IL-9 and Th9 in parasite immunity.
Interleukin-9 is a cytokine classically related to type 2 immune responses whose cellular identity has been recently reevaluated to identify a new specialized T helper subset called Th9 and an innate source referred as innate lymphoid cell type 2. Over the past years, IL-9 has been associated with allergic responses, tumor immunology, and autoimmunity; however, in this review, we will specifically focus on the role of IL-9 and Th9 cells in the context of parasitic infections. We will summarize and discuss all the evidence relating IL-9 expression and function in parasitic infections with a particular emphasis in helminth infections, an important health issue in developing countries; we will also provide a general description and classification of parasites, the immune response and cellular compartments activated in this context, and its implications and future directions towards a complete understanding of this interesting new T helper subset and its potential therapeutic use.


Effects of sulphurous water on human neutrophil elastase release.
Molecules bearing a sulphide (HS) group, such as glutathione, play a fundamental role in the defensive system of human airways, as shown by the fact that the lining fluid covering the epithelia of the respiratory tract contains very high concentrations of glutathione: the lungs and nose, respectively, contain about 140 and 40 times the concentrations found in plasma. Consequently, various low-weight soluble molecules bearing an HS group (including N-acetylcysteine, mesna and thiopronine, and prodrugs such as stepronine and erdosteine) have been used for therapeutic purposes. HS groups can also be therapeutically administered by means of sulphurous thermal water containing HS groups. The aim of this study was to investigate the direct activity of such water on the release of elastase by activated human neutrophils. After the neutrophils were incubated with increasing amounts of sulphurous water or the HS/hydrogen sulphide donor sodium hydrosulphide (NaHS), elastase release was initiated by N-formyl-methionyl-leucyl-phenylalanine and measured by means of spectrofluorimetry using methylsuccinylalanylprolylvalyl-methylcoumarin amide as the fluorogenic substrate. To verify the presence of direct action on elastase we determined the diameter of the area of elastinolysis on elastine-agarose gel plates. The sulphurous water significantly inhibited elastase release at HS concentrations ranging from 4.5 to 18 μg/ml, as assayed using the iodometric method; in the case of NaHS, the inhibition was significant at HS concentrations ranging from 2.2 to 18 μg/ml. The concentration-effect regression lines of both were parallel and neither showed any direct elastolytic activity. Previous claims concerning the activity of sulphurous water have been based on the patients' subjective sense of wellbeing and on symptomatic (or general) clinical improvements that are not easy to define or quantify exactly. Our findings indicate that, in addition to its known mucolytic and antioxidant activity, sulphurous water also has an anti-elastase activity that may help to control the inflammatory processes of upper and lower airway diseases.


Rapid magnetic resonance imaging vs radiographs for patients with low back pain: a randomized controlled trial.
Faster magnetic resonance imaging (MRI) scanning has made MRI a potential cost-effective replacement for radiographs for patients with low back pain. However, whether rapid MRI scanning results in better patient outcomes than radiographic evaluation or a cost-effective alternative is unknown. To determine the clinical and economic consequences of replacing spine radiographs with rapid MRI for primary care patients. Randomized controlled trial of 380 patients aged 18 years or older whose primary physicians had ordered that their low back pain be evaluated by radiographs. The patients were recruited between November 1998 and June 2000 from 1 of 4 imaging centers in the Seattle, Wash, area: a university-based teaching program, a nonuniversity-based teaching program, and 2 private clinics. Patients were randomly assigned to receive lumbar spine evaluation by rapid MRI or by radiograph. Back-related disability measured by the modified Roland questionnaire. Secondary outcomes included Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), pain, preference scores, satisfaction, and costs. At 12 months, primary outcomes of functional disability were obtained from 337 (89%) of the 380 patients enrolled. The mean back-related disability modified Roland score for the 170 patients assigned to the radiograph evaluation group was 8.75 vs 9.34 for the 167 patients assigned the rapid MRI evaluation group (mean difference, -0.59; 95% CI, -1.69 to 0.87). The mean differences in the secondary outcomes were not statistically significant : pain bothersomeness (0.07; 95% CI -0.88 to 1.22), pain frequency (0.12; 95% CI, -0.69 to 1.37), and SF-36 subscales of bodily pain (1.25; 95% CI, -4.46 to 4.96), and physical functioning (2.73, 95% CI -4.09 to 6.22). Ten patients in the rapid MRI group vs 4 in the radiograph group had lumbar spine operations (risk difference, 0.34; 95% CI, -0.06 to 0.73). The rapid MRI strategy had a mean cost of 2380 dollars vs 2059 dollars for the radiograph strategy (mean difference, 321 dollars; 95% CI, -1100 to 458). Rapid MRIs and radiographs resulted in nearly identical outcomes for primary care patients with low back pain. Although physicians and patients preferred the rapid MRI, substituting rapid MRI for radiographic evaluations in the primary care setting may offer little additional benefit to patients, and it may increase the costs of care because of the increased number of spine operations that patients are likely to undergo.


Providing learning support to nursing students: a study of two universities.
In universities where significant numbers of nursing students come from non-traditional backgrounds, and where an equally significant proportion of students have English as a second language, provision of learning support is essential to ensure success and progression, and to prevent attrition. This paper presents an evaluative study of the support services provided to undergraduate nursing students in two universities in the United Kingdom (UK). Both universities have significant numbers of students from non-traditional backgrounds and who have English as a second language, and both institutions have in place a large array of student support mechanisms. The aims of the study were to identify all existing student support mechanisms across the two universities, to illuminate the profile of students who enter pre-registration programmes at the two universities (age, gender, educational background) and to measure the perceptions of students of the use and usefulness of the support mechanisms provided by their university. Survey method evaluative research was the chosen research approach. Findings showed that the support services that appear to have the greatest impact on student success in their nursing programme are the programme leaders/module teachers, small study skills groups (known as APPL and L2L) and, for the 50% of students who required it, academic literacy and numeracy support sessions. For students who have English as a second language and with non-traditional entry qualifications, numeracy and academic literacy support is particularly valued.


Upper and lower urinary tract outcome after surgical repair of cloacal malformations: a three-decade experience.
To report the urological outcome of the surgical correction of persistent cloaca, which is technically demanding and may require many procedures in an effort to preserve renal function and provide urinary continence. A retrospective chart review from 1971 to 2003 identified 23 patients with cloacal malformations (two posterior, 21 classical) that were reconstructed. The confluence of the urethra, vagina and rectum was noted to be high in 16, low in five and unknown in two; one patient was a conjoined twin. The mean (range) follow-up was 9.3 (0.4-31.6) years. Urinary anomalies included 14 patients with renal anomalies (six solitary kidneys, four renal dysplasia, two pelvi-ureteric junction, one each duplex and crossed fused) and two duplicated bladders. Vesico-ureteric reflux was present in 13 patients (57%), hydronephrosis at birth in 13, a bony vertebral abnormality in 14 and the VACTERL association in four. Total urogenital mobilization (TUM) was used in six patients and spinal cord untethering in four; a nephrectomy was required in three and partial nephrectomy in one. Upper tract dilation was still present in six patients. Age-adjusted creatinine levels were abnormal in four (18%) patients and borderline in another six (26%). In the nine patients with a solitary kidney (six solitary, three after nephrectomy), the age-adjusted creatinine level was abnormal in two and borderline in four. A vesicostomy was initially performed in 11 patients. The method of bladder emptying is known in 22; 10 void, 11 require clean intermittent catheterization (five abdominal stoma, six urethral) and one was diverted with a conduit. Of the 18 patients aged > 47 months 15 were continent (14 complete > 4 h, one partial 2-4 h), and three are wet (one conduit). Reconstruction of the lower urinary tract included four bladder augmentations (one ureteric, one ileal, two colon), five bladder neck procedures (two artificial sphincter, one each bladder neck repair, sling, bladder neck division) and six catheterizable channels (one now with a colon conduit). The ureters were re-implanted in 12 patients. Although the surgical correction of this rare malformation is complex, the upper urinary and lower urinary tract outcome can be favourable, albeit after several reconstructive procedures. TUM has emerged as the primary method for vaginal reconstruction, but the long-term lower tract outcome after this procedure is awaited.


