increased. VASH2 stimulated the migration of endothelial cells, and its increased expression in cancer cells is related to the decrease of mir-200b. These results indicate that VASH2 expressed in serous ovarian carcinoma cells promoted tumor growth and peritoneal dissemination by promoting angiogenesis.


Circadian blood pressure during the early course of type 1 diabetes. Analysis of 1,011 ambulatory blood pressure recordings in 354 adolescents and young adults.
Little information is available on the early course of hypertension in type 1 diabetes. The aim of our study, therefore, was to document circadian blood pressure profiles in patients with a diabetes duration of up to 20 years and relate daytime and nighttime blood pressure to duration of diabetes, BMI, insulin therapy, and HbA1c. Ambulatory profiles of 24-h blood pressure were recorded in 354 pediatric patients with type 1 diabetes (age 14.6 +/- 4.2 years, duration of diabetes 5.6 +/- 5.0 years, follow-up for up to 9 years). A total of 1,011 profiles were available for analysis from patients not receiving antihypertensive medication. Although daytime mean systolic pressure was significantly elevated in diabetic subjects (+3.1 mmHg; P < 0.0001), daytime diastolic pressure was not different from from the height- and sex-adjusted normal range (+0.1 mmHg, NS). In contrast, both systolic and diastolic nighttime values were clearly elevated (+7.2 and +4.2 mmHg; P < 0.0001), and nocturnal dipping was reduced (P < 0.0001). Systolic blood pressure was related to overweight in all patients, while diastolic blood pressure was related to metabolic control in young adults. Blood pressure variability was significantly lower in girls compared with boys (P < 0.01). During follow-up, no increase of blood pressure was noted; however, diastolic nocturnal dipping decreased significantly (P < 0.03). Mean daytime blood pressure was significantly related to office blood pressure (r = +0.54 for systolic and r = +0.40 for diastolic pressure); however, hypertension was confirmed by ambulatory blood pressure measurement in only 32% of patients with elevated office blood pressure. During the early course of type 1 diabetes, daytime blood pressure is higher compared with that of healthy control subjects. The elevation of nocturnal values is even more pronounced and nocturnal dipping is reduced. The frequency of white-coat hypertension is high among adolescents with diabetes, and ambulatory blood pressure monitoring avoids unnecessary antihypertensive treatment.


Microtubule organization in the final stages of cytokinesis as revealed by cryo-electron tomography.
The completion of cytokinesis is dominated by the midbody, a tightly-packed microtubule (MT)-based bridge that transiently connects the two daughter cells. Assembled from condensed, spindle-MTs and numerous associated proteins, the midbody gradually narrows down until daughter cell partitioning occurs at this site. Although described many years ago, detailed understanding of the abscission process remains lacking. Applying cryo-electron tomography to purified midbodies, in combination with fluorescence microscopy, we present here new insight into MT organization within the midbody. We find that the midbody is spatially divided into a core bundle of MTs that traverses the electron-dense overlap region (continuous MTs), surrounded by MTs that terminate within the overlap region (polar MTs). Residual continuous MTs remained intact up to the verge of abscission, whereas the residual polar MTs lost their organization and retreated from the overlap region at late cytokinesis stages. A detailed localization of the microtubule-bundling protein PRC1 supports the above notion. Our study thus provides a detailed account of the abscission process and suggests that the midbody, having acquired a distinct MT architecture as compared to the preceding central spindle, actively facilitates the final stage of cytokinesis.


Household food group expenditure patterns are associated with child anthropometry at ages 5, 8 and 12 years in Ethiopia, India, Peru and Vietnam.
Population-level analysis of dietary influences on nutritional status is challenging in part due to limitations in dietary intake data. Household expenditure surveys, covering recent household expenditures and including key food groups, are routinely conducted in low- and middle-income countries. These data may help identify patterns of food expenditure that relate to child growth. We investigated the relationship between household food expenditures and child growth using factor analysis. We used data on 6993 children from Ethiopia, India, Peru and Vietnam at ages 5, 8 and 12y from the Young Lives cohort. We compared associations between household food expenditures and child growth (height-for-age z scores, HAZ; body mass index-for-age z scores, BMI-Z) using total household food expenditures and the "household food group expenditure index" (HFGEI) extracted from household expenditures with factor analysis on the seven food groups in the child dietary diversity scale, controlling for total food expenditures, child dietary diversity, data collection round, rural/urban residence and child sex. We used the HFGEI to capture households' allocations of their finances across food groups in the context of local food pricing, availability and pReferences RESULTS: The HFGEI was associated with significant increases in child HAZ in Ethiopia (0.07), India (0.14), and Vietnam (0.07) after adjusting for all control variables. Total food expenditures remained significantly associated with increases in BMI-Z for India (0.15), Peru (0.11) and Vietnam (0.06) after adjusting for study round, HFGEI, dietary diversity, rural residence, and whether the child was female. Dietary diversity was inversely associated with BMI-Z in India and Peru. Mean dietary diversity increased from age 5y to 8y and decreased from age 8y to 12y in all countries. Household food expenditure data provide insights into household food purchasing patterns that significantly predict HAZ and BMI-Z. Including food expenditure patterns data in analyses may yield important information about child nutritional status and linear growth.


Mortality among children under five years admitted for routine care of severe acute malnutrition: a prospective cohort study from Kampala, Uganda.
Mortality among children under 5 years of age admitted to malnutrition units in sub-Saharan Africa remains high. The burden of HIV infection, a major risk factor for mortality among patients with severe acute malnutrition (SAM), has reduced due to concerted prevention and treatment strategies. None the less, anecdotal reports from the malnutrition unit at Uganda's National Referral Hospital (NRH) indicate that there is high mortality among patients with severe acute malnutrition (SAM) in routine care. Uganda has recently adopted the revised World Health Organization (WHO) treatment guidelines for SAM to improve outcomes. The mortality among children with SAM in routine care has not been recently elucidated. We report the magnitude and factors associated with mortality among children under 5 years of age admitted to the NRH for routine care of SAM. This was a cohort study of all severely malnourished children admitted to the NRH between June and October 2017. The primary outcome was two-week mortality. Mortality was calculated using simple proportions and Cox regression analysis was used to determine factors associated with time to mortality. Data was entered into Epidata and analysed using Stata v14. Two-hundred-sixty (98.5%) children: 59.6% male; mean age 14.4 (SD 9.4) months, completed two weeks of follow-up. Of these, 25.2% (95% CI 19.9-30.4%) died. In-hospital mortality was 20.7% (95% CI15.9-25.6%). The prevalence of HIV infection was 12.2%. Factors associated with mortality included: positive HIV status (AHR 2.2, (95% CI; 1.2-4.2), p = 0.014), bacteraemia (AHR 9 (95% CI 3.4-23.0), p < 0.001, and low glomerular filtration rate (eGFR), AHR 3.2; (95% CI 1.7-6.3), p = 0.001). A 25% mortality among children with severe malnutrition remains unacceptably high despite significant reduction in HIV prevalence. Children with SAM who are HIV infected, have eGFR below 60 mL/min/1.73m2 or have bacteraemia, are more likely to die. Further studies to explore the relationship between eGFR and mortality among children with SAM are needed. Studies to establish efficacious antibiotics are urgently required to inform treatment guidelines for children with SAM.