The impact of prophylaxis on paediatric intensive care unit admissions for RSV infection: a retrospective, single-centre study.
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections and hospitalizations in children aged < 2 years. The aim of this retrospective, single-centre study was to examine the characteristics of patients admitted to a paediatric intensive care unit (PICU) with RSV infection following the implementation of a RSV prophylaxis programme. Electronic hospital medical records of all PICU admissions for RSV infection were searched from 2003 to 2009. Data on baseline demographics, underlying disease, criteria for hospitalization, respiratory diagnosis and management, complications and palivizumab prophylaxis were collected. A total of 181 patients were admitted with RSV infection, accounting for 5.7% of all admissions. Eighty-four percent were ≤ 2 years of age. Majority (70.2%) had no underlying medical illness, and 79.6% received antibiotics as part of their medical treatment. Comparison of children aged ≤ 2 years and those >2 years revealed that fewer of the younger cohort (20.4% versus 79.3%; p < 0.001) had an underlying medical condition. RSV infection occurred in 3.3% (n = 6) children who had received palivizumab prophylaxis, and there were two deaths. The results indicate that > 88% of all PICU admissions would not qualify for RSV prophylaxis under our established guidelines and 66% of the children aged ≤ 2 years were > 36 weeks gestation and are not currently targeted for prophylaxis. The number of high-risk infants admitted to PICU with RSV infection has likely plateaued, and further reductions in admission rates may only be realised with the use of universal, vaccine immunization programmes.


The mammary myoepithelial cell.
Over the last few years, the discovery of basal-type mammary carcinomas and the association of the regenerative potential of the mammary epithelium with the basal myoepithelial cell population have attracted considerable attention to this second major mammary lineage. However, many questions concerning the role of basal myoepithelial cells in mammary morphogenesis, functional differentiation and disease remain unanswered. Here, we discuss the mechanisms that control the myoepithelial cell differentiation essential for their contractile function, summarize new data concerning the roles played by cell-extracellular matrix (ECM), intercellular and paracrine interactions in the regulation of various aspects of the mammary basal myoepithelial cell functional activity. Finally, we analyze the contribution of the basal myoepithelial cells to the regenerative potential of the mammary epithelium and tumorigenesis.


Deep brain stimulation of caudal zona incerta and subthalamic nucleus in patients with Parkinson's disease: effects on diadochokinetic rate.
The hypokinetic dysarthria observed in Parkinson's disease (PD) affects the range, speed, and accuracy of articulatory gestures in patients, reducing the perceived quality of speech acoustic output in continuous speech. Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) and of the caudal zona incerta (cZi-DBS) are current surgical treatment options for PD. This study aimed at investigating the outcome of STN-DBS (7 patients) and cZi-DBS (7 patients) in two articulatory diadochokinesis tasks (AMR and SMR) using measurements of articulation rate and quality of the plosive consonants (using the percent measurable VOT metric). The results indicate that patients receiving STN-DBS increased in articulation rate in the Stim-ON condition in the AMR task only, with no effect on production quality. Patients receiving cZi-DBS decreased in articulation rate in the Stim-ON condition and further showed a reduction in production quality. The data therefore suggest that cZi-DBS is more detrimental for extended articulatory movements than STN-DBS.


Detection of Babesia microti by polymerase chain reaction.
Human babesiosis, which is caused by infection with the intraerythrocytic malarialike protozoan Babesia microti, has recently been diagnosed with increasing frequency in residents of New England. Diagnosis is difficult because of the small size of the parasite and the sparse parasitemia that is characteristic of most infections with this pathogen. We generated B. microti-specific DNA sequence information by universal primer amplification of a portion of the eukaryotic 16S-like gene; this was followed by direct DNA sequence analysis. Specific primers were synthesized on the basis of this sequence information for use in the polymerase chain reaction (PCR). The PCR-based system demonstrates a strong bias for detection of B. microti as opposed to Babesia gibsoni and does not amplify vertebrate DNA. The analytical sensitivity of the system is approximately three merozoites. Blood specimens from 12 patients with clinically diagnosed and parasitologically confirmed babesiosis from Nantucket Island, Mass., were PCR positive in a blinded test of this procedure. Thus, DNA amplification may provide an adjunct to conventional methods for the diagnosis of human babesiosis and may provide a new means of monitoring therapy or enhancing epidemiological surveillance for this emerging pathogen.


Multiplicative interaction between mean corpuscular volume and red cell distribution width in predicting mortality of elderly patients with and without anemia.
Recent studies have shown that an elevated red cell distribution width (RDW) is an important predictor of adverse outcomes. However, the strength of this biomarker has not been tested in a large outpatient elderly population. Also since increased RDW can be due to a variety of etiologies, additional biomarkers are needed to refine the prognostic value of this variable. We assembled a cohort of 36,226 elderly (≥65yo) patients seen at an outpatient facility within the Einstein/Montefiore system from January 1st 1997 to May 1st 2008 who also had a complete blood count performed within 3 months of the initial visit. With a maximum follow-up of 10 years, we found that an elevated RDW (>16.6) was associated with increased risk of mortality in both non-anemic (HR = 3.66, p < 0.05) and anemic patients (HR = 1.87, p < 0.05). The effect of RDW on mortality is significantly increased in non-anemic patients with macrocytosis (HR = 5.22, p < 0.05) compared to those with normocytosis (HR = 3.86, p < 0.05) and microcytosis (HR = 2.46, p < 0.05). When comparing non-anemic patients with both an elevated RDW and macrocytosis to those with neither, we observed an elevated HR of 7.76 (higher than expected in an additive model). This multiplicative interaction was not observed in anemic patients (HR = 2.23). Lastly, we constructed Kaplan-Meier curves for each RDW/MCV subgroup and found worsened survival for those with macrocytosis and an elevated RDW in both anemia and non-anemic patients. Based on our results, the addition of MCV appears to improve the prognostic value of RDW as a predictor of overall survival in elderly patients.


Relationship between patient-reported outcomes of elective surgery and hospital and consultant volume.
Our aim was to analyze the relationship for 3 elective operations between outcome [patient-reported outcome measures (PROMs) for functional status, health-related quality of life, and postoperative complications] and both hospital and consultant volume. Hospitals (NHS and independent) and consultants undertaking at least 10 NHS-funded procedures during 2011/2012 were included (230 hospitals for hip and knee replacement, 257 for hernia repair; 978 consultants for hip replacement, 1172 for knee replacement, and 1288 for hernia repair). Outcomes (disease-specific and generic PROMs, patient-reported complications) were available from the NHS National PROMs Programme for 2009/2010 to 2011/2012. Relationship between case-mix adjusted outcomes and volume investigated using multilevel modeling. There was considerable variation in hospital volumes (about 10-fold) and consultant volumes (about 5-fold). No significant association was observed between hospital volume and outcome for all 3 procedures. For consultant volume, there was no significant association for knee replacement or hernia repair. However, outcomes were statistically significantly better for hip replacement, although the effect was of little clinical significance: an additional 10 cases was associated with a higher Oxford Hip Score (0.06), higher EQ-5D score (0.001), and lower odds ratio of complications (0.992). There are unlikely to be any benefits to patients from centralization of elective surgery into higher volume hospitals as regards the effectiveness of surgery or the avoidance of minor complications. There is some evidence that very low volume consultants achieve poorer outcomes than higher volume colleagues but the difference is slight and of little or no clinical significance.


The spectrum of renal diseases observed in native renal biopsies in a single North Indian tertiary care center.
We analyzed the spectrum of biopsy-proven renal disease in a single tertiary care center in North India from 2007 to 2016. A total of 420 biopsies were analyzed. Patients were excluded if clinical details were unavailable or if either the histopathology core or the IF core was inadequate. In the final analysis, 359 biopsies were included. All clinical, laboratory, histopathological, and immunofluorescence (IF) findings were recorded in each case. The usefulness of IF in reaching a definitive diagnosis was also analyzed. The patients were in the age range of 2-94 years; 23.1% were children and 76.9% were adults. Males (60.4%) outnumbered females (39.6%) in all the disease categories except lupus nephritis (LN). Primary glomerular diseases (PGDs) (n = 297, 82.7%) were more common than secondary glomerular diseases (SGDs) (n = 46, 12.8%) and tubulointerstitial diseases (n = 16, 4.5%). The most common PGD was focal segmental glomerulosclerosis (FSGS) (23.4%), followed by minimal change disease (17%) and membranous nephropathy (12.5%), whereas the most common SGD was LN, seen in 9.2%. In the present study, IF helped in reaching the final diagnosis in 44.3%. The entities in which IF was most useful in reaching the final diagnoses were FSGS (31.5%) and IgA nephropathy (14.5%). The final pathological diagnosis correlated with the first clinical possibility in 207 of 359 (57.7%) cases. This 10-year study provides descriptive data and highlights the changing pattern of renal disease possibly due to an increased awareness and referral to higher centers.


Molecular analysis and organization of the sigmaB operon in Staphylococcus aureus.
The alternative sigma factor sigma(B) of Staphylococcus aureus controls the expression of a variety of genes, including virulence determinants and global regulators. Genetic manipulations and transcriptional start point (TSP) analyses showed that the sigB operon is transcribed from at least two differentially controlled promoters: a putative sigma(A)-dependent promoter, termed sigB(p1), giving rise to a 3.6-kb transcript covering sa2059-sa2058-rsbU-rsbV-rsbW-sigB, and a sigma(B)-dependent promoter, sigB(p3), initiating a 1.6-kb transcript covering rsbV-rsbW-sigB. TSP and promoter-reporter gene fusion experiments indicated that a third promoter, tentatively termed sigB(p2) and proposed to lead to a 2.5-kb transcript, including rsbU-rsbV-rsbW-sigB, might govern the expression of the sigB operon. Environmental stresses, such as heat shock and salt stress, induced a rapid response within minutes from promoters sigB(p1) and sigB(p3). In vitro, the sigB(p1) promoter was active in the early growth stages, while the sigB(p2) and sigB(p3) promoters produced transcripts throughout the growth cycle, with sigB(p3) peaking around the transition state between exponential growth and stationary phase. The amount of sigB transcripts, however, did not reflect the concentration of sigma(B) measured in cell extracts, which remained constant over the entire growth cycle. In a guinea pig cage model of infection, sigB transcripts were as abundant 2 and 8 days postinoculation as values found in vitro, demonstrating that sigB is indeed transcribed during the course of infection. Physical interactions between staphylococcal RsbU-RsbV, RsbV-RsbW, and RsbW-sigma(B) were inferred from a yeast (Saccharomyces cerevisiae) two-hybrid approach, indicating the presence of a partner-switching mechanism in the sigma(B) activation cascade similar to that of Bacillus subtilis. The finding that overexpression of RsbU was sufficient to trigger an immediate and strong activation of sigma(B), however, signals a relevant difference in the regulation of sigma(B) activation between B. subtilis and S. aureus in the cascade upstream of RsbU.


