An association between neighbourhood wealth inequality and HIV prevalence in sub-Saharan Africa.
This paper investigates whether community-level wealth inequality predicts HIV serostatus using DHS household survey and HIV biomarker data for men and women ages 15-59 pooled from six sub-Saharan African countries with HIV prevalence rates exceeding 5%. The analysis relates the binary dependent variable HIV-positive serostatus and two weighted aggregate predictors generated from the DHS Wealth Index: the Gini coefficient, and the ratio of the wealth of households in the top 20% wealth quintile to that of those in the bottom 20%. In separate multilevel logistic regression models, wealth inequality is used to predict HIV prevalence within each statistical enumeration area, controlling for known individual-level demographic predictors of HIV serostatus. Potential individual-level sexual behaviour mediating variables are added to assess attenuation, and ordered logit models investigate whether the effect is mediated through extramarital sexual partnerships. Both the cluster-level wealth Gini coefficient and wealth ratio significantly predict positive HIV serostatus: a 1 point increase in the cluster-level Gini coefficient and in the cluster-level wealth ratio is associated with a 2.35 and 1.3 times increased likelihood of being HIV positive, respectively, controlling for individual-level demographic predictors, and associations are stronger in models including only males. Adding sexual behaviour variables attenuates the effects of both inequality measures. Reporting eleven plus lifetime sexual partners increases the odds of being HIV positive over five-fold. The likelihood of having more extramarital partners is significantly higher in clusters with greater wealth inequality measured by the wealth ratio. Disaggregating logit models by sex indicates important risk behaviour differences. Household wealth inequality within DHS clusters predicts HIV serostatus, and the relationship is partially mediated by more extramarital partners. These results emphasize the importance of incorporating higher-level contextual factors, investigating behavioural mediators, and disaggregating by sex in assessing HIV risk in order to uncover potential mechanisms of action and points of preventive intervention.


New spectrophotometer and tristimulus mask colorimeter.
An apparatus is described which consists of a double grating-mirror dispersion system, and which can be used both as a spectrophotometer and as a tristimulus calorimeter of high accuracy. Three masks, cut to the exact requirements of the CIE distribution coefficients for equal energy stimuli, can be placed alternately in the plane of the spectrum. Chromaticities were calculated for some fluorescent lamps from their spectral irradiance data and also directly measured by utilizing the three masks. These results are compared and discussed. Results are also given of measurements made on a set of fluorescent lamps both by a mask photometer at NPL, Teddington, and by the NPRL mask photometer.


Effect of canrenone on the disturbances of cation handling induced by ouabain in macrophages and vascular smooth muscle cells.
Ouabain induced rapid and profound modifications of Na+ and K+ contents in mouse macrophages and cultured vascular smooth muscle cells. In mouse macrophages, we found a one-to-one net Na+ gain and K+ depletion, with a maximal initial rate of 30 to 35 mmol (l X cells X hr)-1 and with an IC50 of about 100 microM. The one-to-one exchange results from at least two additive effects: inhibition of the Na+,K+-pump and stimulation of a furosemide-sensitive, outward Na+,K+-cotransport by the increase in internal Na+ content. The latter effect helps the cell to maintain a normal cell volume in spite of the large changes in internal cation content. In cultured vascular smooth muscle cells from rat aorta, ouabain provoked net Na+ gain and stimulated a quinidine-sensitive, K+-efflux. This likely reflects the opening of Ca+-dependent, K+-channels in response to an increase in cytosolic-free Ca+ content. Canrenone, an antihypertensive drug, has been shown to behave like a partial agonist at the digitalisreceptor site of the Na+,K+-pump. We observed here in mouse macrophages and cultured vascular smooth muscle cells that: canrenone alone (or at low ouabain concentrations) induces slight Na+ gain and K+ depletion; canrenone partially counterbalances the very rapid cell Na+ gain (and K+ depletion) provoked by high ouabain concentrations, and canrenone reverses the secondary effects of ouabain on the Na+,K+-cotransport system and Ca+-dependent, K+-channels. It appears therefore that canrenone may partially reverse the disturbances of cation handling induced by high concentrations of ouabain in macrophages and vascular smooth muscle cells.


MAP kinase and cAMP filamentation signaling pathways converge on the unusually large promoter of the yeast FLO11 gene.
In Saccharomyces cerevisiae, two major signal transduction pathways, the Kss1 MAPK pathway and the cAMP-regulated pathway, are critical for the differentiation of round yeast form cells to multicellular, invasive pseudohyphae. Here we report that these parallel pathways converge on the promoter of a gene, FLO11, which encodes a cell surface protein required for pseudohyphal formation. The FLO11 promoter is unusually large, containing at least four upstream activation sequences (UASs) and nine repression elements which together span at least 2.8 kb. Several lines of evidence indicate that the MAPK and cAMP signals are received by distinct transcription factors and promoter elements. First, regulation via the MAPK pathway requires the transcription factors Ste12p/Tec1p, whereas cAMP-mediated activation requires a distinct factor, Flo8p. Secondly, mutations in either pathway block FLO11 transcription. Overexpression of STE12 can suppress the loss of FLO8, and overexpression of FLO8 can suppress the loss of STE12. Finally, multiple distinct promoter regions of the FLO11 promoter are required for its activation by either Flo8p or Ste12p/ Tec1p. Thus, like the promoters of the key developmental genes, HO and IME1, the FLO11 promoter is large and complex, endowing it with the ability to integrate multiple inputs.


Genetic predictors of cervical dysplasia in African American HIV-infected women: ACTG DACS 268.
To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naïve studies in the AIDS Clinical Trials Group (ACTG). Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10(-8) for genome-wide associations. No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.


Understanding the axial chirality control of quinidine-derived ammonium cation-directed O-alkylation: a computational study.
As a privileged chiral scaffold, cinchona alkaloid and its derivatives have reached remarkable success in catalytic asymmetric organic synthesis. In addition to the wide applications of point chirality control, Smith and co-workers recently discovered a quinidine-derived ammonium cation-catalyzed O-alkylation of tetralones, providing an effective approach for the synthesis of axially chiral biaryls. Using density functional theory (DFT) calculations, we studied the reaction mechanism and origins of enantioselectivity of this novel transformation. A stepwise strategy is adopted to ensure efficient and thorough exploration of the massive conformational space of transition state. Our computations suggested that enolate oxygen forms two hydrogen bonds with the chiral ammonium catalyst, and the non-covalent interactions between the cationic benzylic fragment and the methoxy group of enolate plays a critical role in determining the enantioselectivity.


A systematic analysis of how medical school characteristics relate to graduates' choices of primary care specialties.
To examine medical school characteristics, in particular federal funding for biomedical research, as they relate to the graduates' choices of family medicine, general internal medicine, general pediatrics, or all three specialties. Data were collected for 121 U.S. medical schools, including information on funding, faculty, curricula, and other school characteristics. In addition, a questionnaire was mailed to the schools requesting information about non-federal funding for primary care, primary care department characteristics, and primary care representation on the admission, curriculum, and promotion and tenure committees. Analyses were carried out separately for each specialty and for all three combined. The first multiple regression analysis was done to predict specialty choice (proximate predictors), the second to predict the predictors of specialty choice (intermediate predictors), and the third to predict those predictors (distal predictors). Prediction was best for family medicine practice. Interest at matriculation and required third-year and fourth-year time in primary care were the two best proximate predictors. The best predictors of initial interest were the percentage of rural students and special programs for primary care, while the best predictors of required time in primary care were funding for family medicine and the percentage of faculty in family medicine (intermediate predictors). The best predictor of the percentage of faculty in family medicine was funding for family medicine (distal predictor). The results suggest that the most effective way to increase the number of physicians with generalist practices is to increase the number of students interested in a family medicine career at matriculation.


[Apparent life-threatening event in infants: think about star anise intoxication!].
In previous years, several publications have reported cases of infants presenting neurological and gastrointestinal symptoms after ingestion of star anise tea. Such teas are sometimes given in various cultures for the treatment of infant colic pains. In most cases, the cause of intoxication was contamination of Chinese star anise (Illicium verum) by Japanese star anise (Illicium anisatum). Indeed, the toxicity of Illicium anisatum, also known as Shikimi, is caused by its content in potent neurotoxins (anisatin, neoanisatin, and pseudoanisatin), due to their activity as non-competitive antagonists of GABA receptors. The main reasons explaining the frequent contaminations are the strong macroscopic resemblance of the 2 substances, as well as the fact that the fruits are often sold partially broken or in ground form. Therefore, in most cases, chemical analysis is required to determine the possible adulterations. A 2-month-old infant, in good general health, was brought to the emergency unit after 3 consecutive episodes of central cyanosis and tetany of the limbs with spontaneous recovery the same afternoon. The child was also very irritable, regurgitated a lot, and positioned himself in opisthotonos. Between these episodes, the neurological exam showed some perturbations (horizontal nystagmus and Bell's phenomenon, hypertony of the extensor muscles, and mild hypotony of the axial flexor muscles) with slow improvement over the following hours. The remaining clinical exam, the laboratory work (complete blood count, renal, hepatic, and muscular tests, capillary blood gas, plasmatic amino acids, and urinary organic acids), and the electroencephalogram findings were all normal. In the course of a detailed interview, the parents reported having given 3 bottles to their child, each one containing 200 mL of an infusion with 4 to 5 fruits of star anise, in the hours preceding the symptoms to relieve colic pains. The last seizure-like event took place approximately 8h after the last ingestion. We could prove the ingestion of anisatin, the toxic substance found in Japanese star anise, and the contamination of Chinese star anise by the Japanese species. Indeed, the anisatin analysis by liquid chromatography and mass spectroscopy (LC-MS) in a urine sample taken 22 h after the last infusion ingestion showed trace amounts of the substance. In another urine sample taken 33 h after ingestion, no anisatin could be detected. Furthermore, the analysis of the fruit sample gave an anisatin concentration of 7800 μg/kg while the maximum tolerance value in Switzerland is 1000 μg/kg. The evaluation of ALTE in infants should always include the possibility of intoxication. Star anise is generally considered a harmless medicine. Nevertheless, it can sometimes cause a severe intoxication resulting in various neurological and gastrointestinal symptoms. To prevent such events, not only the parents, but also the care personnel and pharmacists must be informed about the possible adverse effects caused either by the overdose of Chinese star anise or by the eventual contamination of herbal teas with Japanese star anise. A better control of the substances by the health authorities is also necessary.


