Differential expression of cyclooxygenase-2 (COX-2) in human bile duct epithelial cells and bile duct neoplasm.
It is well known that chronic inflammatory conditions involving the bile ducts predispose to the development of bile duct carcinoma, although the relationship between chronic inflammation and malignant transformation is unclear. In this study, by combining immunohistochemistry and computer imaging techniques, we quantified and compared the cyclooxygenase-2 (COX-2) protein expression levels of epithelial cells according with their histopathological backgrounds. This technique revealed that the highest levels of COX-2 were expressed in bile duct carcinoma cells, mainly in cytoplasm, and the expression pattern was homogenous and abundant. Moderate levels of COX-2 protein expression were also observed in noncancerous epithelial cells with inflammatory reaction, but the staining intensity was heterogeneous among the positive cells exhibiting inflammation. In contrast, only scattered weak reactivity of COX-2 protein was observed in the noncancerous bile duct epithelial cells without inflammatory reaction. Moreover, bile duct epithelial cells in primary sclerosing cholangitis (PSC) showed very strong expression of COX-2 protein, that was comparable with carcinoma cells. On the other hand, primary biliary cirrhosis (PBC) epithelial cells showed moderate levels of COX-2 expression. In addition, specific COX-2 inhibitors, JTE-522 and NS-398, directly inhibited the growth of 4 bile duct carcinoma and 1 gall bladder carcinoma cell lines that expressed COX-2 protein, in vitro. These data suggest that COX-2 expression might regulate carcinogenesis of bile duct epithelial cells in inflammatory regions and tumor progression in this cancer. The data also suggest that COX-2 selective inhibitors might have therapeutic effects not only on bile duct carcinoma, but other hepatobiliary carcinomas.


Adherence to Blended or Face-to-Face Smoking Cessation Treatment and Predictors of Adherence: Randomized Controlled Trial.
Blended face-to-face and web-based treatment is a promising way to deliver smoking cessation treatment. Since adherence has been shown to be an indicator of treatment acceptability and a determinant for effectiveness, we explored and compared adherence and predictors of adherence to blended and face-to-face alone smoking cessation treatments with similar content and intensity. The objectives of this study were (1) to compare adherence to a blended smoking cessation treatment with adherence to a face-to-face treatment; (2) to compare adherence within the blended treatment to its face-to-face mode and web mode; and (3) to determine baseline predictors of adherence to both treatments as well as (4) the predictors to both modes of the blended treatment. We calculated the total duration of treatment exposure for patients (N=292) of a Dutch outpatient smoking cessation clinic who were randomly assigned either to the blended smoking cessation treatment (n=130) or to a face-to-face treatment with identical components (n=162). For both treatments (blended and face-to-face) and for the two modes of delivery within the blended treatment (face-to-face vs web mode), adherence levels (ie, treatment time) were compared and the predictors of adherence were identified within 33 demographic, smoking-related, and health-related patient characteristics. We found no significant difference in adherence between the blended and the face-to-face treatments. Participants in the blended treatment group spent an average of 246 minutes in treatment (median 106.7% of intended treatment time, IQR 150%-355%) and participants in the face-to-face group spent 238 minutes (median 103.3% of intended treatment time, IQR 150%-330%). Within the blended group, adherence to the face-to-face mode was twice as high as that to the web mode. Participants in the blended group spent an average of 198 minutes (SD 120) in face-to-face mode (152% of the intended treatment time) and 75 minutes (SD 53) in web mode (75% of the intended treatment time). Higher age was the only characteristic consistently found to uniquely predict higher adherence in both the blended and face-to-face groups. For the face-to-face group, more social support for smoking cessation was also predictive of higher adherence. The variability in adherence explained by these predictors was rather low (blended R2=0.049; face-to-face R2=0.076). Within the blended group, living without children predicted higher adherence to the face-to-face mode (R2=0.034), independent of age. Higher adherence to the web mode of the blended treatment was predicted by a combination of an extrinsic motivation to quit, a less negative attitude toward quitting, and less health complaints (R2=0.164). This study represents one of the first attempts to thoroughly compare adherence and predictors of adherence of a blended smoking cessation treatment to an equivalent face-to-face treatment. Interestingly, although the overall adherence to both treatments appeared to be high, adherence within the blended treatment was much higher for the face-to-face mode than for the web mode. This supports the idea that in blended treatment, one mode of delivery can compensate for the weaknesses of the other. Higher age was found to be a common predictor of adherence to the treatments. The low variance in adherence predicted by the characteristics examined in this study suggests that other variables such as provider-related health system factors and time-varying patient characteristics should be explored in future research. Netherlands Trial Register NTR5113; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5113.


Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man.
Tumor necrosis factor-alpha (TNF) is believed to be an important mediator in many diseases that are associated with the sick euthyroid syndrome. To investigate the effect of TNF on thyroid hormone metabolism, we performed a controlled study in six healthy postabsorptive males, in whom plasma thyroid hormones and TSH were sequentially measured after iv bolus injections of recombinant human TNF (50 micrograms/m2) and isotonic saline. During the 10.5-h study TNF produced the characteristic changes in circulating thyroid hormones and TSH observed in the sick euthyroid syndrome. Compared with the control experiment, TNF induced significant decreases in T3 (-36 +/- 2%; saline, -20 +/- 3%; P less than 0.05) and TSH levels (-68 +/- 3%; saline, -44 +/- 8%; P less than 0.05) and a significant increase in rT3 values (+48 +/- 11%; saline, -12 +/- 7%; P less than 0.05). T4 and free T4 index were not affected by TNF. Free T4 showed a mean transient increase of 18% in five subjects (nonsignificant), which occurred synchronically with a transient 3.5-fold rise in circulating FFA levels. Our results suggest that TNF is involved, either directly or indirectly, in the pathogenesis of the sick euthyroid syndrome.


Validation of the Global Allergy and Asthma European Network (GA2LEN) chamber for trials in allergy: Innovation of a mobile allergen exposure chamber.
Field clinical trials of pollen allergy are affected by the impossibility of predicting and determining individual allergen exposure because of many factors (eg, pollen season, atmospheric variations, pollutants, and lifestyles). Environmental exposure chambers, delivering a fixed amount of allergen in a controlled environmental setting, can overcome these limitations. Environmental exposure chambers are currently already used in phase 2, 3, and even 4 trials. Unfortunately, few chambers exist in the world, and this makes it difficult to perform large, multicenter clinical trials. The new Global Allergy and Asthma European Network (GA2LEN) mobile exposure chamber is a step forward because the mobility of the chamber makes it convenient for patients to participate in clinical testing. This study was made to validate the reproducibility, sensitivity, and specificity of the results obtained in the new GA2LEN chamber. Seventy-two adult patients (19-61 years old) with allergic rhinitis with or without asthma caused by grass pollen were included in different clinical validation tests. Total symptom scores and total nasal symptom scores were recorded at time zero (0) and every 10 minutes during exposures, along with nasal and respiratory parameters. Exposure tests confirmed the reproducibility between subsequent runs and the sensitivity (P < .00001 vs patients exposed to placebo) and specificity (very low score in nonallergic subjects) in the GA2LEN chamber. No adverse reactions were recorded during the tests. The mobility of the GA2LEN chamber provides a new, potentially effective, and safe way of generating reliable data in allergy multicenter clinical trials.


Review of bone graft and bone substitutes with an emphasis on fracture surgeries.
Autogenous bone graft is the gold standard bone graft material. However, due to limitations of supply and morbidity associated with autograft harvest, various bone substitutes have been considered. This article aims to review the properties of the bone graft and various bone substitutes currently available in orthopedic surgery. Synthetic bone substitutes consist of hydroxyapatite, tricalcium phosphate, calcium sulfate, or a combination of these minerals. Synthetic porous substitutes share several advantages over allografts, including unlimited supply, easy sterilization, and storage. However, they also have some disadvantages, such as brittle properties, variable rates of resorption, and poor performance in some clinical conditions. Recently, attention has been drawn to osteoinductive materials, such as demineralized bone matrix and bone morphogenetic proteins. Despite tremendous efforts toward developing autograft alternatives, a single ideal bone graft substitute has not been developed. The surgeon should understand the properties of each bone graft substitute to facilitate appropriate selection in each specific clinical situation.


Multifunctional Cationic Iridium(III) Complexes Bearing 2-Aryloxazolo[4,5-f][1,10]phenanthroline (N^N) Ligand: Synthesis, Crystal Structure, Photophysics, Mechanochromic/Vapochromic Effects, and Reverse Saturable Absorption.
A series of 2-aryloxazolo[4,5-f][1,10]phenanthroline ligands (N^N ligands) and their cationic iridium(III) complexes (1-11, aryl = 4-NO2-phenyl (1), 4-Br-phenyl (2), Ph (3), 4-NPh2-phenyl (4), 4-NH2-phenyl (5), pyridin-4-yl (6), naphthalen-1-yl (7), naphthalen-2-yl (8), phenanthren-9-yl (9), anthracen-9-yl (10), and pyren-1-yl (11)) were synthesized and characterized. By introducing different electron-donating or electron-withdrawing substituents at the 4-position of the 2-phenyl ring (1-5), or different aromatic substituents with varied degrees of π-conjugation (6-11) on oxazolo[4,5-f][1,10]phenanthroline ligand, we aim to understand the effects of terminal substituents at the N^N ligands on the photophysics of cationic Ir(III) complexes using both spectroscopic methods and quantum chemistry calculations. Complexes with the 4-R-phenyl substituents adopted an almost coplanar structure with the oxazolo[4,5-f][1,10]phenanthroline motif, while the polycyclic aryl substituents (except for naphthalen-2-yl) were twisted away from the oxazolo[4,5-f][1,10]phenanthroline motif. All complexes possessed strong absorption bands below 350 nm that emanated from the ligand-localized 1π,π*/1ILCT (intraligand charge transfer) transitions, mixed with 1LLCT (ligand-to-ligand charge transfer)/1MLCT (metal-to-ligand charge transfer) transitions. At the range of 350-570 nm, all complexes exhibited moderately strong 1ILCT/1LLCT/1MLCT transitions at 350-450 nm, and broad but very weak 3LLCT/3MLCT absorption at 450-570 nm. Most of the complexes demonstrated moderate to strong room temperature phosphorescence both in solution and in the solid state. Among them, complex 7 also manifested a drastic mechanochromic and vapochromic luminescence effect. Except for complexes 1 and 4 that contain NO2 or NPh2 substituent at the phenyl ring, respectively, all other complexes exhibited moderate to strong triplet excited-state absorption in the spectral region of 440-750 nm. Moderate to very strong reverse saturable absorption (RSA) of these complexes appeared at 532 nm for 4.1 ns laser pulses. The RSA strength followed the trend of 7 > 11 > 9 > 3 > 2 ≈ 4 > 5 ≈ 10 ≈ 6 ≈ 8 > 1. The photophysical studies revealed that the different 2-aryl substituents on the oxazole ring impacted the singlet and triplet excited-state characteristics dramatically, which in turn notably influenced the RSA of these complexes.