Transgelin promotes migration and invasion of cancer stem cells.
Recent studies have suggested the existence of a small subset of cancer cells called cancer stem cells (CSCs), which possess the ability to initiate malignancies, promote tumor formation, drive metastasis, and evade conventional chemotherapies. Elucidation of the specific signaling pathway and mechanism underlying the action of CSCs might improve the efficacy of cancer treatments. In this study, we analyzed differentially expressed proteins between tumerigenic and nontumorigenic cells isolated from the human hepatocellular carcinoma (HCC) cell line, Huh7, via proteomic analysis to identify proteins correlated with specific features of CSCs. The expression level of Transgelin was 25-fold higher in tumorigenic cells than nontumorigenic cells. Similar results were also observed in tumorigenic cells derived from colorectal adenocarcinoma and prostate carcinoma. More importantly, the elevated levels of Transgelin significantly increased the invasiveness of tumorigenic cells, whereas reduced levels decreased the invasive potential. Moreover, in tumors derived from Huh7-induced xenografts, Transgelin was also co-expressed with CXCR4, which is responsible for tumor invasion. Taken together, these results indicate that the metastatic potential of CSCs arises from highly expressed Transgelin.


Increasing HIV-1 molecular complexity among men who have sex with men in Bangkok.
In Thailand, new HIV-1 infections are largely concentrated in certain risk groups such as men who have sex with men (MSM), where annual incidence may be as high as 12% per year. The paucity of information on the molecular epidemiology of HIV-1 in Thai MSM limits progress in understanding the epidemic and developing new prevention methods. We evaluated HIV-1 subtypes in seroincident and seroprevalent HIV-1-infected men enrolled in the Bangkok MSM Cohort Study (BMCS) between 2006 and 2011. We characterized HIV-1 subtype in 231 seroprevalent and 194 seroincident subjects using the multihybridization assay (MHA). Apparent dual infections, recombinant strains, and isolates found to be nontypeable by MHA were further characterized by targeted genomic sequencing. Most subjects were infected with HIV-1 CRF01_AE (82%), followed by infections with recombinants (11%, primarily CRF01_AE/B recombinants), subtype B (5%), and dual infections (2%). More than 11 distinct chimeric patterns were observed among CRF01B_AE/B recombinants, most involving recombination within integrase. A significant increase in the proportion of nontypeable strains was observed among seroincident MSM between 2006 and 2011. CRF01_AE and subtype B were the most and least common infecting strains, respectively. The predominance of CRF01_AE among HIV-1 infections in Thai MSM participating in the BMCS parallels trends observed in Thai heterosexuals and injecting drug users. The presence of complex recombinants and a significant rise in nontypeable strains suggest ongoing changes in the genetic makeup of the HIV-1 epidemic in Thailand, which may pose challenges for HIV-1 prevention efforts and vaccine development.


Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease.
Skeletal muscle wasting and dysfunction are strong independent predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). Creatine nutritional supplementation produces increased muscle mass and exercise performance in health. A controlled study was performed to look for similar effects in 38 patients with COPD. Thirty eight patients with COPD (mean (SD) forced expiratory volume in 1 second (FEV(1)) 46 (15)% predicted) were randomised to receive placebo (glucose polymer 40.7 g) or creatine (creatine monohydrate 5.7 g, glucose 35 g) supplements in a double blind trial. After 2 weeks loading (one dose three times daily), patients participated in an outpatient pulmonary rehabilitation programme combined with maintenance (once daily) supplementation. Pulmonary function, body composition, and exercise performance (peripheral muscle strength and endurance, shuttle walking, cycle ergometry) took place at baseline (n = 38), post loading (n = 36), and post rehabilitation (n = 25). No difference was found in whole body exercise performance between the groups: for example, incremental shuttle walk distance mean -23.1 m (95% CI -71.7 to 25.5) post loading and -21.5 m (95% CI -90.6 to 47.7) post rehabilitation. Creatine increased fat-free mass by 1.09 kg (95% CI 0.43 to 1.74) post loading and 1.62 kg (95% CI 0.47 to 2.77) post rehabilitation. Peripheral muscle performance improved: knee extensor strength 4.2 N.m (95% CI 1.4 to 7.1) and endurance 411.1 J (95% CI 129.9 to 692.4) post loading, knee extensor strength 7.3 N.m (95% CI 0.69 to 13.92) and endurance 854.3 J (95% CI 131.3 to 1577.4) post rehabilitation. Creatine improved health status between baseline and post rehabilitation (St George's Respiratory Questionnaire total score -7.7 (95% CI -14.9 to -0.5)). Creatine supplementation led to increases in fat-free mass, peripheral muscle strength and endurance, health status, but not exercise capacity. Creatine may constitute a new ergogenic treatment in COPD.


A comparative study of the visual outcomes between a new trifocal and an extended depth of focus intraocular lens.
To evaluate and compare the visual outcomes and ocular optical performance of the PanOptix trifocal intraocular lens (IOL) and Symfony extended range of vision IOL. Sixty-eight eyes of 34 patients were divided into 2 groups: 20 patients with the PanOptix IOL and 14 patients with the Symfony IOL. Binocular uncorrected distance visual acuity, best-corrected distance visual acuity (BCDVA), distance-corrected intermediate visual acuity (DCIVA) at 80 and 60 cm, and distance-corrected near visual acuity (DCNVA) at 40 cm were evaluated. Additionally, preferred reading distance with best-corrected distance and visual acuity at that distance, binocular defocus curves, mesopic and photopic contrast sensitivity, photic phenomena, and monocular total higher order aberrations (HOAs) were also measured. The visual outcomes for PanOptix and Symfony IOL groups, respectively, were as follows: BCDVA: -0.03 ± 0.03 and -0.02 ± 0.03 logMAR; DCIVA at 80 cm: 0.06 ± 0.06 and 0.06 ± 0.04 logMAR; DCIVA at 60 cm: 0.06 ± 0.10 and 0.05 ± 0.04 logMAR; DCNVA: 0.04 ± 0.06 and 0.20 ± 0.07 logMAR (p<0.001). Similar preferred reading distances were found for both groups (37.0 ± 4.6 and 38.9 ± 5.7 cm, respectively). The visual acuities at those distances were 0.09 ± 0.08 and 0.19 ± 0.08 logMAR (p<0.001), respectively. The defocus curves showed significantly better outcomes for the PanOptix IOL from -2.0 to -4.0 D (p<0.001). No significant differences were found for contrast sensitivity, halometry, or HOAs between the groups. The PanOptix and Symfony IOLs showed comparable visual performance at distance and intermediate. However, the PanOptix IOL provided better near and preferred reading distance VAs and showed a more continuous range of vision than the Symfony IOL.


Generation of polarization entangled photon pairs at telecommunication wavelength using cascaded χ2 processes in a periodically poled LiNbO3 ridge waveguide.
We report the generation of high-purity correlated photon-pairs and polarization entanglement in a 1.5 μm telecommunication wavelength-band using cascaded χ((2)):χ((2)) processes, second-harmonic generation (SHG) and the following spontaneous parametric down conversion (SPDC), in a periodically poled LiNbO(3) (PPLN) ridge-waveguide device. By using a PPLN module with 600%/W of the SHG efficiency, we have achieved a coincidence-to-accidental ratio (CAR) higher than 4000 at 7.45×10(-5) of the mean number of the photon-pair per pulse. We also demonstrated that the maximum reach of the CAR was truly dark-count-limited by the single-photon detectors used here. This indicates that the fake (noise) photons were negligibly small in this system, even though the photon-pairs, the Raman noise photons, and the pump photons were in the same wavelength band. Polarization entangled photon pairs were also generated by constructing a Sagnac-loop-type interferometer which included the PPLN module and an optical phase-difference compensator to observe maximum entanglement. We achieved two-photon interference visibilities of 99.6% in the H/V basis and 98.7% in the diagonal basis. The peak coincidence count rate was approximately 50 counts per second at 10(-3) of the mean number of the photon-pair per pulse.


Diverse effects of type II collagen on osteogenic and adipogenic differentiation of mesenchymal stem cells.
Type II collagen is known to modulate chondrogenesis of mesenchymal stem cells (MSCs). In this study, MSCs from human bone marrow aspirates were used to study the modulating effects of type II collagen on MSC differentiation during the early stages of osteogenesis and adipogenesis. With osteogenic induction, MSCs cultured on the type II collagen-coated surface showed an enhanced calcium deposition level with increasing mRNA expressions of RUNX2, osteocalcin, and alkaline phosphatase. A synthetic integrin binding peptide, which specifically interacts with the I-domain of α(1)β(1)/α(2)β(1) integrins significantly blocks the mineralization-enhancing effect of type II collagen. MSCs attached on the type II collagen-coated plates exhibited expanded cell morphology with increasing spreading area, and the pretreatment of cells with integrin α(1)β(1) or α(2)β(1)-blocking antibody reduced the effect. The phosphorylation levels of FAK, ERK, and JNK significantly increased in the MSCs that attached on the type II collagen-coated plates. On the contrary, the mineralization-enhancing effect of type II collagen was diminished by JNK and MEK inhibitors. Furthermore, type II collagen blocked the adipogenic differentiation of MSCs, and this effect is rescued by JNK and MEK inhibitors. In conclusion, type II collagen facilitates osteogenesis and suppresses adipogenesis during early stage MSC differentiation. Such effects are integrin binding-mediated and conducted through FAK-JNK and/or FAK-ERK signaling cascades. These results inspire a novel strategy encompassing type II collagen in bone tissue engineering.