Vaccines for preventing typhoid fever.
Typhoid fever and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and southeast Asia. Two typhoid vaccines are commercially available, Ty21a (oral) and Vi polysaccharide (parenteral), but neither is used routinely. Other vaccines, such as a new, modified, conjugated Vi vaccine called Vi-rEPA, are in development. To evaluate the efficacy and adverse effects of vaccines used to prevent typhoid fever. In June 2013, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and mRCT. We also searched relevant conference proceedings up to 2013 and scanned the reference lists of all included trials. Randomized and quasi-randomized controlled trials (RCTs) comparing typhoid fever vaccines with other typhoid fever vaccines or with an inactive agent (placebo or vaccine for a different disease). Two review authors independently applied inclusion criteria and extracted data. We computed vaccine efficacy per year of follow-up and cumulative three-year efficacy, stratifying for vaccine type and dose. The outcome addressed was typhoid fever, defined as isolation of Salmonella typhi in blood. We calculated risk ratios (RRs) and efficacy (1-RR as a percentage) with 95% confidence intervals (CIs). In total, 18 RCTs were included in this review; 12 evaluated efficacy (Ty21a: five trials; Vi polysaccharide: six trials; Vi-rEPA: one trial), and 11 reported on adverse events. Ty21a vaccine (oral vaccine, three doses) A three-dose schedule of Ty21a vaccine prevents around one-third to one-half of typhoid cases in the first two years after vaccination (Year 1: 35%, 95% CI 8% to 54%; Year 2: 58%, 95% CI 40% to 71%; one trial, 20,543 participants; moderate quality evidence; data taken from a single trial conducted in Indonesia in the 1980s). No benefit was detected in the third year after vaccination. Four additional cluster-RCTs have been conducted, but the study authors did not adjust for clustering.Compared with placebo, this vaccine was not associated with more participants with vomiting, diarrhoea, nausea or abdominal pain (four trials, 2066 participants; moderate quality evidence) headache, or rash (two trials, 1190 participants; moderate quality evidence); however, fever (four trials, 2066 participants; moderate quality evidence) was more common in the vaccine group. Vi polysaccharide vaccine (injection, one dose) A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (Year 1: 69%, 95% CI 63% to 74%; three trials, 99,979 participants; high quality evidence). In Year 2, the trial results were more variable, with the vaccine preventing between 45% and 69% of typhoid cases (Year 2: 59%, 95% CI 45% to 69%; four trials, 194,969 participants; moderate quality evidence). The three-year cumulative efficacy of the vaccine is around 55% (95% CI 30% to 70%; 11,384 participants, one trial; moderate quality evidence). These data are taken from a single trial in South Africa in the 1980s.Compared with placebo, this vaccine was not associated with more participants with fever (four trials, 133,038 participants; moderate quality evidence) or erythema (three trials, 132,261 participants; low quality evidence); however, swelling (three trials, 1767 participants; moderate quality evidence) and pain at the injection site (one trial, 667 participants; moderate quality evidence) were more common in the vaccine group. Vi-rEPA vaccine (two doses) Administration of two doses of the Vi-rEPA vaccine prevents between 50% and 96% of typhoid cases during the first two years after vaccination (Year 1: 94%, 95% CI 75% to 99%; Year 2: 87%, 95% CI 56% to 96%; one trial, 12,008 participants; moderate quality evidence). These data are taken from a single trial with children 2 to 5 years of age conducted in Vietnam.Compared with placebo, the first and second doses of this vaccine were not associated with increased risk of adverse events. The first dose of this vaccine was not associated with fever (2 studies, 12,209 participants; low quality evidence), erythema (two trials, 12,209 participants; moderate quality evidence) or swelling at the injection site (two trials, 12,209 participants; moderate quality evidence). The second dose of this vaccine was not associated with fever (two trials, 11,286 participants; low quality evidence), erythema (two trials, 11,286 participants; moderate quality evidence) and swelling at the injection site (two trials, 11,286 participants; moderate quality evidence). The licensed Ty21a and Vi polysaccharide vaccines are efficacious. The new and unlicensed Vi-rEPA vaccine is as efficacious and may confer longer immunity.


An in vitro study of pcDNA 3.0-hVEGF165 gene transfection in endothelial progenitor cells derived from peripheral blood of rabbits.
The present study investigated the effect of the VEGF165 gene on adhesion, migration, and proliferation of endothelial progenitor cells (EPCs) derived from peripheral blood of rabbits. Peripheral blood mononuclear cells were isolated from rabbits by density gradient centrifugation with Ficoll-Plaque Plus. EPCs were characterized by immunofluorescence and immunostaining. A pcDNA 3.0-hVEGF165 expression vector was constructed and EPCs were transfected with the pcDNA 3.0-hVEGF165 gene. The EPCs derived from peripheral blood of rabbits were successfully transfected with pcDNA 3.0-hVEGF165. ELISA showed that the expression of VEGF165 increased significantly in the EPCs transfected with the hVEGF165 gene compared to control cells. Compared to control EPCs, EPCs transfected with the hVEGF165 gene had significantly enhanced adhesion, migration, and proliferative ability in vitro.


The influence of RAPTA moieties on the antiproliferative activity of peripheral-functionalised poly(salicylaldiminato) metallodendrimers.
Cationic N,O-chelating dendrimers functionalised on the periphery with RAPTA-like (ruthenium(II)-arene-1,3,5-triaza-7-phosphatricyclo[126.96.36.199]decane) moieties have been synthesised and characterised using NMR and IR spectroscopy, elemental analysis and MALDI-TOF/HR-ESI mass spectrometry. Metallodendrimers from the first to the fourth-generation containing up to 32 peripheral ruthenium-arene-PTA moieties were obtained. Model mononuclear analogues, [{Ru(η(6)-p-cymene)((C(7)H(5)NO)-κ(2)-N,O)(PTA)}((CH(2))(3))][PF(6)] and [{Ru(η(6)hexamethylbenzene)((C(7)H(5)NO)-κ(2)-N,O)(PTA)}((CH(2))(3))][PF(6)], have been prepared and their structures were determined by single crystal X-ray diffraction analysis. The cytotoxicities of the metallodendrimers and their mononuclear analogues were established on A2780 and A2780cisR human ovarian carcinoma cancer cells and model human embryonic kidney (HEK) cells.


Sentinel lymph node biopsy in breast cancer: scientific rationale and patient care.
To describe the history of sentinel lymph node biopsy (SLNB), review the current scientific literature comparing the benefits and shortcomings of SLNB with traditional axillary lymph node dissection, and describe the nursing role that should be employed when instructing patients who are considering SLNB. Journal articles, published research data, and clinical experience. Traditional axillary lymph node dissection has the potential to cause serious complications such as lymphedema, scarring, numbness, pain, and psychological distress. Given that approximately 70% of women with early-stage breast cancer will have no evidence of regional lymph node involvement at the time of surgery, determining who is likely to have negative nodes will spare women these potential complications. SLNB can significantly minimize the morbidity associated with axillary lymph node dissection while providing accurate diagnostic and prognostic information. SLNB has been well documented in the scientific literature from multiple phase III clinical trials as an accurate, safe, and fiscally conservative alternative to traditional axillary lymph node dissection for women who present with early-stage breast cancer. Furthermore, future results from multicenter, randomized clinical trials now under way ultimately will determine the role for SLNB in the years to come. Nurses in the outpatient setting can help to minimize the anxiety and fear that patients have when they are considering SLNB versus the more traditional axillary lymph node dissection. Oncology nurses also serve as resources to other nurses, healthcare professionals, and the public as more information is learned concerning the role of SLNB in early-stage breast cancer.


Diosgenin restores Aβ-induced axonal degeneration by reducing the expression of heat shock cognate 70 (HSC70).
We previously found diosgenin, an herbal drug-derived steroid sapogenin, to be remarkably effective at restoring Aβ-induced axonal degeneration and improving memory function in model of Alzheimer's disease (AD), 5XFAD mouse. In this study, we investigated the downstream signaling of diosgenin and explored new therapeutic targets in AD. We showed that the expression of heat shock cognate (HSC) 70 was increased in Aβ-treated neurons and in 5XFAD mice but was decreased by diosgenin treatment. In addition, knockdown of HSC70 significantly promoted axonal growth in neurons. As an association molecule of HSC70 in neurons, α-tubulin was detected by immunoprecipitation. After Aβ treatment, α-tubulin expression was greatly reduced in the degenerated axons, suggesting that a decline in α-tubulin may be one of the factors which correlates with axonal disruption in AD pathology. We hypothesized that the degradation of α-tubulin is triggered by the chaperone activity of HSC70. However, diosgenin significantly normalized the α-tubulin level, a potentially critical process for axonal formation. Our study indicated that reducing the HSC70 level is a new possible therapeutic target of axonal regeneration in AD.


Specific poly-phenolic compounds in cell culture of Vitis vinifera L. cv. Gamay Fréaux.
Cell cultures established from plants represent an attractive alternative to whole plants for effective production of bioactive secondary metabolites. Cell culture from Vitis vinifera L. cv. Gamay Fréaux accumulated high amounts of hydroxycinnamic acid derivatives and anthocyanins. Two new compounds were identified: 3-O-glucosylresveratrol, a stilbene derivative, abundant in cell suspension culture, and a hydroxyphenol, 4-(3,5-dihydroxyphenyl)-phenol, abundant in callus culture. The major anthocyanin monoglucosides present in cell suspension culture were cyanidin 3-O-glucoside and peonidin 3-O-glucoside, and the major cinnamoyl derivatives were cyanidin 3-O-p-coumaryl glucoside and peonidin 3-O-p-coumaryl glucoside. Three minor anthocyanin compounds were found in V. vinifera cell culture: delphinidin 3-O-glucoside, petunidin 3-O-glucoside, and delphinidin 3-O-pcoumaryl glucoside. Anthocyanin levels of cell suspension cultures increased significantly--about eight fold--after 4-day cultivation in new medium. Salicylic acid at a concentration of 50 μM did not enhance anthocyanin accumulation in cell suspension culture, and similar levels of jasmonic acid significantly reduced the anthocyanin content.