Design of a free-floating polycarbonate-urethane meniscal implant using finite element modeling and experimental validation.
The development of a synthetic meniscal implant that does not require surgical attachment but still provides the biomechanical function necessary for joint preservation would have important advantages. We present a computational-experimental approach for the design optimization of a free-floating polycarbonate-urethane (PCU) meniscal implant. Validated 3D finite element (FE) models of the knee and PCU-based implant were analyzed under physiological loads. The model was validated by comparing calculated pressures, determined from FE analysis to tibial plateau contact pressures measured in a cadaveric knee in vitro. Several models of the implant, some including embedded reinforcement fibers, were tested. An optimal implant configuration was then selected based on the ability to restore pressure distribution in the knee, manufacturability, and long-term safety. The optimal implant design entailed a PCU meniscus embedded with circumferential reinforcement made of polyethylene fibers. This selected design can be manufactured in various sizes, without risking its integrity under joint loads. Importantly, it produces an optimal pressure distribution, similar in shape and values to that of natural meniscus. We have shown that a fiber-reinforced, free-floating PCU meniscal implant can redistribute joint loads in a similar pattern to natural meniscus, without risking the integrity of the implant materials.


Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.
Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes. This response seems to reflect decreased degradation of insulin rather than increased pancreatic output. These observations suggest that treatment with chloroquine or suitable analogues may be a new approach to the management of diabetes.


Diminishing relative jitter in electrooptic sampling of active mm-wave and THz circuits.
In this work a novel approach in synchronization of electrooptic sampling systems for the ultra-broadband characterization of active mm-wave and THz devices is presented. The relative time jitter between sampled circuit and probing electrooptic head is eliminated by using a femtosecond laser system both as the generator of CW driving the device under test as well as the impulsively probing element. Previous ultra-broadband approaches were applicable to passive components driven by THz impulses, only. The presented system is more generally applicable to active mm-wave and THz components driven by conventional CW electronic sources. Broadband analysis on silicon nonlinear transmission line elements up to a frequency of 300 GHz is presented in order to illustrate the capabilities of the concept.


Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy.
Bilirubin/albumin ratio (B/A) may provide a better estimate of free bilirubin than total serum bilirubin (TSB), thus improving identification of newborns at risk for bilirubin encephalopathy. The objective of the study was to identify thresholds and compare specificities of TSB and B/A in detecting patients with acute and posttreatment auditory and neurologic impairment. A total of 193 term/near-term infants, admitted for severe jaundice to Cairo University Children's Hospital, were evaluated for neurologic status and auditory impairment (automated auditory brainstem response), both at admission and posttreatment by investigators blinded to laboratory results. The relationships of TSB and B/A to advancing stages of neurotoxicity were compared by using receiver operating characteristic curves. TSB and B/A ranged from 17 to 61 mg/dL and 5.4 to 21.0 mg/g, respectively; 58 (30%) of 193 subjects developed acute bilirubin encephalopathy, leading to kernicterus in 35 infants (13 lethal). Auditory impairment was identified in 86 (49%) of 173 infants at admission and in 22 of 128 at follow-up. In the absence of clinical risk factors, no residual neurologic or hearing impairment occurred unless TSB exceeded 31 mg/dl. However, transient auditory impairment occurred at lower TSB and B/A (22.9 mg/dL and 5.7 mg/g, respectively). Intervention values of TSB and B/A set at high sensitivity to detect different stages of neurotoxicity had nearly the same specificity. Both TSB and B/A are strong predictors of neurotoxicity, but B/A does not improve prediction over TSB alone. Threshold values detecting all affected patients (100% sensitivity) increase with advancing severity of neurotoxicity.


Alternations in splenocyte and thymocyte subpopulations in B6C3F1 mice exposed to cocaine plus diazinon.
Our laboratory has proposed a working model which asserts that cocaine's effects on immunity are mediated by reactive metabolites generated by the cytochrome P-450 system. This metabolic pathway is normally a minor one in humans, but takes on significance when metabolism of cocaine by the P-450 system is increased, as may occur with excessive alcohol consumption (enzyme induction) or after exposure to organophosphate pesticides (esterase inhibition). Results from our laboratory demonstrate that cocaine exerts its most dramatic effects on immunocompetence when administered to mice that have been pretreated with diazinon, an organophosphate esterase inhibitor. Most notably, we observed decreases in both the splenic T-dependent antibody response to sheep erythrocytes and the splenic T-independent antibody response to DNP-ficoll and a dramatic thymic atrophy in mice exposed to cocaine + diazinon, which were not seen in mice exposed to cocaine alone. The primary objective of the present investigation was to determine whether the exposure conditions used to produce the changes noted above are also capable of causing changes in lymphocyte cell types by use of flow cytometric analysis. Administration of cocaine after pretreatment with diazinon only modestly affected splenic lymphocyte subsets, which caused a slight decrease in the number of B cells. No effect was observed in the macrophage, T-helper or T-suppressor subpopulations in the spleen. These results suggest that changes in splenocyte subpopulations induced by cocaine + diazinon cannot account for the suppression of the antibody response. In contrast, all T-cell subsets in the thymus were decreased significantly, with immature double-positive thymocytes suffering the greatest loss in cell number. These results indicate that T cells, especially immature thymocytes located in the thymus, are sensitive to effects associated with the combined treatment of cocaine + diazinon.


Variability in individual serum cholesterol response to change in diet.
Few systematic data are available on the range of individual blood lipid responsiveness to specific diet changes. Multiple, carefully standardized total serum cholesterol (TC) measurements were made in 58 men under a variety of controlled dietary conditions. Responsiveness was defined for each individual as the change in mean TC per unit change in Diet Score based on the Keys-Minnesota equation. Only 3% were potentially "nonresponders," and even these probably evidenced some response. Of the group, 64% responded within 30% of prediction. We classed 9% as hyporesponders, while in another 9% responsiveness exceeded 1.5 times expectation. We conclude that in metabolically normal individuals the variation in short-term response to dietary change is normally distributed but that nonresponse to diet change is rare. Because metabolic, intrinsic hyporesponsiveness of TC to change in diet composition is uncommon, assessment of the real effectiveness of a dietary regimen in an individual is best based on observed dietary changes. TC changes among individuals under treatment should be based on multiple determinations and interpreted with caution.


The cavefish genome reveals candidate genes for eye loss.
Natural populations subjected to strong environmental selection pressures offer a window into the genetic underpinnings of evolutionary change. Cavefish populations, Astyanax mexicanus (Teleostei: Characiphysi), exhibit repeated, independent evolution for a variety of traits including eye degeneration, pigment loss, increased size and number of taste buds and mechanosensory organs, and shifts in many behavioural traits. Surface and cave forms are interfertile making this system amenable to genetic interrogation; however, lack of a reference genome has hampered efforts to identify genes responsible for changes in cave forms of A. mexicanus. Here we present the first de novo genome assembly for Astyanax mexicanus cavefish, contrast repeat elements to other teleost genomes, identify candidate genes underlying quantitative trait loci (QTL), and assay these candidate genes for potential functional and expression differences. We expect the cavefish genome to advance understanding of the evolutionary process, as well as, analogous human disease including retinal dysfunction.


Social structure in migrating humpback whales (Megaptera novaeangliae).
Although largely solitary, humpback whales exhibit a number of behaviours where individuals co-operate with one another, for example during bubble net feeding. Such cases could be due to reciprocal altruism brought on by exceptional circumstances, for example the presence of abundant shoaling fish. An alternative explanation is that these behaviours have evolved through kin selection. With little restriction to either communication or movement, diffuse groups of relatives could maintain some form of social organization without the need to travel in tight-nit units. To try to distinguish between these hypotheses, we took advantage of the fact that migrating humpback whales often swim together in small groups. If kin selection is important in humpback whale biology, these groups should be enriched for relatives. Consequently, we analysed biopsy samples from 57 groups of humpback whales migrating off Eastern Australia in 1992. A total of 142 whales were screened for eight microsatellite markers. Mitochondrial DNA sequences (371 bp) were also used to verify and assist kinship identification. Our data add support to the notion that mothers travel with their offspring for the first year of the calf's life. However, beyond the presence of mother-calf/yearling pairs, no obvious relatedness pattern was found among whales sampled either in the same pod or on the same day. Levels of relatedness did not vary between migratory phases (towards or away from the breeding ground), nor between the two sexes considered either overall or in the north or south migrations separately. These findings suggest that, if any social organization does exist, it is formed transiently when needed rather than being a constant feature of the population, and hence is more likely based on reciprocal altruism than kin selection.