Mutations in different regions of the genome of hepatitis C virus genotype 1b and association with response to interferon therapy.
The aim of this study was to investigate the association of mutations in the E2/NS1 [hypervariable regions 1 and 2 (HVR1 and HVR2)] and NS5A regions of the hepatitis C virus (HCV) genome and the effectiveness of interferon (IFN) therapy, and assess whether the degree of heterogeneity of HCV quasispecies predicts response to IFN treatment. Fourteen patients infected with HCV genotype 1b (HCV-1b) who were treated with pegylated IFN-α-2a and ribavirin for 24 weeks, were studied. E2/NS1 and NS5A gene segments were amplified by reverse-transcription polymerase chain reaction. HCV quasispecies heterogeneity in the E2/NS1 region was determined by cloning and sequencing. Mutations in the NS5A region were detected by direct sequencing. The heterogeneity of HCV quasispecies in the HVR1 was significantly greater in the non-responder group than in the responder group, but was not significant for HVR2 or NS5A. The correlation between mutations in IFN sensitivity-determining region (ISDR, NS5A2209-2248) and IFN sensitivity could not be supported. The degree of quasispecies heterogeneity in HVR1, but not in HVR2 and NS5A, may be predictive of response to IFN therapy. An ISDR may not apply to patients infected with HCV-1b.


Human indolylamine 2,3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme.
The presence of indolylamine 2,3-dioxygenase was examined in human subjects by determining its activity with L-tryptophan as substrate. Enzyme activity was detected in various tissues, and was relatively high in the lung, small intestine and placenta. Human indolylamine 2,3-dioxygenase, partially purified from the placenta, had an Mr of about 40 000 by gel filtration and exhibited a single pI of 6.9. The human enzyme required a reducing system, ascorbic acid and Methylene Blue, for maximal activity and was able to oxidize D-tryptophan, 5-hydroxy-L-tryptophan as well as L-tryptophan, but kinetic studies indicated that the best substrate of the enzyme was L-tryptophan.


Preoperative endoscopic retrograde cholangiopancreatography (ERCP) in patients with pancreatic pseudocyst associated with resolving acute and chronic pancreatitis.
Experience with patients with pancreatic pseudocysts has led the authors to the hypothesis that preoperative evaluation of the pancreatic and bile ducts by ERCP will define those patients who may be inadequately treated by pseudocyst drainage alone without attention to associated pancreatic and biliary ductal abnormalities. In patients with certain ductal abnormalities, the pseudocyst operation was combined with a definitive operative drainage of the pancreatic duct and/or of the biliary tree where appropriate. A prospective evaluation of routine preoperative ERCP was undertaken over a 36-month period in all patients scheduled for operative treatment of pseudocyst of the pancreas. From an initial group of 44 patients with pseudocysts, three patients who had spontaneous regression of the pseudocyst were excluded. ERCP was successful in 39 of the remaining 41 patients. Among 41 operated patients, 24 were admitted with a diagnosis of pseudocyst that arose after an episode of acute pancreatitis, and 17 had chronic pancreatitis with pseudocyst. Nine patients, initially assumed to have acute pancreatitis, were recognized to have chronic pancreatitis on the basis of ERCP findings. Communication with the main pancreatic duct (MPD) was demonstrated in 18 of 41 pseudocysts, and the rate of communication was similar in patients with acute and chronic pancreatitis. Dilatation of the MPD was seen in 23 of 41 patients and was associated with chronic pancreatitis in 21. Dilatation of the common bile duct was found in 12 patients with chronic pancreatitis. The operative plan was altered by ERCP findings in 24 of 41 patients; 22 of the 24 patients had chronic pancreatitis. There were no complications of ERCP. These data suggest that ERCP should be performed in all patients with pseudocysts to establish correct diagnosis and to allow optimal choice of operation.


An ungracious host for an unwelcome guest.
Persistence of latently infected CD4(+) T cell "reservoirs" presents a major obstacle for current HIV-1 antiretroviral therapies. In Cell Host & Microbe, two separate studies use model systems of latent infection to dissect the influence of host genes on HIV-1 transcription, yielding intriguing, though partially contradictory, conclusions.


Can gender differences be evaluated in a rhesus macaque (Macaca mulatta) model of focal cerebral ischemia?
Gender differences, sex steroid effects, and sex-specific candidate therapeutics in ischemic stroke have been studied in rodents but not in nonhuman primates. In this feasibility study (n = 3 per group), we developed a model of transient focal cerebral ischemia in adult male and female rhesus macaques that consistently includes white matter injury. The animals also were used to determine whether gender-linked differences in histopathologic outcomes could be evaluated in this model in future, larger preclinical trials. Histologic brain pathology was evaluated at 4 d after 90 min of reversible occlusion of the middle cerebral artery (MCA). MCA occlusion was accomplished by using a transorbital approach and temporary placement of an aneurysm clip. Male and female rhesus macaques 7 to 11 y of age were studied. Baseline and intraischemic blood glucose, systolic blood pressure, heart rate, oxygen saturation, end-tidal CO2, and rectal temperatures were not different among groups. The variability in injury volume was comparable to that observed in human focal cerebrovascular ischemia and in other nonhuman primate models using proximal MCA occlusion. In this small sample, the volume of injury was not different between male and female subjects, but observed variability was higher in female caudate nucleus, putamen, and hemisphere. This report is the first to compare cerebral ischemic outcomes in female and male rhesus macaques. The female rhesus macaque ischemic stroke model could be used after rodent studies to provide preclinical data for clinical trials in women.


Relevance of HLA-DQB1*02 Allele in the Genetic Predisposition of Children with Celiac Disease: Additional Cues from a Meta-Analysis.
Background and Objectives: Celiac disease (CD) is a multifactorial immune-mediated disorder, triggered by the ingestion of gluten in genetically-predisposed subjects carrying MHC-DQ2 and -DQ8 heterodimers, which are encoded by four HLA-DQ allelic variants, overall. This meta-analysis aims at providing further epidemiological support to the predominant relevance of one specific allele, namely HLA-DQB1*02, in the predisposition and genetic risk of CD. Materials and Methods: We performed a search of MEDLINE/PubMed, Embase, Web of Science, and Scopus, retrieving all publications (case-control study, cross-sectional, and retrospective cohort study) on the association between HLA class II polymorphisms and first-degree relatives (FDRs) of children with CD. After a critical reading of the articles, two investigators independently performed data extraction according to the following inclusion criteria: HLA class II genes, any DQ and DR molecules, and CD diagnosed following the current clinical guidelines. A third participant was consulted for discussion to reach an agreement concerning discrepancies. Results: Our search strategy selected 14 studies as being eligible for inclusion, and those were submitted for data extraction and analysis. These studies were published between 1999 and 2016 and, collectively, enrolled 3063 FDRs. Positive and negative likelihood ratios (LR+ and LR-, respectively) for CD diagnosis, according to the presence of the HLA-DQ genotype coding a complete MHC-DQ2 and/or MHC-DQ8 molecules, were 1.449 (CI 1.279-1.642) and 0.187 (CI 0.096-0.362), respectively. If only the isolated presence of HLA-DQB1*02 allele is considered, the pooled estimation of LR+ was 1.659 (CI 1.302-2.155) and, importantly, the LR- still showed a very good discriminatory power of 0.195 (CI 0.068-0.558). Conclusions: Through our differential meta-analysis, comparing the presence of the genotype coding the full MHC-DQ2 and/or DQ8 molecules with the isolated presence of HLA-DQB1*02 allelic variant, we found that the LR- of the latter analysis maintained the same value. This observation, along with previous evidences, might be useful to consider potential cost-effective widened screening strategies for CD in children.


The new pooled cohort equations risk calculator.
In the National Cholesterol Education Program Adult Treatment Panel III guidelines published in 2001, estimation of cardiovascular risk was recommended based on the Framingham score for 10-year risk of myocardial infarction and the Canadian Cardiovascular Society currently recommends the Framingham total cardiovascular risk score. During development of joint guidelines released in 2013 by the American College of Cardiology (ACC) and American Heart Association (AHA), the decision was taken to develop a new risk score. This resulted in the ACC/AHA Pooled Cohort Equations Risk Calculator. This risk calculator, based on major National Heart, Lung, and Blood Institute-funded cohort studies, is designed to predict 10-year risk of 'hard' atherosclerotic cardiovascular disease (ASCVD) events, namely, nonfatal myocardial infarction, fatal coronary heart disease, nonfatal, or fatal stroke. Considerable strengths are its inclusion of stroke as an end point and race as a characteristic, which allows better risk prediction especially in African-American individuals, plus provision of lifetime ASCVD risk estimates for adults aged 20-59 years. Notable omissions from the risk factors include chronic kidney disease and any measure of social deprivation. An early criticism of the Pooled Cohort Equations Risk Calculator has been its alleged overestimation of ASCVD risk which, if confirmed in the general population, is likely to result in statin therapy being prescribed to many individuals at lower risk than the intended 7.5% 10-year ASCVD risk threshold for treatment in the joint ACC/AHA cholesterol guidelines. In this review we discuss the development of the new risk calculator, its strengths and weaknesses, and potential implications for its routine use.


Simulation model based approach for long exposure atmospheric point spread function reconstruction for laser guide star multiconjugate adaptive optics.
This paper discusses an innovative simulation model based approach for long exposure atmospheric point spread function (PSF) reconstruction in the context of laser guide star (LGS) multiconjugate adaptive optics (MCAO). The approach is inspired from the classical scheme developed by Véran et al. [J. Opt. Soc. Am. A14, 3057 (1997)] and Flicker et al. [Astron. Astrophys.400, 1199 (2003)] and reconstructs the long exposure optical transfer function (OTF), i.e., the Fourier transformed PSF, as a product of separate long-exposure tip/tilt removed and tip/tilt OTFs, each estimated by postprocessing system and simulation telemetry data. Sample enclosed energy results assessing reconstruction accuracy are presented for the Thirty Meter Telescope LGS MCAO system currently under design and show that percent level absolute and differential photometry over a 30 arcsec diameter field of view are achievable provided the simulation model faithfully represents the real system.