The central role of cAMP in regulating Plasmodium falciparum merozoite invasion of human erythrocytes.
All pathogenesis and death associated with Plasmodium falciparum malaria is due to parasite-infected erythrocytes. Invasion of erythrocytes by P. falciparum merozoites requires specific interactions between host receptors and parasite ligands that are localized in apical organelles called micronemes. Here, we identify cAMP as a key regulator that triggers the timely secretion of microneme proteins enabling receptor-engagement and invasion. We demonstrate that exposure of merozoites to a low K+ environment, typical of blood plasma, activates a bicarbonate-sensitive cytoplasmic adenylyl cyclase to raise cytosolic cAMP levels and activate protein kinase A, which regulates microneme secretion. We also show that cAMP regulates merozoite cytosolic Ca2+ levels via induction of an Epac pathway and demonstrate that increases in both cAMP and Ca2+ are essential to trigger microneme secretion. Our identification of the different elements in cAMP-dependent signaling pathways that regulate microneme secretion during invasion provides novel targets to inhibit blood stage parasite growth and prevent malaria.


NEXUS chest: validation of a decision instrument for selective chest imaging in blunt trauma.
Chest radiography (chest x-ray [CXR] and chest computed tomography [CT]) is the most common imaging in blunt trauma evaluation. Unnecessary trauma imaging leads to greater costs, emergency department time, and patient exposure to ionizing radiation. OBJECTIVE To validate our previously derived decision instrument (NEXUS Chest) for identification of blunt trauma patients with very low risk of thoracic injury seen on chest imaging (TICI). We hypothesized that NEXUS Chest would have high sensitivity (>98%) for the prediction of TICI and TICI with major clinical significance. From December 2009 to January 2012, we enrolled blunt trauma patients older than 14 years who received chest radiography in this prospective, observational, diagnostic decision instrument study at 9 US level I trauma centers. Prior to viewing radiographic results, physicians recorded the presence or absence of the NEXUS Chest 7 clinical criteria (age >60 years, rapid deceleration mechanism, chest pain, intoxication, abnormal alertness/mental status, distracting painful injury, and tenderness to chest wall palpation). Thoracic injury seen on chest imaging was defined as pneumothorax, hemothorax, aortic or great vessel injury, 2 or more rib fractures, ruptured diaphragm, sternal fracture, and pulmonary contusion or laceration seen on radiographs. An expert panel generated an a priori classification of clinically major, minor, and insignificant TICIs according to associated management changes. Of 9905 enrolled patients, 43.1% had a single CXR, 42.0% had CXR and chest CT, 6.7% had CXR and abdominal CT (without chest CT), 5.5% had multiple CXRs without CT, and 2.6% had chest CT alone in the emergency department. The most common trauma mechanisms were motorized vehicle crash (43.9%), fall (27.5%), pedestrian struck by motorized vehicle (10.7%), bicycle crash (6.3%), and struck by blunt object, fists, or kicked (5.8%). Thoracic injury seen on chest imaging was seen in 1478 (14.9%) patients with 363 (24.6%) of these having major clinical significance, 1079 (73.0%) minor clinical significance, and 36 (2.4%) no clinical significance. NEXUS Chest had a sensitivity of 98.8% (95% CI, 98.1%-99.3%), a negative predictive value of 98.5% (95% CI, 97.6%.6-99.1%), and a specificity of 13.3% (95% CI, 12.6%-14.1%) for TICI. The sensitivity and negative predictive value for TICI with clinically major injury were 99.7% (95% CI, 98.2%-100.0%) and 99.9% (95% CI, 99.4%-100.0%), respectively. We have validated the NEXUS Chest decision instrument, which may safely reduce the need for chest imaging in blunt trauma patients older than 14 years.


Neuroplasticity in adult human visual cortex.
Between 1-5:100 people worldwide have never experienced normotypic vision due to a condition called amblyopia, and about 1:4000 suffer from inherited retinal dystrophies that progressively lead to blindness. While a wide range of technologies and therapies are being developed to restore vision, a fundamental question still remains unanswered: would the adult visual brain retain a sufficient plastic potential to learn how to 'see' after a prolonged period of abnormal visual experience? In this review we summarize studies showing that the visual brain of sighted adults retains a type of developmental plasticity, called homeostatic plasticity, and this property has been recently exploited successfully for adult amblyopia recovery. Next, we discuss how the brain circuits reorganize when blindness occurs and when visual stimulation is partially restored by means of a 'bionic eye' in late blind adults with Retinitis Pigmentosa. The primary visual cortex in these patients slowly became activated by the artificial visual stimulation, indicating that sight restoration therapies can rely on a considerable degree of spared plasticity in adulthood.


Distracted by the Unthought - Suppression and Reappraisal of Mind Wandering under Stereotype Threat.
Previous research has found that subtle reminders of negative stereotypes about one's group can lead individuals to underperform on stereotype-relevant tests (e.g., women in math, ethnic minorities on intelligence tests). This so called stereotype threat effect can contribute to systematic group differences in performance that can obscure the true abilities of certain social groups and thereby sustain social inequalities. In the present study, we examined processes underlying stereotype threat effects on women's math performance, specifically focusing on the role of suppression of mind wandering (i.e., task-irrelevant thinking) in stereotype threat (ST) and no threat (NT) situations. Based on a process model of stereotype threat effects on performance, we hypothesized that women under stereotype threat spontaneously suppress mind wandering, and that this suppression impairs performance. An alternative regulation strategy that prevents suppression (i.e., reappraising task-irrelevant thoughts as normal) was predicted to prevent stereotype threat effects on performance. We manipulated stereotype threat (ST vs. NT) and cognitive regulation strategy (suppression, reappraisal, or no strategy) and measured women's performance on a math and a concentration task (N = 113). We expected three groups to perform relatively more poorly: Those in ST with either no strategy or suppression and those in NT with a suppression strategy. We tested the performance of these groups against the remaining three groups hypothesized to perform relatively better: those in NT with no strategy or reappraisal and those in ST with reappraisal. The results showed the expected pattern for participants' math performance, but not for concentration achievement. This pattern suggests that ineffective self-regulation by suppressing mind wandering can at least partly explain stereotype threat effects on performance, whereas a reappraisal strategy can prevent this impairment. We discuss implications for the understanding of processes underlying stereotype threat effects and the benefits of reappraising subjective experience under threat.


Viscerosomatic interaction induced by myocardial ischemia in conscious dogs.
Studies tested the hypothesis that myocardial ischemia induces increased paraspinal muscular tone localized to the T(2)-T(5) region that can be detected by palpatory means. This is consistent with theories of manual medicine suggesting that disturbances in visceral organ physiology can cause increases in skeletal muscle tone in specific muscle groups. Clinical studies in manual and traditional medicine suggest this phenomenon occurs during episodes of myocardial ischemia and may have diagnostic potential. However, there is little direct evidence of a cardiac-somatic mechanism to explain these findings. Chronically instrumented dogs [12 neurally intact and 3 following selective left ventricular (LV) sympathectomy] were examined before, during, and after myocardial ischemia. Circumflex blood flow (CBF), left ventricular contractile function, electromyographic (EMG) analysis, and blinded manual palpatory assessments (MPA) of tissue over the transverse spinal processes at segments T(2)-T(5) and T(11)-T(12) (control) were performed. Myocardial ischemia was associated with a decrease in myocardial contractile function and an increase in heart rate. MPA revealed increases in muscle tension and texture/firmness during ischemia in the T(2)-T(5) segments on the left, but not on the right or in control segments. EMG demonstrated increased amplitude for the T(4)-T(5) segments. After LV sympathectomy, MPA and EMG evidence of increased muscle tone were absent. In conclusion, myocardial ischemia is associated with significant increased paraspinal muscle tone localized to the left side T(4)-T(5) myotomes in neurally intact dogs. LV sympathectomy eliminates the somatic response, suggesting that sympathetic neural traffic between the heart and somatic musculature may function as the mechanism for the interaction.


Modelling the dynamics of growth, development and lipid storage in the marine copepod Calanus finmarchicus.
Mechanistic models are essential tools for interpreting and predicting the consequences of a changing environment and stressors such as pollution on the life histories of marine organisms. Here, we apply the simple and generic energy-budget model DEBkiss to the life history of the marine copepod Calanus finmarchicus. Model modifications were needed to accommodate the copepod life cycle, which deviates in several respects from most other animals (e.g., a sudden stop of growth after the final moult). We identified an acceleration of growth in the early copepodite stages, which could be linked to an increase in the specific feeding rate of the animals. Lipid storage, an essential element of C. finmarchicus biology, was successfully captured with the reproduction buffer of the DEBkiss model. The resulting model was fitted to a detailed data set from the literature and was able to explain growth, development and lipid storage from egg to adult, at different temperatures and food availabilities, within a single consistent framework. The parameterised model could subsequently be used to elucidate the energetic constraints on gonad maturation and reproduction. Interestingly, the overhead costs for egg production seem to be substantially higher than the default value applied in DEB-based studies. The current model provides a solid basis for applications in stress ecology, although our model analysis also identified several knowledge gaps. Specifically, further research is needed to cover the dynamics of diapause and gonad maturation, to explain the dependence of maximum body size on food and temperature, and to verify the predicted high costs for maturity maintenance.


