Relieving Pain in Oral Lesions of Pemphigus Vulgaris Using the Non-ablative, Non-thermal, CO2 Laser Therapy (NTCLT): Preliminary Results of a Novel Approach.
Introduction: Pemphigus vulgaris (PV) is a chronic, serious autoimmune mucocutaneous bullous disease. Oral lesions in PV may be extremely painful. This pain may adversely affect the patients' oral intake and quality of life. This before-after clinical trial was designed to assess the pain relieving effects of single session of non-ablative, non-thermal CO2 laser therapy (NTCLT) in oral lesions of PV. Methods: Fifty painful oral lesions of fourteen patients with PV were illuminated by CO2 laser (power: 1 W, scanning the lesions with rapid circular motion of the handpiece) passing through a thick layer of transparent gel with high water content. The pain severity of the oral lesions was reported by the patients up to the fourth postoperative day. They were also asked to continue their existing systemic treatment during the course of this study as a precondition for the participation. Results: The severity of contact and non-stimulate (non-contact) pain declined immediately and significantly after NTCLT (P < 0.001). The pain relieving effect was sustained during the four successive days of follow-up. The procedure was pain free and no kind of analgesics was required. Following NTCLT, there were no visible thermal complications such as destruction, ablation or irritation of the oral lesions. Conclusion: The results of the trial proposed that single session of NTCLT could immediately and significantly relieve pain in oral lesions of PV, without any visible thermal complications.


Coordination of health coverage for Medicare enrollees: a case study of HIV/AIDS.
When people with HIV/AIDS become eligible for Medicare, they find that it does not pay for a significant share of their health care needs. As enrollees seek supplemental health coverage (e.g., Medicaid, employer-sponsored and individually-purchased insurance, and premium payment programs), they find that though there are numerous potential benefit and insurance options, the rules are complex and often conflicting. The search for comprehensive health coverage is further complicated by the fact that each program is separately administered, with different eligibility requirements and application processes. Because each program and agency's staff knows little about other programs, they are often unable to help coordinate coverage. Respondents to the study believe that people with a serious chronic condition would benefit from reforms that make Medicare's benefits more comprehensive and its eligibility, coverage, and payment rules less complicated. They also said that enrollees need better access to Medicare information and enhanced mechanisms to coordinate Medicare with supplemental health coverage. Some HIV/AIDS organizations have developed benefits counseling programs that help their clients piece together a synthetic health coverage "system." These and other issues discussed in this Medicare Brief illustrate possible policy reforms that could help enrollees with HIV/AIDS and other serious chronic conditions.


Demineralized intramembranous bone matrix augments the healing of endochondral bone graft.
The aim of this study was to examine the osteogenic potential of demineralized bone matrix prepared from intramembranous bone (DBMIM) and to examine its effects on the healing of endochondral autogenous bone grafts. Twenty-four defects in 24 New Zealand white rabbits were used as experimental groups. Twelve defects were grafted with endochondral bone, and the other 12 defects were grafted with endochondral bone with DBMIM (EC-DBMIM). One rabbit from each group was sacrificed on days 1, 2, 3, 4, 5, 6, and 7 postgrafting, and the remaining 5 rabbits from each group were sacrificed on day 14 postgrafting. Another 8 defects in 4 rabbits were used as control groups: 4 defects were left empty (passive control), and 4 defects were grafted with rabbit skin collagen (positive control). They were all sacrificed at 14 days after grafting. Serial sections were made across the whole defect. Quantitative analysis was performed on 100 sections of the 14-day experimental groups by image analysis. Four hundred fourteen percent more new bone was formed in defects grafted with composite EC-DBMIM than in those grafted with endochondral bone alone (P < 0.0001). No bone was formed in either passive or positive controls. Histologic examination of the bone grafts revealed intermediate-stage cartilage, and immunohistochemical examination revealed earlier vascularization in the composite EC-DBMIM groups. In conclusion, DBMIM has extremely high osteoinductive properties and greatly enhances the integration of endochondral bone with defects of intramembranous bone in origin.


Characterization of a novel human scavenger receptor cysteine-rich molecule SCART1 expressed by lymphocytes.
The scavenger receptor cysteine-rich (SRCR) superfamily is a group of membrane bound and secreted proteins expressed by cells of the immune system. Several members act as pattern recognition receptors that bind to conserved molecular structures of pathogens. We have previously characterized a member of the SRCR superfamily, mSCART1, which primarily is expressed on a large subset of γδ T cells in mice. Here we report the cloning and characterization of human SCART1 (hSCART1) mainly expressed by CD4(+) and CD8(+) T lymphocytes. The hSCART1 gene maps to chromosome 10, region q26.3, a region that displays synteny to the position of mSCART1 in the murine genome. The primary structure of hSCART1 was established by molecular cloning. The longest cDNA sequence of hSCART1 that was found is 2200bp and encodes a protein composed of a signal peptide, 5 SRCR domains, and an in-frame potential cytoplasmic domain. Shorter splice forms have also been isolated. Quantitative real-time PCR analysis on human blood-fractions has shown that hSCART1 is expressed primarily by CD4(+) and CD8(+) T lymphocytes with either αβ or γδ T cell receptors, and real-time PCR on 22 different human tissues showed high expression of hSCART1 in the small intestine and colon. An antibody raised against an N-terminal hSCART1 peptide stains a subset of cells in the small intestine, stomach, and gall bladder, and it also stains placental villi. In conclusion, the characterization of hSCART1 at the mRNA and protein level suggests that the protein plays a role in the immune system, perhaps as a co-receptor on αβ and γδ T cells.


Survey of home hemodialysis patients and nursing staff regarding vascular access use and care.
Vascular access infections are of concern to hemodialysis patients and nurses. Best demonstrated practices (BDPs) have not been developed for home hemodialysis (HHD) access use, but there have been generally accepted practices (GAPs) endorsed by dialysis professionals. We developed a survey to gather information about training provided and actual practices of HHD patients using the NxStage System One HHD machine. We used GAP to assess training used by nurses to teach HHD access care and then assess actual practice (adherence) by HHD patients. We also assessed training and adherence where GAPs do not exist. We received a 43% response rate from patients and 76% response from nurses representing 19 randomly selected HHD training centers. We found that nurses were not uniformly instructing HHD patients according to GAP, patients were not performing access cannulation according to GAP, nor were they adherent to their training procedures. Identification of signs and symptoms of infection was commonly trained appropriately, but we observed a reluctance to report some signs and symptoms of infection by patients. Of particular concern, when aggregating all steps surveyed, not a single nurse or patient reported training or performing all steps in accordance with GAP. We also identified practices for which there are no GAPs that require further study and may or may not impact outcomes such as infection. Further research is needed to develop strategies to implement and expand GAP, measure outcomes, and ultimately develop BDP for HHD to improve infectious complications.


Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment.
The Gly-to-Arg substitution at the 16 position (rs1042713) in the β2-adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β2-receptors. We sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children. Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study). A history of recent exacerbation and asthma treatment was determined from questionnaire data. DNA was extracted, and the Gly16Arg genotype was determined. Data from 4226 children of white Northern European and Latino origin were analyzed, and the odds ratio for exacerbation increased by 1.52 (95% CI, 1.17-1.99; P = .0021) for each copy of the A allele among the 637 children treated with inhaled corticosteroids (ICSs) plus LABAs but not for treatment with ICSs alone (n = 1758) or ICSs plus leukotriene receptor antagonist (LTRAs; n = 354) or ICSs plus LABAs plus LTRAs (n = 569). The use of a LABA but not an LTRA as an "add-on controller" is associated with increased risk of asthma exacerbation in children carrying 1 or 2 A alleles at rs1042713. Prospective genotype-stratified clinical trials are now required to explore the potential role of rs1042713 genotyping for personalized asthma therapy in children.


The degree of processing of foods which are most widely consumed by the French elderly population is associated with satiety and glycemic potentials and nutrient profiles.
Food processing impacts both food structure and nutritional density. The effect of food structure on satiety and glycemic potentials is well recognized. However, the association between processing, satiety and glycemic potentials and nutrient profiles has not been much studied, especially in the diets of the elderly. Therefore, this study aimed at exploring relations between the level of food processing, consumption and nutrient profiles and satiety and glycemic potentials among 6686 French elderly people (≥65 years). Dietary assessment was realized through a web-based 24 h dietary record tool. Among a total of 2688 foods, 280 generic foods were aggregated based on a consumption threshold of at least 5% by the population. The satiety potential was calculated using the Fullness Factor equation, and the glycemic potential using the glycemic index and the glucose glycemic equivalent. Foods and dishes were ranked according to an adapted international NOVA classification as raw/minimally-processed (G1), processed (G2) and ultra-processed (G3). ANOVA and correlation analyses showed that the more food is processed, the lower its satiety potential and nutrient density and the higher its glycemic impact, especially when comparing G1 and G3. Besides, the foods consumed in the greatest quantity daily tend to be the most satiating, and ultra-processed foods were among the less frequently consumed both in terms of percentage and daily quantity (around two-fold difference between minimally- and ultra-processed foods). In conclusion, because it is partly related to health food potential, the degree of processing, especially for ultra-processed products, should be taken into consideration more when evaluating consumption profiles of different populations.