Design and performance of an ESI interface for selective external ion accumulation coupled to a Fourier transform ion cyclotron mass spectrometer.
The coupling of Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) with electrospray ionization has advanced the analysis of large biopolymers and provided the basis for high-throughput protein characterization (e.g., for rapid "proteome" analyses). In this work, the combination of high-performance capillary liquid chromatography with FTICR mass spectrometry and external ion accumulation has been shown to increase both sensitivity and analysis duty cycle. Instrument versatility is further improved by ion preselection followed by ion accumulation in an external linear quadrupole ion trap. The interface was tested with a 3.5-T FTICR mass spectrometer and evaluated with a number of peptides and proteins whose molecular weights ranged from 500 to 66000. A significant increase in the sensitivity, duty cycle, and dynamic range over that of the previously used accumulated trapping was achieved, exhibiting a detection limit of approximately 10 zmol (approximately 6000 molecules) for smaller proteins such as cytochrome c. Capillary LC external accumulation interface with FTICR was successfully applied for the study of whole-proteome mouse tryptic digests.


Method for correcting the joint error of a laser writer.
We present what we believe to be a new method for correcting the joint error of a laser writer without reduction of throughput. By digitization, we optimize the intensity data of the incident beam at the vicinity of the start point and the end point. The joint error will not be sensitive to lengthening of the start or end point by optimization. The advantage of this method over multipass writing and error scattering is that it requires only a single pass, and thus 80% of the fabrication time will be saved. Experimentation shows the method to be effective.


The association between observed non-verbal maternal responses at 12 months and later infant development at 18 months and IQ at 4 years: a longitudinal study.
An infant's early environment has an important influence on their development. For example, the sensitivity and warmth of a mother's responses towards her infant is associated with the infant's later socio-emotional development. However, it is less clear whether maternal responses are associated with the infant's later cognitive development. We used data from a large UK cohort study to investigate the association between non-verbal maternal responses and later infant development and IQ. Maternal responses were rated at 12 months during an observed mother-infant interaction. Infant development was assessed using the Griffiths scales at 18 months and IQ at 4 years was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). Data on the infant's developmental level at 6 months (prior to the maternal response ratings) was also available. The complete case sample comprised 732 mother-infant pairs. There was evidence for an association between positive maternal responses and infant development at 18 months. After adjusting for infant developmental level at 6 months and other confounders, we found a difference of 0.25 standard deviations (coef 2.0, 95% CI (0.8-3.2), p=0.002) on the Griffiths scales between infant's whose mothers showed positive compared to neutral non-verbal responses at 12 months. However, an association between positive maternal responses and IQ at 4 years diminished following adjustment for maternal educational attainment. The results provide evidence that positive maternal responses are associated with improved development in infants at 18 months. However, the association between maternal response and IQ at 4 years may be explained by higher educational attainment in mothers who show positive responses. Future studies are needed to explore the influence of maternal responses on different aspects of infant development as well as the role of maternal factors such as education.


Induction of synthesis of bovine adrenocortical cytochromes P-450scc, P-45011 beta, P-450C21, and adrenodoxin by prostaglandins E2 and F2 alpha and cholera toxin.
To further elucidate the mechanisms by which ACTH (adrenocorticotropin) exerts its long-term action to maintain normal levels of adrenocortical cytochromes P-450 and related enzymes, the abilities of cholera toxin and prostaglandins E2 and F2 alpha to induce the synthesis of cytochromes P-450scc, P-45011 beta, and P-450C21 and adrenodoxin have been examined. These effectors stimulate the production of cyclic AMP and thus steroidogenesis in the adrenal cortex. Using bovine adrenocortical cells in primary monolayer culture, we have shown that treatment with cholera toxin results in increased synthesis of cytochromes P-450scc and P-45011 beta and adrenodoxin, similar to the effect observed upon ACTH treatment. Prostaglandins E2 and F2 alpha are less effective at inducing the synthesis of the mitochondrial cytochromes P-450, and do not seem to induce the synthesis of adrenodoxin. Furthermore, cholera toxin was found to be less effective at inducing the synthesis of microsomal cytochrome P-450C21 than ACTH, and no more effective than the prostaglandins. Thus, while it appears that elevation of cyclic AMP levels is a necessary step leading to increased synthesis of adrenocortical forms of cytochrome P-450, the detailed mechanism of this induction will be found to be different for each of the different enzymes.


Regulation and localization of estrogen and progestin receptors in the pituitary of steroid-treated monkeys.
PRL increases during pregnancy in primates with rising levels of placental estradiol (E) and progesterone (P). However, while E will increase PRL secretion in monkey pituitary cell cultures, P has no effect. We recently localized progestin receptors (PR) to gonadotropes, but not lactotropes, with an immunocytochemical technique to double stain monkey pituitary cell cultures. The following studies were performed to confirm the immunocytochemical localization of PR in intact pituitary tissue and to determine the effect of E and P on the levels of estrogen receptors (ER) and PR in the pituitary. ER and PR levels were determined in the endometrium of the same animals for an internal comparison. Thirteen adult cycling female cynomolgus monkeys were ovariectomized and treated for 28 days with 1) an empty Silastic capsule (Spay), 2) a 2-cm E-filled capsule (E), or 3) a 2-cm E-filled capsule for 14 days plus a 6-cm P-filled capsule implanted for an additional 14 days (E + P). Blood samples were drawn daily for assay of serum E, P, and PRL levels. Serum PRL was not significantly affected by E, but the sequential addition of P significantly increased serum PRL levels over those observed in Spray animals. The anterior pituitary and endometrium were removed for measurement of ER and PR levels by a sucrose gradient shift assay incorporating monoclonal antibodies against ER and PR. Pituitary ER levels did not vary significantly with steroid treatment (158.2 +/- 33.6, 135.5 +/- 24.9, 104.3 +/- 13.4 fmol/mg DNA in Spay, E, and E + P animals, respectively). Pituitary PR levels were undetectable in Spay animals, were induced by E (393.3 +/- 53.4 fmol/mg DNA), and were suppressed to undetectable levels by the addition of P. A portion of the pituitary was frozen for immunocytochemical single staining for ER, PR, PRL, and LH and double staining for PRL + PR and LH + PR. ER staining was observed in many parenchymal cells, but there was no apparent change with steroid treatment. PR staining was absent in the Spay animals; many PR-positive cells were observed in E-treated females, and only a small number of faintly staining cells were detected in the E + P animals. Double staining for PRL + PR and LH + PR revealed PR in gonadotropes, but not lactotropes. In conclusion, PR, but not ER, are regulated by E and P in the monkey pituitary. Importantly, PR is regulated within gonadotropes, but not lactotropes. Therefore, P probably increases PRL secretion through a hypothalamic action.


Implementing the package of CDC and WHO recommended linkage services: Methods, outcomes, and costs of the Bukoba Tanzania Combination Prevention Evaluation peer-delivered, linkage case management program, 2014-2017.
Although several studies have evaluated one or more linkage services to improve early enrollment in HIV care in Tanzania, none have evaluated the package of linkage services recommended by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). We describe the uptake of each component of the CDC/WHO recommended package of linkage services, and early enrollment in HIV care and antiretroviral therapy (ART) initiation among persons with HIV who participated in a peer-delivered, linkage case management (LCM) program implemented in Bukoba, Tanzania, October 2014 -May 2017. Of 4206 participants (88% newly HIV diagnosed), most received recommended services including counseling on the importance of early enrollment in care and ART (100%); escort by foot or car to an HIV care and treatment clinic (CTC) (83%); treatment navigation at a CTC (94%); telephone support and appointment reminders (77% among clients with cellphones); and counseling on HIV-status disclosure and partner/family testing (77%), and on barriers to care (69%). During three periods with different ART-eligibility thresholds [CD4<350 (Oct 2014 -Dec 2015, n = 2233), CD4≤500 (Jan 2016 -Sept 2016, n = 1221), and Test & Start (Oct 2016 -May 2017, n = 752)], 90%, 96%, and 97% of clients enrolled in HIV care, and 47%, 67%, and 86% of clients initiated ART, respectively, within three months of diagnosis. Of 463 LCM clients who participated in the last three months of the rollout of Test & Start, 91% initiated ART. Estimated per-client cost was $44 United States dollars (USD) for delivering LCM services in communities and facilities overall, and $18 USD for a facility-only model with task shifting. Well accepted by persons with HIV, peer-delivered LCM services recommended by CDC and WHO can achieve near universal early ART initiation in the Test & Start era at modest cost and should be considered for implementation in facilities and communities experiencing <90% early enrollment in ART care.


Public health implications of a case of haemolytic-uraemic syndrome associated with a concomitant outbreak of mild gastroenteritis in a small rural community.
The concomitant occurrence of a case of haemolytic-uraemic syndrome (HUS) and 62 cases of mild gastroenteritis in schools of a small rural community in southern Italy induced the health authorities to suspect a foodborne outbreak of shiga-toxin-producing Escherichia coli (STEC) infection. The schools were closed and the catering service involved was investigated. However, STEC were not isolated from the HUS case or from the 56 cases of gastroenteritis examined, and the HUS case and the outbreak of gastroenteritis were probably just coincidental. A retrospective cohort study failed to show any correlation with consumption of school meals and suggested that the outbreak probably started outside the school setting and then spread within the schools by person-to-person transmission. All the cases examined were negative for common enteric pathogens and the responsible agent for the cases of gastroenteritis was not identified. The concern raised in the small community by the occurrence of a severe case of HUS and the lack of a rapid epidemiological assessment excluding the occurrence of a STEC outbreak, turned an epidemic episode of mild gastroenteritis into a public health emergency with relevant socioeconomic consequences. Prompt intervention in outbreaks following timely and effective risk communication are crucial for taking the most appropriate control measures and avoiding the spread of fear and panic in the community.