Structure-activity relationship investigations of leishmanicidal N-benzylcytisine derivatives.
In vitro leishmanicidal activity of 16 N-benzylcytisine derivatives has been evaluated using Leishmania donovani axenic amastigotes. In general, halogen (bromo-, chloro-) derivatives appeared to be more toxic against parasites than their parent compounds. Quantum-chemical calculations helped to recognize certain patterns in the structure of frontier orbitals related to bioactivity of compounds. Thus, the presence of halogen atom is shown to have a significant effect on both distribution and the energy of LUMOs thereby on potent activity that was also confirmed by Quantitative-Structure Activity Relationship (QSAR) analysis. Experimentally and theoretically observed structure-cytotoxicity relationships are described.


A Psychophysiological Study of Processing HIV/AIDS Public Service Announcements: The Effects of Novelty Appeals, Sexual Appeals, Narrative Versus Statistical Evidence, and Viewer's Sex.
This study used self-reports and physiological measures-heart rate (HR) and skin conductance level (SCL)-to examine the effects of novelty appeals, sexual appeals, narrative versus statistical evidence, and viewer's sex on cognitive and emotional processing of HIV/AIDS public service announcements (PSAs) among heterosexually active single college students. Novelty or sexual appeals differently affected self-reported attention and cognitive effort as measured by HR. High- rather than low-novelty HIV/AIDS PSAs, perceived as more attention-eliciting, did not lead to more cognitive effort. High- rather than low-sex HIV/AIDS PSAs, not perceived as more attention-eliciting, led to more cognitive effort as reflected by greater HR deceleration. Novelty or sexual appeals also affected self-reported emotional arousal and SCL differently. HIV/AIDS PSAs with high rather than low levels of novelty or sexual appeals led to greater self-reported arousal, but not greater SCL. Message evidence interacted with message appeals to affect cognitive effort. Participants exerted greater cognitive effort during high- rather than low-novelty narrative HIV/AIDS PSAs, and during low- rather than high-novelty statistical ones. The advantage of high over low sexual appeals was more obvious in statistical than in narrative HIV/AIDS PSAs. Males reported greater emotional arousal than females during high- rather than low-sex HIV/AIDS PSAs.


Atypical postictal transient subcortical T2 hypointensity in a newly diagnosed diabetic patient with seizures.
Common postictal MRI findings include transient cortical T2 hyperintensity, restricted diffusion, and gyral and/or adjacent leptomeningeal contrast enhancement. In certain uncommon pathological conditions, other signal abnormalities can be present, suggesting a different underlying pathogenic mechanism. We report the case of a 66-year-old man, recently diagnosed with diabetes mellitus type 2, presenting with new-onset visual and auditory hallucinations, "absence" seizures, and repeated peaks of hyperglycaemia without hyperketonaemia or increased serum osmolarity. EEG confirmed epileptic discharges in the right temporal region and MRI showed vast subcortical T2 hypointensity in the right temporal lobe, without any cortical hyperintensity, restricted diffusion, or contrast enhancement. Subcortical signal abnormality and EEG discharges resolved after a month of follow-up, with a small juxtacortical gliotic focus as a sequela. Peaks in hyperglycaemia have been reported to be responsible for T2 hypointense subcortical abnormalities through a proconvulsant mechanism linked to increased ketone body concentrations. Hyperosmolarity and hyperketonaemia were not evident in this case, however, transient accumulation of free radicals that alter the intercellular space can be considered the presumable cause of this finding. In summary, it is important to consider any unusual findings on postictal MRI in order to avoid errors in interpretation.


Evidence of cross-cutting and redox reaction in Khatyrka meteorite reveals metallic-Al minerals formed in outer space.
We report on a fragment of the quasicrystal-bearing CV3 carbonaceous chondrite Khatyrka recovered from fine-grained, clay-rich sediments in the Koryak Mountains, Chukotka (Russia). We show higher melting-point silicate glass cross-cutting lower melting-point Al-Cu-Fe alloys, as well as unambiguous evidence of a reduction-oxidation reaction history between Al-Cu-Fe alloys and silicate melt. The redox reactions involve reduction of FeO and SiO2 to Fe and Fe-Si metal, and oxidation of metallic Al to Al2O3, occurring where silicate melt was in contact with Al-Cu-Fe alloys. In the reaction zone, there are metallic Fe and Fe-Si beads, aluminous spinel rinds on the Al-Cu-Fe alloys, and Al2O3 enrichment in the silicate melt surrounding the alloys. From this and other evidence, we demonstrate that Khatyrka must have experienced at least two distinct events: first, an event as early as 4.564 Ga in which the first Al-Cu-Fe alloys formed; and, second, a more recent impact-induced shock in space that led to transformations of and reactions between the alloys and the meteorite matrix. The new evidence firmly establishes that the Al-Cu-Fe alloys (including quasicrystals) formed in outer space in a complex, multi-stage process.


UGT2B17 Genotype and the Pharmacokinetic Serum Profile of Testosterone during Substitution Therapy with Testosterone Undecanoate. A Retrospective Experience from 207 Men with Hypogonadism.
Testosterone (T) is mainly excreted in the urine as testosterone glucuronide (TG). This glucuronidation is partly dependent on the UGT2B17 genotype, and TG excretion is therefore lower in men having the UGT2B17 deletion. However, the possible influence of UGT2B17 genotype on serum T during androgen therapy is unknown. We retrospectively investigated the possible association between the UGT2B17 gene polymorphism and serum T levels in hypogonadal men during Testosterone undecanoate (TU) substitution therapy. Two hundred and seven patients treated with TU (Nebido(®)) were genotyped by quantitative polymerase chain reaction for the UGT2B17 deletion polymorphism. All were given 1000 mg TU per injection at 0, 6, and 18 weeks. Blood samples were taken 2 and 6 weeks after the first and second injection, prior to the third injection, and after 2-3 years of treatment. We analyzed for the levels of T, luteinizing hormone (LH), sex-hormone-binding globulin, estradiol, prostate specific antigen, hematocrit, hemoglobin, and total cholesterol. The UGT2B17 genotype frequency was: ins/ins: 42%, ins/del: 44%, and del/del: 14%. During the initial 18 weeks of TU treatment, large intra- and inter-individual variations in serum T levels were observed. Large peaks in T levels, ranging from 6.7 to 69.5 nmol/l, were noted 2 weeks after injections, regardless of the genotype. T levels did not differ between the three genotypes prior to the third injection, but the del/del group had significantly lower levels of LH. At follow-up after 2-3 years, the injection interval or daily T dosage was not dependent on the UGT2B17 genotype. In conclusion, we found large intra- and inter-individual variations in serum T during standard TU treatment regimen in hypogonadal men. Only subtle differences in serum T and LH were noted according to UGT2B17 genotype, which however suggest that the UGT2B17 genotype exert modest influence on the pharmacokinetic profile of T after TU treatment.


Correlation of intraoperative parathyroid hormone levels with parathyroid gland size.
To study the relationship of intraoperative intact parathyroid hormone levels (iPTH) with parathyroid adenoma weight and volume in patients with primary hyperparathyroidism. Retrospective evaluation of consecutive patients undergoing minimally invasive parathyroidectomy with iPTH measurement. Data collected include preoperative serum calcium, ionized calcium, and serum parathyroid hormone (PTH) levels, iPTH levels at baseline, 5 minutes, and 10 minutes, and parathyroid adenoma weight. Adenoma volume was calculated using an equation for the volume of a spheroid object. Thirty patients underwent minimally invasive parathyroidectomy with iPTH measurement for a single parathyroid adenoma between March 2004 and January 2006. There were 8 men and 22 women, with a mean age of 59.3 (range 26-92) years. A significant correlation between preoperative serum calcium and ionized calcium levels and parathyroid adenoma weight was identified (P = .0008 and P = .03, respectively). A significant correlation was also shown between baseline iPTH measurements and parathyroid adenoma volume (P = .03). There was no correlation between baseline iPTH levels and parathyroid adenoma weight. There was a significant correlation between parathyroid adenoma weight and percentage decrease of iPTH levels at 10 minutes compared to baseline (P = .04). Preoperative serum calcium and baseline iPTH levels may be useful in predicting parathyroid adenoma weight and volume, respectively. Adenoma weight may relate to the percentage decrease of iPTH levels at the 10-minute postparathyroidectomy interval.


Measurements of stiffness of extraocular muscles of the rabbit.
1. The stiffness of the eye and the extraocular muscles of the conscious rabbit was measured and compared with similar measurements made on human subjects. 2. The extraocular muscles of the rabbit developed less than 0.5 g at optimal isometric length when the contralateral eye was in "primary position". Deviations of the eye of the rabbit from primary position were accomplished by an increase in force of the agonist muscle with only a nominal decrease in force in the antagonist. 3. With all muscles attached to the globe, the stiffness of the eye for displacements of up to 35 degrees from primary position was 0.11 +/- 0.03 g/deg. 4. The stiffness of the human eye to lateral rotations was 1.09 +/- 0.24 g/deg. Hence, identical disturbances in force would cause deviations in the position of the eye of the rabbit which are nearly an order of magnitude greater than those of man. 5. The stiffness of the extraocular muscles of the rabbit was sensitive to levels of muscle activation produced either by indirect electrical stimulation or by the vestibuloocular reflex. 6. The implications of these findings for the development of eye position control in animals with good binocular vision are discussed.