The evaluation of quality of life in fibromyalgia syndrome: a comparison with rheumatoid arthritis by using SF-36 Health Survey.
Musculoskeletal disorders are the most common causes of deterioration in quality of life (QOL). We in this study aimed to assess (1) the impact of fibromyalgia syndrome (FS) on QOL comparing with that of rheumatoid arthritis (RA) patients and control subjects and (2) the impact of these two musculoskeletal disorders on various components of QOL using SF-36 Health Survey. Thirty-five patients with RA, 30 patients with FS, and 30 voluntary control subjects were included in the study. The groups were comparable in terms of demographic characteristics. QOL was evaluated by using Short-Form (SF)-36 Health Survey in all study participants, and Fibromyalgia Impact Questionnaire (FIQ), which is a specific health-status instrument for FS, was used in FS patients. Physical functioning, physical role, social functioning, bodily pain, general health, vitality, emotional role, and mental health scores were significantly lower in RA and FS patients than in control subjects (p<0.05). The between-groups comparisons revealed that FS patients had significantly lower mental health scores than RA patients (49.87 vs 62.51, respectively), (p<0.001). Total FIQ score correlated significantly with physical functioning, physical role, and bodily pain in FS patients. All parameters of SF-36 Health Survey except for social functioning correlated significantly with some of the variables of FIQ. FS has a negative impact on QOL, like RA. Furthermore, mental health was more severely affected in FS patients when compared with RA patients.


The chemical MUPpeteer.
Rodents exhibit an innate fear-like behavior when they sense the chemical traces of predators. In this issue, Papes et al. (2010) report that the major urinary proteins (Mups) released by predators are detected by sensory neurons in the mouse vomeronasal organ (which also detects pheromones involved in aggression), triggering a fear response.


Single Ni sites distributed on N-doped carbon for selective hydrogenation of acetylene.
We prepared single Ni atoms embedded in an N-doped carbon catalyst with the assistance of metal organic frameworks. The dispersion of Ni atoms was verified by taking X-ray absorption fine structure measurements. Under the typical conditions for hydrogenation of acetylene, this single-site heterogeneous catalyst showed great potential as an alternative to Pd-based materials.


High-salt diet upregulates kininogen and downregulates tissue kallikrein expression in Dahl-SS and SHR rats.
Tissue kallikrein cleaves low-molecular-weight (low-M(r)) kininogen to produce the vasoactive kinin peptide. It has been suggested that hypertensive patients with low urinary kallikrein excretion may have a defect in sodium handling. In this study, we examined the effect of a high-salt diet on the expression of tissue kallikrein and kininogen genes in Dahl salt-sensitive rats (Dahl-SS), spontaneously hypertensive rats (SHR), and normotensive Sprague-Dawley rats (SD) by Northern and Western blot analysis and radioimmunoassay. Control and experimental groups received normal and high-salt diets containing 0.4% and 8% NaCl, respectively, for 6 wk. High-salt diet induced a significant time-dependent increase of blood pressure in both strains of hypertensive rats and a slight but significant increase of blood pressure in normotensive SD rats. Hepatic kininogen mRNA levels of both Dahl-SS and SHR on a high-salt diet increased 2.4-fold and 2.0-fold, respectively, while alpha 1-antitrypsin mRNA levels were not changed in rats receiving high-salt diet. Immunoreactive total kininogen and low-M(r) kininogen (58 kDa) levels in sera increased in response to high-salt diet in both strains of hypertensive rats. In SD rats, the low-M(r) kininogen level in sera was unaltered, whereas total kininogen increased in response to high-salt diet. Tissue kallikrein mRNAs in the kidney and salivary glands of Dahl-SS, SHR, and SD rats were reduced, whereas beta-actin mRNA was not altered by high-salt diet. Similarly, immunoreactive intrarenal kallikrein levels were reduced in these rats in response to high-salt diet. These studies show that increases in blood pressure after salt loading in Dahl-SS and SHR are accompanied by increases in low-M(r) kininogen. Tissue kallikrein gene expression in hypertensive Dahl-SS and SHR and normotensive SD rats is suppressed after salt loading. These findings show that reduced renal kallikrein expression and increased kininogen expression is regulated at the transcriptional level during salt loading.


The clinical significance of cytokeratin 20 staining pattern in Merkel cell carcinoma.
In the present study, to identify the clinical significance of the cytokeratin (CK) 20 staining pattern in Merkel cell carcinoma (MCC), we retrospectively analyzed the major clinicopathological and immunohistochemical characteristics of 12 cases of MCC. Typical dot-like pattern was seen in eight of our patients, while four patients showed peripheral staining pattern. Interestingly, all cases of MCC with dot-like CK20 tumor cells occurred in the head and neck region, while those with peripheral CK20 pattern tended to be located in other lesions (forearm, knee, or buttock): The difference of frequency in the head and neck regions was statistically significant. Dot-like CK20 staining pattern may therefore be resulted from ultraviolet exposure. Additionally, although without significance, metastasis was more frequent in those with dot-like CK20 than in peripheral CK20 staining: All patients with peripheral CK20 pattern had complete remission by surgical excision with or without radiation therapy. CK20 staining pattern may be a novel predictor of prognosis.


[Characteristics of hospitalized alcoholics].
The background characteristics of 1,173 alcoholics hospitalized for 3 months in this center during December 1982 to December 1994 were reviewed. Socio-demographic variables and termination-of-treatment data, are described. The profile of the typical hospitalized alcoholic was that of a Jewish, urban, married, unemployed man, born in Asia-Africa (or in Israel) who had been living for many years in Israel and had many children and a low educational level. They usually start drinking in adolescence and come to the center after more than 15 years of drinking, mainly at home and alone, and also have family relatives who drink. Implications of the data for treatment and for family physicians are presented.


Hepatitis B virus reactivation after fludarabine-based regimens for indolent non-Hodgkin's lymphomas: high prevalence of acquired viral genomic mutations.
Chemotherapy can cause hepatitis flare-up through viral reactivation in patients who have had contact with hepatitis viruses. Few data are available on the genotype of the reactivated viruses. In 40 consecutive adult patients with indolent non-Hodgkin's lymphoma (NHL) receiving fludarabine-based front-line chemotherapy, we performed a prospective study on viral hepatitis reactivation and analyzed the genotype of the reactivated viruses. Before chemotherapy, 4 patients were healthy carriers of hepatitis B surface antigen (HBsAg), 2 had HB core antigen antibodies (anti-HBc), 6 anti-HBs and 6 anti-HCV; 22 were seronegative. Hepatitis flare-up occurred in the 4 HBsAg-positive patients and in 1 anti-HBc-positive patient at a median of 1 month (range 1-4) after chemotherapy, when the CD4/CD8 ratio was still inverted. HBV reactivation was documented in all 5 instances (HBV-DNA 2-8 x 10(6) copies/mL). Two of the 5 patients responded to lamivudine, whereas 1 died of acute liver failure and 2 had persistent severe hepatitis. HBV genome sequencing at hepatitis flare-up showed that deviation from the closest related published sequences was 1.0% and 1.1% in the 2 lamivudine-responsive patients, and 1.5%, 1.8% and 1.7% in the 3 lamivudine-resistant patients. The polymerase open reading frame (ORF) and the HBs ORF of lamivudine-resistant strains contained several novel amino acid substitutions. These results suggest that fludarabine treatment of HBV-infected patients is frequently associated with acute hepatitis due to viral reactivation, and that lamivudine may be less effective in this situation than in other settings of immunocompromised hosts because of the emergence of resistant mutant strains.


Needs of Kinship Care Families and Pediatric Practice.
As many as 3% of children in the United States live in kinship care arrangements with caregivers who are relatives but not the biological parents of the child. A growing body of evidence suggests that children who cannot live with their biological parents fare better, overall, when living with extended family than with nonrelated foster parents. Acknowledging this, federal laws and public policies increasingly favor kinship care over nonrelative foster care when children are unable to live with their biological parents. Despite overall better outcomes, families providing kinship care experience many hardships, and the children experience many of the same adversities of children in traditional foster care. This policy statement reviews both the strengths and vulnerabilities of kinship families and suggests strategies for pediatricians to use to address the needs of individual patients and families. Strategies are also outlined for community, state, and federal advocacy on behalf of these children and their families.


Fueling the vegetarian (vegan) athlete.
Vegetarian diets are associated with several health benefits, but whether a vegetarian or vegan diet is beneficial for athletic performance has not yet been defined. Based on the evidence in the literature that diets high in unrefined plant foods are associated with beneficial effects on overall health, lifespan, immune function, and cardiovascular health, such diets likely would promote improved athletic performance as well. In this article, we review the state of the literature on vegetarian diets and athletic performance, discuss prevention of potential micronutrient deficiencies that may occur in the vegan athlete, and provide strategies on meeting the enhanced caloric and protein needs of an athlete with a plant-based diet.