Combined effects of short-term exposure to elevated CO2 and decreased O2 on the physiology and energy budget of the thick shell mussel Mytilus coruscus.
Hypoxia and ocean acidification are two consequences of anthropogenic activities. These global trends occur on top of natural variability. In environments such as estuarine areas, short-term acute pH and O2 fluctuations are occurring simultaneously. The present study tested the combined effects of short-term seawater acidification and hypoxia on the physiology and energy budget of the thick shell mussel Mytilus coruscus. Mussels were exposed for 72 h to six combined treatments with three pH levels (8.1, 7.7 and 7.3) and two dissolved oxygen (DO) levels (2 mg L(-1), 6 mg L(-1)). Clearance rate (CR), food absorption efficiency (AE), respiration rate (RR), ammonium excretion rate (ER), O:N ratio and scope for growth (SFG) were significantly reduced, and faecal organic dry weight ratio (E) was significantly increased at low DO. Low pH did not lead to a reduced SFG. Interactive effects of pH and DO were observed for CR, E and RR. Principal component analysis (PCA) revealed positive relationships among most physiological indicators, especially between SFG and CR under normal DO conditions. These results demonstrate that Mytilus coruscus was sensitive to short-term (72 h) exposure to decreased O2 especially if combined with decreased pH levels. In conclusion, the short-term oxygen and pH variation significantly induced physiological changes of mussels with some interactive effects.


Iconicity can ground the creation of vocal symbols.
Studies of gestural communication systems find that they originate from spontaneously created iconic gestures. Yet, we know little about how people create vocal communication systems, and many have suggested that vocalizations do not afford iconicity beyond trivial instances of onomatopoeia. It is unknown whether people can generate vocal communication systems through a process of iconic creation similar to gestural systems. Here, we examine the creation and development of a rudimentary vocal symbol system in a laboratory setting. Pairs of participants generated novel vocalizations for 18 different meanings in an iterative 'vocal' charades communication game. The communicators quickly converged on stable vocalizations, and naive listeners could correctly infer their meanings in subsequent playback experiments. People's ability to guess the meanings of these novel vocalizations was predicted by how close the vocalization was to an iconic 'meaning template' we derived from the production data. These results strongly suggest that the meaningfulness of these vocalizations derived from iconicity. Our findings illuminate a mechanism by which iconicity can ground the creation of vocal symbols, analogous to the function of iconicity in gestural communication systems.


Contrasting levels of clonal and within-population genetic diversity between the 2 ecologically different herbs Polygonatum stenophyllum and Polygonatum inflatum (Liliaceae).
Comparative studies on clonal and genetic structure between ecologically contrasting congeners may provide valuable insights into the mechanisms promoting the maintenance of genetic diversity in clonal plant species. Polygonatum stenophyllum has long rhizomes (ca. 30-40 cm long) and largely occurs on sandy soils in open river banks, whereas its congener Polygonatum inflatum has short ones (ca. 5-10 cm long) and occurs on humic soils under deciduous forests. Using 21 allozyme loci, we comparatively assessed levels of clonal and genetic diversity in the 2 clonal species. Seven populations of P. stenophyllum consisted of single clones, and levels of within-population clonal and genetic variation were considerably lower than those of P. inflatum. However, when samples were pooled, P. stenophyllum harbored higher genetic variation than P. inflatum, which is due to higher among-population genetic differentiation in the former species compared with the latter (FST=0.636 vs. FST=0.165). Our data suggest that populations of P. stenophyllum have been mainly founded by a single seed or rhizome (through river water) or by a few seeds, whereas populations of P. inflatum would have been established through multiple, repeated seedling recruitment. Moderate levels of genetic diversity in a population of P. stenophyllum located at the foot of the Baekdudaegan Mountains and in all the populations of P. inflatum are consistent with the previous hypothesis that these mountains served as a glacial refugium for many boreal species of the Korean Peninsula.


Gray Matter Network Disruptions and Regional Amyloid Beta in Cognitively Normal Adults.
The accumulation of amyloid plaques is one of the earliest pathological changes in Alzheimer's disease (AD) and may occur 20 years before the onset of symptoms. Examining associations between amyloid pathology and other early brain changes is critical for understanding the pathophysiological underpinnings of AD. Alterations in gray matter networks might already start at early preclinical stages of AD. In this study, we examined the regional relationship between amyloid aggregation measured with positron emission tomography (PET) and gray matter network measures in elderly subjects with subjective memory complaints. Single-subject gray matter networks were extracted from T1-weigthed structural MRI in cognitively normal subjects (n = 318, mean age 76.1 ± 3.5, 64% female, 28% amyloid positive). Degree, clustering, path length and small world properties were computed. Global and regional amyloid load was determined using [18F]-Florbetapir PET. Associations between standardized uptake value ratio (SUVr) values and network measures were examined using linear regression models. We found that higher global SUVr was associated with lower clustering (β = -0.12, p < 0.05), and small world values (β = -0.16, p < 0.01). Associations were most prominent in orbito- and dorsolateral frontal and parieto-occipital regions. Local SUVr values showed less anatomical variability and did not convey additional information beyond global amyloid burden. In conclusion, we found that in cognitively normal elderly subjects, increased global amyloid pathology is associated with alterations in gray matter networks that are indicative of incipient network breakdown towards AD dementia.


Bacteria localization and chorion thinning among preterm premature rupture of membranes.
Bacterial colonization of the fetal membranes and its role in pathogenesis of membrane rupture is poorly understood. Prior retrospective work revealed chorion layer thinning in preterm premature rupture of membranes (PPROM) subjects. Our objective was to prospectively examine fetal membrane chorion thinning and to correlate to bacterial presence in PPROM, preterm, and term subjects. Paired membrane samples (membrane rupture and membrane distant) were prospectively collected from: PPROM = 14, preterm labor (PTL = 8), preterm no labor (PTNL = 8), term labor (TL = 10), and term no labor (TNL = 8), subjects. Sections were probed with cytokeratin to identify fetal trophoblast layer of the chorion using immunohistochemistry. Fluorescence in situ hybridization was performed using broad range 16 s ribosomal RNA probe. Images were evaluated, chorion and choriodecidua were measured, and bacterial fluorescence scored. Chorion thinning and bacterial presence were compared among and between groups using Student's t-test, linear mixed effect model, and Poisson regression model (SAS Cary, NC). In all groups, the fetal chorion cellular layer was thinner at rupture compared to distant site (147.2 vs. 253.7 µm, p<0.0001). Further, chorion thinning was greatest among PPROM subjects compared to all other groups combined, regardless of site sampled [PPROM(114.9) vs. PTL(246.0) vs. PTNL(200.8) vs. TL(217.9) vs. TNL(246.5)]. Bacteria counts were highest among PPROM subjects compared to all other groups regardless of site sampled or histologic infection [PPROM(31) vs. PTL(9) vs. PTNL(7) vs. TL(7) vs. TNL(6)]. Among all subjects at both sites, bacterial counts were inversely correlated with chorion thinning, even excluding histologic chorioamnionitis (p<0.0001 and p = 0.05). Fetal chorion was uniformly thinner at rupture site compared to distant sites. In PPROM fetal chorion, we demonstrated pronounced global thinning. Although cause or consequence is uncertain, bacterial presence is greatest and inversely correlated with chorion thinning among PPROM subjects.