Nuclear Dbf2-related protein kinases (NDRs) in isolated cardiac myocytes and the myocardium: activation by cellular stresses and by phosphoprotein serine-/threonine-phosphatase inhibitors.
The nuclear Dbf2-related protein kinases 1 and 2 (NDR1/2) are closely-related AGC family kinases that are strongly conserved through evolution. In mammals, they are activated inter alia by phosphorylation of an hydrophobic domain threonine-residue [NDR1(Thr-444)/NDR2(Thr-442)] by an extrinsic protein kinase followed by autophosphorylation of a catalytic domain serine-residue [NDR1(Ser-281)/NDR2(Ser-282)]. We examined NDR1/2 expression and regulation in primary cultures of neonatal rat cardiac myocytes and in perfused adult rat hearts. In myocytes, transcripts for NDR2, but not NDR1, were induced by the hypertrophic agonist, endothelin-1. NDR1(Thr-444) and NDR2(Thr-442) were rapidly phosphorylated (maximal in 15-30 min) in myocytes exposed to some phosphoprotein Ser-/Thr-phosphatase 1/2 inhibitors (calyculin A, okadaic acid) and, to a lesser extent, by hyperosmotic shock, low concentrations of H(2)O(2), or chelerythrine. In myocytes adenovirally-transduced to express FLAG-NDR2 (which exhibited a mainly-cytoplasmic localisation), the same agents increased FLAG-NDR2 activity as assessed by in vitro protein kinase assays, indicative of FLAG-NDR2(Ser-282/Thr-442) phosphorylation. Calyculin A-induced phosphorylation of NDR1(Thr-444)/NDR2(Thr-442) and activation of FLAG-NDR2 were inhibited by staurosporine, but not by other protein kinase inhibitors tested. In ex vivo rat hearts, NDR1(Thr-444)/NDR2(Thr-442) were phosphorylated in response to ischaemia-reperfusion or calyculin A. From a pathological viewpoint, we conclude that activities of NDR1 and NDR2 are responsive to cytotoxic stresses in heart preparations and this may represent a previously-unidentified response to myocardial ischaemia in vivo.


Hybrid approach to obtain high-quality BaMO3 perovskite nanocrystals.
A novel hybrid solvothermal approach for perovskite nanocrystal formation via accurate control of the hydrolytic process is reported. This new synthetic methodology sets a whole general route to successfully tune the sizes of high-quality BaMO3 (M = Ti4+, Zr4+, and Hf4+) perovskite nanocrystals. Purely cubic-phase nanocrystals (stable in alcohol media) were obtained using controlled water amounts, combining the well-known aqueous sol-gel process with the classic solvothermal method. Exhaustive optimizations revealed feasibility of a fast (1 hour) and reproducible synthesis with small variations in the crystal size or agglomeration parameters. The study also reveals water content as the pivotal factor to achieve this wide range of sizes through a controlled hydrolytic step. Finally, the study of the hydrolytic process made it possible to shed some light on mechanistic insights of this synthetic route.


Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin.
Recently, we have demonstrated that a spectrum of human adenocarcinoma cell lines express binding sites for interleukin 13 (IL-13). These cells are killed by a chimeric protein composed of human (h) IL-13 and a derivative of Pseudomonas exotoxin, PE38QQR (Debinski et al., J. Biol. Chem., 270: 16775-16780, 1995). The cell killing was hIL-13- and hIL-4-specific, indicating that a common binding site for the two cytokines is present in several solid tumor cell lines. Herein, we report that an array of established glioma cell lines is killed by very low concentrations of hIL-13-PE38QQR, often reaching <1 ng/ml (<20 pM). Glioma cells express up to 30,000 molecules of IL-13 receptor/cell which has intermediate affinity toward hIL-13. hIL-13-PE38QQR is more active (up to 3 logs difference in cytotoxic activities) than are the corresponding chimeric toxins containing hIL-4 or hIL-6. The cytotoxic action of hIL-13-PE38QQR is blocked by an excess of hIL-13 on all cell lines studied, and it is not neutralized by hIL-4 on some of these cells. Our results show that human brain cancers richly express receptors for IL-13. Furthermore, the interaction detected previously between receptors for IL-13 and IL-4 on solid tumors cell lines is of a qualitatively different character in U-251 MG and U-373 MG glioma cells. The receptor for IL-13 may represent a new marker of brain cancers and an attractive target for anticancer therapies.


Lipopolysaccharide-activated IL-10-secreting dendritic cells suppress experimental autoimmune uveoretinitis by MHCII-dependent activation of CD62L-expressing regulatory T cells.
Dendritic cells (DC) are key regulators of immune responses. Mature DC are traditionally considered to be immunogenic, although there is accumulating evidence that they can also be tolerogenic and induce Ag-specific regulatory T cells (Tregs). However, the mechanism of this Treg induction and the site of Treg action in vivo are yet to be defined. In this study, using the experimental model of interphotoreceptor retinoid-binding protein peptide (1-20)-induced experimental autoimmune uveoretinitis, we show that s.c. inoculation of IRBP-peptide-pulsed IL-10-producing LPS-activated mature DC (IL-10-DC) at one site (the cervical region) suppresses autoimmunity induced at a separate site (the inguinal region). Our data show that s.c. IL-10-DC correlates with an increase in the number of CD4(+)CD25(+)Foxp3(+) Tregs at the DC-draining lymph nodes (DC-dLN). However, although MHCII(-/-) IL-10-DC also induces Treg expansion at this DC-dLN, they failed to suppress experimental autoimmune uveoretinitis. Furthermore, unlike wild-type IL-10-DC, MHCII(-/-) IL-10-DC did not correlate with an increase in the percentage of Tregs expressing CD62L at the DC-dLN, nor did they associate with an increase in Treg number at a distal site. Similar effects were also observed after s.c. hen egg lysozyme-pulsed IL-10-DC, which produced a strong reduction in the number and activation of proliferating Ag-specific CD4(+) 3A9 T effector cells. We therefore propose that IL-10-DC require MHCII-dependent Ag presentation, and hence TCR ligation, to promote CD62L-mediated trafficking of Tregs to the site of T effector cell priming, where they suppress autoimmunity.


Organizational and External Factors Associated with Video Telehealth Use in the Veterans Health Administration Before and During the COVID-19 Pandemic.
Objectives: To identify organizational and external factors associated with medical center video telehealth uptake (i.e., the proportion of patients using telemedicine) before and early in the coronavirus disease 2019 (COVID-19) pandemic. Materials and Methods: We conducted a retrospective, observational study using cross-sectional data for all 139 U.S. Veterans Affairs Medical Centers (VAMCs). We used logistic regression analyses to identify factors that predicted whether a VAMC was in the top quartile of VA Video Connect (VVC) telehealth uptake for primary care and mental health care. Results: All 139 VAMCs increased their VVC uptake at least 2-fold early in the pandemic, with most increasing uptake between 5- and 10-fold. Pre-COVID-19, higher VVC uptake in primary care was weakly and positively associated with having more high-risk patients, negatively associated with having more long-distance patients, and positively associated with the prior fiscal year's VVC uptake. During COVID-19, the positive association with high-risk patients and the negative association with long-distance patients strengthened, while weaker broadband coverage was negatively associated with VVC uptake. For mental health care, having more long-distance patients was positively associated with higher VVC uptake pre-COVID-19, but this relationship reversed during COVID-19. Discussion: Despite the marked increase in VVC uptake early in the COVID-19 pandemic, significant VAMC-level variation indicates that VVC adoption was more difficult for some medical centers, particularly those with poorer broadband coverage and less prior VVC experience. Conclusions and Relevance: These findings highlight opportunities for medical centers, VA Central Office, and other federal entities to ensure equitable access to video telehealth.


Sex and geographic patterns of human herpesvirus 8 infection in a nationally representative population‐based sample in Uganda.
Human herpesvirus 8 (HHV8), the infectious cause of Kaposi sarcoma, varies dramatically across Africa, suggesting that cofactors correlated with large-area geographic or environmental characteristics may influence risk of infection. Variation in HHV8 seropositivity across small-area regions within countries in Africa is unknown. We investigated this issue in Uganda, where Kaposi sarcoma distribution is uneven and well described. Archival samples from individuals aged 15-59 years randomly selected from a nationally representative 2004-2005 human immunodeficiency virus-AIDS serobehavioral survey were tested for HHV8 seropositivity with use of enzyme immunoassays based on synthetic peptides from the K8.1 and orf65 viral genes. Adjusted odds ratios and 95% confidence intervals (CIs) of association of HHV8 seropositivity with demographic risk factors were estimated. Among 2681 individuals tested, HHV8 seropositivity was 55.4%. HHV8 seropositivity was lower in female than in male persons (adjusted odds ratio, 0.82 [95% CI, 0.69-0.97]) and increased 2.2% (95% CI, 1.0%-3.6%) in female persons and 1.2% (95% CI, 1.0%-2.3%) in male persons per year of age. HHV8 seropositivity was inversely associated with education ( P = .01, for trend) and was elevated in the West Nile region, compared with the Central region (adjusted odds ratio, 1.49 [95% CI, 1.02-2.18]) but not with other regions. Our findings suggest that HHV8 seropositivity in Uganda may be influenced by cofactors correlated with small-area geography, age, sex, and education.


Effects of low-frequency stimulation of the superior colliculus on spontaneous and visually guided saccades.
1. The first experiment of this study determined the effects of low-frequency stimulation of the monkey superior colliculus on spontaneous saccades in the dark. Stimulation trains, subthreshold for eliciting short-latency fixed-vector saccades, were highly effective at biasing the metrics (direction and amplitude) of spontaneous movements. During low-frequency stimulation, the distribution of saccade metrics was biased toward the direction and amplitude of movements induced by suprathreshold stimulation of the same collicular location. 2. Low-frequency stimulation biased the distribution of saccade metrics but did not initiate movements. The distribution of intervals between stimulation onset and the onset of the next saccade did not differ significantly from the distribution of intervals between an arbitrary point in time and the onset of the next saccade under unstimulated conditions. 3. Results of our second experiment indicate that low-frequency stimulation also influenced the metrics of visually guided saccades. The magnitude of the stimulation-induced bias increased as stimulation current or frequency was increased. 4. The time course of these effects was analyzed by terminating stimulation immediately before, during, or after visually guided saccades. Stimulation trains terminated at the onset of a movement were as effective as stimulation trains that continued throughout the movement. No effects were observed if stimulation ended 40-60 ms before the movement began. 5. These results show that low-frequency collicular stimulation can influence the direction and amplitude of spontaneous or visually guided saccades without initiating a movement. These data are compatible with the hypothesis that the collicular activity responsible for specifying the horizontal and vertical amplitude of a saccade differs from the type of collicular activity that initiates a saccade.