Scaling-up the Systems Analysis and Improvement Approach for prevention of mother-to-child HIV transmission in Mozambique (SAIA-SCALE): a stepped-wedge cluster randomized trial.
The introduction of option B+-rapid initiation of lifelong antiretroviral therapy regardless of disease status for HIV-infected pregnant and breastfeeding women-can dramatically reduce HIV transmission during pregnancy, birth, and breastfeeding. Despite significant investments to scale-up Option B+, results have been mixed, with high rates of loss to follow-up, sub-optimal viral suppression, continued pediatric HIV transmission, and HIV-associated maternal morbidity. The Systems Analysis and Improvement Approach (SAIA) cluster randomized trial demonstrated that a package of systems engineering tools improved flow through the prevention of mother-to-child HIV transmission (PMTCT) cascade. This five-step, facility-level intervention is designed to improve understanding of gaps (cascade analysis), guide identification and prioritization of low-cost workflow modifications (process mapping), and iteratively test and redesign these modifications (continuous quality improvement). This protocol describes a novel model for SAIA delivery (SAIA-SCALE) led by district nurse supervisors (rather than research nurses), and evaluation procedures, to serve as a foundation for national scale-up. The SAIA-SCALE stepped wedge trial includes three implementation waves, each 12 months in duration. Districts are the unit of assignment, with four districts randomly assigned per wave, covering all 12 districts in Manica province, Mozambique. In each district, the three highest volume health facilities will receive the SAIA-SCALE intervention (totaling 36 intervention facilities). The RE-AIM framework will guide SAIA-SCALE's evaluation. Reach describes the proportion of clinics and population in Manica province reached, and sub-groups not reached. Effectiveness assesses impact on PMTCT process measures and patient-level outcomes. Adoption describes the proportion of districts/clinics adopting SAIA-SCALE, and determinants of adoption using the Organizational Readiness for Implementing Change (ORIC) tool. Implementation will identify SAIA-SCALE core elements and determinants of successful implementation using the Consolidated Framework for Implementation Research (CFIR). Maintenance describes the proportion of districts sustaining the intervention. We will also estimate the budget and program impact from the payer perspective for national scale-up. SAIA packages user-friendly systems engineering tools to guide decision-making by frontline health workers, and to identify low-cost, contextually appropriate PMTCT improvement strategies. By integrating SAIA delivery into routine management structures, this pragmatic trial is designed to test a model for national intervention scale-up. ClinicalTrials.gov NCT03425136 (registered 02/06/2018).


Jobs and Career Plans of New Pediatric Subspecialists.
The issues of importance in selecting a first job for new pediatric subspecialists, and their ability to find positions that match their professional and clinical goals, are unknown. The objectives were to (1) describe current employment patterns, practice characteristics, factors influencing choice of first position, and future work goals of new pediatric subspecialists; and (2) examine the relationship of these variables with the actual professional time allocation and clinical responsibilities compared with the desired first job. The authors surveyed 3010 individuals sitting for ≥1 of the 14 subspecialty certification exams. The main outcomes were (1) most important factors in choosing employment; (2) ability to gain employment in positions that matched their goals; and (3) variation in employment characteristics among men versus women, time since completion of training, and part-time versus full-time status. Response rate was 97%. Lifestyle/spousal or family considerations was the factor identified as most important in the choice of first position after fellowship training for half of respondents (50%; n = 1277). There was a median of 75% of actual time spent in direct and/or consultative inpatient or outpatient care, with 5% in medical education, 5% in administration, and 5% in research. A majority (74%; n = 1825) reported this proportion to be approximately what they wanted. Most respondents (89%; n = 2194) reported that their allocation of patient care responsibilities (ie, inpatient versus outpatient) was approximately what they wanted. A large majority of pediatric subspecialists found initial positions matching their goals for professional responsibilities and clinical care.


Unexpected shock in a fallen older adult: a case report.
Falls are common in older adults and frequently require ambulance service assistance. They are the most frequent cause of injury and associated morbidity and mortality in older adults. In recent years, the typical major trauma patient has changed from being young and male to being older in age, with falls of < 2 metres being the most common mechanism of injury. We present a case of an 84-year-old male who had fallen in his home. This case highlights the complex nature of a relatively common incident. The patient was laid on the floor in the prone position unable to move for 12 hours. He did not complain of any pain in his neck, back, hips or legs, and wished to be lifted off the floor promptly. On examination, he had bruising to his chest and abdomen and had suffered a suspected cervical spine injury due to a step-like protrusion around C5-C6. Distal sensory and motor function was intact. While in the ambulance his blood pressure dropped from 154/119 mmHg to 49/28 mmHg unexpectedly. We successfully reversed the shock using the modified Trendelenburg position and intravenous fluids. On follow-up he was diagnosed with dislocated C3, C6 and C7 vertebrae. The unexpected episode of shock witnessed in this patient may have been caused by a number of phenomena, including but not limited to crush syndrome, spinal cord concussion and orthostatic hypotension. We recommend that clinicians anticipate sudden shock in older adult patients who have fallen and a) have remained static on the floor for an extended period of time or b) are suspected of a spinal injury. We recommend assertive management of these patients to mitigate the impact of shock through postural positioning and consideration of early cannulation.


Use of complementary medicine among patients with allergic rhinitis: an Italian nationwide survey.
A growing use of complementary alternative medicine (CAM) has been found in Europe as well in Italy for chronic diseases, including the allergic rhinitis. The study aims at investigating the prevalence and the pattern of use of CAM amongst patient with allergic rhinitis. A 12-item questionnaire was developed by a panel of experts and administered to patients with moderate/severe allergic rhinitis consecutively referring during the study time-frame to seven allergy clinics placed all around Italy. The items covered several topics including reason for choosing CAM, its clinical efficacy, schedule of treatment, costs, type of therapy. Overall 359 questionnaires were analysed. 20% of patients declared CAM use. A significant correlation between the use of CAM and female sex (p < 0.01) and with a higher level of education (p < 0.01) was observed. CAM users were adults (36% in the range between 20 and 40 years and 32% between 41 and 60 years). Youngsters (< 20 years) (7%) and elderly (> 60) (25%) less frequently used CAM.The most used type of CAM was homoeopathy (77% of patients). 60% of users would recommend CAM despite a poor clinical efficacy according to 67% of them. Although no evidence supports CAM efficacy and safety, the number of patients who relies on it is not negligible. As allergic rhinitis is not a trivial disease, the use of CAM as the only treatment for it should be discouraged at any level, but by general practitioner and specialist in particular.


Clinical challenges of classification based targeted therapies for non-specific low back pain: What do physiotherapy practitioners and managers think?
Classification of non-specific low back pain (NSLBP) was recommended to better target care and so maximise treatment potential. This study investigated physiotherapy practitioners' (PPs) and managers' (PMs) views, experiences and perceptions of barriers and enablers for using classification systems (CSs) to better target treatment for NSLBP in the NHS primary care setting. Qualitative focus group and interviews. Data from semi-structured interviews of three PMs and a focus group with five PPs, considered local opinion leaders in physiotherapy, was thematically analysed. Five themes emerged (i) CS knowledge: PPs and PMs were aware of CSs and agreed with its usefulness. PPs were mostly aware of CSs informing specific treatments whilst PMs were aware of prognosis based CSs. (ii) Using CSs: PPs classify by experience and clinical reasoning skills, shifting between multiple CSs. PMs were confident that evidence-based practice takes place but believed CSs may not be always used. (iii) Advantages/disadvantages of CSs: Effective targeting of treatments to patients was perceived as advantageous; but the amount of training required was perceived as disadvantageous. (iv) Barriers: Patients' expectations, clinicians' perceptions, insufficiently complex CSs, lack of training resources. (v) Enablers: Development of sufficiently complex CSs, placed within the clinical reasoning process, mentoring, positive engagement with stakeholders and patients. PPs and PMs were aware of CSs and agreed with its usefulness. The current classification process was perceived to be largely influenced by individual practitioner knowledge and clinical reasoning skills rather than being based on one CS alone. Barriers and enablers were identified for future research.


A study of factors associated with response to electroconvulsive therapy in patients with schizophrenic symptoms.
Seventeen patients with schizophrenic symptoms were assessed before and after ECT to elicit possible factors predictive of outcome. The strongest associations with good outcome were shown by short duration of illness and paucity of pre-morbid schizoid personality traits; significant associations were also shown by short duration of current episode, paucity of paranoid pre-morbid personality traits, and the presence of perplexity. The diagnosis of schizoaffective disorder was not related to outcome. Questionnaires completed by 16 patients after ECT showed their attitudes to be generally favourable to the procedure.


Navigation and the developing brain.
As babies rapidly acquire motor skills that give them increasingly independent and wide-ranging access to the environment over the first two years of human life, they decrease their reliance on habit systems for spatial localization, switching to their emerging inertial navigation system and to allocentric frameworks. Initial place learning is evident towards the end of the period. From 3 to 10 years, children calibrate their ability to encode various sources of spatial information (inertial information, geometric cues, beacons, proximal landmarks and distal landmarks) and begin to combine cues, both within and across systems. Geometric cues are important, but do not constitute an innate and encapsulated module. In addition, from 3 to 10 years, children build the capacity to think about frames of reference different from their current one (i.e. to perform perspective taking). By around 12 years, we see adult-level performance and adult patterns of individual differences on cognitive mapping tasks requiring the integration of vista views of space into environmental space. These lines of development are continuous rather than stage-like. Spatial development builds on important beginnings in the neural systems of newborns, but changes in experience-expectant ways with motor development, action in the world and success-failure feedback. Human systems for integrating and manipulating spatial information also benefit from symbolic capacities and technological inventions.