Does the presence of mediastinal adenopathy confer a risk for disseminated infection in immunocompetent persons with pulmonary coccidioidomycosis?
Pulmonary coccidioidomycosis is caused by inhaling airborne arthroconidia of Coccidioides, a soil-dwelling fungus endemic to the desert southwestern United States. Although uncommon, disseminated coccidioidal infection can be associated with well-defined risk factors, such as cell-mediated immunodeficiency, certain racial heritages (e.g. African or Filipino), male sex, or pregnancy. Before widespread use of computed tomography (CT), the presence or persistence of mediastinal lymphadenopathy was postulated to be a risk factor for disseminated coccidioidal infection. To investigate the use of CT scanning to identify the presence of mediastinal lymphadenopathy in patients with pulmonary coccidioidomycosis, and to correlate such lymphadenopathy with disseminated coccidioidal infection, we performed a retrospective review of patients with pulmonary coccidioidomycosis who were evaluated by chest CT. Two radiologists independently interpreted 150 CT scans from patients with pulmonary coccidioidomycosis. Forty-nine patients met CT criteria for mediastinal lymphadenopathy, whereas 101 patients did not. Disseminated coccidioidal infection was observed in 5 (10%) of the 49 patients with mediastinal lymphadenopathy and in 6 of the 101 (6%; P = .34) without such adenopathy. Among patients with coccidioidomycosis, patients with mediastinal lymphadenopathy, as assessed by CT, had a higher rate of disseminated infection, but the difference was not statistically significant.


Negative bias in interpretation and facial expression recognition in late life depression: A case control study.
While cognitive bias in younger adults with depression has been extensively researched, there have been relatively few investigations of the presence of cognitive bias in late life depression (LLD). This exploratory study aimed to ascertain whether negative cognitive bias exists across a range of cognitive domains in participants with LLD. Participants were 19 patients with LLD and 19 matched non-depressed older adults. Participants completed standardised tests to assess bias in facial expression recognition, attention, recall of adjectives and interpretation. LLD participants were slower to identify surprised faces, and more likely to create negative statements in the interpretation task. There was no evidence of negative bias in memory or attention, but participants with LLD performed more poorly on the recall task. This study provides new evidence of negative bias in interpretation in LLD, but the findings are not consistent with a global cognitive bias Further work is needed to investigate cognitive bias in LLD. It may be that interventions which target negative interpretation biases, such as cognitive bias modification, could be helpful in treating LLD.


Emergency department triage scales and their components: a systematic review of the scientific evidence.
Emergency department (ED) triage is used to identify patients' level of urgency and treat them based on their triage level. The global advancement of triage scales in the past two decades has generated considerable research on the validity and reliability of these scales. This systematic review aims to investigate the scientific evidence for published ED triage scales. The following questions are addressed: 1. Does assessment of individual vital signs or chief complaints affect mortality during the hospital stay or within 30 days after arrival at the ED?2. What is the level of agreement between clinicians' triage decisions compared to each other or to a gold standard for each scale (reliability)? 3. How valid is each triage scale in predicting hospitalization and hospital mortality? A systematic search of the international literature published from 1966 through March 31, 2009 explored the British Nursing Index, Business Source Premier, CINAHL, Cochrane Library, EMBASE, and PubMed. Inclusion was limited to controlled studies of adult patients (≥ 15 years) visiting EDs for somatic reasons. Outcome variables were death in ED or hospital and need for hospitalization (validity). Methodological quality and clinical relevance of each study were rated as high, medium, or low. The results from the studies that met the inclusion criteria and quality standards were synthesized applying the internationally developed GRADE system. Each conclusion was then assessed as having strong, moderately strong, limited, or insufficient scientific evidence. If studies were not available, this was also noted.We found ED triage scales to be supported, at best, by limited and often insufficient evidence.The ability of the individual vital signs included in the different scales to predict outcome is seldom, if at all, studied in the ED setting. The scientific evidence to assess interrater agreement (reliability) was limited for one triage scale and insufficient or lacking for all other scales. Two of the scales yielded limited scientific evidence, and one scale yielded insufficient evidence, on which to assess the risk of early death or hospitalization in patients assigned to the two lowest triage levels on a 5-level scale (validity).


Long-lasting insecticidal nets no longer effectively kill the highly resistant Anopheles funestus of southern Mozambique.
Chemical insecticides are crucial to malaria control and elimination programmes. The frontline vector control interventions depend mainly on pyrethroids; all long-lasting insecticidal nets (LLINs) and more than 80% of indoor residual spraying (IRS) campaigns use chemicals from this class. This extensive use of pyrethroids imposes a strong selection pressure for resistance in mosquito populations, and so continuous resistance monitoring and evaluation are important. As pyrethroids have also been used for many years in the Manhiça District, an area in southern Mozambique with perennial malaria transmission, an assessment of their efficacy against the local malaria vectors was conducted. Female offspring of wild-caught Anopheles funestus s.s. females were exposed to deltamethrin, lambda-cyhalothrin and permethrin using the World Health Organization (WHO) insecticide-resistance monitoring protocols. The 3-min WHO cone bioassay was used to evaluate the effectiveness of the bed nets distributed or available for purchase in the area (Olyset, permethrin LLIN; PermaNet 2.0, deltamethrin LLIN) against An. funestus. Mosquitoes were also exposed to PermaNet 2.0 for up to 8 h in time-exposure assays. Resistance to pyrethroids in An. funestus s.s. was extremely high, much higher than reported in 2002 and 2009. No exposure killed more than 25.8% of the mosquitoes tested (average mortality, deltamethrin: 6.4%; lambda-cyhalothrin: 5.1%; permethrin: 19.1%). There was no significant difference in the mortality generated by 3-min exposure to any net (Olyset: 9.3% mortality, PermaNet 2.0: 6.0%, untreated: 2.0%; p = 0.2). Six hours of exposure were required to kill 50% of the An. funestus s.s. on PermaNet 2.0. Anopheles funestus s.s. in Manhiça is extremely resistant to pyrethroids, and this area is clearly a pyrethroid-resistance hotspot. This could severely undermine vector control in this district if no appropriate countermeasures are undertaken. The National Malaria Control Programme (NMCP) of Mozambique is currently improving its resistance monitoring programme, to design and scale up new management strategies. These actions are urgently needed, as the goal of the NMCP and its partners is to reach elimination in southern Mozambique by 2020.


The "Boyfriend Loophole" and Intimate Partner Homicides: A Longitudinal Analysis Using the National Violent Death Reporting System.
Intimate partner homicides (IPHs) often occur in the context of violent relationships, and firearms often facilitate lethal outcomes. Accordingly, policies have been implemented to reduce firearm access among individuals with histories of intimate partner violence (IPV) or violent propensities. There is considerable variation, however, in the enactment and implementation of such state-level firearm protection laws. Some states fail to extend IPV-related firearm related protections to dating partners, creating what has been referred to elsewhere as the "boyfriend loophole", or what will be referred to here as the "partner loophole". The goal of this analysis was to examine trends in National Violent Death Reporting System (NVDRS) data to assess the relationship of IPHs among unmarried victims in association with state partner loopholes. State policies were abstracted to identify partner loopholes. A series of negative binomial generalized estimating equations were performed using lagged policy variables, year fixed-effects, robust standard errors, and errors clustered by state. Model findings suggest that increased firearm access is related to higher rates of unmarried IPH victimization, however, the associations between the presence of a partner loophole and IPH rates amongst unmarried victims varied between racial subgroups. Significant, protective relationships with closed partner loopholes were identified for the IPH rates amongst white unmarried victims, however, not amongst victims of color. The partner loophole policies considered here, and other individual IPV-related and/or firearm-related policies may be an important component of protections, however, our findings suggest they are not independently sufficient to equitably reduce the burden of IPH. Continuing to develop public health and policy evaluation literature will be essential to progressing towards a policy landscape and cultural environment that are equitably protective.