Pesticide appliers with mixed pesticide exposure: G-banded analysis and possible relationship to non-Hodgkin's lymphoma.
To further investigate the possible relationships between agricultural pesticide exposure and the increased risk of non-Hodgkin's Lymphoma among farm workers in the north central United States, we performed G-banded chromosome analyses of peripheral blood from workers classified according to primary types of pesticide exposure: herbicides (n = 20), insecticides (n = 18), fumigants (n = 23), and occupationally unexposed controls (n = 33). Significantly increased rearrangement frequencies were demonstrated in fumigant and insecticide appliers compared to control subjects. At certain chromosome bands there were significant excesses of breaks observed in pesticide appliers, but no breaks were observed in controls. Some of these bands contained genes with potential implications for cancer risk, including oncogenes and genes involved in tumor suppression and apoptosis. Of particular interest with regard to lymphoma risk were the excess rearrangement and breaks involving band 14q32 in fumigant appliers and the excess breaks involving band 18q21 in herbicide appliers; translocations linking 14q32 and 18q21 are the most common rearrangements observed in non-Hodgkin's lymphoma patients. The potential pathobiological relevance of these cytogenetic events warrants additional investigation at the molecular level.


Patient satisfaction and the impact of written material about postpartum contraceptive decisions.
The purpose of this study was to evaluate the impact of written educational material about patient satisfaction and decision-making regarding postpartum contraception. Baseline patient satisfaction and effectiveness of contraceptive counseling on a postpartum unit was evaluated with the use of a self-administered questionnaire. Data were compared with patients who received additional comprehensive written educational material during their postpartum hospitalization. A total of 109 women participated in the study (control subjects, 53; intervention group, 56). Demographics and patient satisfaction with contraceptive counseling were similar between groups. Thirty-four percent of the control subjects reported having received some sort of written information; all women in the intervention group received a standardized comprehensive booklet of information during their postpartum stay (P <.01). Among the women who received written information, the intervention group was more likely to state that written material contributed to their ultimate choice in birth control (P <.01). The postpartum distribution of written material about contraceptive options increases a woman's ability to make an informed decision regarding birth control.


Effect of histamine on phosphoinositide turnover and intracellular calcium in human ciliary muscle cells.
This report describes the effect of histamine on phospholipase C (PLC) activity and calcium mobilization in cultured human ciliary muscle cells. PLC activity was assessed by measuring the production of inositol phosphates and intracellular calcium mobilization was assessed by Fura 2 ratio fluorometry. The stimulation of PLC by histamine was concentration dependent with an EC50 of 0.96 microM. The H1 antagonist chlorpheniramine blocked the response with an IC50 of 0.53 microM. Calcium fluorometry experiments indicated a mean basal calcium concentration of 36 nM with a 10(-4) M histamine induced mean peak value of 1132 nM followed by a gradually declining plateau phase. EC50 and IC50 (chlorpheniramine) values from histamine induced peak calcium concentrations agreed with the PLC results. Pretreatment of the cells with the PLC inhibitor U73122 at 10(-6) M completely blocked histamine induced calcium mobilization. Removal of extracellular calcium eliminated the plateau phase but not the initial calcium peak indicating that both intra and extracellular calcium sources are required for a normal response. The calcium ATPase inhibitor thapsigargin caused depletion of intracellular calcium stores and prevented a subsequent normal calcium mobilization response to histamine. Ryanodine, a release inhibitor of certain intracellular calcium stores, had no effect on the histamine induced response. The results of these experiments indicate that histamine, via an H1 receptor, activated the PLC second messenger pathway, and caused a multi-phasic mobilization of both intracellular and extracellular calcium. The entry of the extracellular calcium was shown to be dependent upon release of calcium from a ryanodine insensitive intracellular store.


In vivo and in vitro effects of cyclosporin A on Trypanosoma cruzi.
The in vivo and in vitro effects of cyclosporin A on T. cruzi were examined. Mice receiving 150 or 75 mg/kg/day of cyclosporin A and infected with T. cruzi 48 hr later had significantly higher parasitemias and earlier mortality than controls. Mice receiving cyclosporin A after infection had parasitemias similar to controls. Infections with both the reticulotropic Y and the miotropic CL strains of T. cruzi were enhanced by cyclosporin A. The in vitro replication of epimastigotes, but not the intracellular replication of amastigotes, in mouse macrophages was inhibited by 5 micrograms cyclosporin A/ml. Enhancement of the infection by cyclosporin A was not due to an effect on macrophages since the drug did not prevent development of activated macrophages capable of killing intracellular T. cruzi.


Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells.
Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and HER2 (erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185(HER2) oncoprotein expression and tyrosine-kinase activity in breast and ovarian HER2 overexpressors. Similarly, p185(HER2) expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulated HER2 mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor of HER2. A cytoplasmic redistribution of p185(HER2) was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185(HER2). The simultaneous targeting of FAS and HER2 by chemical FAS inhibitors and the humanized antibody directed against p185(HER2) trastuzumab, respectively, was synergistically cytotoxic toward HER2 overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS and HER2 genes synergistically stimulated apoptotic cell death in HER2 overexpressors. p185(HER2) was synergistically down-regulated after simultaneous inhibition of FAS and HER2 by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting that HER2 oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.


Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis.
Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role for the CCR2-dependent infiltration of classical Gr1/Ly6C(+) monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14(+)CD16(-) and non-classical CD14(+)CD16(+) cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that 'non-classical' monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD) and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14(+)CD16(+) subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14(+)CD16(+) macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC) in vitro. CD14(+)CD16(+) monocytes released abundant proinflammatory cytokines. Furthermore, CD14(+)CD16(+), but not CD14(+)CD16(-) monocytes could directly activate collagen-producing HSC. Our data demonstrate the expansion of CD14(+)CD16(+) monocytes in the circulation and liver of CLD-patients upon disease progression and suggest their functional contribution to the perpetuation of intrahepatic inflammation and profibrogenic HSC activation in liver cirrhosis. The modulation of monocyte-subset recruitment into the liver via chemokines/chemokine receptors and their subsequent differentiation may represent promising approaches for therapeutic interventions in human liver fibrosis.


A heparin-binding domain from N-CAM is involved in neural cell-substratum adhesion.
Cell-substratum adhesion in the embryonic chicken nervous system has been shown to be mediated in part by a 170,000-mol-wt polypeptide that is a component of adherons. Attachment of retinal cells to the 170,000-mol-wt protein is inhibited by the C1H3 monoclonal antibody and by heparan sulfate (Cole, G. J., D. Schubert, and L. Glaser, 1985, J. Cell Biol., 100:1192-1199). In the present study we have demonstrated that the 170,000-mol-wt C1H3 polypeptide is immunologically identical to the neural cell adhesion molecule N-CAM, and that the 170,000-mol-wt component of N-CAM is preferentially secreted by cells as a component of adherons. We have identified a monoclonal antibody, designated B1A3, that inhibits heparin binding to N-CAM and cell-to-substratum adhesion. A 25,000-mol-wt heparin (heparan sulfate)-binding domain of N-CAM has been identified by limited proteolysis, and this fragment promotes cell attachment when bound to glass surfaces. The fragment also partially inhibits cell binding to adherons when bound to retinal cells, and the B1A3 monoclonal antibody inhibits retinal cell attachment to substrata composed of intact N-CAM or the heparin-binding domain. These data are the first evidence that N-CAM is a multifunctional protein that contains both cell-and heparin (heparan sulfate)-binding domains.


Defective colony formation by B lymphocytes from CBA/N and C3H/HeJ mice.
B cells from CBA/N mice did not form colonies in semisolid agar cultures under circumstances where normal B-cell clonal proliferation is linear with respect to the number of functional cells cultured. This was no due to the unresponsiveness of CBA/N cells to mitogens, and under appropriate liquid culture conditions many CBA/N lymphocytes differentiated to plasma cells containing large amounts of IgM in response to LPS. On the other hand, the same cells proliferated and matured poorly in liquid cultures prepared at low-cell density. The frequency of granulocyte-macrophage progenitors and multipotential hemopoietic stem cells in bone marrow, ability of peritoneal macrophages to elaborate soluble enhancing factors, and levels of serum inhibitors were normal in CBA/N mice. Together with the results of cell-mixing experiments, these findings confirm the selective and intrinsic nature of the CBA/N deficiency. It is suggested that the B-cell cloning technique may be of value in selectively enumerating and assessing functional capability of thymus-independent B cells. C3H/HeJ mice which have previously only been known to be hyporesponsive to certain forms of lipopolysaccharide had a subnormal incidence of colony-forming B cells.


Genetic relationship between cocirculating Human enteroviruses species C.
Recombination events between human enteroviruses (HEV) are known to occur frequently and to participate in the evolution of these viruses. In a previous study, we reported the isolation of a panel of viruses belonging to the Human enterovirus species C (HEV-C) that had been cocirculating in a small geographic area of Madagascar in 2002. This panel included type 2 vaccine-derived polioviruses (PV) that had caused several cases of acute flaccid paralysis in humans. Previous partial sequencing of the genome of these HEV-C isolates revealed considerable genetic diversity, mostly due to recombination. In the work presented herein, we carried out a more detailed characterization of the genomes of viruses from this collection. First, we determined the full VP1 sequence of 41 of these isolates of different types. These sequences were compared with those of HEV-C isolates obtained from other countries or in other contexts. The sequences of the Madagascan isolates of a given type formed specific clusters clearly differentiated from those formed by other strains of the same type isolated elsewhere. Second, we sequenced the entire genome of 10 viruses representing most of the lineages present in this panel. All but one of the genomes appeared to be mosaic assemblies of different genomic fragments generated by intra- and intertypic recombination. The location of the breakpoints suggested potential preferred genomic regions for recombination. Our results also suggest that recombination between type HEV-99 and other HEV-C may be quite rare. This first exhaustive genomic analysis of a panel of non-PV HEV-C cocirculating in a small human population highlights the high frequency of inter and intra-typic genetic recombination, constituting a widespread mechanism of genetic plasticity and continually shifting the HEV-C biodiversity.