Comparative efficacy and safety of anticoagulant strategies for acute coronary syndromes. Comprehensive network meta-analysis of 42 randomised trials involving 117,353 patients.
International guidelines differ in strengths of recommendation for anticoagulation strategies in acute coronary syndromes (ACS). We performed a comprehensive network meta-analysis (NMA) of randomised controlled trials (RCTs) to investigate the comparative efficacy and safety of parenteral anticoagulants in ACS. MEDLINE, Cochrane, EMBASE, Google Scholar, major cardiology websites, and abstracts/presentations were searched. Six treatments were identified: 1) unfractionated heparin (UFH) + glycoprotein IIb/IIIa inhibitor (GPI) [UFH+GPI], 2) UFH±GPI, 3) bivalirudin, 4) low-molecular-weight heparins (LMWHs), 5) otamixaban, and 6) fondaparinux. Prespecified outcomes (death, myocardial infarction [MI], revascularisation, major bleeding [MB], minor bleeding, and stent thrombosis [ST]) were evaluated up to 30 days. Forty-two RCTs involving 117,353 patients were included. No significant differences in mortality rates were found among strategies. Compared to UFH+GPI, bivalirudin reduced the odds of MB but increased the odds of ST and MI. LMWHs vs bivalirudin reduced MI risk at the price of MB excess. UFH±GPI significantly increased the odds of MI vs LMWHs, of ST vs UFH+GPI, and of MB vs bivalirudin. Reduced ST risk with otamixaban vs UFH±GPI and vs bivalirudin was offset by a marked 2.5- to four-fold MB excess. Fondaparinux showed an intermediate profile. Results for ST-segment elevation MI were consistent with the overall findings. Early anticoagulant strategies for ACS differ in efficacy and safety, with UFH+GPI and LMWHs reducing ischaemic but increasing bleeding risk, and bivalirudin reducing MB but increases MI and ST. The findings support individualised therapy based on patients' bleeding and ischaemic risks.


Principal components of functional connectivity: a new approach to study dynamic brain connectivity during rest.
Functional connectivity (FC) as measured by correlation between fMRI BOLD time courses of distinct brain regions has revealed meaningful organization of spontaneous fluctuations in the resting brain. However, an increasing amount of evidence points to non-stationarity of FC; i.e., FC dynamically changes over time reflecting additional and rich information about brain organization, but representing new challenges for analysis and interpretation. Here, we propose a data-driven approach based on principal component analysis (PCA) to reveal hidden patterns of coherent FC dynamics across multiple subjects. We demonstrate the feasibility and relevance of this new approach by examining the differences in dynamic FC between 13 healthy control subjects and 15 minimally disabled relapse-remitting multiple sclerosis patients. We estimated whole-brain dynamic FC of regionally-averaged BOLD activity using sliding time windows. We then used PCA to identify FC patterns, termed "eigenconnectivities", that reflect meaningful patterns in FC fluctuations. We then assessed the contributions of these patterns to the dynamic FC at any given time point and identified a network of connections centered on the default-mode network with altered contribution in patients. Our results complement traditional stationary analyses, and reveal novel insights into brain connectivity dynamics and their modulation in a neurodegenerative disease.


From crossbreeding to biotechnology-facilitated improvement of banana and plantain.
The annual harvest of banana and plantain (Musa spp.) is approximately 145 million tons worldwide. About 85% of this global production comes from small plots and kitchen or backyard gardens from the developing world, and only 15% goes to the export trade. Musa acuminata and Musa balbisiana are the ancestors of several hundreds of parthenocarpic Musa diploid and polyploid cultivars, which show multiple origins through inter- and intra-specific hybridizations from these two wild diploid species. Generating hybrids combining host plant resistance to pathogens and pests, short growth cycles and height, high fruit yield, parthenocarpy, and desired quality from the cultivars remains a challenge for Musa crossbreeding, which started about one century ago in Trinidad. The success of Musa crossbreeding depends on the production of true hybrid seeds in a crop known for its high levels of female sterility, particularly among polyploid cultivars. All banana export cultivars grown today are, however, selections from somatic mutants of the group Cavendish and have a very narrow genetic base, while smallholders in sub-Saharan Africa, tropical Asia and Latin America use some bred-hybrids (mostly cooking types). Musa improvement goals need to shift to address emerging threats because of the changing climate. Innovative cell and molecular biology tools have the potential to enhance the pace and efficiency of genetic improvement in Musa. Micro-propagation has been successful for high throughput of clean planting materials while in vitro seed germination assists in obtaining seedlings after inter-specific and across ploidy hybridization. Flow cytometry protocols are used for checking ploidy among genebank accessions and breeding materials. DNA markers, the genetic maps based on them, and the recent sequencing of the banana genome offer means for gaining more insights in the genetics of the crops and to identifying genes that could lead to accelerating Musa betterment. Likewise, DNA fingerprinting has been useful to characterize Musa diversity. Genetic engineering provides a complementary tool to Musa breeders who can introduce today transgenes that may confer resistance to bacteria, fungi and nematodes, or enhance pro-vitamin A fruit content. In spite of recent advances, the genetic improvement of Musa depends on a few crossbreeding programs (based in Brazil, Cameroon, Côte d'Ivoire, Guadeloupe, Honduras, India, Nigeria, Tanzania and Uganda) or a handful of genetic engineering endeavors (Australia, Belgium, India, Kenya, Malaysia and Uganda). Development investors (namely international aid and philanthropy) should therefore increase their funding to genetically enhance this crop that ranks among the 10-top staple foods of the developing world.


Green Coffee Extract Improves Cardiometabolic Parameters and Modulates Gut Microbiota in High-Fat-Diet-Fed ApoE-/- Mice.
Chlorogenic acids (CGA) are the most abundant phenolic compounds in green coffee beans and in the human diet and have been suggested to mitigate several cardiometabolic risk factors. Here, we aimed to evaluate the effect of a water-based standardized green coffee extract (GCE) on cardiometabolic parameters in ApoE-/- mice and to explore the potential underlying mechanisms. Mice were fed an atherogenic diet without (vehicle) or with GCE by gavage (equivalent to 220 mg/kg of CGA) for 14 weeks. We assessed several metabolic, pathological, and inflammatory parameters and inferred gut microbiota composition, diversity, and functional potential. Although GCE did not reduce atherosclerotic lesion progression or plasma lipid levels, it induced important favorable changes. Specifically, improved metabolic parameters, including fasting glucose, insulin resistance, serum leptin, urinary catecholamines, and liver triglycerides, were observed. These changes were accompanied by reduced weight gain, decreased adiposity, lower inflammatory infiltrate in adipose tissue, and protection against liver damage. Interestingly, GCE also modulated hepatic IL-6 and total serum IgM and induced shifts in gut microbiota. Altogether, our results reveal the cooccurrence of these beneficial cardiometabolic effects in response to GCE in the same experimental model and suggest potential mediators and pathways involved.


Group V secretory phospholipase A2 translocates to the phagosome after zymosan stimulation of mouse peritoneal macrophages and regulates phagocytosis.
We have previously reported that group V secretory phospholipase A2 (sPLA2) amplifies the action of cytosolic phospholipase A2(cPLA2) alpha in regulating eicosanoid biosynthesis by mouse peritoneal macrophages stimulated with zymosan (Satake, Y., Diaz, B. L., Balestrieri, B., Lam, B. K., Kanaoka, Y., Grusby, M. J., and Arm, J. P. (2004) J. Biol. Chem. 279, 16488-16494). To further understand the role of group V sPLA2, we studied its localization in resting mouse peritoneal macrophages before and after stimulation with zymosan and the effect of deletion of the gene encoding group V sPLA2 on phagocytosis of zymosan. We report that group V sPLA2 is present in the Golgi apparatus and recycling endosome in the juxtanuclear region of resting peritoneal macrophages. Upon ingestion of zymosan by mouse peritoneal macrophages, group V sPLA2 is recruited to the phagosome. There it co-localizes with cPLA2alpha, 5-lipoxygenase, 5-lipoxygenase-activating protein, and leukotriene C4 synthase. Using immunostaining for the cysteinyl leukotrienes in carbodiimide-fixed cells, we show, for the first time, that the phagosome is a site of cysteinyl leukotriene formation. Furthermore, peritoneal macrophages from group V sPLA2-null mice demonstrated a >50% attenuation in phagocytosis of zymosan particles, which was restored by adenoviral expression of group V sPLA2 but IIA not group sPLA2. These data demonstrate that group V sPLA2 contributes to the innate immune response both through regulation of eicosanoid generation in response to a phagocytic stimulus and also as a component of the phagocytic machinery.


Computational models of the heart and their use in assessing the actions of drugs.
Models of cardiac cells are sufficiently well developed to answer questions concerning the actions of drugs on repolarization and the initiation of arrhythmias. These models can be used to characterize drug-receptor action profiles that would be expected to avoid arrhythmia and so help to identify drugs that may be safer. Several examples of such action profiles are presented here, including a recently-developed blocker of persistent sodium current, ranolazine. The models have also been incorporated into tissue and organ models that enable arrhythmia to be modelled also at these levels. Work at these levels can reproduce both re-entrant arrhythmia and fibrillation.


Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease.
Precise stratification of cardiovascular risk in patients with coronary heart disease (CHD) is needed to inform treatment decisions. To derive and validate a score to predict risk of cardiovascular outcomes among patients with CHD, using large-scale analysis of circulating proteins. Prospective cohort study of participants with stable CHD. For the derivation cohort (Heart and Soul study), outpatients from San Francisco were enrolled from 2000 through 2002 and followed up through November 2011 (≤11.1 years). For the validation cohort (HUNT3, a Norwegian population-based study), participants were enrolled from 2006 through 2008 and followed up through April 2012 (5.6 years). Using modified aptamers, 1130 proteins were measured in plasma samples. A 9-protein risk score was derived and validated for 4-year probability of myocardial infarction, stroke, heart failure, and all-cause death. Tests, including the C statistic, were used to assess performance of the 9-protein risk score, which was compared with the Framingham secondary event model, refit to the cohorts in this study. Within-person change in the 9-protein risk score was evaluated in the Heart and Soul study from paired samples collected 4.8 years apart. From the derivation cohort, 938 samples were analyzed, participants' median age at enrollment was 67.0 years, and 82% were men. From the validation cohort, 971 samples were analyzed, participants' median age at enrollment was 70.2 years, and 72% were men. In the derivation cohort, C statistics were 0.66 for refit Framingham, 0.74 for 9-protein, and 0.75 for refit Framingham plus 9-protein models. In the validation cohort, C statistics were 0.64 for refit Framingham, 0.70 for 9-protein, and 0.71 for refit Framingham plus 9-protein models. Adding the 9-protein risk score to the refit Framingham model increased the C statistic by 0.09 (95% CI, 0.06-0.12) in the derivation cohort, and in the validation cohort, the C statistic was increased by 0.05 (95% CI, 0.02-0.09). Compared with the refit Framingham model, the integrated discrimination index for the 9-protein model was 0.12 (95% CI, 0.08-0.16) in the derivation cohort and 0.08 (95% CI, 0.05-0.10) in the validation cohort. In analysis of paired samples among 139 participants with cardiovascular events after the second sample, absolute within-person annualized risk increased more for the 9-protein model (median, 1.86% [95% CI, 1.15%-2.54%]) than for the refit Framingham model (median, 1.00% [95% CI, 0.87%-1.19%]) (P = .002), while among 375 participants without cardiovascular events, both scores changed less and similarly (P = .30). Among patients with stable CHD, a risk score based on 9 proteins performed better than the refit Framingham secondary event risk score in predicting cardiovascular events, but still provided only modest discriminative accuracy. Further research is needed to assess whether the score is more accurate in a lower-risk population.


Antigiardial effect of Anethum graveolens aqueous extract in children.
Giardia lamblia is the most common intestinal parasite of humans identified worldwide. In spite of metronidazole (Met) is the most commonly used drug for the treatment of giardiasis in humans, low patient compliance and side-effects, especially in children encourage efforts to look for new and safe agent; many plants used in folk medicine thought to have antigiardial effect, Anethum graveolens (AG) (dill) is an annual herb cultivated in Iraq used both as a medicinal agent and as food spice. The aim of this study was to investigate the effect of aqueous extract (AE) of AG leave in the treatment of giardiasis, compared with that of standard drug Met. A prospective randomized clinical trial was carried out on 28 pediatric patients of both sexes with age of <1 year ranging from 3 to 11 months, who attend to outpatient private clinic in Baghdad for a period of 6 months from June 2013 to December 2013,Patients participate in this study were allocated into two groups Group A composed of 14 patients treated with Met 15 mg/kg 3 times a day for 5 days. Group B composed of 14 patients treated with AGAE 1 ml 3 times a day for 5 days. Stool samples were collected at 0 time before administration of treatment, after 5 days and after 14 days from starting the treatments to check the efficacy of treatment. Administration of AGAE results in a significant decrease in incidence of G. lamblia after 5 days of treatment indicating the efficacy of AGAE in the treatment of giardiasis a result that is comparable to that of Met. This study showed that pediatric patients with giardiasis may benefit from 5 days treatment with AGAE administered as 1 ml 3 times daily, the improvement in the symptom with this herbal agent was comparable to the standard pharmacological agent Met; results showed that AG is safe and tolerable over treatment course.


The photovoice method: researching the experiences of Aboriginal health workers through photographs.
This paper discusses the methodological framework and perspectives that were used in a larger study aiming at examining the experience of working life among female Aboriginal health care workers. Currently, the voice of Aboriginal women who work in the Australian health system has not received much attention. In comparison to other occupations and backgrounds, there is virtually no literature on Aboriginal woman health care workers despite 15% of health care and social service industry employees in Australia being Aboriginal. In this study, we selected female participants because of the fact that of these 15% of health workers in the Victorian health system, 76% of them are women. This paper outlines some of the barriers in researching Indigenous communities. These barriers were overcome in this study by framing the research in feminist theory, decolonising theory, empowerment and by employing the photovoice method. The photovoice method was used because it is relatively unobtrusive and has the capacity to be empowering. All data was extrapolated from the participants' own narratives that were prompted by the photographs they had taken. The data produced were rich descriptions and narratives that were oral as well as visual. Finally, the article discusses the experience of using the photovoice method from the researcher and participants' perspective.


Phenotypic plasticity and population viability: the importance of environmental predictability.
Phenotypic plasticity plays a key role in modulating how environmental variation influences population dynamics, but we have only rudimentary understanding of how plasticity interacts with the magnitude and predictability of environmental variation to affect population dynamics and persistence. We developed a stochastic individual-based model, in which phenotypes could respond to a temporally fluctuating environmental cue and fitness depended on the match between the phenotype and a randomly fluctuating trait optimum, to assess the absolute fitness and population dynamic consequences of plasticity under different levels of environmental stochasticity and cue reliability. When cue and optimum were tightly correlated, plasticity buffered absolute fitness from environmental variability, and population size remained high and relatively invariant. In contrast, when this correlation weakened and environmental variability was high, strong plasticity reduced population size, and populations with excessively strong plasticity had substantially greater extinction probability. Given that environments might become more variable and unpredictable in the future owing to anthropogenic influences, reaction norms that evolved under historic selective regimes could imperil populations in novel or changing environmental contexts. We suggest that demographic models (e.g. population viability analyses) would benefit from a more explicit consideration of how phenotypic plasticity influences population responses to environmental change.


Human versus porcine insulin in patients with insulin-dependent diabetes mellitus: differences in sleep and the sleep EEG during near-normoglycemia.
To investigate whether porcine insulin (PI) and human insulin (HI) have different effects on brain functions outside of hypoglycemia, sleep and the sleep EEG were recorded in eight insulin-dependent diabetes mellitus (IDDM) patients in three separate sessions of 2 consecutive nights. Near-normoglycemia was confirmed by measurements of capillary blood glucose before and after sleep and at 0145 hours. The treatment effect (PI compared to HI) consisted of a change in the NREM sleep EEG in the spindle frequency range. Spectral power density in the 14-Hz bin was reduced upon transfer from PI (session 1) to HI (session 2) in all subjects, and increased upon reversal to PI (session 3) in all but one subject. There were no significant treatment effects on any other sleep EEG variable or on sleep stages. The subjects rated their sleep as more sound and their state in the morning as more relaxed during PI treatment. They were, however, not blinded to the type of insulin they were using. Porcine insulin and human insulin may exert differential effects on spindle-generating mechanisms in the thalamocortical system. The results indicate that human insulin may affect brain functions differently compared to animal insulin under near-normoglycemic conditions.


Traffic jams and intermittent flows in microfluidic networks.
We investigate both experimentally and theoretically the traffic of particles flowing in microfluidic obstacle networks. We show that the traffic dynamics is a nonlinear process: the particle current does not scale with the particle density even in the dilute limit where no particle collision occurs. We demonstrate that this nonlinear behavior stems from long-range hydrodynamic interactions. Importantly, we also establish that there exists a maximal current above which no stationary particle flow can be sustained. For higher current values, intermittent traffic jams form, thereby inducing the ejection of the particles from the initial path and the subsequent invasion of the network. Eventually, we put our findings in the broader context of the transport processes of driven particles in low dimension.


The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema.
Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction. To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury. Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage. These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).


The impact of certain underlying comorbidities on the risk of developing hospitalised pneumonia in England.
UK specific data on the risk of developing hospitalised CAP for patients with underlying comorbidities is lacking. This study compared the likelihood of hospitalised all-cause community acquired pneumonia (CAP) in patients with certain high-risk comorbidities and a comparator group with no known risk factors for pneumococcal disease. This retrospective cohort study interrogated data in the Hospital Episodes Statistics (HES) dataset between financial years 2012/13 and 2016/17. In total 3,078,623 patients in England (aged ≥18 years) were linked to their hospitalisation records. This included 2,950,910 individuals with defined risk groups and a comparator group of 127,713 people who had undergone tooth extraction with none of the risk group diagnoses. Risk groups studied were chronic respiratory disease (CRD), chronic heart disease (CHD), chronic liver disease (CLD), chronic kidney disease (CKD), diabetes (DM) and post bone marrow transplant (BMT). The patients were tracked forward from year 0 (2012/13) to Year 3 (2016/17) and all diagnoses of hospitalised CAP were recorded. A Logistic regression model compared odds of developing hospitalised CAP for patients in risk groups compared to healthy controls. The model was simultaneously adjusted for age, sex, strategic heath authority (SHA), index of multiple deprivation (IMD), ethnicity, and comorbidity. To account for differing comorbidity profiles between populations the Charlson Comorbidity Index (CCI) was applied. The model estimated odds ratios (OR) with 95% confidence intervals of developing hospitalised CAP for each specified clinical risk group. Patients within all the risk groups studied were more likely to develop hospitalised CAP than patients in the comparator group. The odds ratios varied between underlying conditions ranging from 1.18 (95% CI 1.13, 1.23) for those with DM to 5.48 (95% CI 5.28, 5.70) for those with CRD. Individuals with any of 6 pre-defined underlying comorbidities are at significantly increased risk of developing hospitalised CAP compared to those with no underlying comorbid condition. Since the likelihood varies by risk group it should be possible to target patients with each of these underlying comorbidities with the most appropriate preventative measures, including immunisations.


Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.
To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise. Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments. No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls. At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.