Innovation in catheter design for intra-arterial liver cancer treatments results in favorable particle-fluid dynamics.
Liver tumors are increasingly treated with radioembolization. Here, we present first evidence of catheter design effect on particle-fluid dynamics and downstream branch targeting during microsphere administrations. A total of 7 experiments were performed in a bench-top model of the hepatic arterial vasculature with recreated hemodynamics. Fluorescent microspheres and clinically used holmium microspheres were administered with a standard microcatheter (SMC) and an anti-reflux catheter (ARC) positioned at the same level along the longitudinal vessel axis. Catheter-related particle flow dynamics were analyzed by reviewing video recordings of UV-light illuminated fluorescent microsphere administrations. Downstream branch distribution was analyzed by quantification of collected microspheres in separate filters for two first-order branches. Mean deviation from a perfectly homogenous distribution (DHD) was used to compare the distribution homogeneity between catheter types. The SMC administrations demonstrated a random off-centered catheter position (in 71 % of experiments), and a laminar particle flow pattern with an inhomogeneous downstream branch distribution, dependent on catheter position and injection force. The ARC administrations demonstrated a fixed centro-luminal catheter position, and a turbulent particle flow pattern with a more consistent and homogenous downstream branch distribution. Quantitative analyses confirmed a significantly more homogeneous distribution with the ARC; the mean DHD was 40.85 % (IQR 22.76 %) for the SMC and 15.54 % (IQR 6.46 %) for the ARC (p = 0.047). Catheter type has a significant impact on microsphere administrations in an in-vitro hepatic arterial model. A within-patient randomized controlled trial has been initiated to investigate clinical catheter-related effects during radioembolization treatment.


Assessing individual differences in the speed and accuracy of intersensory processing in young children: The intersensory processing efficiency protocol.
Detecting intersensory redundancy guides cognitive, social, and language development. Yet, researchers lack fine-grained, individual difference measures needed for studying how early intersensory skills lead to later outcomes. The intersensory processing efficiency protocol (IPEP) addresses this need. Across a number of brief trials, participants must find a sound-synchronized visual target event (social, nonsocial) amid five visual distractor events, simulating the "noisiness" of natural environments. Sixty-four 3- to 5-year-old children were tested using remote eye-tracking. Children showed intersensory processing by attending to the sound-synchronous event more frequently and longer than in a silent visual control, and more frequently than expected by chance. The IPEP provides a fine-grained, nonverbal method for characterizing individual differences in intersensory processing appropriate for infants and children. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


A comprehensive investigation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) metabolism in the mouse using a multivariate data analysis approach.
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent rodent carcinogen and a potential human carcinogen because of its existence in the normal human diet. N2-OH-PhIP, a major PhIP metabolite, has been identified as a precursor of genotoxic species. In vitro data supported the view that CYP1A2 is the major enzyme responsible for the formation of N2-OH-PhIP. However, disruption of the CYP1A2 gene in mouse failed to inhibit PhIP-induced carcinogenesis. To investigate the mechanism underlying this observation, the metabolism of PhIP in wild-type, Cyp1a2-null, and CYP1A2-humanized mice was examined in detail using a metabolomic approach. Following data acquisition in a high-resolution LC-MS system, urinary metabolomes of the control and PhIP-treated mice were characterized in a principal component analysis (PCA) model. Comprehensive metabolite profiles of PhIP in high dose (10 mg/kg) and low dose (100 microg/kg) were established through analyzing urinary ions contributing to the separation of three mouse lines in the multivariate model and by measuring radiolabled PhIP metabolite in a radio-HPLC assay, respectively. The genotoxicity of PhIP to three mouse lines was evaluated by measuring DNA adduction levels in liver, lung, colon, and mammary gland. On the basis of the chemical identities of 17 urinary PhIP metabolites, including eight novel metabolites, multivariate data analysis revealed the role of CYP1A2 in PhIP metabolism and a human-mouse interspecies difference in the catalytic activity of CYP1A2. In addition, the results also showed that Cyp1a2-null mice still possess significant N2-hydroxylation and DNA adduction activities, which may be partially attributed to mouse CYP2C enzymes according to the results from in vitro microsome and Supersome incubations and antibody inhibition experiments.


Descriptive epidemiology of autism in a California population: who is at risk?
We investigated the association between selected infant and maternal characteristics and autism risk. Children with autism born in California in 1989-1994 were identified through service agency records and compared with the total population of California live births for selected characteristics recorded on the birth certificate. Multivariate models were used to generate adjusted risk estimates. From a live birth population of more than 3.5 million, 4381 children with autism were identified. Increased risks were observed for males, multiple births, and children born to black mothers. Risk increased as maternal age and maternal education increased. Children born to immigrant mothers had similar or decreased risk compared with California-born mothers. Environmental factors associated with these demographic characteristics may interact with genetic vulnerability to increase the risk of autism.


New methods to clean ICU rooms.
Hospital-acquired infections (HAI) represent the most common adverse event in the intensive care unit (ICU). Their prevalence is high and they are associated with increased morbidity and mortality. The environment plays a central role in the transmission of hospital-acquired pathogens (HAP) and in the pathogenesis of HAI. Many bacteria, especially multidrug resistant ones, can survive for several months in the hospital environment in particular in areas close to the patients. It has been proven that pathogens are transmitted from the environment to the patients. Many studies have concluded that current cleaning methods are microbiologically ineffective. This failure concerns daily cleaning as well as terminal cleaning after patient discharge. It has been demonstrated that improvements in environmental cleaning are associated with a decrease in the rate of HAP and of HAI. New cleaning methods could enhance hospital cleaning efficiency. Three new technologies seem promising because they are microbiologically effective, easy and safe to use: (1) hydrogen peroxide vapor and (2) UV light decontamination are used for terminal cleaning. These techniques are effective even in difficultly accessible areas. (3) ultramicrofibers which can be associated with a copper-based biocide can be used for daily cleaning. Other methods such as ozone, steam or high-efficiency particulate air filtration are not efficient enough to be considered serious contenders for the improvement of the quality of the hospital environment. These new technologies have not been yet linked to a decrease in the prevalence and the incidence in HAP and HAI. It remains difficult to justify the extra-cost associated with these new methods until more studies can confirm their effectiveness in the management of HAI.


The Effects of Precautionary Messages about Electromagnetic Fields from Mobile Phones and Base Stations Revisited: The Role of Recipient Characteristics.
Precautionary messages have been shown to increase recipients' threat perceptions about radio-frequency electromagnetic fields (RF-EMFs) emitted by mobile phones and mobile phone base stations. The current study explored the interplay of variables on the side of message recipients with this effect. The individual difference variables of interest were gender, trait anxiety, personal need for structure, and personal fear of invalidity. Furthermore, the study determined whether the increased threat perception is accompanied by emotional distress. A total of 298 university students answered a survey after reading either a basic text about RF-EMFs or a text including precautionary information. Linear multiple regression with interactions analyses showed that the effect of precautionary messages differed for people with different levels of trait anxiety. How trait anxiety was related to the effect of precautionary messages in turn depended on participants' gender. Personal need for structure and personal fear of invalidity were mostly unrelated to the effect of precautionary messages. Regarding participants' emotional distress, we found no difference in state anxiety scores between those participants who received precautionary information and those who did not. The findings show that the effects of precautionary messages on threat perception depend on individual difference variables such as recipients' trait anxiety and gender. Also, the fact that precautionary communication did not result in heightened state anxiety challenges the assumption that precautionary messages induce fear or anxiety.


Paraboea dolomitica (Gesneriaceae), a new species from Guizhou, China.
Here we describe Paraboea dolomitica Z.Y. Li, X.G. Xiang & Z.Y. Guo, a new species of Gesneriaceae from Guizhou, China. Based on recent extensive observations, this new species is morphologically similar to Paraboea filipes (Hance) Burtt, in having obovate leaf blades, 1-4-flowered cymes and purplish corolla, but differs from that species by the combination of denticulate leathery leaves, sparsely brown haired peduncles, two woolly bracts, reniform anthers and two glabrous staminodes. Additionally, molecular data support this new species as a member of a clade that includes P. crassifolia, P. tetrabracteata, P. peltifolia, P. vetutina, P. dushanensis, P. dictyoneura, P xiangguiensis and P. guilinensis, but it is distinct from them in leaf position, inflorescence, penduncle, bract and capsule. The conservation status of this species is considered to be "Vulnerable" (VU) according to the IUCN Red List Categories and Criteria.


Estimating and testing haplotype-trait associations in non-diploid populations.
Malaria is an infectious disease that is caused by a group of parasites of the genus Plasmodium. Characterizing the association between polymorphisms in the parasite genome and measured traits in an infected human host may provide insight into disease aetiology and ultimately inform new strategies for improved treatment and prevention. This, however, presents an analytic challenge since individuals are often multiply infected with a variable and unknown number of genetically diverse parasitic strains. In addition, data on the alignment of nucleotides on a single chromosome, which is commonly referred to as haplotypic phase, is not generally observed. An expectation-maximization algorithm for estimating and testing associations between haplotypes and quantitative traits has been described for diploid (human) populations. We extend this method to account for both the uncertainty in haplotypic phase and the variable and unknown number of infections in the malaria setting. Further extensions are described for the human immunodeficiency virus quasi-species setting. A simulation study is presented to characterize performance of the method. Application of this approach to data arising from a cross-sectional study of n=126 multiply infected children in Uganda reveals some interesting associations requiring further investigation.


Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.
Recently developed technologies for the treatment of type 1 diabetes mellitus include a variety of pumps and pumps with glucose sensors. In this 1-year, multicenter, randomized, controlled trial, we compared the efficacy of sensor-augmented pump therapy (pump therapy) with that of a regimen of multiple daily insulin injections (injection therapy) in 485 patients (329 adults and 156 children) with inadequately controlled type 1 diabetes. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary end point was the change from the baseline glycated hemoglobin level. At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P<0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person-years, P=0.58). There was no significant weight gain in either group. In both adults and children with inadequately controlled type 1 diabetes, sensor-augmented pump therapy resulted in significant improvement in glycated hemoglobin levels, as compared with injection therapy. A significantly greater proportion of both adults and children in the pump-therapy group than in the injection-therapy group reached the target glycated hemoglobin level. (Funded by Medtronic and others; ClinicalTrials.gov number, NCT00417989.)