Prognostic implications of resting distal coronary-to-aortic pressure ratio compared with fractional flow reserve: a 10-year follow-up study after deferral of revascularisation.
The distal coronary-to-aortic pressure ratio (Pd/Pa) is a non-hyperaemic physiological index to assess the functional severity of coronary stenoses. Studies comparing Pd/Pa with fractional flow reserve (FFR) show superior diagnostic efficiency for myocardial ischaemia. Nevertheless, a direct comparison regarding long-term clinical outcomes is still not available. The present observational study compared the prognostic value of Pd/Pa and FFR for major adverse cardiac events (MACE) during a 10-year follow-up period after deferral of revascularisation. Between April 1997 and September 2006, we evaluated 154 coronary stenoses (154 patients) in which revascularisation was deferred with intracoronary pressure and flow measurements during the resting and hyperaemic state. Long-term follow-up (median: 11.8 years) was performed to document the occurrence of MACE, defined as a composite of cardiac death, myocardial infarction and target vessel revascularisation. The study population comprised angiographically intermediate coronary stenoses, with a mean diameter stenosis of 53 ± 8%, and intermediate physiological severity with a median FFR of 0.82 (Q1, Q3: 0.76, 0.88). The association of Pd/Pa with long-term MACE was similar to that of FFR [FFR-standardised hazard ratio (sHR): 0.77, 95% confidence interval (CI): 0.61-0.98; Pd/Pa-sHR: 0.80, 95% CI: 0.67-0.96]. In the presence of disagreement between Pd/Pa and FFR, normal Pd/Pa was generally associated with high coronary flow reserve (CFR) and a favourable clinical outcome, whereas abnormal Pd/Pa was generally associated with CFR around the ischaemic cut-point and an impaired clinical outcome, regardless of the accompanying FFR value. The present study suggests that Pd/Pa provides at least equivalent prognostic value compared with FFR. When Pd/Pa disagreed with FFR, the baseline index conferred superior prognostic value in this study population.


Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells.
Transforming growth factor-beta proteins (TGF-βs) are multifunctional growth factors and powerful modulators of the epithelial-mesenchymal transition (EMT) in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR) on tumor growth and metastasis of triple negative breast cancer (TNBC) cells via suppression of TGF-β1 expression. The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-β1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. In a clinical data set, aberrant TGF-β1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 and the capacity for cell migration were increased by TGF-β1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-β receptor I inhibitor, SB431542. In addition, TGF-β1-induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-β1, but not TGF-β2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-β1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC.


Controlling binding dynamics of corrin-based chemosensors for cyanide.
This paper describes a strategy to control the binding dynamics between cyanide and aquacyanocorrinoids on the molecular level. Aquacyanocorrinoids represent an important class of chemosensors and convert upon cyanide coordination to the corresponding dicyano derivatives. Structure-reactivity relationships were investigated for the first time by synthesizing and studying three diastereomerically pure aquacyanocorrinoids differing either in the configuration of the axially bound ligands or in the nature of remote side chains located at the periphery of the corrin macrocycle. Substitution of cobalt-coordinated water with cyanide was investigated using stopped-flow measurements between 5 and 30 °C, and second order rate constants and activation parameters were determined. In particular, it is demonstrated that the binding kinetics depend not only on (i) the configuration at the central metal center but also on (ii) the remote structural modifications of the macrocycle.


RNA-Sequencing Analysis of Messenger RNA/MicroRNA in a Rabbit Aneurysm Model Identifies Pathways and Genes of Interest.
Rabbit aneurysm models are used for the testing of embolization devices and elucidating the mechanisms of human intracranial aneurysm growth and healing. We used RNA-sequencing technology to identify genes relevant to induced rabbit aneurysm biology and to identify genes and pathways of potential clinical interest. This process included sequencing microRNAs, which are important regulatory noncoding RNAs. Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery in 6 rabbits. Messenger RNA and microRNA were isolated from the aneurysm and from the control left common carotid artery at 12 weeks and processed by using RNA-sequencing technology. The results from RNA sequencing were analyzed by using the Ingenuity Pathway Analysis tool. A total of 9396 genes were analyzed by using RNA sequencing, 648 (6.9%) of which were found to be significantly differentially expressed between the aneurysms and control tissues (P < .05; false-discovery rate, <0.01; fold change, >2 or <.5). Of these genes, 614 were mapped successfully, 143 were down-regulated, and 471 were up-regulated in the aneurysms as compared with controls. Using the same criteria for significance, 3 microRNAs were identified as down-regulated and 5 were identified as up-regulated. Pathway analysis associated these genes with inflammatory response, cellular migration, and coagulation, among other functions and pathologies. RNA-sequencing analysis of rabbit aneurysms revealed differential regulation of some key pathways, including inflammation and antigen presentation. ANKRD1 and TACR1 were identified as genes of interest in the regulation of matrix metalloproteinases.


Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade.
Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have antiinflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells. NCI-H838 lung cancer cells were incubated with tumor necrosis factor-α in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM-100 μM). Cell migration and total cell lysate Src-activation and intercellular adhesion molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated. Ropivacaine treatment (100 μM) of H838 cells for 20 min decreased basal Src activity by 62% (P=0.003), and both ropivacaine and lidocaine coadministered with tumor necrosis factor-α statistically significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 h was inhibited by 26% (P=0.005) in presence of 1 μM ropivacaine and 21% by 1 μM lidocaine (P=0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition. This study indicates that amide-, but not ester-linked, local anesthetics may provide beneficial antimetastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of tumor necrosis factor-α-induced Src-activation and intercellular adhesion molecule-1 phosphorylation, providing the first evidence of a molecular mechanism that appears to be independent of their known role as sodium-channel blockers.


Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.
Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up.


The effect of cycling on cognitive function and well-being in older adults.
It has been demonstrated that, on their own, both exercise and stimulation from the environment can improve cognitive function and well-being in older adults. The combined effect of exercising in the outdoor environment on psychological function is less well studied. The aim of the current study was to investigate the effect of an outdoor cycling intervention on cognitive function and mental health and well-being in older adults. A total of 100 older adults took part in the study (aged 50-83), 26 of which were non-cycling controls, 36 were conventional pedal cyclists and 38 were participants using an e-bike (a bike fitted with an electric motor to provide assistance with pedaling), as part of a larger project (www.cycleboom.org). Participants took part in the study for an eight-week period, with cycling participants required to cycle at least three times a week for thirty minutes in duration for each cycle ride. Cognitive function and well-being were measured before and after the intervention period. For executive function, namely inhibition (the Stroop task) and updating (Letter Updating Task), both cycling groups improved in accuracy after the intervention compared to non-cycling control participants. E-bike participants also improved in processing speed (reaction times in go trials of the Stop-It task) after the intervention compared to non-cycling control participants. Finally, e-bike participants improved in their mental health score after the intervention compared to non-cycling controls as measured by the SF-36. This suggests that there may be an impact of exercising in the environment on executive function and mental health. Importantly, we showed a similar (sometimes larger) effect for the e-bike group compared to the pedal cyclists. This suggests that it is not just the physical activity component of cycling that is having an influence. Both pedal cycles and e-bikes can enable increased physical activity and engagement with the outdoor environment with e-bikes potentially providing greater benefits.


Ten lessons on the epidemiology of migraine.
The epidemiologic studies of the last 15 years have taught many lessons that will help define the clinical and research agenda in migraine for the next 15 years. Because the condition is common, disabling, and costly (Lesson 1) and because it has major comorbidities (Lesson 2), migraine is an important target for treatment. Because consultation, diagnosis, and effective treatment rates are low (Lessons 3 and 4) it is important to develop strategies for closing the gap between treatment available and treatment delivered in the primary care setting where the majority of patients seek care (Lesson 5 and 6). Strategies include public and provider education as well as the use of screening tools such as ID-migraine to improve the recognition of migraine in primary care (Lesson 7). In addition, strategies that measure disability, with tools such as MIgraine Disability ASssessment, when coupled with treatment guidelines which consider illness severity in the selection of treatment provide great hope for improving patient outcomes (Lesson 8). Finally, the emerging evidence that migraine is progressive in a subgroup (Lesson 9) mandates the development of strategies to reduce the risk of progression by addressing modifiable risk factors and by assessing the effects of treatment on headache progression (Lesson 10).