Comparison of the transcriptional profiles of head and body lice.
Head and body lice are both blood-feeding parasites of humans although only the body louse is a potent disease vector. In spite of numerous morphological and life history differences, head and body lice have recently been hypothesized to be ecotypes of the same species. We took a comparative genomics approach to measure nucleotide diversity by comparing expressed sequence tag data sets from head and body lice. A total of 10 771 body louse and 10 770 head louse transcripts were predicted from a combined assembly of Roche 454 and Illumina sequenced cDNAs from whole body tissues collected at all life stages and during pesticide exposure and bacterial infection treatments. Illumina reads mapped to the 10 775 draft body louse gene models from the whole genome assembly predicted nine presence/absence differences, but PCR confirmation resulted in a single gene difference. Read per million base pair estimates indicated that 14 genes showed significant differential expression between head and body lice under our treatment conditions. One novel microRNA was predicted in both lice species and 99% of the 544 transcripts from Candidatus riesia indicate that they share the same endosymbiont. Overall, few differences exist, which supports the hypothesis that these two organisms are ecotypes of the same species.


Sexual and reproductive health in HIV-related proposals supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria.
To assess the sexual and reproductive health interventions included by countries in HIV-related proposals approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund). We examined the Global Fund database for elements and indicators of sexual and reproductive health in all approved HIV-related proposals (214) submitted by 134 countries, from rounds 1 to 7, and in an illustrative sample of 35 grant agreements. At least 70% of the HIV-related proposals included one or more of the four broad elements: sexual and reproductive health information, education and communication; condom promotion/distribution; diagnosis and treatment of sexually transmitted infections; and prevention of mother-to-child transmission of HIV. Between 20% and 30% included sexual health counselling, gender-based violence, and the linking of voluntary counselling and testing for HIV with sexual and reproductive health services. Less than 20% focused on adolescent sexual and reproductive health, the rights and needs of people living with HIV, or safe abortion services. All these elements were rarely featured, if at all, in the grant agreements reviewed. Overall, however, sexual and reproductive health indicators did appear in most HIV-related proposals and in more than 80% of the grant agreements. Country coordinating mechanisms and national-level stakeholders see in funding for sexual and reproductive health a means to address the problem of HIV infection in their respective national settings. However, we highlight some missed opportunities for linking HIV and sexual and reproductive health services.


Thyroidectomy in the cat.
Thyroidectomy in cats is most commonly indicated to treat hyperthyroidism because of adenomatous hyperplasia of the thyroid glands. Preoperative stabilization of the hyperthyroid cat with antithyroid drugs is preferred to minimize anesthetic and surgical complications. Multiple surgical techniques for thyroidectomy have been reported, and results of surgery and complications differ between techniques. The extracapsular technique offers the most complete removal of abnormal thyroid tissue, while still being associated with a low incidence of postoperative hypoparathyroidism. Important postoperative considerations are to carefully monitor serum calcium concentrations and treat hypocalcemia if necessary, and to monitor the cat for evidence of relapse of hyperthyroidism.


Influence of smoking and oral contraceptives on bone mineral density and bone remodeling in young women: a 2-year study.
The objective of the study was to explore the influence of menstrual irregularities, oral contraceptives and smoking on bone mineral density (BMD) development and bone turnover with time. Healthy young women (n = 118) were divided into four categories: (a) women neither smoking nor using oral contraceptives; (b) women who were smokers; (c) women using oral contraceptives; (d) women who were smoking and using oral contraceptives. They responded to a validated questionnaire with 34 questions concerning lifestyle and the Sense of Coherence scale (SOC). BMD was measured by dual energy x-ray absorptiometry (DEXA). Deoxypyridinoline (DPD) was measured in urine. Data were analyzed by multiple linear regression analysis. Among smokers, BMD level decreased during a 2-year period and smoking was associated with a larger negative change in BMD. Use of oral contraceptives moderated the negative impact of smoking. Women using oral contraceptives at baseline and with regular bleeding induced by contraceptive pills had a significantly higher BMD at baseline and at follow-up. They also had lower SOC than women who had natural regular bleedings. Use of oral contraceptives in combination with smoking was linked to high alcohol consumption and higher frequency of self-reported body weight reduction, which reduced the negative BMD change in this category. DPD level and difference were strongly associated with estrogen influence. It is concluded that smokers without OCs had a negative BMD development and BMD in young women with irregular menstruations seems to be improved by OC.


Climate change and macro-economic cycles in pre-industrial europe.
Climate change has been proven to be the ultimate cause of social crisis in pre-industrial Europe at a large scale. However, detailed analyses on climate change and macro-economic cycles in the pre-industrial era remain lacking, especially within different temporal scales. Therefore, fine-grained, paleo-climate, and economic data were employed with statistical methods to quantitatively assess the relations between climate change and agrarian economy in Europe during AD 1500 to 1800. In the study, the Butterworth filter was adopted to filter the data series into a long-term trend (low-frequency) and short-term fluctuations (high-frequency). Granger Causality Analysis was conducted to scrutinize the associations between climate change and macro-economic cycle at different frequency bands. Based on quantitative results, climate change can only show significant effects on the macro-economic cycle within the long-term. In terms of the short-term effects, society can relieve the influences from climate variations by social adaptation methods and self-adjustment mechanism. On a large spatial scale, temperature holds higher importance for the European agrarian economy than precipitation. By examining the supply-demand mechanism in the grain market, population during the study period acted as the producer in the long term, whereas as the consumer in the short term. These findings merely reflect the general interactions between climate change and macro-economic cycles at the large spatial region with a long-term study period. The findings neither illustrate individual incidents that can temporarily distort the agrarian economy nor explain some specific cases. In the study, the scale thinking in the analysis is raised as an essential methodological issue for the first time to interpret the associations between climatic impact and macro-economy in the past agrarian society within different temporal scales.


Diketopyrrolopyrrole-based semiconducting polymer nanoparticles for in vivo second near-infrared window imaging and image-guided tumor surgery.
A diketopyrrolopyrrole-based semiconducting polymer nanoparticle (PDFT1032) has been developed as a NIR-II (near infrared window II, 1000-1700 nm) fluorescent probe. It shows high photostability, a favorable absorption peak at 809 nm, a large Stokes shift of 223 nm, outstanding biocompatibility and minimal in vivo toxicity. More importantly, the versatile use of PDFT1032 for several important biomedical applications in the NIR-II window has been demonstrated, including the NIR-II optical imaging of tumors on a subcutaneous osteosarcoma model, assessing the vascular embolization therapy of tumors, and NIR-II image-guided orthotopic tumor surgery and sentinel lymph node biopsy (SLNB) with high spatial and temporal resolution. Overall, excellent biocompatibility, favorable hydrophilicity, and desirable chemical and optical properties make the semiconducting polymer nanoparticle PDFT1032 a highly promising NIR-II imaging probe with the potential to be widely applicable in clinical imaging and the surgical treatment of malignancy.


Transfer studies of polystyrene nanoparticles in the ex vivo human placenta perfusion model: key sources of artifacts.
Nanotechnology is a rapidly expanding and highly promising new technology with many different fields of application. Consequently, the investigation of engineered nanoparticles in biological systems is steadily increasing. Questions about the safety of such engineered nanoparticles are very important and the most critical subject with regard to the penetration of biological barriers allowing particle distribution throughout the human body. Such translocation studies are technically challenging and many issues have to be considered to obtain meaningful and comparable results. Here we report on the transfer of polystyrene nanoparticles across the human placenta using an ex vivo human placenta perfusion model. We provide an overview of several challenges that can potentially occur in any translocation study in relation to particle size distribution, functionalization and stability of labels. In conclusion, a careful assessment of nanoparticle properties in a physiologically relevant milieu is as challenging and important as the actual study of nanoparticle-cell interactions itself.


Pelvic incidence-lumbar lordosis mismatch results in increased segmental joint loads in the unfused and fused lumbar spine.
Symptomatic adjacent segment disease (ASD) has been reported to occur in up to 27 % of lumbar fusion patients. A previous study identified patients at risk according to the difference of pelvic incidence and lordosis. Patients with a difference between pelvic incidence and lumbar lordosis >15° have been found to have a 20 times higher risk for ASD. Therefore, it was the aim of the present study to investigate forces acting on the adjacent segment in relation to pelvic incidence-lumbar lordosis (PILL) mismatch as a measure of spino-pelvic alignment using rigid body modeling to decipher the underlying forces as potential contributors to degeneration of the adjacent segment. Sagittal configurations of 81 subjects were reconstructed in a musculoskeletal simulation environment. Lumbar spine height was normalized, and body and segmental mass properties were kept constant throughout the population to isolate the effect of sagittal alignment. A uniform forward/backward flexion movement (0°-30°-0°) was simulated for all subjects. Intervertebral joint loads at lumbar level L3-L4 and L4-L5 were determined before and after simulated fusion. In the unfused state, an approximately linear relationship between sagittal alignment and intervertebral loads could be established (shear: 0° flexion r = 0.36, p < 0.001, 30° flexion r = 0.48, p < 0.001; compression: 0° flexion r = 0.29, p < 0.01, 30° flexion r = 0.40, p < 0.001). Additionally, shear changes during the transition from upright to 30° flexed posture were on average 32 % higher at level L3-L4 and 14 % higher at level L4-L5 in alignments that were clinically observed to be prone to ASD. Simulated fusion affected shear forces at the level L3-L4 by 15 % (L4-L5 fusion) and 23 % (L4-S1 fusion) more for alignments at risk for ASD. Higher adjacent segment shear forces in alignments at risk for ASD already prior to fusion provide a mechanistic explanation for the clinically observed correlation between PILL mismatch and rate of adjacent segment degeneration.