Long-Term Effects of Stressors on Relationship Well-Being and Parenting Among Rural African American Women.
This investigation of the effects of stressful life events on rural African American women's relationship well-being, psychological functioning, and parenting included 361 married or long-term cohabiting women. Associations among stressful events, socioeconomic status, perceived racial discrimination, coping strategies, psychological functioning, relationship well-being, and parenting were tested. Stressful events were related directly to diminished relationship well-being and heightened psychological distress and indirectly to compromised parenting. The results can inform research and intervention with African American women.


Nonlinear optical security system based on a joint transform correlator in the Fresnel domain.
A new optical security system for image encryption based on a nonlinear joint transform correlator (JTC) in the Fresnel domain (FrD) is proposed. The proposal of the encryption process is a lensless optical system that produces a real encrypted image and is a simplified version of some previous JTC-based encryption systems. We use a random complex mask as the key in the nonlinear system for the purpose of increasing the security of the encrypted image. In order to retrieve the primary image in the decryption process, a nonlinear operation has to be introduced in the encrypted function. The optical decryption process is implemented through the Fresnel transform and the fractional Fourier transform. The security system proposed in this paper preserves the shift-invariance property of the JTC-based encryption system in the Fourier domain, with respect to the lateral displacement of the key random mask in the decryption process. This system shows an improved resistance to chosen-plaintext and known-plaintext attacks, as they have been proposed in the cryptanalysis of the JTC encrypting system. Numerical simulations show the validity of this new optical security system.


High-fidelity all-fiber amplification of a gain-switched laser diode.
We demonstrate a multistage erbium fiber amplifier seeded by a gain-switched laser diode operating at a wavelength of 1550 nm and a repetition rate of 1 MHz. The pulse energy is 0.5 μJ, and the pulse duration is 40 ps, resulting in a peak power of 11.4 kW. The three-stage all-fiber amplifier system is designed to avoid any spectral distortions induced by gain saturation or nonlinear effects and high levels of amplified spontaneous emission. The output pulses are close to transform limited with a Gaussian pulse envelope.


Impact of an Adherence Program on the Health and Outlook of HIV-Infected Patients Failing Antiretroviral Therapy.
We prospectively studied the impact of an adherence counselor on the outcome of patients failing antiretroviral therapy because of nonadherence. Forty-six patients, identified as chronically nonadherent were enrolled. Individual attention was provided using the information, motivation and behavioral methodology. HIV RNA (viral load, in copies/mL), CD4 count (in cells/mm(3)), and body weight before and after the adherence counselor were measured. Qualitative outcome and patient satisfaction were assessed by deidentified third-party interviews. Over half completed at least 1 year; only 8 patients were lost to follow-up. Mean CD4 counts increased significantly (P < .05) for completers at 6 and 12 months. Viral loads decreased between baseline and 6 months. Most clients reported subjective benefit from working with the adherence counselor. Although few clients showed complete virologic suppression, the value of an adherence counselor was validated. Longer term adherence programs should be evaluated.


Roles of myosin Va and Rab3D in membrane remodeling of immature secretory granules.
Neuroendocrine secretory granules (SGs) are formed at the trans-Golgi network (TGN) as immature intermediates. In PC12 cells, these immature SGs (ISGs) are transported within seconds to the cell cortex, where they move along actin filaments and complete maturation. This maturation process comprises acidification-dependent processing of cargo proteins, condensation of the SG matrix, and removal of membrane and proteins not destined to mature SGs (MSGs) into ISG-derived vesicles (IDVs). We investigated the roles of myosin Va and Rab3 isoforms in the maturation of ISGs in neuroendocrine PC12 cells. The expression of dominant-negative mutants of myosin Va or Rab3D blocked the removal of the endoprotease furin from ISGs. Furthermore, expression of mutant Rab3D, but not of mutant myosin Va, impaired cargo processing of SGs. In conclusion, our data suggest an implication of myosin Va and Rab3D in the maturation of SGs where they participate in overlapping but not identical tasks.


Pfiesteria in Maryland: preliminary epidemiologic findings.
In the fall of 1996, fish kills in Maryland rivers were attributed to the dinoflagellate, Pfiesteria piscicida. After a group of researchers established a potential link between exposure to Pfiesteria and an illness causing memory problems, state health authorities closed a portion of the Pocomoke River. To determine the extent of illness, the range of symptoms, potential risk factors for disease, and to provide information to concerned citizens, a toll-free hotline was created. All symptomatic persons who called the toll-free number were administered a standardized questionnaire. Persons who had been exposed to Pfiesteria or Pfiesteria-laden waters were more likely to have respiratory, neurologic, dermatologic, and gastrointestinal problems than those persons without exposure. Among the persons calling the hotline, many had extensive neuropsychologic testing. Of the neuropsychologic test battery, low scores on the Rey Auditory Verbal Learning Test (RAVLT), a standardized measure of learning and memory, best characterized illness related to Pfiesteria exposure. Patients with low RAVLT scores were more likely to have neurologic symptoms and skin lesions than control subjects. Low RAVLT scores were associated with fishing (OR, 9.00, 95% CI, 106, 409.87), catching fish with lesions (OR, 6.17, 95% CI 1.27, 32.10), and handling fish with lesions (OR, 5.34, 95% CI, 1.05, 29.92), but not with consumption of seafood. While preliminary, these results do suggest that some risk factors for Pfiesteria-related illness may be easy to modify and used to prevent unnecessary human exposure.


Visceral adipose tissue volume is associated with premature atherosclerosis in early type 2 diabetes mellitus independent of traditional risk factors.
Type 2 diabetes mellitus (T2DM) is commonly associated with abdominal obesity, predominantly with high visceral adipose tissue (VAT), and is accompanied by premature atherosclerosis. However, the association between VAT and subcutaneous adipose tissue (SAT) with premature atherosclerosis and (i.e. arterial) inflammation is not completely understood. To provide more insight into this association, we investigated the association between arterial 18F-fluordeoxyglucose (FDG) positron emission tomography (PET) uptake, as a measure of arterial inflammation, and metabolic syndrome (MetS) markers in early T2DM patients. Forty-four patients with early T2DM, without glucose lowering medication, were studied (median age 63 [IQR 54-66] years, median BMI 30.4 [IQR 27.5-35.8]). Arterial inflammation was quantified using glucose corrected maximum standardized uptake value (SUVmax) FDG of the aorta, carotid, iliac, and femoral arteries, and corrected for background activity (blood pool) as target-to-background ratio (meanTBR). VAT and SAT volumes (cm3) were automatically segmented using computed tomography (CT) between levels L1-L5. Non-alcoholic fatty liver disease (NAFLD) was assessed by liver function test and CT. VAT volume, but not SAT volume, correlated with meanTBR (r = 0.325, p = 0.031). Linear regression models showed a significant association, even after sequential adjustment for potentially influencing MetS components. Interaction term VAT volume * sex and additional components including HbA1c, insulin resistance, NAFLD, adiponectin, leptin, and C- reactive protein (CRP) did not change the independent association between VAT volume and meanTBR. CT-assessed VAT volume is positively associated with FDG-PET assessed arterial inflammation, independently of factors thought to potentially mediate these effects. These findings suggest that VAT in contrast to SAT is linked to early atherosclerotic changes in T2DM patients.


Diagnostic compared with abstinence outcomes of day treatment and contingency management among cocaine-dependent homeless persons.
Substance use disorder diagnoses were used as a treatment outcome measure in a randomized comparison of day treatment (DT) and day treatment plus contingency management (DT+) among homeless persons with primarily crack/cocaine disorders. Participants (N = 127, DT+ = 69, DT = 58, 73.2% male, 82.7% African American) were assessed at baseline and 6-month treatment completion. Binary positive and negative diagnostic outcomes for cocaine, marijuana, and alcohol were compared by treatment group. DT+ was 2.1 times more likely to have a positive treatment outcome than DT. Concordance between diagnostic change and point and continuous abstinence outcomes were found. The use of diagnostic change can be a practical addition to drug toxicology and self-report treatment outcome measures for research and practice.


Complex and segmental uniparental disomy updated.
To review all cases with segmental and/or complex uniparental disomy (UPD) and to discuss the impact of these cases on medical genetics. Searching for published reports in PubMed and in the abstract books of the annual meetings of the American Society of Human Genetics and the European Society of Human Genetics up to March 2008. In total, 26 cases with segmental UPD and a normal karyotype, 38 cases with UPD of a whole chromosome and a simple reciprocal or non-homologous Robertsonian translocation, four cases each with two isochromosomes and UPD of the short arm isochromosome and opposite UPD of the long arm isochromosome, three cases with UPD and an isochromosome of the short arm and the long arm of a metacentric or a submetacentric chromosome, one case with maternal UPD and an isochromosome 8 associated with a homozygous deletion (8)(p23.3pter), 42 cases with UPD and an isochromosome of the long arm of an acrocentric chromosome, 33 cases with UPD and a supernumerary marker or ring chromosome, 17 cases with UPD of a whole or parts of a chromosome and a complex karyotype, 13 cases with most likely mosaicism for genome wide paternal UPD, and three cases with most likely mosaicism for genome wide maternal UPD were found. This update shows that, in particular, the number of reported cases with segmental UPD or UPD associated with a marker chromosome clearly increased within the last few years, and that the investigation of both parents in cases with homozygosity of an autosomal recessively inherited mutation in some cases might help improve genetic counselling, resulting in a reduced recurrence risk in the case of UPD. Moreover, cases with segmental or complex UPD show that meiosis and early postzygotic mitoses seem to be more complex events than previously thought. For the formation of all kinds of segmental or complex UPD or genome wide UPD mosaicism, always a fortunate co-occurrence of meiotic or mitotic recombination, abnormal segregation, and subsequent correction are necessary. No case of recurrence has been reported until now. Therefore, in subsequent pregnancies invasive prenatal diagnosis is not necessarily indicated.