System size reduction in stochastic simulations of the facilitated diffusion mechanism.
Site-specific Transcription Factors (TFs) are proteins that bind to specific sites on the DNA and control the activity of a target gene by enhancing or decreasing the rate at which the gene is transcribed by RNA polymerase. The process by which TF molecules locate their target sites is a key component of transcriptional regulation. Therefore it is essential to gain insight into the mechanisms by which TFs search for the target sites.Research in this area uses experimental and analytical approaches, but also stochastic simulations of the search process. Previous work based on stochastic simulations focussed only on short sequences, primarily for reasons of technical feasibility. Many of these studies had to disregard possible biases introduced by reducing a genome-wide system to a smaller subsystem. In particular, we identified crucial parameters that require adjustment, which were not adequately changed in these previous studies. We investigated several methods that adequately adapt the parameters of stochastic simulations of the facilitated diffusion, when the full sequence space is reduced to smaller regions of interest. We found two methods that scale the system accordingly: the copy number model and the association rate model. We systematically compared the results produced by simulations of the subsystem with respect to the original system. Our results confirmed that the copy number model is adequate only for high abundance TFs, while for low abundance TFs the association rate model is the only one that reproduces with high accuracy the results of the full system. We propose a strategy to reduce the size of the system that adequately adapts important parameters to capture the behaviour of the full system. This enables correct simulations of a smaller sequence space (which can be as small as 100 Kbp) and, thus, provides independence from computationally intensive genome-wide simulations of the facilitated diffusion mechanism.


A sea urchin cell-free system to study male pronuclear assembly and activation.
Typically sperm nuclei are genetically inert and contain extremely compacted chromatin. Following fertilization, the first steps in their conversion to somatic nuclei (male pronuclei) which will support further development involve chromatin decondensation and the formation of a new nuclear envelope. We have studied the reactivation of sea urchin sperm nuclei in a cell-free system derived from homogenates of activated sea urchin egg cytoplasm. The cell-free system has provided several novel insights including requirements for sperm-specific histone phosphorylation on N- and C-terminal extensions and disassembly of the sperm nuclear lamina for decondensation, the utilization of remnant regions of the sperm nuclear envelope to direct polarized binding and fusion of egg membranes to form the new nuclear envelope, and a role for phosphoinositide metabolism in initiation of membrane fusion through binding of a minor membrane fraction enriched in PtdIns (4,5)P2, PLCγ and SFK1 which locally produces a fusigenic lipid, diacylglycerol.


The effect of Virkon S fogging on survival of Salmonella enterica and Staphylococcus aureus on surfaces in a veterinary teaching hospital.
The objective of the study was to determine the disinfection efficacy of aerosolizing (cold fogging) Virkon S on survival of Stahpylococcus aureus and Salmonella enterica on different surfaces. Two experiments were conducted in different locations. Salmonella enterica and S. aureus were grown in broth culture and then seeded into pre-marked areas in each location and allowed to dry. Virkon S (1%) was aerosolized into the rooms (approximately 1L of per 30 m(3)). Samples were collected pre- and post-fogging for quantitative cultures to evaluate the efficacy of aerial disinfection. The reduction of S. enterica or S. aureus counts ranged from 3.40 to 0.95 log(10) (Salmonella) or 4.92 to 0.02 log(10) (Staphylococcus). The greatest reduction was evident in samples collected from non-porous horizontal surfaces, which were not obstructed from the air flow. These results indicate that fogging with Virkon S could be beneficial in routine disinfection of pre-cleaned surfaces. The benefits of routine use of cold fogging with Virkon S in veterinary hospital settings would include its wide-range antimicrobial action and minimal working-men power required to disinfect large areas. Also, fogging would potentially minimize microbial contamination in the hard to reach areas.


Chest ultrasonography versus supine chest radiography for diagnosis of pneumothorax in trauma patients in the emergency department.
Chest X-ray (CXR) is a longstanding method for the diagnosis of pneumothorax but chest ultrasonography (CUS) may be a safer, more rapid, and more accurate modality in trauma patients at the bedside that does not expose the patient to ionizing radiation. This may lead to improved and expedited management of traumatic pneumothorax and improved patient safety and clinical outcomes. To compare the diagnostic accuracy of chest ultrasonography (CUS) by frontline non-radiologist physicians versus chest X-ray (CXR) for diagnosis of pneumothorax in trauma patients in the emergency department (ED). To investigate the effects of potential sources of heterogeneity such as type of CUS operator (frontline non-radiologist physicians), type of trauma (blunt vs penetrating), and type of US probe on test accuracy. We conducted a comprehensive search of the following electronic databases from database inception to 10 April 2020: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, Database of Abstracts of Reviews of Effects, Web of Science Core Collection and Clinicaltrials.gov. We handsearched reference lists of included articles and reviews retrieved via electronic searching; and we carried out forward citation searching of relevant articles in Google Scholar and looked at the "Related articles" on PubMed. We included prospective, paired comparative accuracy studies comparing CUS performed by frontline non-radiologist physicians to supine CXR in trauma patients in the emergency department (ED) suspected of having pneumothorax, and with computed tomography (CT) of the chest or tube thoracostomy as the reference standard. Two review authors independently extracted data from each included study using a data extraction form. We included studies using patients as the unit of analysis in the main analysis and we included those using lung fields in the secondary analysis. We performed meta-analyses by using a bivariate model to estimate and compare summary sensitivities and specificities. We included 13 studies of which nine (410 traumatic pneumothorax patients out of 1271 patients) used patients as the unit of analysis; we thus included them in the primary analysis. The remaining four studies used lung field as the unit of analysis and we included them in the secondary analysis. We judged all studies to be at high or unclear risk of bias in one or more domains, with most studies (11/13, 85%) being judged at high or unclear risk of bias in the patient selection domain. There was substantial heterogeneity in the sensitivity of supine CXR amongst the included studies. In the primary analysis, the summary sensitivity and specificity of CUS were 0.91 (95% confidence interval (CI) 0.85 to 0.94) and 0.99 (95% CI 0.97 to 1.00); and the summary sensitivity and specificity of supine CXR were 0.47 (95% CI 0.31 to 0.63) and 1.00 (95% CI 0.97 to 1.00). There was a significant difference in the sensitivity of CUS compared to CXR with an absolute difference in sensitivity of 0.44 (95% CI 0.27 to 0.61; P < 0.001). In contrast, CUS and CXR had similar specificities: comparing CUS to CXR, the absolute difference in specificity was -0.007 (95% CI -0.018 to 0.005, P = 0.35). The findings imply that in a hypothetical cohort of 100 patients if 30 patients have traumatic pneumothorax (i.e. prevalence of 30%), CUS would miss 3 (95% CI 2 to 4) cases (false negatives) and overdiagnose 1 (95% CI 0 to 2) of those without pneumothorax (false positives); while CXR would miss 16 (95% CI 11 to 21) cases with 0 (95% CI 0 to 2) overdiagnosis of those who do not have pneumothorax. The diagnostic accuracy of CUS performed by frontline non-radiologist physicians for the diagnosis of pneumothorax in ED trauma patients is superior to supine CXR, independent of the type of trauma, type of CUS operator, or type of CUS probe used. These findings suggest that CUS for the diagnosis of traumatic pneumothorax should be incorporated into trauma protocols and algorithms in future medical training programmes; and that CUS may beneficially change routine management of trauma.


Expression of parathyroid hormone-related protein in human inflamed dental pulp.
The aim of this study was to investigate the presence and the role of the parathyroid hormone-related protein (PTH-rP) in the inflamed pulp. Thirty-four pulp tissue specimens (24 inflamed and 10 normal pulps) from extracted third molars were studied. The presence of PTH-rP was observed by using immunohistochemistry. Negative controls were performed using non immunized rabbit or mouse serum, omitting the primary antibody. The analysis of all the sections of normal pulps showed the presence of PTHrP positive cells only in the odontoblastic zone and in few fibroblasts. Instead all inflamed pulps showed PTHrP positive cells both in vascular zone and in pulp stroma, as well as in the odontoblastic and subodontoblastic zone. Several works proved that this peptide plays a role even in angiogenesis process, but its function is controversial. It is possible to hypothesize that PTHrP stimulates angiogenesis, but it is recommended to further conduct research on this area.


Rare CpG island methylator phenotype in ulcerative colitis-associated neoplasias.
We previously reported that a high degree of age-related methylation was found in both the dysplastic and nondysplastic mucosa of patients with ulcerative colitis (UC). Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known. We evaluated the methylation status of 11 genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT, HPP1, SFRP1, ERalpha, and LINE-1) in 48 UC-Cs, 21 UC-associated dysplasias, and 69 sporadic colorectal cancers (S-CRCs) using a quantitative bisulfite pyrosequencing analysis. Methylation levels in UC-Cs were lower than S-CRCs for all the genes except MGMT. A methylation index based on the average of Z-scores, for type C (cancer-specific genes: MINT1, MINT2, MINT31, hMLH1, p16, and p14) was -.97 in UC-Cs and .92 in S-CRCs (P = .009). That of type A (age-related genes: HPP1, SFRP1, and ERalpha) was -1.97 in UC-Cs and 1.24 in S-CRCs (P < .001). We observed a significant difference in the incidence of CpG island methylator phenotype between UC-Cs and S-CRCs (8 of 48 [17%] and 26 of 69 [38%]; P = .022). UC-associated dysplasias had significantly higher methylation of type A gene than UC-Cs (Z-score: .07 and -1.97, respectively; P < .001). By contrast, global DNA methylation measured using a LINE-1 assay was significantly higher in UC-Cs than in S-CRCs (58.2% vs 51.0%, P < .001). DNA methylation alterations are uncommon in UC cancers. Given that both genetic and epigenetic changes are common in UC mucosa and dysplasias, we speculate that the genetic changes lead to a more aggressive clinical course than epigenetic changes.