Desmin as a marker of proteinuria in early stages of membranous nephropathy in elderly patients.
Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults worldwide. Many patients with IMN are elderly, but little is known about the relationship regarding the morphological stage determined by electron microscopy (EM), the amount of proteinuria, and the expression of glomerular podocyte markers such as desmin and nephrin in nephrotic glomeruli in IMN. We studied 59 patients with histopathologically proven IMN. We compared the clinical features, EM stage classification, and the immunohistochemical features of glomerular expression of podocyte markers, including desmin and nephrin, between older (age > or = 60 years) and younger (age < 60 years) patients. We also investigated these parameters in patients with minimal-change nephrotic syndrome (MCNS), minor glomerular abnormalities (MGA), and normal kidneys as age-matched controls. Prevalence of nephrotic syndrome was significantly higher in the older (52.9%) than the younger group (20.0%) of IMN. The level of proteinuria was higher in early stages (Stages I + II) than in late stages (Stages III + IV) in IMN. The glomerular expression of desmin in podocytes was significantly higher in IMN as compared to MCNS, MGA, or age-matched controls. Desmin expression was significantly increased in earlier EM stages (Stages I + II) and in higher proteinuric group (daily proteinuria > or = 1 g) of older patients with IMN. Reciprocally, the reduced expression of nephrin was associated with the early EM stages (Stages I + II) of patients with IMN. We conclude that the expression of desmin in podocytes is upregulated in patients with IMN as compared to other glomerular diseases including MCNS or MGA, or to controls. In elderly patients with IMN, desmin expression was associated with early EM stages and heavy proteinuria, which may reflect phenotypic alteration of the podocyte.


Gender is a determinative factor in the initial clinical presentation of eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease resulting in symptoms of esophageal dysmotility. Abnormalities include dysphagia, food impaction and reflux. Although men appear to comprise a majority of the EoE population, few studies have directly assessed gender-associated clinical differences. The aim of this study is to identify the effect of gender on the initial clinical presentation of adult-onset EoE patients. We reviewed our electronic medical record database from January 2008 to December 2011 for adults diagnosed with EoE per the 2011 updated consensus guidelines. Patient demographics, presenting symptoms, endoscopy findings and complications were recorded. Proportions were compared using chi-squared analysis, and means were compared using the Student's t-test. A total of 162 patients met the inclusion criteria and 71 (44%) were women. Women were more likely to report chest pain (P = 0.03) and heartburn (P = 0.06), whereas men more commonly reported dysphagia (P = 0.04) and a history of food impaction (P = 0.05). Endoscopic findings were similar between groups. No patients suffered esophageal perforations. These data suggest that men report more fibrostenotic symptoms and women report more inflammatory symptoms at the time of diagnosis. There was no difference in endoscopic findings between genders. This is one of the only reviews comparing differences in clinical presentation, endoscopic findings and complications between gender for EoE. The current recommended guidelines state that any patient with symptoms of esophageal dysfunction should be biopsied for EoE. Our findings support biopsying patients with typical and atypical symptoms of dysmotility including heartburn and chest pain.


From mechanostat theory to development of the "Functional Muscle-Bone-Unit".
Bone densitometric data are often difficult to interpret in children and adolescents because of large inter- and intraindividual variations in bone size. Here, we propose a functional approach to bone densitometry that addresses two questions: is bone strength normally adapted to the largest physiological loads, that is, muscle force? Is muscle force adequate for body size? The theoretical background for this approach is provided by the mechanostat theory, which proposes that bones adapt their strength to keep the strain caused by physiological loads close to a set point. Because the largest physiological loads are caused by muscle contractions, there should be a close relationship between bone strength and muscle force or size. The proposed two-step diagnostic algorithm requires a measure of muscle force or size and a measure of bone mineral content (BMC) at a corresponding location. The results can be combined into four diagnostic groups. In the first situation, muscle force or size is adequate for height. If the skeleton is adapted normally to the muscle system, the result is interpreted as "normal". If it is lower than expected for muscle force or size, a "primary bone defect" is diagnosed. In the second situation, muscle force or size is too low for height. Even if the skeleton is adapted adequately to the decreased mechanical challenge, this means that bone mass and presumably strength are still too low for body height. Therefore, a "secondary bone defect" is diagnosed. It is hoped that the more detailed insights thus gained could help to devise targeted strategies for the prevention and treatment of pediatric bone diseases.


Design Optimization in Lower Limb Prostheses: A Review.
This paper aims to develop a knowledge base and identify the promising research pathways toward designing lower limb prostheses for optimal biomechanical and clinical outcomes. It is based on the literature search representing the state of the art in the lower limb prosthesis joint design and biomechanical analysis. Current design solutions are organized in terms of fulfilling four key functional roles: body support, propulsion, task flexibility, and loading relief. Biomechanical analyses of these designs reveal that the hypothesized outcomes are not consistently observed. We suggest that these outcomes may be improved by incorporating tools that can predict user performance metrics to optimize the device during the initial design process. We also note that the scope of the solution space of most current designs is limited by focusing on the anthropomorphic design approaches that do not account for the person's altered anatomy post-amputation. The effects of the prosthetic joint behavior on whole-body gait biomechanics and user experience are likewise under-explored. Two research paths to support the goal of better predicting the user outcomes are proposed: experimental parameterization of designs and model-based simulations. However, while work in these areas has introduced promising new possibilities, connecting both to improve real-world performance remains a challenge.


Neuropathic pain: is quantitative sensory testing helpful?
Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system and is characterised by a combination of positive and negative sensory symptoms. Quantitative sensory testing (QST) examines the sensory perception after application of different mechanical and thermal stimuli of controlled intensity and the function of both large (A-beta) and small (A-delta and C) nerve fibres, including the corresponding central pathways. QST can be used to determine detection, pain thresholds and stimulus-response curves and can thus detect both negative and positive sensory signs, the second ones not being assessed by other methods. Similarly to all other psychophysical tests QST requires standardised examination, instructions and data evaluation to receive valid and reliable results. Since normative data are available, QST can contribute also to the individual diagnosis of neuropathy, especially in the case of isolated small-fibre neuropathy, in contrast to the conventional electrophysiology which assesses only large myelinated fibres. For example, detection of early stages of subclinical neuropathy in symptomatic or asymptomatic patients with diabetes mellitus can be helpful to optimise treatment and identify diabetic foot at risk of ulceration. QST assessed the individual's sensory profile and thus can be valuable to evaluate the underlying pain mechanisms which occur in different frequencies even in the same neuropathic pain syndromes. Furthermore, assessing the exact sensory phenotype by QST might be useful in the future to identify responders to certain treatments in accordance to the underlying pain mechanisms.


Peptidoglycan N-acetylglucosamine deacetylases from Bacillus cereus, highly conserved proteins in Bacillus anthracis.
The genomes of Bacillus cereus and its closest relative Bacillus anthracis contain 10 polysaccharide deacetylase homologues. Six of these homologues have been proposed to be peptidoglycan N-acetylglucosamine deacetylases. Two of these genes, namely bc1960 and bc3618, have been cloned and expressed in Escherichia coli, and the recombinant enzymes have been purified to homogeneity and further characterized. Both enzymes were effective in deacetylating cell wall peptidoglycan from the Gram(+) Bacillus cereus and Bacillus subtilis and the Gram(-) Helicobacter pylori as well as soluble chitin substrates and N-acetylchitooligomers. However, the enzymes were not active on acetylated xylan. These results provide insight into the substrate specificity of carbohydrate esterase family 4 enzymes. It was revealed that both enzymes deacetylated only the GlcNAc residue of the synthetic muropeptide N-acetyl-D-glucosamine-(beta-1,4)-N-acetylmuramyl-L-alanine-D-isoglutamine. Analysis of the constituent muropeptides of peptidoglycan from B. subtilis and H. pylori resulting from incubation of the enzymes BC1960 and BC3618 with these polymers and subsequent hydrolysis by Cellosyl and mutanolysin, respectively, similarly revealed that both enzymes deacetylate GlcNAc residues of peptidoglycan. Kinetic analysis toward GlcNAc(2-6) revealed that GlcNAc4 was the favorable substrate for both enzymes. Identification of the sequence of N-acetychitooligosaccharides (GlcNAc(2-4)) following enzymatic deacetylation by using 1H NMR revealed that both enzymes deacetylate all GlcNAc residues of the oligomers except the reducing end ones. Enzymatic deacetylation of chemically acetylated vegetative peptidoglycan from B. cereus by BC1960 and BC3618 resulted in increased resistance to lysozyme digestion. This is the first biochemical study of bacterial peptidoglycan N-acetylglucosamine deacetylases.


Escherichia coli-derived virus-like particles in vaccine development.
Recombinant virus-like particle-based vaccines are composed of viral structural proteins and mimic authentic native viruses but are devoid of viral genetic materials. They are the active components in highly safe and effective vaccines for the prevention of infectious diseases. Several expression systems have been used for virus-like particle production, ranging from Escherichia coli to mammalian cell lines. The prokaryotic expression system, especially Escherichia coli, is the preferred expression host for producing vaccines for global use. Hecolin, the first licensed virus-like particle vaccine derived from Escherichia coli, has been demonstrated to possess good safety and high efficacy. In this review, we focus on Escherichia coli-derived virus-like particle based vaccines and vaccine candidates that are used for prevention (immunization against microbial pathogens) or disease treatment (directed against cancer or non-infectious diseases). The native-like spatial or higher-order structure is essential for the function of virus-like particles. Thus, the tool box for analyzing the key physicochemical, biochemical and functional attributes of purified virus-like particles will also be discussed. In summary, the Escherichia coli expression system has great potentials for producing a range of proteins with self-assembling properties to be used as vaccine antigens given the proper epitopes were preserved when compared to those in the native pathogens or disease-related target molecules.