Δ9-Tetrahydrocannabinol Prevents Mortality from Acute Respiratory Distress Syndrome through the Induction of Apoptosis in Immune Cells, Leading to Cytokine Storm Suppression.
Acute Respiratory Distress Syndrome (ARDS) causes up to 40% mortality in humans and is difficult to treat. ARDS is also one of the major triggers of mortality associated with coronavirus-induced disease (COVID-19). We used a mouse model of ARDS induced by Staphylococcal enterotoxin B (SEB), which triggers 100% mortality, to investigate the mechanisms through which Δ9-tetrahydrocannabinol (THC) attenuates ARDS. SEB was used to trigger ARDS in C3H mice. These mice were treated with THC and analyzed for survival, ARDS, cytokine storm, and metabolome. Additionally, cells isolated from the lungs were used to perform single-cell RNA sequencing and transcriptome analysis. A database analysis of human COVID-19 patients was also performed to compare the signaling pathways with SEB-mediated ARDS. The treatment of SEB-mediated ARDS mice with THC led to a 100% survival, decreased lung inflammation, and the suppression of cytokine storm. This was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell RNA sequencing. A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment. In addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice. THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets. Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS. Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.


Increased bronchoalveolar granulocytes and granulocyte/macrophage colony-stimulating factor during exacerbations of chronic bronchitis.
Although inflammatory changes are found throughout the airways of patients with chronic bronchitis, the mechanisms of the pathogenesis of chronic bronchitis are still unclear. The aim of this study was to investigate airways inflammation in patients with and without an exacerbation of bronchitis. Thirteen chronic bronchitic patients and nine normal subjects were studied. Eight of the patients were studied under baseline conditions (B), and five during an exacerbation of bronchitis (E). Bronchoscopy and bronchoalveolar lavage (BAL) with cytological analysis were performed, and the levels of granulocyte/macrophage colony-stimulating factor (GM-CSF) were determined in sera and in BAL supernatants by a solid phase enzyme immunoassay. Compared with patients under baseline conditions, chronic bronchitic patients with an exacerbation had increased numbers of BAL neutrophils (10+/-3 and 83+/-18x10(3) cells x mL(-1), respectively; p<0.0001) and of BAL eosinophils (1.9+/-0.5 and 6.7/-1.9x10(3) cells x mL(-1), respectively; p=0.014). Patients with chronic bronchitis, as a whole, had significantly increased levels of BAL GM-CSF compared to control subjects (36+/-5 and 19+/-4 pg x mL(-1), respectively; p=0.035), and similar levels of serum GM-CSF. Serum levels of GM-CSF were markedly increased in chronic bronchitic patients with an exacerbation, as compared with patients under baseline conditions (1.4+/-0.4 and 13+/-1 pg x mL(-1), respectively; p <0.0001). BAL levels of GM-CSF were also increased in chronic bronchitic patients with an exacerbation (25+/-5 and 54+/-8 pg x mL(-1), respectively; p=0.009). During exacerbations of chronic bronchitis there are changes in the cell populations in bronchoalveolar lavage of patients consistent with a recruitment of polymorphonuclear leucocytes in the airway lumen. The increased levels of granulocyte/macrophage colony-stimulating factor might suggest a role for this cytokine in the inflammatory processes of chronic bronchitis.


Marsupials in the age of genomics.
Marsupials are "alternative mammals" that differ from eutherians most spectacularly in their mode of reproduction and sexual differentiation. They represent a 160-million-year-old isolate from the more numerous eutherians, making them particularly valuable for comparative genome studies that enlarge and enhance our understanding of the function and evolution of the mammalian genome. The genomes of three sequenced marsupial species are similar in size to those of mice and humans but show informative differences in base composition and repetitive elements. Small differences in gene sets and gene families between marsupials and eutherians may relate to physiological and environmental differences. Marsupial karyotypes are highly conserved in chromosome numbers, sizes, and G-banding patterns, and an ancestor with a 2n = 14 karyotype can be deduced. Marsupial sex chromosomes, partly homologous to those of eutherians, represent the ancestral therian XY pair. Epigenetic regulation of X inactivation in marsupials differs markedly from that of eutherians and has apparently retained an ancient silencing mechanism. Genomic imprinting of a smaller set of genes occurs in the marsupial placenta and, uniquely, in the mammary gland.


Model acquisition and invariant tracking of unknown materials in hyperspectral images.
We consider the problem of acquiring models for unknown materials in airborne 0.4-2.5 microm hyperspectral imagery and using these models to identify the unknown materials in image data obtained under significantly different conditions. The material models are generated with use of an airborne sensor spectrum measured under unknown conditions and a physical model for spectral variability. For computational efficiency, the material models are represented by using low-dimensional spectral subspaces. We demonstrate the effectiveness of the material models by using a set of material tracking experiments in HYDICE images acquired in forest and desert environments over widely varying conditions. We show that techniques based on the new representation significantly outperform methods based on direct spectral matching.


Sensory, somatomotor and internal mentation networks emerge dynamically in the resting brain with internal mentation predominating in older age.
Age-related changes in the brain are associated with a decline in functional flexibility. Intrinsic functional flexibility is evident in the brain's dynamic ability to switch between alternative spatiotemporal states during resting state. However, the relationship between brain connectivity states, associated psychological functions during resting state, and the changes in normal aging remain poorly understood. In this study, we analyzed resting-state functional magnetic resonance imaging (rsfMRI) data from the Human Connectome Project (HCP; N = 812) and the UK Biobank (UKB; N = 6,716). Using signed community clustering to identify distinct states of dynamic functional connectivity, and text-mining of a large existing literature for functional annotation of each state, our findings from the HCP dataset indicated that the resting brain spontaneously transitions between three functionally specialized states: sensory, somatomotor, and internal mentation networks. The occurrence, transition-rate, and persistence-time parameters for each state were correlated with behavioural scores using canonical correlation analysis. We estimated the same brain states and parameters in the UKB dataset, subdivided into three distinct age ranges: 50-55, 56-67, and 68-78 years. We found that the internal mentation network was more frequently expressed in people aged 71 and older, whereas people younger than 55 more frequently expressed sensory and somatomotor networks. Furthermore, analysis of the functional entropy - a measure of uncertainty of functional connectivity - also supported this finding across the three age ranges. Our study demonstrates that dynamic functional connectivity analysis can expose the time-varying patterns of transition between functionally specialized brain states, which are strongly tied to increasing age.


Glutathione-S-Transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility.
Several polymorphic genes have been reported to be possibly involved in modifying lung cancer risk in smokers. The gene GSTM1 is frequently deleted in human populations, and the null genotype has been reported to be a risk factor for developing lung carcinoma. A germline polymorphism of p53 with a single-base change at codon 72 that causes an amino acid replacement of arginine (Arg; CGC) by proline (PRO; CCC) has also been reported to be associated with cancer susceptibility in a Japanese population. Both polymorphisms were genotyped by PCR in a northwestern Mediterranean healthy population (n = 147) and in a group of lung cancer patients (n = 139). The results showed that the frequency of the GSTM1 null genotype was higher in the lung cancer patients compared to the controls [odds ratio (OR), 1.57; 95% confidence interval (CI), 0.99-2.51]. The histological subtypes most clearly modified were small cell carcinoma (OR, 1.89; CI, 0.97-3.65) and adenocarcinoma (OR, 1.93; CI, 0.90-4.14). The null GSTM1 genotype was more frequent among those cancer patients who were medium/ light smokers (< or = 50 pack-years) and in those who showed an onset of the disease at a more advanced age. The study of the p53 polymorphism in the healthy population showed allele frequencies of 0.79 (Arg) and 0.21 (Pro). The frequencies found in the lung cancer patients were statistically similar. Both polymorphisms were studied together, and the relative risk of the combination null GSTM1 and Pro/Pro or Arg/Pro genotypes was calculated taking the combination of GTSM1 + together with Arq/Arg as a baseline. The OR found (1.97; CI, 1.03-3.73) suggests that the Pro allele of the p53 germline polymorphism may slightly increase the risk fo the GSTM1 null genotype among smokers.