Factors associated with long-term sick leave in sick-listed employees: a systematic review.
The objective of this systematic review was to investigate which factors are associated with continued sick leave among workers on sick leave for at least 6 weeks. A systematic literature search was performed in Medline, EMBASE and PsycINFO, based on combinations of MeSH terms and free text words. Only cohort studies of workers on sick leave for more than 6 weeks at baseline were included. Outcome was measured in terms of factors related to long-term sick leave. The factors were classified first as predisposing, precipitating or perpetuating factors, and then as individual or work-related factors. Methodological quality was assessed for all studies and the strength of the evidence for each factor was assessed using the levels of evidence rating system. Five cohort studies fulfilled all inclusion criteria and 77 factors were investigated. Of these, 16 different significant factors associated with long-term sick leave were identified and were all classified as predisposing factors. Evidence was found for 14 individual factors and two work-related factors. The level of evidence was found to be insufficient for all factors except older age and history of sick leave, which were found to have weak evidence. Based on this review, there is weak evidence that older age and history of sickness absence are factors associated with long-term sick leave in sick-listed employees. There is insufficient evidence for an effect of other individual or work-related factors on long-term sick leave. There are no published studies on perpetuating factors related to long-term sick leave.


Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia.
Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal. Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop®) or artemether-lumefantrine (AL, Coartem®), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28. Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p < 0.001), vomiting (7.1% vs 1.6%, p < 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis). Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT. The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).


Food supplementation with rice bran enzymatic extract prevents vascular apoptosis and atherogenesis in ApoE-/- mice.
Atherosclerosis is associated with reduced mononuclear cell (MNC) telomere length, and senescent cells have been detected in atherosclerotic plaques. Rice bran is a source of γ-oryzanol, phytosterols and tocols with potential lipid-lowering, antioxidant and anti-inflammatory activities. Here, we tested the hypothesis that rice bran enzymatic extract (RBEE) impacts on apoptosis, telomere length and atherogenesis in mice. Seven-week-old male ApoE-/- mice were fed high-fat diet (HFD) or isocaloric HFD supplemented with 5 % (w/w) RBEE for 23 weeks. Wild-type mice of the same age were kept under standard diet as controls. RBEE treatment reduced total cholesterol (19.24 ± 1.63 vs 24.49 ± 1.71 mmol/L) and triglycerides (1.13 ± 0.18 vs 1.75 ± 0.22 mmol/L) and augmented HDL-cholesterol (1.86 ± 0.20 vs 1.07 ± 0.20 mmol/L). RBEE attenuated macrophage infiltration by 56.69 ± 4.65 % and plaque development (7737 ± 836 vs 12,040 ± 1001 μm2) in the aortic sinus. In the aorta, RBEE treatment reduced expression of the apoptosis pathway components p16, p53 and bax/bcl-2 ratio. RBEE prevented apoptosis of aortic endothelial cells (2.81 ± 0.71-1.14 ± 0.35 apoptotic nuclei/ring for ApoE-/- HFD and ApoE-/- HFD 5 % RBEE, respectively). In contrast, MNC of RBEE-fed mice exhibited enhanced apoptosis marker expression with increased p53 and bax/bcl-2 protein levels. Compared to WT, ApoE-/- mice on HFD were characterized by significant telomere shortening in aorta (11 ± 2 %) and MNC (73 ± 7 %), which was reduced by supplementation with RBEE (aorta: 40 ± 7 %; MNC: 105 ± 10 %). Expression of telomere repeat-binding factor 2 was increased in RBEE-fed mice. Long-term food supplementation with RBEE lowers cholesterol and prevents atherosclerotic plaque development in ApoE-/- mice. Differential regulation of vascular and MNC apoptosis and senescence were identified as potential mechanisms.


[Eating behaviors and the social status of families of malnourished children].
The objective of this study was to learn about the everyday eating behaviors and the social status of the families of malnourished children. This qualitative study involved eight families. Data were collected by participant observation and semi-structured interviews. Thematic analysis revealed the following themes: family eating; the family's social status and eating during childhood; and the presence of social programs and equipment. The family did not gather for meals and their food consisted basically of different sources of carbohydrates. Fruits and vegetables were very limited and considered to be food choices that did not provide sustenance. Differences were observed between the family's' and the children's' eating habits. Social programs and equipment provided important support, especially regarding the positive attachment with institutions and professionals and following the children's health. The family's social status does not allow the offering of appropriate quantities and quality of food throughout the month, thus compromising the nutritional status of the children, who are deprived of appropriate foods of adequate nutritional value.


Determination of specific oxygen uptake rates in human hematopoietic cultures and implications for bioreactor design.
Oxygen plays an important role in the cultivation of primary cells ex vivo. In this study, we used hermetically sealed tissue culture well inserts equipped with oxygen electrodes to measure the oxygen utilization of cultured human bone marrow mononuclear cells (BM MNCs). The oxygen uptake rate (OUR) of BM MNCs was determined during a 14-day culture in which both adherent and nonadherent cells were present. Early in the culture, the cells exhibited very low OURs. The specific OURs (uptake rate per cell) were at approximately 0.005 mumol/10(6) cells/hr shortly after the initiation of culture. The OUR then increased as the cultures developed. After about 8 to 10 days of cultivation the specific OURs had increased to 0.038 +/- 0.006 and 0.025 +/- 0.005 mumol/10(6) cells/hr for adherent and nonadherent cells, respectively, after which no further increase was observed. Based on these oxygen uptake rate data, a mathematical model of oxygen diffusion was formulated and use to investigate issues associated with hematopoietic bioreactor design, including initial cell density, medium depth, reactor configuration, and oxygen partial pressure. In situ OUR measurements confirmed predicted oxygen limitations based on the mathematical model and the experimentally determined OURs. High-density hematopoietic cultures present design challenges in terms of sufficient and uniform delivery of oxygen to an active hematopoietic culture. These challenges can be met by using parallel-plate bioreactors with thin liquid layers.


EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes.
The t(11;22) chromosomal translocation specifically linked to Ewing sarcoma and primitive neuroectodermal tumor results in a chimeric molecule fusing the amino-terminus-encoding region of the EWS gene to the carboxyl-terminal DNA-binding domain encoded by the FLI-1 gene. As the function of the protein encoded by the EWS gene remains unknown, we investigated the putative role of EWS in RNA polymerase II (Pol II) transcription by comparing its activity with that of its structural homolog, hTAFII68. We demonstrate that a portion of EWS is able to associate with the basal transcription factor TFIID, which is composed of the TATA-binding protein (TBP) and TBP-associated factors (TAFIIs). In vitro binding studies revealed that both EWS and hTAFII68 interact with the same TFIID subunits, suggesting that the presence of EWS and that of hTAFII68 in the same TFIID complex may be mutually exclusive. Moreover, EWS is not exclusively associated with TFIID but, similarly to hTAFII68, is also associated with the Pol II complex. The subunits of Pol II that interact with EWS and hTAFII68 have been identified, confirming the association with the polymerase. In contrast to EWS, the tumorigenic EWS-FLI-1 fusion protein is not associated with either TFIID or Pol II in Ewing cell nuclear extracts. These observations suggest that EWS and EWS-FLI-1 may play different roles in Pol II transcription.


A methylation-dependent electrostatic switch controls DNA repair and transcriptional activation by E. coli ada.
The transcriptional activity of many sequence-specific DNA binding proteins is directly regulated by posttranslational covalent modification. Although this form of regulation was first described nearly two decades ago, it remains poorly understood at a mechanistic level. The prototype for a transcription factor controlled by posttranslational modification is E. coli Ada protein, a chemosensor that both repairs methylation damage in DNA and coordinates the resistance response to genotoxic methylating agents. Ada repairs methyl phosphotriester lesions in DNA by transferring the aberrant methyl group to one of its own cysteine residues; this site-specific methylation enhances tremendously the DNA binding activity of the protein, thereby enabling it to activate a methylation-resistance regulon. Here, we report solution and X-ray structures of the Cys-methylated chemosensor domain of Ada bound to DNA. The structures reveal that both phosphotriester repair and methylation-dependent transcriptional activation function through a zinc- and methylation-dependent electrostatic switch.


Effects of a dairy supplement and resistance training on lean mass and insulin-like growth factor in women.
To examine the effect of yogurt supplementation pre- and postexercise on changes in body composition in overweight women engaged in a resistance-training program. Participants (age = 36.8 ± 4.8 yr) with a body-mass index of 29.1 ± 2.1 kg/m2 were randomized to yogurt supplement (YOG; n = 15) or isoenergetic sucrose beverage (CONT; n = 14) consumed before and after exercise for 16 wk. Participants were also instructed to reduce energy intake daily (-1,046 kJ) during the study. Body composition was assessed by dual-energy X-ray absorptiometry, waist circumference, and sagittal diameter. Strength was measured with 1-repetition maximum. Dietary recalls were obtained by a multipass approach using Nutrition Data System software. Insulin-like growth factor-1 and insulin-like growth-factor-binding protein-3 were measured with ELISA. Significant weight losses of 2.6 ± 4.5 kg (YOG) and 1.2 ± 2.5 kg (CONT) were observed. Total lean weight increased significantly over time in both YOG (0.8 ± 1.2 kg) and CONT (1.1 ± 0.9 kg). Significant reductions in total fat (YOG = 3.4 ± 4.1 kg vs. CONT = 2.3 ± 2.4 kg) were observed over time. Waist circumference, sagittal diameter, and trunk fat decreased significantly over time without group differences. Both groups significantly decreased energy intake while maintaining protein intake. Strength significantly increased over time in both groups. No changes over time or between groups were observed in hormone levels. These data suggest that yogurt supplementation offered no added benefit for increasing lean mass when combined with resistance training and modest energy restriction.