Dietary sodium, aldosterone, and left ventricular mass changes during long-term inhibition of the renin-angiotensin system.
In essential hypertension, the regression of left ventricular hypertrophy is an important goal of treatment. In addition to treatment-associated changes in blood pressure (BP), the roles of other determinants of left ventricular hypertrophy regression, including dietary sodium intake, deserve investigation. In the present study, the change in echographic left ventricular mass index (LVMI) was assessed in 182 patients with never-treated essential hypertension at baseline and after 3 years of treatment by angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists given at recommended doses and associated with other antihypertensive agents. Treatment was associated with satisfactory control of BP (<140/90 mm Hg) in 64% of patients, and left ventricular hypertrophy prevalence decreased from 56% to 39%. Twenty-four-hour urinary sodium was positively related to LVMI at baseline and at the end of the study, independently of age, sex, and systolic BP. Supine plasma aldosterone concentration was correlated with LVMI only at baseline but not in multivariate analysis. In response to treatment, the percentage of change in LVMI was positively correlated with the absolute changes in systolic BP, urinary sodium, and plasma aldosterone concentration, independently of baseline LVMI. The population was divided into 3 tertiles according to final values of gender-specific urinary sodium. When, within each urinary sodium tertile, patients were divided into those with plasma aldosterone concentration below and above the median (11.6 ng/dL), LVMI progressively increased across sodium tertiles only in patients with high plasma aldosterone concentration. Systolic BP was similar across all of the groups. In conclusion, aldosterone requires the presence of high dietary salt for the expression of its unfavorable effect on the heart.


Enhancing effect of medium-chain triglycerides on intestinal absorption of d-alpha-tocopherol acetate from lecithin-dispersed preparations in the rat.
The effect of formulations of lecithin-dispersed preparation on the absorption of d-alpha-tocopherol acetate (VEA) from the small intestine was investigated in rats. When lecithin-dispersed preparations containing VEA or polysorbate 80 (PS-80)-solubilized solution of VEA were intraduodenally administered, VEA was hydrolyzed to d-alpha-tocopherol (VE) and was not detected in the plasma nor in the thoracic lymph. The maximum plasma concentration (Cmax) of VE after the intraduodenal administration of a preparation consisting of VEA, soybean phosphatidylcholine (PC) and medium-chain triglycerides (MCTG) (VEA/PC/MCTG, 5/16/1 by weight) was highest among the VEA preparations, and PS-80-solubilized solution gave the lowest Cmax. AUC of VE up to 24 h was also increased by the addition of MCTG to VEA/PC preparation. In the thoracic duct-fistula rat, the transport of VE into the thoracic lymph was increased by the administration of the VEA/PC/MCTG preparation significantly more than the VEA/PC preparation; the cumulative amounts of VE recovered in the thoracic lymph up to 24 h were 23.2 +/- 0.5% and 10.9 +/- 1.5% of dose, respectively. The plasma concentration of VE was not increased in the thoracic duct-fistula rat even after the intraduodenal administration of VEA preparations, suggesting that VE is not transported directly to the systemic circulation, but by way of the lymphatic route. The lymphatic transport of VE following the intraduodenal administration of VEA/PC/MCTG preparation was markedly diminished by the simultaneous administration of Pluronic L-81 emulsion, an inhibitor of chylomicron formation. It is suggested that the chylomicron is essential to the lymphatic transport of VE from VEA preparations.


Physiological impacts of ABA-JA interactions under water-limitation.
Plant responses to drought stress depend on highly regulated signal transduction pathways with multiple interactions. This complex crosstalk can lead to a physiological outcome of drought avoidance or tolerance/resistance. ABA is the principal mediator of these responses due to the regulation of stomatal closure that determines plant growth and survival, but also other strategies of drought resistance such as osmotic adjustment. However, other hormones such as JA seem responsible for regulating a subset of plant responses to drought by regulating ABA biosynthesis and accumulation and ABA-dependent signalling, but also by ABA independent pathways. Here, we review recent reports of ABA-JA hormonal and molecular interactions within a physiological framework of drought tolerance. Understanding the physiological significance of this complex regulation offers opportunities to find strategies of drought tolerance that avoid unwanted side effects that limit growth and yield, and may allow biotechnological crop improvement.


Sled Towing: The Optimal Overload for Peak Power Production.
The effects of different loads on kinematic and kinetic variables during sled towing were investigated with the aim to identify the optimal overload for this specific sprint training. Thirteen male sprinters (100-m personal best: 10.91 ± 0.14 s) performed 5 maximal trials over a 20-m distance in the following conditions: unloaded and with loads from 15% to 40% of the athlete's body mass (BM). In these calculations the sled mass and friction were taken into account. Contact and flight times, stride length, horizontal hip velocity (vh), and relative angles of hip, knee, and ankle (at touchdown and takeoff) were measured step by step. In addition, the horizontal force (Fh) and power (Ph) and maximal force (Fh0) and power (Ph0) were calculated. vh, flight time, and step length decreased while contact time increased with increasing load (P < .001). These variables changed significantly also as a function of the step number (P < .01), except between the 2 last steps. No differences were observed in Fh among loads, but Fh was larger in sled towing than in unloaded. Ph was unaffected by load up to +20%BM but decreased with larger loads. Fh0 and Ph0 were achieved at 20%BM. Up to 20%BM, no significant effects on joint angles were observed at touchdown and takeoff, while at loads >30%BM joint angles tended to decrease. The 20%BM condition represents the optimal overload for peak power production-at this load sprinters reach their highest power without significant changes in their running technique (eg, joint angles).


Feelings into words: contributions of language to exposure therapy.
A growing body of research has revealed that labeling an emotion, or putting one's feelings into words, can help to downregulate that affect, as occurs with intentional forms of emotion regulation, such as reappraisal and distraction. We translated this basic research to a real-world clinical context, in which spider-fearful individuals were repeatedly exposed to a live spider. Using a between-subjects design, we compared the effects of affect labeling, reappraisal, distraction from the feared stimulus, and exposure alone during this brief course of exposure therapy on subsequent fear responding. At a 1-week posttest involving a different spider in another context, the affect-labeling group exhibited reduced skin conductance response relative to the other groups and marginally greater approach behavior than the distraction group; however, the affect-labeling group did not differ from the other groups in self-reported fear. Additionally, greater use of anxiety and fear words during exposure was associated with greater reductions in fear responding. Thus, perhaps surprisingly, affect labeling may help to regulate aspects of emotion in a clinical context.


Meta-analysis of mortality and cancer incidence among workers in the synthetic rubber-producing industry.
Production of synthetic rubber involves exposure to several potentially harmful chemicals. The authors carried out a systematic review and meta-analysis of cohort studies of workers in the rubber-producing industry. Data were obtained from computerized literature searches of several databases from their inception through December 2003. The reference lists of identified articles were inspected for further relevant articles. The authors conducted random-effects meta-analyses of log standardized mortality ratios (SMRs)/standardized incidence ratios. Heterogeneity between study results was explored through subgroup analyses and meta-regression on cohort demographic factors and study quality indicators. The authors identified 36 published articles reporting information on 31 different cohort groups. The meta-SMR was 0.86 (95% confidence interval (CI): 0.82, 0.91) for all-cause mortality (28 cohorts) and 0.94 (95% CI: 0.89, 1.01) for all malignant neoplasms (27 cohorts). Heterogeneity was observed for these endpoints and for the majority of disease-specific outcomes. Statistically significant excesses were observed for diabetes (meta-SMR=1.36, 95% CI: 1.17, 1.59) (five cohorts) and leukemia (meta-SMR=1.21, 95% CI: 1.03, 1.43) (16 cohorts), the latter particularly for persons working exclusively in nontire manufacturing (meta-SMR=1.70, 95% CI: 1.14, 2.54) (four cohorts). Excesses highlighted in previous narrative reviews were not substantiated. Interpretation of these results is complicated by substantial unexplainable heterogeneity; small excesses in specific mortality outcomes may have been disguised by the healthy worker effect.


Lipopolysaccharide-stimulated human monocytes secrete, apart from neutrophil-activating peptide 1/interleukin 8, a second neutrophil-activating protein. NH2-terminal amino acid sequence identity with melanoma growth stimulatory activity.
Purification of monocyte-derived NAP-1/IL-8 by preparative reversed-phase (RP)-HPLC led to the detection of a second peak with polymorphonuclear leukocyte (PMNL)-activating (degranulation, chemotaxis) properties. The monokine responsible for this biological activity, which we tentatively termed NAP-3, could be purified to homogeneity by three different RP-HPLC steps. Tricine-SDS-PAGE analysis gave a single line at Mr 5.3 kD (NAP-1/IL-8 = 5.8 kD). NH2-terminal amino acid sequence analysis read as a major sequence (ASVATELRXCXLQT. .), which shows greater than 40% homology to that of NAP-1/IL-8. The sequence is identical to that found for the 13-kD moiety of melanoma growth stimulating activity (MGSA) and the product of the oncogene gro. Determination of neutrophil chemotactic activity of NAP-3 revealed a typical bell-shaped dose-response curve (ED50 = 2 ng/ml) with no significant neutrophil chemotactic activity at doses greater than 200 ng/ml. Also, in cytochalasin B-pretreated PMNL, NAP-3 elicited release of myeloperoxidase and beta-glucuronidase. Crossdesensitization studies in PMNL enzyme release revealed crossreactivities with the NAP-1/IL-8-R on PMNL. NAP-3 (MGSA/gro) appears to represent the first member of the novel supergene family of beta-thromboglobulin-like host defense cytokines, which expresses both mitogenic as well as proinflammatory properties at the nanogram level.


Strong leadership and teamwork drive culture and performance change: Ohio State University Medical Center 2000-2006.
Several characteristics of academic health centers have the potential to create high levels of internal conflict and misalignment that can pose significant leadership challenges. In September 2000, the positions of Ohio State University (OSU) senior vice president for health sciences, dean of the medical school, and the newly created position of chief executive officer of the OSU Medical Center (OSUMC) were combined under a single leader to oversee the OSUMC. This mandate from the president and trustees was modeled after top institutions with similar structures. The leader who assumed the role was tasked with improving OSUMC's academic, clinical, and financial performance. To achieve this goal, the senior vice president and his team employed the service value chain model of improving performance, based on the premise that leadership behavior/culture drives employee engagement/satisfaction, leading to customer satisfaction and improved organizational performance. Implementing this approach was a seven-step process: (1) selecting the right leadership team, (2) assessing the challenges and opportunities, (3) setting expectations for performance and leadership behavior, (4) aligning structures and functions, (5) engaging constituents, (6) developing leadership skills, and (7) defining strategies and tracking goals. The OSUMC setting during this period provides an observational case study to examine how these stepwise changes, instituted by strong leadership and teamwork, were able to make and implement sound decisions that drove substantial and measurable improvements in the engagement and satisfaction of faculty and staff; the satisfaction of students and patients; and academic, clinical, and financial performance.