CC chemokine receptor 8 in the central nervous system is associated with phagocytic macrophages.
CC chemokine receptor 8 (CCR8) has been detected in vitro on type 2 helper and regulatory lymphocytes, which might exert beneficial functions in multiple sclerosis (MS) and on macrophages and microglia, possibly promoting tissue injury in MS lesions. To discriminate the relevant expression pattern in vivo, we defined the cell types that expressed CCR8 in MS lesions and determined the relationship of CCR8 expression and demyelinating activity. CCR8 was not expressed on T cells but was associated with phagocytic macrophages and activated microglia in MS lesions and directly correlated with demyelinating activity. To identify factors associated with CCR8 expression, the study was extended to other central nervous system (CNS) pathologies. CCR8 was consistently expressed on phagocytic macrophages and activated microglia in stroke and progressive multifocal leukoencephalopathy, but not expressed on microglia in pathologies that lacked phagocytic macrophages such as senile change of the Alzheimer's type. CCR8 was up-regulated by macrophage differentiation and activating stimuli in vitro. In summary CNS CCR8 expression was associated with phagocytic macrophages and activated microglial cells in human CNS diseases, suggesting that CCR8 may be a feasible target for therapeutic intervention in MS. CCR8 expression may also indicate a selective program of mononuclear phagocyte gene expression.


Proteomic profiling of the TRAF3 interactome network reveals a new role for the ER-to-Golgi transport compartments in innate immunity.
Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) is a central mediator important for inducing type I interferon (IFN) production in response to intracellular double-stranded RNA (dsRNA). Here, we report the identification of Sec16A and p115, two proteins of the ER-to-Golgi vesicular transport system, as novel components of the TRAF3 interactome network. Notably, in non-infected cells, TRAF3 was found associated with markers of the ER-Exit-Sites (ERES), ER-to-Golgi intermediate compartment (ERGIC) and the cis-Golgi apparatus. Upon dsRNA and dsDNA sensing however, the Golgi apparatus fragmented into cytoplasmic punctated structures containing TRAF3 allowing its colocalization and interaction with Mitochondrial AntiViral Signaling (MAVS), the essential mitochondria-bound RIG-I-like Helicase (RLH) adaptor. In contrast, retention of TRAF3 at the ER-to-Golgi vesicular transport system blunted the ability of TRAF3 to interact with MAVS upon viral infection and consequently decreased type I IFN response. Moreover, depletion of Sec16A and p115 led to a drastic disorganization of the Golgi paralleled by the relocalization of TRAF3, which under these conditions was unable to associate with MAVS. Consequently, upon dsRNA and dsDNA sensing, ablation of Sec16A and p115 was found to inhibit IRF3 activation and anti-viral gene expression. Reciprocally, mild overexpression of Sec16A or p115 in Hec1B cells increased the activation of IFNβ, ISG56 and NF-κB -dependent promoters following viral infection and ectopic expression of MAVS and Tank-binding kinase-1 (TBK1). In line with these results, TRAF3 was found enriched in immunocomplexes composed of p115, Sec16A and TBK1 upon infection. Hence, we propose a model where dsDNA and dsRNA sensing induces the formation of membrane-bound compartments originating from the Golgi, which mediate the dynamic association of TRAF3 with MAVS leading to an optimal induction of innate immune responses.


The Anatomy of Research Scandals.
For the past two years, I have taught a seminar on medical research scandals. The syllabus looks like a highlight reel of exploitation and abuse: children fed plutonium-laced breakfast cereal, prisoners dosed with the active ingredient in Agent Orange, mental patients given psychedelic drugs and massive electroconvulsive therapy before being sent into curare-induced paralysis and a coma. I designed the seminar to crush the idealism of future physicians by illuminating the dark patterns that research scandals typically follow. The most recent scandal we examined happened to be one of the most lurid.


The effect of probiotics on functional constipation in adults: a systematic review and meta-analysis of randomized controlled trials.
Functional constipation is a prevalent, burdensome gastrointestinal disorder whose treatment remains challenging. Probiotics have been increasingly investigated in its management. The aim was to investigate the effect of probiotics on gut transit time, stool output, and constipation symptoms in adults with functional constipation via a systematic review and meta-analysis of randomized controlled trials (RCTs). Studies were identified by searching 4 electronic databases, back-searching reference lists, contacting authors, and hand-searching abstracts. RCTs that reported administration of probiotics in adults with functional constipation were included. Two reviewers independently performed the screening, data extraction, and bias assessment. Outcome data were synthesized by using weighted mean differences (WMDs) or standardized mean differences (SMDs) with the use of a random-effects model. A total of 660 records were identified of which 14 were eligible (1182 patients). Overall, probiotics significantly reduced whole gut transit time by 12.4 h (95% CI: -22.3, -2.5 h) and increased stool frequency by 1.3 bowel movements/wk (95% CI: 0.7, 1.9 bowel movements/wk), and this was significant for Bifidobacterium lactis (WMD: 1.5 bowel movements/wk; 95% CI: 0.7, 2.3 bowel movements/wk) but not for Lactobacillus casei Shirota (WMD: -0.2 bowel movements/wk; 95% CI: -0.8, 0.9 bowel movements/wk). Probiotics improved stool consistency (SMD: +0.55; 95% CI: 0.27, 0.82), and this was significant for B. lactis (SMD: +0.46; 95% CI: 0.08, 0.85) but not for L. casei Shirota (SMD: +0.26; 95% CI: -0.30, 0.82). No serious adverse events were reported. Attrition and reporting bias were high, whereas selection bias was unclear due to inadequate reporting. Probiotics may improve whole gut transit time, stool frequency, and stool consistency, with subgroup analysis indicating beneficial effects of B. lactis in particular. However, caution is needed with the interpretation of these data due to their high heterogeneity and risk of bias. Adequately powered RCTs are required to better determine the species or strains, doses, and duration of use of probiotics that are most efficacious.


F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach.
Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [124I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [124I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [124I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, ∼14-fold higher than that of the control antibody [124I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (∼7×) fibronectin ED-A expression in these tissues. In conclusion, [124I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [124I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.


[Accidents by external causes in adolescents: care in sentinel urgency and emergency services in the Brazilian State Capitals--2009].
Adolescents are seeking new references and experiences, which may involve attitudes of risk and exposure to accidents and violence from external causes. These events constitute a serious Public Health problem. The scope of this study was to analyze the occurrence of accidents by external causes in adolescents from 10 to 19 years of age attended at sentinel urgency and emergency services in Brazil. Data from the 2009 Surveillance System for Violence and Accidents (VIVA 2009) was analyzed in 74 emergency units in 23 state capitals and the Federal District. The findings revealed that 6,434 adolescents (89.8%) were victims of accidents and 730 (10.2 %) were victims of violence. The main causes of the accidents were falls and traffic accidents, and assaults were predominant in violence. For both accidents and violence, non-white male adolescents were predominant and the events occurred most frequently on the public highways. A marked increase was detected, with hospitalization of victims of violence between 15 and 19 years of age. Understanding the epidemiological reality of external causes among adolescents represents an important tool for health prevention and promotion policies and the culture of peace seeking to reduce morbidity and mortality.


Plasmodium falciparum in vitro susceptibility to antimalarial drugs in Casamance (southwestern Senegal) during the first 5 years of routine use of artesunate-amodiaquine.
We have monitored the in vitro sensitivities of Plasmodium falciparum isolates predeployment and during the deployment of artesunate plus amodiaquine treatment in Mlomp, Casamance (southwestern Senegal) during 2000 to 2004. Parasites remained susceptible to both drugs. Chloroquine resistance levels were high but stable. Quinine continues to be effective.


Visual outcome after cataract surgery at the university college hospital, ibadan.
The aim of this study was to determine the visual outcome of patients who had cataract surgery in the University College Hospital Ibadan. This is an observational descriptive, longitudinal study of consecutive patients undergoing cataract surgery at the University College Hospital conducted between May and October 2007. A total of 184 patients who presented to the hospital and met the inclusion criteria were recruited into the study. Patients were examined preoperatively, 1st day postoperatively and 8th week postoperatively. The mean age was 66.5 years; and the male to female ratio was 1.2:1. Preoperatively, 137 patients (74.5%) were blind in the operated eye, while 39 patients (23.6%) were blind in both eyes at presentation. At 1st day postoperatively, 87 patients (47.3%) had pinhole visual acuity of 6/6-6/18. Best corrected vision after refraction eight weeks postoperatively showed that 127 patients out of 161 patients (78.8%) had good vision while 28 patients (17.4%) had borderline vision, and six patients (3.8%) had severe visual impairment after refraction. The number of bilaterally blind patients also reduced from 39 (23.6%) to one (0.6%). Uncorrected refractive error was the commonest cause of poor vision prior to refraction. Glaucoma was the commonest ocular co-morbidity accounting for poor vision in 9.1% of patients eight weeks after cataract surgery. This study demonstrates that good results can be obtained with cataract surgery and intraocular lens implantation in the developing world. More attention should be directed towards ensuring that successful outcomes are indeed being realized by continued monitoring of postoperative visual outcomes and prompt refraction for all patients.


A long-range restriction map between the alpha-globin complex and a marker closely linked to the polycystic kidney disease 1 (PKD1) locus.
Two polymorphic loci and two additional probes that map close to CMM65, which is tightly linked to the polycystic kidney disease 1 (PKD1) locus in chromosome band 16p13.3, are described. These new probes were isolated from a library that was enriched by preparative pulsed-field gel electrophoresis (PFGE) for sequences from a 320-kb NotI fragment that includes CMM65. Through the use of a panel of somatic cell hybrids and PFGE, the new polymorphic loci, PNL56S and NKISP1, were localized within 60 kb and approximately 250 kb distal to CMM65, respectively. A long-range restriction map linking these new probes and the distal markers EKMDA2, CMM103, and alpha-globin was constructed. These latter probes have been localized to regions approximately 900 kb, 1.2 Mb, and 1.9 Mb distal to CMM65, respectively. The entire region was found to be unusually rich in CpG dinucleotides. The new polymorphic probes and the long-range map will aid both the search for the PKD1 locus and the detailed characterization of this distal region of 16p.