Return to play after anterior cruciate ligament reconstruction in major league baseball athletes.
The purpose of the study was to (1) investigate the rate of return to play among Major League Baseball (MLB) athletes after anterior cruciate ligament reconstruction (ACLR), (2) determine the impact of ACL injury on ability to perform baseball-specific planting and pivoting tasks (batting and stealing bases), and (3) to explore the effect of the injured side on these metrics. ACL injury data from 1999 to 2012 were compiled, along with player performance statistics recorded for players with at least 30 games before ACL injury. Predictor variables included side of injury and outcome variables focused on batting average, stolen bases, and number of times caught stealing before injury and after surgery. Twenty-three of 26 (88%) players were able to return to at least 30 games after ACLR, although they experienced a decline of 21.2% in number of games played (P = .004). Those who had a ACLR for a rear batting leg injury averaged a 12.3% decline in batting average, whereas those who had ACLR for a lead leg injury had a 6.4% increase in batting average (P = .04). Side of injury was not predictive of stolen base metrics. The overall rate of return to play among MLB position players after ACLR was 88%, although there was a 21.2% decline in the number of games played postoperatively. Injury to the rear batting leg resulted in a lower returning batting average compared with an injury to the lead batting leg. Side of injury had no effect on stolen bases or on the number of times a player was caught stealing. Level IV, therapeutic case series.


Cognitive functions in primary central nervous system lymphoma: literature review and assessment guidelines.
Treatment-related neurotoxicity has been recognized as a significant problem in patients with primary central nervous system lymphoma (PCNSL) as effective treatment has increased survival rates. There is, however, a paucity of research on cognitive functions in this population. In a review of the literature, a total of 17 articles that described cognitive outcome in adult PCNSL patients were identified. The studies that assessed cognitive functions after whole-brain radiotherapy combined with chemotherapy reported cognitive impairment in most patients. Patients treated with chemotherapy alone had either stable or improved cognitive performance in most studies. Methodological problems, however, limited the ability to ascertain the specific contribution of disease and various treatment interventions to cognitive outcome. On the basis of the literature review, a battery of cognitive and quality-of-life (QoL) measures to be used in prospective clinical trials was proposed. The battery is composed of five standardized neuropsychological tests, covering four domains sensitive to disease and treatment effects (attention, executive functions, memory, psychomotor speed), and QoL questionnaires, and meets criteria for use in collaborative trials. The incorporation of formal and systematic cognitive evaluations in PCNSL studies will improve our understanding of treatment-related neurotoxicity in this population.


New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.


Henoch-Schönlein Purpura in the Adult, a Case Report.
This case report describes a dermatologic finding that is not typical in the adult population, but may be medically significant. A 39-year-old female patient with a past medical history that was negative for autoimmune disorders, vasculitides, or chronic infectious disease presented to our emergency department for evaluation of a painful rash on the bilateral lower extremities. She complained of two days of worsening raised, erythematous, pruritic and painful patches around both ankles, some of which had opened to become weeping sores. There was surrounding edema of both extremities. She denied any systemic symptoms. Online literature, primarily UpToDate was reviewed, and it was suspected that her rash may have been Henoch-Schönlein Purpura (HSP), given her lack of other medical history and a visual appearance that seemed consistent with the condition. To evaluate for renal involvement and systemic inflammation, labs were drawn and were grossly unremarkable except for a mild elevation in her C-reactive protein with a level of 37.6 mg/L. She was treated with intravenous (IV) hydration and IV ketorolac, with resultant symptomatic improvement. Since she did not have any apparent systemic involvement, she was discharged to follow up with rheumatology, with a recommendation to take over the counter non-steroidal anti-inflammatory drugs (NSAIDs). The patient was ultimately seen by rheumatology several months later, and a biopsy of the lesions demonstrated what appeared to be Henoch-Schönlein Purpura given her clinical presentation. Henoch-Schönlein Purpura can occur in adults, however rare, requiring close follow-up since in the adult population, it may result in renal failure and need for dialysis. Rash, Henoch-Schönlein purpura, dermatology, nephrology, rheumatology, vasculitis.


What Is the Frequency of Noise Generation in Modern Knee Arthroplasty and Is It Associated With Residual Symptoms?
Prior investigations have recognized the presence of patient-perceived noise generation after total knee arthroplasty (TKA). However, questions remain regarding its overall frequency after both TKA and unicompartmental knee arthroplasty (UKA) as well as with respect to its association with demographic and prosthesis-related factors and its association with patient-reported outcomes. The purposes of this study were (1) to determine the frequency with which patients report noise coming from the knee after TKA or UKA; (2) to identify patient and prosthesis-related factors associated with noise generation; and (3) to ascertain whether noise coming from the knee is associated with residual symptoms after knee arthroplasty. A five-center survey study was designed to identify patient-perceived noise and to quantify the degree of residual symptoms and functional deficits in patients after TKA or UKA. Data were collected by an independent, third-party survey center, which administered questions about residual symptoms, function, and pre- and postoperative activity levels. Patients meeting prespecified inclusion criteria were specifically questioned regarding perceived noises from their knee within the last 30 days; those who reported hearing noises sometimes, often, or extremely often were categorized as positive. We retrospectively identified 2671 patients who underwent TKA and 744 patients who underwent UKA and who met inclusion criteria; the final survey population included 1580 patients who underwent TKA and 476 patients who underwent UKA (68% response rate). TKA implant types included cruciate-retaining (59%), posterior-stabilized (16%), rotating-platform (13%), gender-specific (7%), and high-flex (5%). Differences in baseline demographic variables were accounted for using multiple logistic regression statistical analyses. Chi square analyses were used to compare the frequency of residual symptoms in those patients with and without noise generation. Overall, 27% (557 of 2056; 95% confidence interval [CI], 25-29) of all patients undergoing knee arthroplasty reported hearing grinding, popping, or clicking from their operative knee in the last 30 days. Men (odds ratio [OR], 1.3; 95% CI, 1.0-1.6; p = 0.02) and younger patients (χ2 [df = 7] = 67.3; p < 0.001) were more likely to report noise generation. After controlling for potential confounding variables, noise generation was more common after TKA (29%) than UKA (21%; OR, 1.5; 95% CI, 1.2-2.0; p < 0.001). Among TKA designs, the likelihood of noise generation was greater in posterior-stabilized (41%; OR, 2.5; 95% CI, 1.8-3.7; p < 0.001), rotating-platform (45%; OR, 2.8; 95% CI, 1.9-4.2; p < 0.001), and gender-specific (36%; OR, 2.0; 95% CI, 1.2-3.2; p = 0.007) designs than in cruciate-retaining (23%) knees. Patient-perceived noise generation was associated with residual symptoms, including difficulty getting in and out of a chair (38% versus 25%, p < 0.001), limp (39% versus 25%, p < 0.001), swelling (42% versus 24%, p < 0.001), and stiffness (40% versus 23%, p < 0.001) compared with those who did not report noise generation after TKA. Patients frequently perceive noises coming from the knee after arthroplasty, more so in TKA than UKA. Patients reporting noises from the knee were more likely to report functional limitations and the presence of a limp, swelling, and stiffness. Surgeons should inform patients preoperatively of this possibility, because unmet patient expectations are known to negatively impact patient satisfaction after surgery. Subsequent investigations should focus on determining if there is a causal relationship between noise generation and residual symptoms after knee arthroplasty. Level III, therapeutic study.


RNase E and HupB dynamics foster mycobacterial cell homeostasis and fitness.
RNA turnover is a primary source of gene expression variation, in turn promoting cellular adaptation. Mycobacteria leverage reversible mRNA stabilization to endure hostile conditions. Although RNase E is essential for RNA turnover in several species, its role in mycobacterial single-cell physiology and functional phenotypic diversification remains unexplored. Here, by integrating live-single-cell and quantitative-mass-spectrometry approaches, we show that RNase E forms dynamic foci, which are associated with cellular homeostasis and fate, and we discover a versatile molecular interactome. We show a likely interaction between RNase E and the nucleoid-associated protein HupB, which is particularly pronounced during drug treatment and infection, where phenotypic diversity increases. Disruption of RNase E expression affects HupB levels, impairing Mycobacterium tuberculosis growth homeostasis during treatment, intracellular replication, and host spread. Our work lays the foundation for targeting the RNase E and its partner HupB, aiming to undermine M. tuberculosis cellular balance, diversification capacity, and persistence.