Manipulating cardiovascular indices of challenge and threat using resource appraisals.
Challenge and threat reflect two distinct psychophysiological approaches to motivated performance situations. Challenge is related to superior performance in a range of tasks compared to threat, thus methods to promote challenge are valuable. In this paper we manipulate challenge and threat cardiovascular reactivity using only resource appraisals, without altering perceived task demands between challenge and threat conditions. Study 1 used a competitive throwing task and Study 2 used a physically demanding climbing task. In both studies challenge task instructions led to challenge cardiovascular reactivity and threat task instructions led to threat cardiovascular reactivity. In Study 1, participants who received challenge instructions performed better than participants who received threat instructions. In Study 2, attendance at the climbing task did not differ across groups. The findings have implications for stress management in terms of focusing on manipulating appraisals of upcoming tasks by promoting self-efficacy and perceived control and focusing on approach goals. Future research could more reliably assess the influence of similar task instructions on performance.


Implementation of a nondeterministic optical noiseless amplifier.
Quantum mechanics imposes that any amplifier that works independently on the phase of the input signal has to introduce some excess noise. The impossibility of such a noiseless amplifier is rooted in the unitarity and linearity of quantum evolution. A possible way to circumvent this limitation is to interrupt such evolution via a measurement, providing a random outcome able to herald a successful-and noiseless-amplification event. Here we show a successful realization of such an approach; we perform a full characterization of an amplified coherent state using quantum homodyne tomography, and observe a strong heralded amplification, with about a 6 dB gain and a noise level significantly smaller than the minimal allowed for any ordinary phase-independent device.


Crystal Structure of the Apicoplast DNA Polymerase from Plasmodium falciparum: The First Look at a Plastidic A-Family DNA Polymerase.
Plasmodium falciparum, the primary cause of malaria, contains a non-photosynthetic plastid called the apicoplast. The apicoplast exists in most members of the phylum Apicomplexa and has its own genome along with organelle-specific enzymes for its replication. The only DNA polymerase found in the apicoplast (apPOL) was putatively acquired through horizontal gene transfer from a bacteriophage and is classified as an atypical A-family polymerase. Here, we present its crystal structure at a resolution of 2.9Å. P. falciparum apPOL, the first structural representative of a plastidic A-family polymerase, diverges from typical A-family members in two of three previously identified signature motifs and in a region not implicated by sequence. Moreover, apPOL has an additional N-terminal subdomain, the absence of which severely diminishes its 3' to 5' exonuclease activity. A compound known to be toxic to Plasmodium is a potent inhibitor of apPOL, suggesting that apPOL is a viable drug target. The structure provides new insights into the structural diversity of A-family polymerases and may facilitate structurally guided antimalarial drug design.


Tendon is covered by a basement membrane epithelium that is required for cell retention and the prevention of adhesion formation.
The ability of tendons to glide smoothly during muscle contraction is impaired after injury by fibrous adhesions that form between the damaged tendon surface and surrounding tissues. To understand how adhesions form we incubated excised tendons in fibrin gels (to mimic the homeostatic environment at the injury site) and assessed cell migration. We noticed cells exiting the tendon from only the cut ends. Furthermore, treatment of the tendon with trypsin resulted in cell extravagation from the shaft of the tendons. Electron microscopy and immunolocalisation studies showed that the tendons are covered by a novel cell layer in which a collagen type IV/laminin basement membrane (BM) overlies a keratinised epithelium. PCR and western blot analyses confirmed the expression of laminin β1 in surface cells, only. To evaluate the cell retentive properties of the BM in vivo we examined the tendons of the Col4a1(+/Svc) mouse that is heterozygous for a G-to-A transition in the Col4a1 gene that produces a G1064D substitution in the α1(IV) chain of collagen IV. The flexor tendons had a discontinuous BM, developed fibrous adhesions with overlying tissues, and were acellular at sites of adhesion formation. In further experiments, tenotomy of wild-type mice resulted in expression of laminin throughout the adhesion. In conclusion, we show the existence of a novel tendon BM-epithelium that is required to prevent adhesion formation. The Col4a1(+/Svc) mouse is an effective animal model for studying adhesion formation because of the presence of a structurally-defective collagen type IV-containing BM.


Branched-chain ketoacid overload inhibits insulin action in the muscle.
Branched-chain α-keto acids (BCKAs) are catabolites of branched-chain amino acids (BCAAs). Intracellular BCKAs are cleared by branched-chain ketoacid dehydrogenase (BCKDH), which is sensitive to inhibitory phosphorylation by BCKD kinase (BCKDK). Accumulation of BCKAs is an indicator of defective BCAA catabolism and has been correlated with glucose intolerance and cardiac dysfunction. However, it is unclear whether BCKAs directly alter insulin signaling and function in the skeletal and cardiac muscle cell. Furthermore, the role of excess fatty acids (FAs) in perturbing BCAA catabolism and BCKA availability merits investigation. By using immunoblotting and ultra-performance liquid chromatography MS/MS to analyze the hearts of fasted mice, we observed decreased BCAA-catabolizing enzyme expression and increased circulating BCKAs, but not BCAAs. In mice subjected to diet-induced obesity (DIO), we observed similar increases in circulating BCKAs with concomitant changes in BCAA-catabolizing enzyme expression only in the skeletal muscle. Effects of DIO were recapitulated by simulating lipotoxicity in skeletal muscle cells treated with saturated FA, palmitate. Exposure of muscle cells to high concentrations of BCKAs resulted in inhibition of insulin-induced AKT phosphorylation, decreased glucose uptake, and mitochondrial oxygen consumption. Altering intracellular clearance of BCKAs by genetic modulation of BCKDK and BCKDHA expression showed similar effects on AKT phosphorylation. BCKAs increased protein translation and mTORC1 activation. Pretreating cells with mTORC1 inhibitor rapamycin restored BCKA's effect on insulin-induced AKT phosphorylation. This study provides evidence for FA-mediated regulation of BCAA-catabolizing enzymes and BCKA content and highlights the biological role of BCKAs in regulating muscle insulin signaling and function.


ERBB signaling attenuates proinflammatory activation of nonclassical monocytes.
Immune activation in chronic systolic heart failure (HF) correlates with disease severity and prognosis. Recombinant neuregulin-1 (rNRG-1) is being developed as a possible therapy for HF, based on the activation of ERBB receptors in cardiac cells. Work in animal models of HF led us to hypothesize that there may be direct effects of NRG-1 on immune system activation and inflammation. We investigated the expression of ERBB receptors and the effect of rNRG-1 isoform glial growth factor 2 (GGF2) in subpopulations of peripheral blood mononuclear cells (PB MNCs) in subjects with HF. We found that human monocytes express both ERBB2 and ERBB3 receptors, with high interindividual variability among subjects. Monocyte surface ERBB3 and TNF-α mRNA expression were inversely correlated in subjects with HF but not in human subjects without HF. GGF2 activation of ERBB signaling ex vivo inhibited LPS-induced TNF-α production, specifically in the CD14lowCD16+ population of monocytes in a phosphoinositide 3-kinase-dependent manner. GGF2 suppression of TNF-α correlated directly with the expression of ERBB3. In vivo, a single dose of intravenous GGF2 reduced TNF-α expression in PB MNCs of HF subjects participating in a phase I safety study of GGF2. These results support a role for ERBB3 signaling in the regulation of TNF-α production from CD14lowCD16+ monocytes and a need for further investigation into the clinical significance of NRG-1/ERBB signaling as a modulator of immune system function.NEW & NOTEWORTHY This study identified a novel role of neuregulin-1 (NRG-1)/ERBB signaling in the control of proinflammatory activation of monocytes. These results further improve our fundamental understanding of cardioprotective effects of NRG-1 in patients with heart failure.


Constitutively overexpressed 21 kDa protein in Hodgkin lymphoma and aggressive non-Hodgkin lymphomas identified as cytochrome B5b (CYB5B).
We have previously reported a novel constitutively overexpressed 21 kDa protein in Hodgkin Lymphoma (HL) and aggressive Non-Hodgkin Lymphomas (NHL). The objective of the current study was to 1) identify this protein using two independent methods, 2) study the expression of the protein and its encoding mRNA in reactive lymph nodes, normal lymphocytes and CD34+ bone marrow precursor cells, 3) analyse patterns of expression of the protein in tissue microarrays assembled from a large number of diagnostic clinical biopsies from patients with HL, and 4) determine the copy number variation and mutation status of the encoding gene in HL cell lines. Peptide sequencing by LC-MS/MS and protein identification by protein array screening identified a single protein, CYB5B. No mutations were detected in the CYB5B gene in HL cell lines. Quantitative PCR showed CYB5B gene expression was increased in HL and NHL cell lines. Array CGH using a submegabase resolution tiling array revealed gains in the CYB5B locus in HL cell lines KMH2 and L428. Membrane expression was seen in Reed-Sternberg cells in clinical biopsies from patients with HL but not in reactive lymph nodes. Bone marrow CD34+ precursor cells were CYB5B negative on the cell surface. RT-PCR assays of RNA extracted from T and B cell enriched fractions obtained from normal peripheral blood mononuclear cells, reactive lymph nodes, tonsils and normal bone marrow samples showed no evidence of increased mRNA levels of CYB5B in comparison to housekeeping gene GAPDH. The 21 kDa protein overexpressed in HL and aggressive NHL is identical to CYB5B. CYB5B gene expression is increased in a subset of HL and NHL cell lines tested. This is associated with CYB5B gene amplification in HL cell lines KMH2 and L428. CYB5B may be a potential target for antibody-based therapy of HL and aggressive NHL as although cytoplasmic expression is present in reactive lymphocytes, it is not expressed on the cell surface of non-neoplastic lymphocytes or bone marrow precursor cells.