Policy interventions implemented through sporting organisations for promoting healthy behaviour change.
Sporting organisations provide an important setting for health promotion strategies that involve policies, communication of healthy messages and creation of health promoting environments. The introduction of policy interventions within sporting organisations is one strategy to target high risk behaviours such as smoking, alcohol consumption, excess sun exposure, unhealthy eating and discrimination. To update a review of all controlled studies evaluating policy interventions organised through sporting settings to increase healthy behaviour (related to smoking, alcohol, healthy eating, sun protection, discrimination, safety and access). We updated the original (2004) searches in May 2007. We searched: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2 2007); MEDLINE and MEDLINE In-Process and Other Non-Indexed Citations (2004 to Week 3 April 2007); EMBASE (2004 to Week 17 2007); PsyclNFO (2004 to April Week 1 2007); CINAHL (2004 to Week 1 May 2007); SPORTDiscus (2004 to April 2007); Sociological Abstracts (2004 to 2007); Dissertation Abstracts (2004 to May 2007), ERIC (2000 to 2007), freely available online health promotion and sports-related databases hosted by leading agencies, and the internet using sport and policy-related key words. Controlled studies evaluating any policy intervention implemented through sporting organisations to instigate and/or sustain healthy behaviour change, intention to change behaviour, or changes in attitudes, knowledge or awareness of healthy behaviour, in people of all ages. Policies must address any of the following: smoking, alcohol, healthy eating, sun protection, access for disadvantaged groups, physical safety (not including injuries), and social and emotional health (e.g. anti-vilification, anti-discrimination). Uncontrolled studies which met the other inclusion criteria were to be reported in an annex to the review. We assessed whether identified citations met the inclusion criteria. Abstracts were inspected independently by two review authors and full papers were obtained where necessary. As we located no controlled evaluation studies, we did not undertake data collection or analysis. We found no uncontrolled studies meeting other inclusion criteria, and therefore present no annex to the review. We found no rigorous studies evaluating the effectiveness of policy interventions organised through sporting organisations to increase healthy behaviours, attitudes, knowledge or the inclusion of health-oriented policies within the organisations. We found no controlled studies to guide the use of policy interventions used in sporting settings. The original (2004) searches identified a number of case studies with anecdotal reporting of outcomes. We strongly recommend that rigorous evaluation techniques are employed more commonly in this field to illuminate the impact of health promoting policy on outcomes, and the contexts and processes which are likely to be effective in reducing harmful behaviours.


[Rheumatic heart disease: future prospects].
Acute rheumatic fever develops after an inadequate immune response to throat streptococcal infection that induces the production of antibodies reacting against cardiac endothelial cells. Valve damage may lead to irreversible cardiac valve sequela (rheumatic heart disease) with further evolution towards severe valve dysfunction and heart failure. The disease has been almost eradicated in Western countries with the development of living conditions and prevention policies, including primary prevention (treatment of sore throats) and secondary prevention (long term administration of antibiotics). However, rheumatic heart disease remains a major health problem in developing countries. Recently, echocardiography identified children with mild features of the disease, thereby allowing early treatment.


Biased agonists of the chemokine receptor CXCR3 differentially signal through Gαi:β-arrestin complexes.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and signal through the proximal effectors, G proteins and β-arrestins, to influence nearly every biological process. The G protein and β-arrestin signaling pathways have largely been considered separable; however, direct interactions between Gα proteins and β-arrestins have been described that appear to be part of a distinct GPCR signaling pathway. Within these complexes, Gαi/o, but not other Gα protein subtypes, directly interacts with β-arrestin, regardless of the canonical Gα protein that is coupled to the GPCR. Here, we report that the endogenous biased chemokine agonists of CXCR3 (CXCL9, CXCL10, and CXCL11), together with two small-molecule biased agonists, differentially formed Gαi:β-arrestin complexes. Formation of the Gαi:β-arrestin complexes did not correlate well with either G protein activation or β-arrestin recruitment. β-arrestin biosensors demonstrated that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We also found that Gαi:β-arrestin complexes did not couple to the mitogen-activated protein kinase ERK, as is observed with other receptors such as the V2 vasopressin receptor, but did couple with the clathrin adaptor protein AP-2, which suggests context-dependent signaling by these complexes. These findings reinforce the notion that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of the spectrum of biased agonism.


Role of the Epigenome in Heart Failure.
Gene expression is needed for the maintenance of heart function under normal conditions and in response to stress. Each cell type of the heart has a specific program controlling transcription. Different types of stress induce modifications of these programs and, if prolonged, can lead to altered cardiac phenotype and, eventually, to heart failure. The transcriptional status of a gene is regulated by the epigenome, a complex network of DNA and histone modifications. Until a few years ago, our understanding of the role of the epigenome in heart disease was limited to that played by histone deacetylation. But over the last decade, the consequences for the maintenance of homeostasis in the heart and for the development of cardiac hypertrophy of a number of other modifications, including DNA methylation and hydroxymethylation, histone methylation and acetylation, and changes in chromatin architecture, have become better understood. Indeed, it is now clear that many levels of regulation contribute to defining the epigenetic landscape required for correct cardiomyocyte function, and that their perturbation is responsible for cardiac hypertrophy and fibrosis. Here, we review these aspects and draw a picture of what epigenetic modification may imply at the therapeutic level for heart failure.


Functional capacity in heart failure. Comparison of methods for assessment and their relation to other indexes of heart failure. The V-HeFT VA Cooperative Studies Group.
Left ventricular (LV) dysfunction plays a primary role in the pathogenesis of congestive heart failure and correlates with prognosis, but a strong quantitative relation between exercise performance and indexes of LV function has not been demonstrated. We examined the relation between LV ejection fraction at rest, oxygen consumption at peak exercise (VO2), patient and physician assessments of clinical severity, and other clinical attributes in 804 patients with moderate heart failure. Ejection fraction correlated weakly with VO2, and mean ejection fraction was related to severity of symptoms. There was a statistical association between the patient's self-assessed quality of life questionnaire score and the physician-assigned New York Heart Association (NYHA) functional class; NYHA class was statistically associated with exercise performance. To identify other factors that might influence exercise capacity, comparisons of clinical attributes were made between patients grouped by VO2 within each stratum of LV function. Exercise performance was inversely related to plasma norepinephrine levels within the ejection fraction < 25% stratum. The percentage of patients reaching their anaerobic threshold was not different between groups, yet the peak heart rate increased with VO2 within all strata. Elevated venous pressure and cardiomegaly were inversely related to exercise performance. Clinical scales based on physician and patient assessment of symptoms were statistically associated with exercise capacity but do not accurately predict individual exercise performance. The strong association of heart rate response to exercise performance suggests that the variability of the chronotropic response to exercise contributes to differences in exercise capacity among patients with a similar degree of LV dysfunction.


Exposures and asthma outcomes using two different job exposure matrices in a general population study in northern Europe.
We have recently published a study on new-onset asthma in a large population in northern Europe using a modified job exposure matrix (N-JEM) to better reflect exposure assignment in these countries. The aim of this paper was to investigate how the N-JEM differs in exposure assignment and asthma risks from an already established JEM. The study comprised 6253 men and 7031 women from northern Europe, born 1945-1973, who had answered both a screening (1989-1992) and a follow-up questionnaire (1999-2001). During the study period (1980-2000), there were 136 men and 293 women with new-onset asthma. Hazard ratios of new-onset asthma were calculated for both JEMs using Cox regression models. The analyses were made separately for men and women and were also stratified for atopy. Cohen's kappa (κ) was used to show agreements in exposure assignment (yes/no) between the JEMs. Population attributable risks (PARs) were calculated as well. The agreement in exposure assignment between the JEMs was substantial for the group 'any exposure' to asthma agents (κ = 0.78). The agreement between comparable exposure groups in the JEMs varied from κ = 1.00 (pharmaceutical product antigens, textile dust, cleaning agents) to κ = 0.27 (low molecular weight agents). Significant increased asthma risks were seen for men exposed to isocyanates and accidental peak exposure with both JEMs. With the N-JEM, increased asthma risks were seen for men exposed to plant-associated antigens (all and non-atopic), epoxy compounds (all and non-atopic), and acrylates (non-atopic). With the other JEM, increased asthma risks were seen in men and women exposed to 'possible exposure to irritant gases or fumes' (all and non-atopic), a group classified as having low asthma risk. Men and women exposed to cleaning agents also showed significant asthma risks with both JEMs. PAR with the N-JEM was 14.3% for men and 6.6% for women, compared with 12.9% and 8.3% with the other JEM. Acrylates, epoxy compounds, and isocyanates are three exposure groups in the modified asthma JEM that might better reflect exposure situations in northern Europe than the already established JEM. Exposure to 'possible exposure to irritant gases or fumes', a low asthma risk group in the established JEM, seems to be a group with high asthma risk in northern Europe. It is important to continuously update JEMs, which are based only on occupational titles, in order to find new risk groups and to better reflect changes in work exposures when old risks disappear and new emerge.


Patients rebuilt: Dr Auguste Rollier's heliotherapeutic portraits, c.1903-1944.
This article explores and critically contextualises the photographic production of heliotherapist Auguste Rollier (1874-1954), specifically the 'patient portraits' photographed at his Leysin sanatoria over a substantial period of four decades, c.1903-1944. It argues that these photographs, ignored in secondary literature, were particularly persuasive in communicating the natural healing powers of sunlight and through their international dissemination brought Rollier's work professional acclaim and prestige. Always presenting anonymous patients, and most often children, the images produced for Rollier's work interweave aesthetic and medical interests. Whether through the aesthetics of the photograph, of the positioning and appearance of the patient's body, or of the language used to describe these, issues of beauty and harmony were significant preoccupations for Rollier and the dissemination of his heliotherapeutic practice. The article argues that these aesthetic preoccupations drove his work, that the patient's progress and final cure, and thus the therapy's efficacy, were determined by aesthetic criteria-read through the body itself and its photographic representation. This legibility, of the body and its photography, was crucial to articulating the sun's perceived natural ability to improve, heal and even 'rebuild' individual patients into socially and physically productive citizens. As such, the article contends, Rollier privileged image over word, conceiving the former as possessing an unequalled 'eloquence' to communicate the efficacy and social potential of heliotherapy.