Allelic variation in HLA-B and HLA-C sequences and the evolution of the HLA-B alleles.
Several new HLA-B (B8, B51, Bw62)- and HLA-C (Cw6, Cw7)-specific genes were isolated either as genomic cosmid or cDNA clones to study the diversity of HLA antigens. The allele specificities were identified by sequence analysis in comparison with published HLA-B and -C sequences, by transfection experiments, and Southern and northern blot analysis using oligonucleotide probes. Comparison of the classical HLA-A, -B, and -C sequences reveals that allele-specific substitutions seem to be rare events. HLA-B51 codes only for one allele-specific residue: arginine at position 81 located on the alpha 1 helix, pointing toward the antigen binding site. HLA-B8 contains an acidic substitution in amino acid position 9 on the first central beta sheet which might affect antigen binding capacity, perhaps in combination with the rare replacement at position 67 (F) on the alpha 1 helix. HLA-B8 shows greatest homology to HLA-Bw42, -Bw41, -B7, and -Bw60 antigens, all of which lack the conserved restriction sites Pst I at position 180 and Sac I at position 131. Both sites associated with amino acid replacements seem to be genetic markers of an evolutionary split of the HLA-B alleles, which is also observed in the leader sequences. HLA-Cw7 shows 98% sequence identity to the JY328 gene. In general, the HLA-C alleles display lower levels of variability in the highly polymorphic regions of the alpha 1 and alpha 2 domains, and have more distinct patterns of locus-specific residues in the transmembrane and cytoplasmic domains. Thus we propose a more recent origin for the HLA-C locus.


Rates of claims for cumulative trauma disorder of the upper extremity in Ontario workers during 1997.
Surveillance of work-related cumulative trauma disorder of the upper extremity (CTDUE) requires valid and reliable claim extraction strategies and should examine for confounding and interaction. This research estimated crude and specific rates of CTDUE claims in Ontario workers during 1997 while acknowledging misclassification and testing for confounding and interaction. Lower and upper limit event estimates were obtained by means of an algorithm applied to the Ontario Workplace Safety and Insurance Board (OWSIB) database and were combined with "at-risk" estimates obtained from the Canadian Labour Force Survey (LFS). Poisson regression was used to evaluate confounding and interaction. The method used to identify CTDUE claims had a substantial impact on the magnitude of rates, female to male rate ratios, the most commonly affected part of the upper extremity and the highest risk occupational categories. Poisson regression identified sex interactions. It allowed rigorous evaluation of the data and indicated that rates should be examined separately for men and women. Researchers should clearly define extraction strategies and examine the impact of misclassification.


RNA Intereference: a powerful laboratory tool and its therapeutic implications.
Ever since RNA interference (RNAi) was discovered in the early 1990s, a number of scientists from the academic and biotechnology world have continued to view it as the revolutionary discovery of the century. Unequivocally, RNAi can be considered as an important regulator of gene expression in many eukaryotic cells. The term RNAi describes a natural process by which a double-stranded RNA molecule, when introduced into the cell is processed into short RNA duplexes and drives gene silencing by specific and distinct mechanisms. Many of the players involved in this cellular defense network have been elucidated but a more complete understanding of the process is essential. Worldwide interest on RNAi in the last decade is mainly attributed to its power as a laboratory tool for the experimental manipulation of gene expression. RNAi assisted already in the dissection of numerous cellular pathways and revealed the role of many proteins in an approach aimed to drug discovery. This new technology has the potential to improve our understanding of physiologic and pathologic processes and lead to the discovery of new drugs. More importantly, there is growing interest among the scientific community for the potential therapeutic applications of RNAi.


Age-related variations in hematologic and plasma biochemical test results in Beagles and Labrador Retrievers.
To investigate age-related variations in results of hematologic and plasma biochemical tests performed on dogs of 2 common breeds. Prospective cohort study. 34 Beagles and 44 Labrador Retrievers. Blood samples were collected throughout the dogs' lives; 589 samples were collected from the Beagles and 964 samples were collected from the Labrador Retrievers (age at the time of sample collection ranged from 22 days to 15 years). White blood cell and RBC counts; hemoglobin concentration; Hct; mean cell volume; mean cell hemoglobin concentration; alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase activities; and calcium, phosphorus, cholesterol, urea, protein, and albumin concentrations were measured. For all tests, there were significant effects of age on test results. There was a significant interaction between age and breed for all tests except hemoglobin, albumin, and phosphorus concentrations. Results suggested that there were age-related changes in hematologic and plasma biochemical test results in these 2 breeds of dogs. Changes were most evident during the first year of life, reflecting growth and maturation of the puppies. In some instances, values for puppies diverged markedly from those for adults, necessitating the use of age-specific reference ranges for the interpretation of clinical data.


Therapeutic angiogenesis for critical limb ischemia: design of the hepatocyte growth factor therapeutic angiogenesis clinical trial.
The objective of the HGF-STAT clinical trial is to determine whether perfusion can be improved by gene transfer with a plasmid DNA containing hepatocyte growth factor (HGF) in the affected limb of patients with unreconstructable critical limb ischemia (CLI). CLI results in a high rate of limb loss and impaired quality of life. The current therapeutic strategies, including bypass surgery and percutaneous interventions, are only successful in treating a subset of patients. Therapeutic angiogenesis is an investigational method that seeks to favorably impact tissue perfusion in CLI. HGF-STAT is a double-blind, parallel-group, placebo-controlled, dose-response study in 100 patients with unreconstructable CLI. Eligible subjects will be randomized 1:1:1:1 to receive saline placebo or one of three dose/regimens of HGF plasmid DNA. The selection of outcome measures, including the primary endpoint, and changes in transcutaneous oxygen pressure (TcPO2) from baseline to 3 months will be discussed. In conclusion, this study will help to determine whether therapeutic angiogenesis with HGF is a viable option in the treatment of patients with CLI.


MicroRNAs in Esophageal Adenocarcinoma: Functional Significance and Potential for the Development of New Molecular Disease Markers.
Esophageal adenocarcinoma (EAC) originates from the neoplastic changes in the esophageal epithelium. Barrett's esophagus (BE) precedes EAC. In BE metaplasia, the normal stratified squamous epithelium is replaced by the intestinal columnar epithelium. Esophageal metaplasia might further progress to dysplasia, neoplasia, and EAC. The neoplastic progression from BE to EAC is accompanied with marked histological and molecular changes including deregulation of key signaling pathways and expression of various genes including microRNA (miRNA). To date, stable and progressive changes in expression levels of different miRNA subsets are shown for each stage of EAC carcinogenesis. This suggests that miRNAs might become promising markers for BE/EAC diagnosis and prognosis of survival of EAC patients and lymph node tumor metastases. Development of new molecular markers based on the assessment of miRNAs circulating in patients' biofluids would improve the effectiveness and cost-effectiveness of esophageal cancer surveillance regimens and open new possibilities for high throughput screening programs to identify BE patients who are at high-risk for the development of highgrade dysplasia or progression to EAC.


Secondary mapping of lymphatic filariasis in Haiti-definition of transmission foci in low-prevalence settings.
To eliminate Lymphatic filariasis (LF) as a public health problem, the World Health Organization (WHO) recommends that any area with infection prevalence greater than or equal to 1% (denoted by presence of microfilaremia or antigenemia) should receive mass drug administration (MDA) of antifilarial drugs for at least five consecutive rounds. Areas of low-antigen prevalence (< 1%) are thought to pose little risk for continued transmission of LF. Five low-antigen prevalence communes in Haiti, characterized as part of a national survey, were further assessed for transmission in this study. An initial evaluation of schoolchildren was performed in each commune to identify antigen-positive children who served as index cases for subsequent community surveys conducted among households neighboring the index cases. Global positioning system (GPS) coordinates and immunochromatographic tests (ICT) for filarial antigenemia were collected on approximately 1,600 persons of all ages in the five communes. The relationship between antigen-positive cases in the community and distance from index cases was evaluated using multivariate regression techniques and analyses of spatial clustering. Community surveys demonstrated higher antigen prevalence in three of the five communes than was observed in the original mapping survey; autochthonous cases were found in the same three communes. Regression techniques identified a significantly increased likelihood of being antigen-positive when living within 20 meters of index cases when controlling for age, gender, and commune. Spatial clustering of antigen-positive cases was observed in some, but not all communes. Our results suggest that localized transmission was present even in low-prevalence settings and suggest that better surveillance methods may be needed to detect microfoci of LF transmission.