Individual characteristics and relocation factors affecting adjustment among relocated American and Egyptian older adults.
Worldwide, the population of elders is increasing significantly. Relocation can be a positive or a negative experience, depending on many factors, including culture. The purpose of this study is to compare individual characteristics (age, gender, marital status, education, perceived health status, activities of daily living), relocation factors (movement preparation, time passed since relocation, closeness of prior home to the present, and whether relocation was from home or another facility), and adjustment in relocated American and Egyptian elders. This secondary analysis study merged data from two cross-sectional descriptive studies of a 104 elders relocated to retirement communities in Northeast Ohio and 94 elders relocated to retirement communities in Alexandria, Egypt. Our findings indicated that American elders have greater independence in daily activities (t (161.23) = -3.03, p = .003); better perceived health (χ(2)[3, N = 198] = 53.21, p < .001), better education (χ(2)[1, N = 198] = 47.28, p < .001), better preparation before the move (χ(2)[1, N = 198] = 40.58, p < .001), and better relocation adjustment (t (196) = 9.42, p < .001) than relocated Egyptian elders. Our results indicate that culture should be taken into account when caring for older adults who relocate to retirement communities. Additionally, interventions, such as counseling, and preparation before relocation are needed to help elders adjust to relocation.


Elevated levels of circulating IL-7 and IL-15 in patients with early stage prostate cancer.
Chronic inflammation has been suggested to favour prostate cancer (PCA) development. Interleukins (IL) represent essential inflammation mediators. IL-2, IL-7, IL-15 and IL-21, sharing a common receptor γ chain (c-γ), control T lymphocyte homeostasis and proliferation and play major roles in regulating cancer-immune system interactions. We evaluated local IL-2, IL-7, IL-15 and IL-21 gene expression in prostate tissues from patients with early stage PCA or benign prostatic hyperplasia (BPH). As control, we used IL-6 gene, encoding an IL involved in PCA progression. IL-6, IL-7 and IL-15 titres were also measured in patients' sera. Eighty patients with BPH and 79 with early (1 to 2c) stage PCA were enrolled. Gene expression in prostate tissues was analyzed by quantitative real-time PCR (qRT-PCR). Serum IL concentrations and acute phase protein titres were evaluated by ELISA. Mann-Whitney, Wilcoxon and χ(2) tests were used to compare IL gene expression and serum titers in the two groups of patients. Receiver operating characteristic (ROC) curves were constructed to evaluate the possibility to distinguish sera from different groups of patients based on IL titers. IL-2 and IL-21 gene expression was comparably detectable, with low frequency and at low extents, in PCA and BPH tissues. In contrast, IL-6, IL-7 and IL-15 genes were expressed more frequently (p < 0.0001, p = 0.0047 and p = 0.0085, respectively) and to significantly higher extents (p = 0.0051, p = 0.0310 and p = 0.0205, respectively) in early stage PCA than in BPH tissues. Corresponding proteins could be detected to significantly higher amounts in sera from patients with localized PCA, than in those from patients with BPH (p = 0.0153, p = 0.0174 and p = 0.0064, respectively). Analysis of ROC curves indicates that IL-7 (p = 0.0039), but not IL-6 (p = 0.2938) or IL-15 (p = 0.1804) titres were able to distinguish sera from patients with malignancy from those from patients with benign disease. Serum titres of C reactive (CRP), high mobility group B1 (HMGB1) and serum amyloid A (SAA) acute phase proteins were similar in both groups of patients. Expression IL-7 and IL-15 genes in prostate tissues and corresponding serum titres are significantly increased in patients with early stage PCA as compared with patients with BPH.


Overexpression of Prdx6 and resistance to peroxide-induced death in Hepa1-6 cells: Prdx suppression increases apoptosis.
Peroxiredoxins are thiol-specific antioxidants that catalyze the reduction of cellular peroxides and protect cells from ROS-mediated damage and death. Peroxiredoxin gene expression is up-regulated in a number of cancers, suggesting a possible role in cancer cell maintenance. Prdx6, a cytoplasmic protein elevated in certain cancers, is highly expressed in liver and transcriptionally regulated by various oxidative stresses. In the present study, we found that the cancerous Hepa1-6 hepatoma cell line is significantly more resistant to peroxide-induced cytotoxicity than the non-cancerous H2.35 cell line. We also demonstrated that Hepa1-6 cells express approximately 3-fold more Prdx6 mRNA and 2.5-fold more Prdx6 protein than H2.35 cells. Treatment with mithramycin A resulted in a nearly 20% reduction in Prdx6 mRNA in Hepa1-6 cells, suggesting a possible role for Sp1 in Prdx6 up-regulation. We hypothesized that suppression of Prdx6 in Hepa1-6 cells would increase susceptibility to peroxide-induced cell death. Transient transfection of Hepa1-6 cells with Prdx6 siRNA led to a marked reduction in Prdx6 expression, and an increase in peroxide-induced cytotoxicity by apoptosis. Together, these data demonstrate an important anti-apoptotic function for Prdx6 in cancerous liver cells, and suggest that its up-regulation may be a tumor-supportive adaptation in cancerous states.


Reorganization of functionally connected brain subnetworks in high-functioning autism.
Previous functional connectivity studies have found both hypo- and hyper-connectivity in brains of individuals having autism spectrum disorder (ASD). Here we studied abnormalities in functional brain subnetworks in high-functioning individuals with ASD during free viewing of a movie containing social cues and interactions. Twenty-six subjects (13 with ASD) watched a 68-min movie during functional magnetic resonance imaging. For each subject, we computed Pearson's correlation between haemodynamic time-courses of each pair of 6-mm isotropic voxels. From the whole-brain functional networks, we derived individual and group-level subnetworks using graph theory. Scaled inclusivity was then calculated between all subject pairs to estimate intersubject similarity of connectivity structure of each subnetwork. Additional 54 individuals (27 with ASD) from the ABIDE resting-state database were included to test the reproducibility of the results. Between-group differences were observed in the composition of default-mode and ventro-temporal-limbic (VTL) subnetworks. The VTL subnetwork included amygdala, striatum, thalamus, parahippocampal, fusiform, and inferior temporal gyri. Further, VTL subnetwork similarity between subject pairs correlated significantly with similarity of symptom gravity measured with autism quotient. This correlation was observed also within the controls, and in the reproducibility dataset with ADI-R and ADOS scores. Our results highlight how the reorganization of functional subnetworks in individuals with ASD clarifies the mixture of hypo- and hyper-connectivity findings. Importantly, only the functional organization of the VTL subnetwork emerges as a marker of inter-individual similarities that co-vary with behavioral measures across all participants. These findings suggest a pivotal role of ventro-temporal and limbic systems in autism.


Defective intestinal phosphate absorption in familial and non-familial hypophosphataemia.
With an oral phosphate tolerance test a primary defect in intestinal phosphate absorption was found in patients with untreated familial and non-familial hypophosphataemia. It is suggested that this plays a major part in the aetiology of rickets and osteomalacia in these disorders. Vitamin D was shown to have a beneficial effect on intestinal transport of phosphate, though defective absorption was not completely corrected. If intestinal phosphate absorption is normal, oral phosphate supplements will maintain normal plasma phosphate levels even in the presence of a pronounced renal phosphate leak.In familial and non-familial hypophosphataemia the phosphate tolerance test may be a more sensitive index of genetic abnormality than a low plasma phosphate. It may be helpful in distinguishing several syndromes at present classified under non-familial hypophosphataemia, as well as assessing the response to treatment with vitamin D and in investigating intestinal transport of phosphate.


Phylogeography of two moray eels indicates high dispersal throughout the indo-pacific.
Reef fishes disperse primarily as oceanic "pelagic" larvae, and debate continues over the extent of this dispersal, with recent evidence for geographically restricted (closed) populations in some species. In contrast, moray eels have the longest pelagic larval stages among reef fishes, possibly providing opportunities to disperse over great distances. We test this prediction by measuring mitochondrial DNA (mtDNA) and nuclear DNA variation in 2 species of moray eels, Gymnothorax undulatus (N = 165) and G. flavimarginatus (N = 124), sampled at 14-15 locations across the Indo-Pacific. The mtDNA data comprise 632 bp of cytochrome b and 596 bp of cytochrome oxidase I. Nuclear markers include 2 recombination-activating loci (421 bp of RAG-1 and 754 bp of RAG-2). Analyses of molecular variance and Mantel tests indicate little or no genetic differentiation, and no isolation by distance, across 22 000 km of the Indo-Pacific. We estimate that mitochondrial genetic variation coalesces within the past about 2.3 million years (My) for G. flavimarginatus and within the past about 5.9 My for G. undulatus. Permutation tests of geographic distance on the mitochondrial haplotype networks indicate recent range expansions for some younger haplotypes (estimated within approximately 600 000 years) and episodic fragmentation of populations at times of low sea level. Our results support the predictions that the extended larval durations of moray eels enable ocean-wide genetic continuity of populations. This is the first phylogeographic survey of the moray eels, and morays are the first reef fishes known to be genetically homogeneous across the entire Indo-Pacific.


Changes in adrenal steroidogenesis in spontaneous bacterial peritonitis and sterile ascites.
Adrenal androgens, particularly dehydroepiandrosterone (DHEA), may have important regulatory effects on the immune system in humans. This study measured the changes in adrenal steroidogenesis in 13 non-infected cirrhosis patients with sterile ascites and 13 patients with spontaneous bacterial peritonitis and the relation with circulating interleukin-6 (IL-6) levels. Comparisons were made with 10 healthy age-matched control subjects. The severity of bacterial peritonitis in liver cirrhosis was significantly associated with enhanced serum IL-6 and cortisol levels, and a decrease in serum DHEA sulfate in relation to serum IL-6 concentrations. Careful, long-term studies on DHEA administered to cirrhosis patients are needed to assess its safety in improving a number of pathological conditions that complicate liver cirrhosis.