Afatinib for the treatment of metastatic non-small cell lung cancer.
Targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harboring sensitizing mutations in the tyrosine kinase (TKI) domain has led to a significant change in the management of this disease. The classic or sensitizing mutations are G719X mutation in exon 18, in-frame deletions or insertion of exon 19, L858R or L861Q mutation in exon 21. Approximately 90% of these mutations are exon 19 deletion or exon 21 L858R point mutation. Gefitinib and erlotinib are reversible first-generation inhibitors of mutant EGFR, and treatment with these agents in the first-line setting has demonstrated a progression-free survival of 9.5-13.7 months. However, the majority of these patients ultimately develop resistance to these drugs. Afatinib is an irreversible pan-ErbB inhibitor that was developed to circumvent the problem of resistance to first-generation TKIs. The LUX-Lung studies have evaluated the efficacy and toxicities of afatinib in treatment-naïve and refractory NSCLC patients. The promising results of some of these trials led to approval of afatinib by the US Food and Drug Administration for patients with advanced NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib causes toxicities similar to those of the first-generation EGFR TKIs, such as diarrhea, rash, acne, and stomatitis, and overall is well tolerated. This article focuses on the clinical studies of afatinib in patients with NSCLC.


Guidelines for Periodontal Therapy.
The American Academy of Periodontology offers the following Guidelines for Periodontal Therapy. These guidelines are intended to fulfill the Academy's obligation to the public and to the dental profession. This paper sets forth the clinical objectives and scope of periodontal therapy. These guidelines are designed to give guidance to state legislatures and agencies that regulate the practice of periodontology and should be considered in their entirety.


Characterization of the transcriptional divergence between the subspecies of cultivated rice (Oryza sativa).
Cultivated rice consists of two subspecies, Indica and Japonica, that exhibit well-characterized differences at the morphological and genetic levels. However, the differences between these subspecies at the transcriptome level remains largely unexamined. Here, we provide a comprehensive characterization of transcriptome divergence and cis-regulatory variation within rice using transcriptome data from 91 accessions from a rice diversity panel (RDP1). The transcriptomes of the two subspecies of rice are highly divergent. Japonica have significantly lower expression and genetic diversity relative to Indica, which is likely a consequence of a population bottleneck during Japonica domestication. We leveraged high-density genotypic data and transcript levels to identify cis-regulatory variants that may explain the genetic divergence between the subspecies. We identified significantly more eQTL that were specific to the Indica subspecies compared to Japonica, suggesting that the observed differences in expression and genetic variability also extends to cis-regulatory variation. Using RNA sequencing data for 91diverse rice accessions and high-density genotypic data, we show that the two species are highly divergent with respect to gene expression levels, as well as the genetic regulation of expression. The data generated by this study provide, to date, the largest collection of genome-wide transcriptional levels for rice, and provides a community resource to accelerate functional genomic studies in rice.


Characterization of hemizygous deletions in citrus using array-comparative genomic hybridization and microsynteny comparisons with the poplar genome.
Many fruit-tree species, including relevant Citrus spp varieties exhibit a reproductive biology that impairs breeding and strongly constrains genetic improvements. In citrus, juvenility increases the generation time while sexual sterility, inbreeding depression and self-incompatibility prevent the production of homozygous cultivars. Genomic technology may provide citrus researchers with a new set of tools to address these various restrictions. In this work, we report a valuable genomics-based protocol for the structural analysis of deletion mutations on an heterozygous background. Two independent fast neutron mutants of self-incompatible clementine (Citrus clementina Hort. Ex Tan. cv. Clemenules) were the subject of the study. Both mutants, named 39B3 and 39E7, were expected to carry DNA deletions in hemizygous dosage. Array-based Comparative Genomic Hybridization (array-CGH) using a Citrus cDNA microarray allowed the identification of underrepresented genes in these two mutants. Subsequent comparison of citrus deleted genes with annotated plant genomes, especially poplar, made possible to predict the presence of a large deletion in 39B3 of about 700 kb and at least two deletions of approximately 100 and 500 kb in 39E7. The deletion in 39B3 was further characterized by PCR on available Citrus BACs, which helped us to build a partial physical map of the deletion. Among the deleted genes, ClpC-like gene coding for a putative subunit of a multifunctional chloroplastic protease involved in the regulation of chlorophyll b synthesis was directly related to the mutated phenotype since the mutant showed a reduced chlorophyll a/b ratio in green tissues. In this work, we report the use of array-CGH for the successful identification of genes included in a hemizygous deletion induced by fast neutron irradiation on Citrus clementina. The study of gene content and order into the 39B3 deletion also led to the unexpected conclusion that microsynteny and local gene colinearity in this species were higher with Populus trichocarpa than with the phylogenetically closer Arabidopsis thaliana. This work corroborates the potential of Citrus genomic resources to assist mutagenesis-based approaches for functional genetics, structural studies and comparative genomics, and hence to facilitate citrus variety improvement.


A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: quality-of-life outcomes of a randomized controlled trial of supervised treatment of psoriasis in a day-care setting.
Calcipotriol ointment and short-contact dithranol cream therapy are well-established topical treatments for psoriasis. Quality of life, i.e. the physical, psychological, and social functioning and well-being of the patient, has become an essential outcome measure in chronic skin disease. To compare the quality-of-life outcomes of calcipotriol ointment with that of short-contact dithranol cream in a supervised treatment regimen, and to determine the degree of improvement in quality of life these topical treatments can accomplish. In a multicentre randomized controlled trial in six centres in the Netherlands, 106 patients with chronic plaque psoriasis were included, 54 receiving calcipotriol ointment twice daily and 52 dithranol cream once daily in a 12-week intensive treatment programme. Patients were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. Quality of life was assessed with the Skindex-29 and the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). At the end of treatment, no statistically significant differences were found between the calcipotriol and the dithranol group in any of the quality-of-life domains or scales of the Skindex-29 and the SF-36. Over time, a significant improvement of quality of life was found on all three scales of the dermatology-specific Skindex-29, predominantly of a moderate magnitude. In the calcipotriol group, a significant change of a small magnitude was found in the Physical Component Summary of the SF-36. No significant changes were found in the Mental Component Summary (or on any of the eight scales composing the questionnaire) of the SF-36. The hypothesis was confirmed, that no statistically significant differences in improvement of quality of life could be found between calcipotriol ointment and dithranol short-contact cream in a day-care setting. Given this result, both calcipotriol and dithranol can be welcome alternatives for the patient. Calcipotriol, being more practical and patient friendly, can be considered as a first-line approach in clinical practice. However, in patients recalcitrant to calcipotriol and/or other topical treatments, preference should be given to the dithranol regimen. Topical treatment in combination with interventions explicitly focusing on improvement of coping behaviour and psychosocial functioning may further increase the degree of improvement in the psychosocial domains of quality of life. The results of this study are likely to give further evidence to the notion that the generic SF-36 is little or not responsive to small to moderate changes in quality of life in mild to moderate psoriasis.


Perioperative evaluation of myasthenia gravis.
Myasthenia gravis (MG) is the prototype of antibody mediated autoimmune disease and results from the production of autoantibodies against the acetylcholine receptor (AChR) of the neuromuscular synapse. Adequate preoperative evaluation of the myasthenic patient must be carried out carefully. Age, sex, onset and duration of the disease as well as the presence of thymoma may determine the response to thymectomy. Specific attention should be paid to voluntary and respiratory muscle strength. The preoperative preparation of MG patients is essential for the success of surgery. It depends on the severity of clinical status and changes if myasthenic patients receive anticholinesterase therapy. Myasthenic patients may have little respiratory reserve, and hence depressant drugs for preoperative premedication should be used with caution and avoided in patients with bulbar symptoms. The anaesthetic management of myasthenic patient must be individualized in according to the severity of the disease and the type of surgery required. The use of regional or local anaesthesia seems warranted whenever possible. General anaesthesia can be performed safely when patient is optimally prepared and neuromuscular transmission is adequately monitored during and after surgery. Adequate postoperative pain control, pulmonary toilet, and avoidance of drugs that interfere with neuromuscular transmission will facilitate tracheal extubation. Myasthenia gravis is a disease with many implications for the safe administration of anaesthesia. The potential for respiratory compromise in these patients requires the anaesthesiologist to be familiar with the underlying disease state, as well as the interaction of anaesthetic and non-anaesthetic drugs with MG.


Diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle biopsy in mediastinal lymphadenopathy: a systematic review and meta-analysis.
To perform a systematic review and meta-analysis of prospectively conducted studies to define diagnostic performance of endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNB) in mediastinal and hilar lymphadenopathy. A comprehensive search was performed using the Embase, Ovid Medline, Ovid Medline In-Process and Other Non-Indexed Citations, All Evidence Based Medicine Reviews-Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CCTR), Health Technology Assessment (HTA), and SCOPUS databases, in the second week of November 2010. Studies were selected in 2 phases by 2 reviewers, independently. Data extraction from each study was performed using a standardized data extraction form. Quality assessment of study methodology was done using a checklist that was developed based on a Quality Assessment of Diagnostic Accuracy Studies tool and the nature of the test. Using the 2 × 2 tables, we computed the sensitivity, specificity, and likelihood ratios. The 14 studies included for quantitative data synthesis had a pooled cohort of 1,658 patients, from 8 different countries. The EBUS-TBNB had excellent pooled specificity of 100% (95% CI 0.90-1.00) and a positive likelihood ratio of 5.1 (95% CI 2.7-9.7). The pooled sensitivity was 0.92 (95% CI 0.91-0.93), and the pooled negative likelihood ratio was 0.13 (95% CI 0.09-0.19). The sensitivity of this intervention was not dependent on rapid on-site evaluation use or size of needle used. The pooled diagnostic odds ratio was 62.7 (95% CI 25.7-153.0). Only one major complication was reported, which resulted in early termination of the procedure. Evidence of moderate quality confirms the high diagnostic performance of EBUS-TBNB for mediastinal and hilar lymphadenopathy, both in malignant and non-malignant conditions. Available evidence also demonstrates the safety of this procedure.


Coronary calcium score as an adjunct to nuclear myocardial perfusion imaging for risk stratification before noncardiac surgery.
The purpose of this study was to evaluate the added value of coronary artery calcium score (CACS) as an adjunct to myocardial perfusion imaging (MPI) with SPECT for cardiac risk stratification before noncardiac surgery. SPECT MPI is a well-established and widely used tool for preoperative risk stratification before noncardiac surgery. The potential added value of combining SPECT MPI with CACS is unknown. We included 326 consecutive patients who were referred for SPECT MPI for preoperative cardiac risk assessment before elective noncardiac surgery. All patients underwent an additional low-dose CT scan for CACS and SPECT MPI. Patients were followed up for 40 d after their index surgical procedure, and the occurrence of major adverse cardiovascular events (MACE), including death, myocardial infarction, revascularization, stroke, and sudden cardiac death, was registered. Postoperative MACE occurred in 30 patients (9%). Cumulative MACE rate was highest in patients with abnormal SPECT and high CACS (22%), defined by a cutoff value CACS of 1,314 or more, and lowest in patients with normal SPECT MPI findings and low CACS (5%) (CACS < 1,314). A CACS score of 1,314 or more was independently associated with a higher MACE rate in patients with normal (12% vs. 5%) or abnormal perfusion (22% vs. 12%, P < 0.05 for all intergroup comparisons). SPECT MPI findings and CACS are strong preoperative risk predictors. CACS allows further risk stratification, indicating very low risk when CACS less than 1,314 is associated with normal SPECT MPI findings. Conversely, in patients with abnormal SPECT MPI findings, a CACS of 1,314 or more confers an added value for predicting adverse outcomes.


Elevated Membrane and Soluble CD64: A Novel Marker Reflecting Altered FcγR Function and Disease in Early Rheumatoid Arthritis That Can Be Regulated by Anti-Rheumatic Treatment.
Fc receptors (FcR) interacting with immune complexes (ICs) is a central event in the immune pathogenesis of rheumatoid arthritis (RA). Here we asked if a specific FcR is linked to RA pathogenesis and if FcR activities relate to disease and treatment outcome in early RA. Twenty autoantibody-positive RA patients and 33 HC were included. The patients were evaluated before and after treatment with methotrexate and prednisolone. At follow-up, the EULAR response criteria were applied to determine the individual treatment outcomes. Serum immunoglobulin levels were measured and the expression of FcR for IgG (FcγR) and IgA (FcαR) on peripheral blood monocytes were determined by flow cytometry. The monocytic FcγR function was evaluated by human IgG1 and IgG3 IC-binding and TNFα stimulated release. Plasma levels of soluble FcRs (sFcRs) were determined with ELISA. The IgG1 and IgG3 levels were elevated in the RA sera. The RA monocytes expressed more CD64 and cell surface-bound IgG than HC monocytes, and showed an impaired FcγR function as reflected by changes in IC-binding and decreased IC-stimulated TNFα secretion. These findings correlated significantly with different disease activity markers. Furthermore, sFcRs were elevated in the patient plasma, and sCD64 was specific for RA (compared with a reference group of patients with active psoriatic arthritis). Following treatment, immunoglobulins and sFcR levels were reduced, whereas membrane CD64 was only decreased in patients with good response to treatment. Early RA patients display increased membrane and soluble CD64 and an impaired FcγR function correlating with joint disease activity. Beneficial responses of anti-rheumatic treatment in patients reduce CD64. These data suggest sCD64 as an important objective biomarker in RA.


Effect of antilymphoma antibody, 131I-Lym-1, on peripheral blood lymphocytes in patients with non-Hodgkin's lymphoma.
Anti-CD20 monoclonal antibodies (mAbs), unlabeled rituximab (Rituxan, Biogen Idec Inc., Cambridge, MA; and Genentech Inc., South San Francisco, CA) or radiolabeled 90Y-ibritumomab (Zevalin, Biogen Idec Inc., Cambridge, MA) and 131I-tositumomab (Bexxar; Glaxo Smith Kline, Research Triangle Park, NC), have proven to be effective therapy for non-Hodgkin's lymphoma (NHL), but also induce immediate and persistent decreases in normal peripheral blood lymphocytes (PBLs). Lym-1, a mAb that selectively targets malignant lymphocytes, also has induced therapeutic responses and prolonged survival in patients with NHL when labeled with iodine-131 (131I). We have retrospectively examined its effect on PBLs in 41 NHL patients that had received 131I-Lym-1 therapy. Absolute lymphocyte counts (ALCs) were evaluated before and after the first and last 131I-Lym-1 infusion. Modest decreases in PBLs were observed in most of the patients. Using strict criteria to define recovery, time to recovery was determined for 19 patients, with the remainder censored because of insufficient follow-up (median follow up for censored patients: 22 days). Using Kaplan-Meier estimates, it would be predicted that 31% of patients would recover by 28 days and that median time to recovery would be 44 days after the last 131I-Lym-1 infusion. No predictors were found for time to recovery, considering such factors as the administered Lym-1 or 131I dose, spleen volume, or radiation doses to the body, marrow, or spleen. The data suggest that the effect of 131I-Lym-1 on ALC is the result of a nonspecific radiation effect, rather than a specific Lym-1 mAb effect. The shorter time required for ALC recovery after 131I-Lym-1 when compared to that reported for anti-CD20 mAbs, whether radiolabeled or otherwise, is probably related to differing mechanisms for lymphocytotoxicity and lesser Lym-1 antigenic density on normal B-lymphocytes.


Efficacy of a homeopathic complex on acute viral tonsillitis.
Acute viral tonsillitis is an upper respiratory tract infection prevalent in school-aged children. Because this condition is self-limiting, conventional treatment options are usually palliative. Homeopathic remedies are a useful alternative to conventional medications in acute uncomplicated upper respiratory tract infections in children, offering earlier symptom resolution, cost-effectiveness, and fewer adverse effects. This study aimed to determine the efficacy of a homeopathic complex on the symptoms of acute viral tonsillitis in African children in South Africa. This was a randomized, double-blind, placebo-controlled, 6-day pilot study. Thirty children, age 6 to 12 years, with acute viral tonsillitis were recruited from a primary school in Gauteng, South Africa. Participants took two tablets of the medication four times daily. The treatment group received lactose tablets medicated with the homeopathic complex (Atropa belladonna D4, Calcarea phosphoricum D4, Hepar sulphuris D4, Kalium bichromat D4, Kalium muriaticum D4, Mercurius protoiodid D10, and Mercurius biniodid D10). The placebo consisted of the unmedicated vehicle only. The Wong-Baker FACES Pain Rating Scale measured pain intensity, and a Symptom Grading Scale assessed changes in tonsillitis signs and symptoms. The treatment group had a statistically significant improvement in the following symptoms compared with the placebo group: pain associated with tonsillitis, pain on swallowing, erythema and inflammation of the pharynx, and tonsil size. The homeopathic complex used in this study exhibited significant anti-inflammatory and pain-relieving qualities in children with acute viral tonsillitis. No patients reported any adverse effects. These preliminary findings are promising; however, the sample size was small and therefore a definitive conclusion cannot be reached. A larger, more inclusive research study should be undertaken to verify the findings of this study.


Sex, sport, and body-size dependency of hematology in highly trained athletes.
Blood hemoglobin concentration, hematocrit, red cell count, white cell count (WBC), and plasma ferritin concentration were measured on 1604 occasions from 706 nationally ranked athletes in 12 sports. The blood samples were taken from a forearm vein amidst periods of moderate to intense training but at least 6 h after a training session. A multiple regression model, accounting for correlations between variables and incorporating the categorical variables of sex and sport revealed the following. Each blood variable was found to be dependent on body mass index, (mass/height2, BMI), with the exception of WBC in the males. As BMI increased so did the magnitude of these blood variables (P less than 0.01). Each blood variable was also dependent on the sport (P less than 0.01), significant differences being observed between several sports in each case. Furthermore, as has been previously reported, the magnitude of the blood variables was dependent on the sex of the athlete, each being significantly greater in males (P less than 0.01), with the exception of the WBC, which was greater in females (P less than 0.01). These data indicate that the rationality of interpreting the hematology in highly trained athletes may be increased by taking BMI and sport into account, as well as gender.