Fluid challenges in intensive care: the FENICE study: A global inception cohort study.
Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC. This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC. 2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500-1000). The median time was 24 min (40-60 min), and the median rate of FC was 1000 [500-1333] ml/h. The main indication for FC was hypotension in 1211 (59%, CI 57-61%). In 43% (CI 41-45%) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36%, CI 34-37%). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22%, CI 20-24%). No safety variable for the FC was used in 72% (CI 70-74%) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response. The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account.


Does an offer for a free on-line continuing medical education (CME) activity increase physician survey response rate? A randomized trial.
Achieving a high response rate in a physician survey is challenging. Monetary incentives increase response rates but obviously add cost to a survey project. We wondered whether an offer of a free continuing medical education (CME) activity would be effective in improving survey response rate. As part of a survey of a national sample of physicians, we randomized half to an offer for a free on-line CME activity upon completion of a web-based survey and the other half to no such offer. We compared response rates between the groups. A total of 1214 out of 8477 potentially eligible physicians responded to our survey, for an overall response rate of 14.3%. The response rate among the control group (no offer of CME credit) was 16.6%, while among those offered the CME opportunity, the response rate was 12.0% (p < 0.0001). An offer for a free on-line CME activity did not improve physician survey response rate. On the contrary, the offer for a free CME activity actually appeared to worsen the response rate.


Towards the clinical implementation of iterative low-dose cone-beam CT reconstruction in image-guided radiation therapy: cone/ring artifact correction and multiple GPU implementation.
Compressed sensing (CS)-based iterative reconstruction (IR) techniques are able to reconstruct cone-beam CT (CBCT) images from undersampled noisy data, allowing for imaging dose reduction. However, there are a few practical concerns preventing the clinical implementation of these techniques. On the image quality side, data truncation along the superior-inferior direction under the cone-beam geometry produces severe cone artifacts in the reconstructed images. Ring artifacts are also seen in the half-fan scan mode. On the reconstruction efficiency side, the long computation time hinders clinical use in image-guided radiation therapy (IGRT). Image quality improvement methods are proposed to mitigate the cone and ring image artifacts in IR. The basic idea is to use weighting factors in the IR data fidelity term to improve projection data consistency with the reconstructed volume. In order to improve the computational efficiency, a multiple graphics processing units (GPUs)-based CS-IR system was developed. The parallelization scheme, detailed analyses of computation time at each step, their relationship with image resolution, and the acceleration factors were studied. The whole system was evaluated in various phantom and patient cases. Ring artifacts can be mitigated by properly designing a weighting factor as a function of the spatial location on the detector. As for the cone artifact, without applying a correction method, it contaminated 13 out of 80 slices in a head-neck case (full-fan). Contamination was even more severe in a pelvis case under half-fan mode, where 36 out of 80 slices were affected, leading to poorer soft tissue delineation and reduced superior-inferior coverage. The proposed method effectively corrects those contaminated slices with mean intensity differences compared to FDK results decreasing from ∼497 and ∼293 HU to ∼39 and ∼27 HU for the full-fan and half-fan cases, respectively. In terms of efficiency boost, an overall 3.1 × speedup factor has been achieved with four GPU cards compared to a single GPU-based reconstruction. The total computation time is ∼30 s for typical clinical cases. The authors have developed a low-dose CBCT IR system for IGRT. By incorporating data consistency-based weighting factors in the IR model, cone/ring artifacts can be mitigated. A boost in computational efficiency is achieved by multi-GPU implementation.


Image registration of ex-vivo MRI to sparsely sectioned histology of hippocampal and neocortical temporal lobe specimens.
Intractable or drug-resistant epilepsy occurs in up to 30% of epilepsy patients, with many of these patients undergoing surgical excision of the affected brain region to achieve seizure control. Recent magnetic resonance imaging (MRI) sequences and analysis techniques have the potential to detect abnormalities not identified with diagnostic MRI protocols. Prospective studies involving pre-operative imaging and collection of surgically-resected tissue provide a unique opportunity for verification and tuning of these image analysis techniques, since direct comparison can be made against histopathology, and can lead to better prediction of surgical outcomes and potentially less invasive procedures. To carry out MRI and histology comparison, spatial correspondence between the MR images and the histology images must be found. Towards this goal, a novel pipeline is presented here for bringing ex-vivo MRI of surgically-resected temporal lobe specimens and digital histology into spatial correspondence. The sparsely-sectioned histology images represent a challenge for 3D reconstruction which we address with a combined 3D and 2D registration algorithm that alternates between slice-based and volume-based registration with the ex-vivo MRI. We evaluated our registration method on specimens resected from patients undergoing anterior temporal lobectomy (N=7) and found our method to have a mean target registration error of 0.76±0.66 and 0.98±0.60 mm for hippocampal and neocortical specimens respectively. This work allows for the spatially-local comparison of histology with post-operative MRI and paves the way for eventual correlation with pre-operative MRI image analysis techniques.


JC virus urinary excretion and seroprevalence in natalizumab-treated multiple sclerosis patients.
The risk of developing progressive multifocal leukoencephalopathy (PML), as a consequence of infection/reactivation with JC virus (JCV), is consistent in natalizumab-treated multiple sclerosis (MS) patients, with 430 cases of PML reported so far. The risk of PML is higher in JCV seropositive patients, and it is recommended that only MS patients without JCV antibodies should be enrolled in the treatment postulating that they do not have JCV infection.We have studied forty-two natalizumab-treated MS patients, and urine and blood were collected monthly for up to 60 months. JCV and BK virus (BKV) DNA presence was verified using quantitative real-time PCR assays, and serum anti-JCV antibodies were measured with the Stratify and/or Stratify DxSelect tests.JCV and BKV DNA were not found in the blood samples, whereas they were found at least once in the urine of 21 of 42 (50 %) and of 25/42 (59.5 %) patients, respectively. JCV DNA urinary shedding increased up to month 24 of natalizumab treatment (45.2 %), and the effect of time was significant for JCV (p = 0.04), but not for BKV (p = 0.39). JCV viruria and seropositivity did not completely correlate, since three patients shedding JCV DNA in the urine were seronegative according to the serological tests.The results indicated that natalizumab therapy may increase the rate of JCV urinary shedding. Additionally, we confirmed that the identification of JCV carriers cannot solely rely on serological tests, but sensitive methods for viral DNA detection should be adopted to more precisely identify the truly JCV uninfected cases.


Mechanisms of the effects of grains on insulin and glucose responses.
Consumption of a number of grains and grain extracts has been reported to control or improve glucose tolerance and reduce insulin resistance. The inability of the body to maintain normal glucose levels or to require excessive levels of insulin to do so has been called glucose intolerance, impaired glucose tolerance and insulin resistance. These conditions are associated with obesity and may be preliminary steps in the progression to type 2 diabetes mellitus. Although dietary goals recommend the consumption of three servings of whole grains per day, average consumption in the United States is less than one serving per day. There are a number of mechanisms by which grains may improve glucose metabolism and delay or prevent the progression of impaired glucose tolerance to insulin resistance and diabetes. These mechanisms are related to the physical properties and structure of grains. The composition of the grain, including particle size, amount and type of fiber, viscosity, amylose and amylopectin content all affect the metabolism of carbohydrates from grains. Increasing whole grain intake in the population can result in improved glucose metabolism and delay or reduce the risk of developing type 2 diabetes mellitus. Whole grains can provide a substantial contribution to the improvement of the diets of Americans. A number of whole grain foods and grain fiber sources are beneficial in reduction of insulin resistance and improvement in glucose tolerance. Form, amount and method of cooking of these foods as well as the health characteristics, age and gender of the group of subjects studied are all important factors in the effectiveness of the foods in altering these responses. Dietary recommendations of health organizations suggest consumption of three servings a day of whole grain foods; however, Americans generally fall below this standard. Recent research using various grains and grain products effective in improving insulin resistance or lowering glycemic index will be discussed below by possible mechanisms of action.


Hypothesis: breast cancer regression under oestrogen therapy.
Recent reports have thrown doubt on both of the major mechanisms which have been suggested for the regression of breast cancer under high-dosage oestrogen therapy-a direct effect on binding sites and an indirect inhibition of prolactin release. A searching review on the clinical response of 407 patients with advanced breast cancer treated by oestrogen therapy under my direction showed certain anomalies, including age determined tumour inhibition and stimulation, dose dependence of tumour inhibition and stimulation, differential site sensitivity, and tumour regression with oestrogen withdrawal. The hypothesis usually postulated to explain these anomalies is that the tumour may in the same individual be composed of multiple genetically distinct clones of cells. It is suggested instead that the effect of high-dosage oestrogen therapy in breast cancer may depend critically on the absolute and relative concentrations of prolactin and oestrogen actively available at the tumour. On this basis the clinical manifestation of tumour stimulation in response to oestrogen administration suggests that the oestrogen concentration at the target is inadequate. Differences in site sensitivity in the same patient may depend on tumoral factors such as the level of oestradiol and prolactin binding receptors in the tissue.


International training programs on eating disorders for professionals, caregivers, and the general public: A scoping review.
This review identified and synthesized published training programs on eating disorders (ED) (anorexia nervosa or bulimia nervosa) for professionals, natural supporters of people with ED, or the public. A scoping review using the Arksey and O'Malley (2005) framework was conducted. Four data bases were searched, for all years, and manual searches from three additional sources were also conducted. Experts on ED were consulted for validation of the identified studies. A narrative synthesis was performed. A total of 20 evaluation studies from five countries were identified, and reviewed in relation to 14 ED training programs. Characteristics of the training programs, and study characteristics, were highly diverse, as shown on Table 1 which compiles results from the charted data. Evaluations were equally divided between training for healthcare and education professionals (9), and training for families or other carers of people with ED (10). One study evaluated ED training for the general public. We found that training orientation varies with the interests and needs of different trainee groups. While most studies assessed trainee outcomes, future research needs to give greater consideration to patient perspectives, and to the relationship between training and evaluation approaches, improved knowledge, and better care.