Effectiveness of daily and weekly iron supplementation in the prevention of anemia in infants.
To evaluate the effectiveness of universal prophylactic targeting with iron sulfate on daily or weekly basis in the prevention of anemia in infants. Randomized clinical field trial with children between ages six and 12 months seen at primary health care units in the municipality of Rio de Janeiro, Brazil, between 2004 and 2005. Three concurrent cohorts were compared: daily group (n=150; 12.5mg Fe/day); weekly group (n=147; 25mg Fe/week) and control group. The intervention consisted of universal supplementation with iron sulfate for 24 weeks, combined with educational adherence-promoting measures. mean serum hemoglobin concentration, distribution and prevalence of anemia (Hb<110.0 g/l) at age 12 months. Effectiveness was evaluated considering both intent to treat and adherence to protocol, using multiple regression analysis (linear and Poisson). Groups were homogeneous in terms of descriptive variables. The intervention was implemented successfully, with high adhesion to protocol in both groups, and no statistical difference between them. After adjustment, only the daily regimen showed a protective effect. Adherence analysis demonstrated an evident dose-response effect on mean Hb and prevalence of anemia only for the daily regimen. No protective effect was detected for the weekly regimen. Universal supplementation with iron sulfate from six to 12 months of age was effective in increasing serum Hb and decreasing risk of anemia only when administered on a daily basis.


Cancer worry among Norwegian male BRCA1/2 mutation carriers.
This qualitative study explored the experiences of Norwegian men after being identified as BRCA 1/2 mutation-positive. Only limited knowledge is available on this topic; therefore, the aim of this study was to gain a deeper insight from the men's own perspectives. Data were collected from in-depth interviews with 15 men and seven of their partners. The participants described fear of cancer development, and two main narrative patterns were identified: fear for their own health, including fear of developing cancer, and negative feelings about responsibility for others' health. The men expressed fear of developing cancer themselves and described a need for genetic risk information. They were also deeply concerned about how the mutation might affect their children and other relatives. There is a need for guidelines concerning genetic risk information and follow-up programs for male BRCA 1/2 mutation carriers. This study adds valuable contextual insights into their experiences of living with fear of cancer.


Why some tumours trigger neovascularisation and others don't: the story thus far.
Angiogenesis is not essential for tumours to develop and expand, as cancer can also grow in a non-angiogenic fashion, but why this type of growth occurs is unknown. Surprisingly, our data from mRNA transcription profiling did not show any differences in the classical angiogenic pathways, but differences were observed in mitochondrial metabolic pathways, suggesting a key role for metabolic reprogramming. We then validated these results with mRNA profiling by investigating differential protein expression via immunohistochemistry in angiogenic and non-angiogenic non-small cell lung cancers (NSCLCs). Immunohistochemical staining for 35 angiogenesis- and hypoxia-related biomarkers were performed on a collection of 194 angiogenic and 73 non-angiogenic NSCLCs arranged on tissue microarrays. Sequencing of P53 was performed with frozen tissue samples of NSCLC. The non-angiogenic tumours were distinguished from the angiogenic ones by having higher levels of proteins associated with ephrin pathways, mitochondria, cell biogenesis, and hypoxia-inducible factor 1 (HIF1) regulation by oxygen and transcription of HIF-controlled genes but lower levels of proteins involved in the stroma, cell-cell signaling and adhesion, integrins, and Delta-Notch and epidermal growth factor (EGF)-related signaling. However, proteins classically associated with angiogenesis were present in both types of tumours at very comparable levels. Cytoplasmic expression of P53 was strongly associated with non-angiogenic tumours. A pilot investigation showed that P53 mutations were observed in 32.0% of angiogenic cases but in 71.4% of non-angiogenic tumours. Our observations thus far indicate that both angiogenic and non-angiogenic tumours experience hypoxia/HIF and vascular endothelial growth factor (VEGF) pathway protein expression in a comparable fashion. However, angiogenesis does not ensue in the non-angiogenic tumours. Surprisingly, metabolic reprogramming seems to distinguish these two types of neoplastic growth. On the basis of these results, we raise the hypothesis that in some, but not in all cases, initial tissue remodeling and/or inflammation could be one of the secondary steps necessary to trigger angiogenesis. In the non-angiogenic tumours, in which neovascularisation fails to occur, HIF pathway activation could be the driving force toward metabolic reprogramming.


An analysis of the effect of statin use on the efficacy of bacillus calmette-guerin treatment for transitional cell carcinoma of the bladder.
Bacillus Calmette-Guerin is an effective immunotherapy for carcinoma in situ of the bladder and it reduces recurrence from resected papillary transitional cell carcinoma of the bladder. Many patients receiving bacillus Calmette-Guerin therapy are concurrently taking statin agents, which have known immunomodulatory properties and may alter the performance of bacillus Calmette-Guerin. Some data have suggested that patients taking a statin while on bacillus Calmette-Guerin therapy experience reduced clinical efficacy. We conducted a retrospective review of 952 consecutive patients from 1978 through 2006. Time to recurrence and progression to surgery were compared between those taking and those not taking a statin by Kaplan-Meier methods and multivariable Cox regression controlling for stage and grade. There were 245 (26%) patients taking a statin before bacillus Calmette-Guerin therapy and 707 not on statin therapy (74%). A total of 796 patients had recurrence overall with 214 in the statin group and 582 in the other group. Median time to recurrence was similar between those who did and those who did not use a statin. On multivariable analysis statin use was not significantly associated with recurrence (hazard ratio 1.04; 95% CI 0.81, 1.34; p = 0.7) or progression to surgery (hazard ratio 0.77; 95% CI 0.52, 1.13; p = 0.17) after bacillus Calmette-Guerin therapy. This retrospective study in a large cohort of patients showed no statistically significant association between statin use and recurrence or progression to open surgery in patients treated with bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. Based on these data patients should not be discouraged from taking statins while undergoing bacillus Calmette-Guerin treatment.


'Omics' approaches for studying the microbiome in Alopecia areata.
Nowadays, the involvement of the microbiome in human health and many human diseases, including that strictly related to the scalphas been brought to the light. Indeed, more recently, authors highlighted the presence of a significant microbial shift both in nonscarring (Androgenetic alopecia and Alopecia areata) and scarring Alopecias. The advent of novel technologies together with the effort of many scientists in the microbiome field could provide in the nearest future a clearest framework about the strict relationship between human healthiness and symbiotic microorganism resident on different ecosystem of our body. In this view, the use of Omics approaches has to be considered as no longer negligible when studying the microbiome implication in human health and disease.


From antibody insult to fibrosis in neonatal lupus - the heart of the matter.
Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often referred to as a model of passively acquired autoimmunity. In essence, this disease encompasses two patients, both the mother and her child. The signature histologic lesion of autoimmune-associated congenital heart block is fibrosis of the conducting tissue, and in some cases the surrounding myocardium. It is astounding how rapid and, in most cases, irreversible is the fibrotic response to injury. The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and perpetuate inflammation, and eventuate in scarring of the atrioventricular node, is not yet defined. In vitro and in vivo studies suggest that one pathologic cascade leading to scarring may be initiated via apoptosis, resulting in translocation of SSA/Ro-SSB/La antigens and subsequent surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors that transdifferentiate fibroblasts into myofibroblasts, a scarring phenotype. Dissecting the individual components in this fibrotic pathway should provide insights into the rarity of irreversible injury and should form the basis of rational approaches to prevention and treatment.


The burden and determinants of HIV and sexually transmitted infections in a population-based sample of female sex workers in Goa, India.
Interventions targeting sex workers are central to the National AIDS Control programme of India's third 5-year plan. Understanding the way in which societal and individual factors interact to shape sex workers' vulnerability would better inform interventions. 326 female sex workers, recruited throughout Goa using respondent-driven sampling, completed interviewer-administered questionnaires. Biological samples were tested for Trichomonas vaginalis, Neisseria gonorrhoea, Chlamydia trachomatis and antibodies to herpes simplex virus type 2 (HSV-2) and HIV. Multivariate analysis was used to define the determinants of HIV infection and any bacterial sexually transmitted infection (STI). Infections were common, with 25.7% prevalence of HIV and 22.5% prevalence of bacterial STI; chlamydia 7.3%, gonorrhoea 8.9% and trichomonas 9.4%. Antibodies to HSV-2 were detected in 57.2% of women. STI were independently associated with factors reflecting gender disadvantage and disempowerment, namely young age, lack of schooling, no financial autonomy, deliberate self-harm, sexual abuse and sex work-related factors, such as having regular customers and working on the streets. Other factors associated with STI were Goan ethnicity, not having an intimate partner and being asymptomatic. Having knowledge about HIV and access to free STI services were associated with a lower likelihood of STI. HIV was independently associated with being Hindu, recent migration to Goa, lodge or brothel-based sex work and dysuria. Sex workers working in medium prevalence states of India are highly vulnerable to HIV and STI and need to be rapidly incorporated into existing interventions. Structural and gender-based determinants of HIV and STI are integral to HIV prevention strategies.


Clinical decision making about child and adolescent anxiety disorders using the Achenbach system of empirically based assessment.
Anxiety disorders are common among children but can be difficult to diagnose. An actuarial approach to the diagnosis of anxiety may improve the efficiency and accuracy of the process. The objectives of this study were to determine the clinical utility of the Achenbach Child Behavior Checklist (CBCL) and Youth Self Report (YSR), two widely used assessment tools, for diagnosing anxiety disorders in youth and to aid clinicians in incorporating scale scores into an actuarial approach to diagnosis through a clinical vignette. Demographically diverse youth, 5 to 18 years of age, were drawn from two samples; one (N = 1,084) was recruited from a research center, and the second (N = 651) was recruited from an urban community mental health center. Consensus diagnoses integrated information from semistructured interview, family history, treatment history, and clinical judgment. The CBCL and YSR internalizing problems T scores discriminated cases with any anxiety disorder or with generalized anxiety disorder from all other diagnoses in both samples (ps < .0005); the two scales had equivalent discriminative validity (ps > .05 for tests of difference). No other scales, nor any combination of scales, significantly improved on the performance of the Internalizing scale. In the highest risk group, Internalizing scores greater than 69 (CBCL) or greater than 63 (YSR) resulted in a Diagnostic Likelihood Ratio of 1.5; low scores reduced the likelihood of anxiety disorders by a factor of 4. Combined with other risk factor information in an actuarial approach to assessment and diagnosis, the CBCL and YSR Internalizing scales provide valuable information about whether a youth is likely suffering from an anxiety disorder.