Integrative analyses of speciation and divergence in Psammodromus hispanicus (Squamata: Lacertidae).
Genetic, phenotypic and ecological divergence within a lineage is the result of past and ongoing evolutionary processes, which lead ultimately to diversification and speciation. Integrative analyses allow linking diversification to geological, climatic, and ecological events, and thus disentangling the relative importance of different evolutionary drivers in generating and maintaining current species richness. Here, we use phylogenetic, phenotypic, geographic, and environmental data to investigate diversification in the Spanish sand racer (Psammodromus hispanicus). Phylogenetic, molecular clock dating, and phenotypic analyses show that P. hispanicus consists of three lineages. One lineage from Western Spain diverged 8.3 (2.9-14.7) Mya from the ancestor of Psammodromus hispanicus edwardsianus and P. hispanicus hispanicus Central lineage. The latter diverged 4.8 (1.5-8.7) Mya. Molecular clock dating, together with population genetic analyses, indicate that the three lineages experienced northward range expansions from southern Iberian refugia during Pleistocene glacial periods. Ecological niche modelling shows that suitable habitat of the Western lineage and P. h. edwardsianus overlap over vast areas, but that a barrier may hinder dispersal and genetic mixing of populations of both lineages. P. h. hispanicus Central lineage inhabits an ecological niche that overlaps marginally with the other two lineages. Our results provide evidence for divergence in allopatry and niche conservatism between the Western lineage and the ancestor of P. h. edwardsianus and P. h. hispanicus Central lineage, whereas they suggest that niche divergence is involved in the origin of the latter two lineages. Both processes were temporally separated and may be responsible for the here documented genetic and phenotypic diversity of P. hispanicus. The temporal pattern is in line with those proposed for other animal lineages. It suggests that geographic isolation and vicariance played an important role in the early diversification of the group, and that lineage diversification was further amplified through ecological divergence.


A histologic study of the biocompatibility of a dentinal bonding system.
To assess the biocompatibility of an adhesive system, standard Class V cavities were prepared in vivo in human premolars that were to be extracted for orthodontic purposes. Histologic observation revealed that the Gluma Bond System elicited slight to severe pulpal responses, altered odontoblastic layers, and inhibited dentinogenesis. These alterations were observed after in vivo periods of up to 120 days. In this experiment, the dentinal adhesive was polymerized separately from the composite resin, a procedure not recommended by the manufacturer. This may explain the differences in the present results and those reported by the manufacturer.


Modulation of flagellum attachment zone protein FLAM3 and regulation of the cell shape in Trypanosoma brucei life cycle transitions.
The cell shape of Trypanosoma brucei is influenced by flagellum-to-cell-body attachment through a specialised structure - the flagellum attachment zone (FAZ). T. brucei exhibits numerous morphological forms during its life cycle and, at each stage, the FAZ length varies. We have analysed FLAM3, a large protein that localises to the FAZ region within the old and new flagellum. Ablation of FLAM3 expression causes a reduction in FAZ length; however, this has remarkably different consequences in the tsetse procyclic form versus the mammalian bloodstream form. In procyclic form cells FLAM3 RNAi results in the transition to an epimastigote-like shape, whereas in bloodstream form cells a severe cytokinesis defect associated with flagellum detachment is observed. Moreover, we demonstrate that the amount of FLAM3 and its localisation is dependent on ClpGM6 expression and vice versa. This evidence demonstrates that FAZ is a key regulator of trypanosome shape, with experimental perturbations being life cycle form dependent. An evolutionary cell biology explanation suggests that these differences are a reflection of the division process, the cytoskeleton and intrinsic structural plasticity of particular life cycle forms.


Age-related macular degeneration in the aspect of chronic low-grade inflammation (pathophysiological parainflammation).
The products of oxidative stress trigger chronic low-grade inflammation (pathophysiological parainflammation) process in AMD patients. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, CFH, CD35, and CD46. The complement system, mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD, especially in the Y402H gene polymorphism, which causes hypofunction/lack of the protective complement factor H (CFH) and facilitates chronic inflammation mediated by C-reactive protein (CRP). Microglial activation induces photoreceptor cells injury and leads to the development of dry AMD. Many autoantibodies (antibodies against alpha beta crystallin, alpha-actinin, amyloid, C1q, chondroitin, collagen I, collagen III, collagen IV, elastin, fibronectin, heparan sulfate, histone H2A, histone H2B, hyaluronic acid, laminin, proteoglycan, vimentin, vitronectin, and aldolase C and pyruvate kinase M2) and overexpression of Fcc receptors play role in immune-mediated inflammation in AMD patients and in animal model. Macrophages infiltration of retinal/choroidal interface acts as protective factor in early AMD (M2 phenotype macrophages); however it acts as proinflammatory and proangiogenic factor in advanced AMD (M1 and M2 phenotype macrophages).


The impact of prison-based treatment on sex offender recidivism: evidence from Minnesota.
Using a retrospective quasi-experimental design, this study evaluates the effectiveness of prison-based treatment by examining recidivism outcomes among 2,040 sex offenders released from Minnesota prisons between 1990 and 2003 (average follow-up period of 9.3 years). To reduce observed selection bias, the authors used propensity score matching to create a comparison group of 1,020 untreated sex offenders who were not significantly different from the 1,020 treated offenders. In addition, intent-to-treat analyses and the Rosenbaum bounds method were used to test the sensitivity of the findings to treatment refuser and unobserved selection bias. Results from the Cox regression analyses revealed that participating in treatment significantly reduced the hazard ratio for rearrest by 27% for sexual recidivism, 18% for violent recidivism, and 12% for general recidivism. These findings are consistent with the growing body of research supporting the effectiveness of cognitive-behavioral treatment for sex offenders.


On clustering fMRI time series.
Analysis of fMRI time series is often performed by extracting one or more parameters for the individual voxels. Methods based, e.g., on various statistical tests are then used to yield parameters corresponding to probability of activation or activation strength. However, these methods do not indicate whether sets of voxels are activated in a similar way or in different ways. Typically, delays between two activated signals are not identified. In this article, we use clustering methods to detect similarities in activation between voxels. We employ a novel metric that measures the similarity between the activation stimulus and the fMRI signal. We present two different clustering algorithms and use them to identify regions of similar activations in an fMRI experiment involving a visual stimulus.


North American Contact Dermatitis Group patch test results: 2009 to 2010.
Patch testing is an important diagnostic tool for determination of substances responsible for allergic contact dermatitis. This study reports the North American Contact Dermatitis Group (NACDG) patch testing results from January 1, 2009, to December 31, 2010. At 12 centers in North America, patients were tested in a standardized manner with a screening series of 70 allergens. Data were manually verified and entered into a central database. Descriptive frequencies were calculated, and trends were analyzed using χ2 statistics. A total of 4308 patients were tested. Of these, 2614 (60.7%) had at least 1 positive reaction, and 2284 (46.3%) were ultimately determined to have a primary diagnosis of allergic contact dermatitis. Four hundred twenty-seven (9.9%) patients had occupationally related skin disease. There were 6855 positive allergic reactions. As compared with the previous reporting period (2007-2008), the positive reaction rates statistically decreased for 20 allergens (nickel, neomycin, Myroxylon pereirae, cobalt, formaldehyde, quaternium 15, methydibromoglutaronitrile/phenoxyethanol, methylchlorisothiazolinone/methylisothiazolinone, potassium dichromate, diazolidinyl urea, propolis, dimethylol dimethylhydantoin, 2-bromo-2-nitro-1,3-propanediol, methyl methacrylate, ethyl acrylate, glyceryl thioglycolate, dibucaine, amidoamine, clobetasol, and dimethyloldihydroxyethyleneurea; P < 0.05) and statistically increased for 4 allergens (fragrance mix II, iodopropynyl butylcarbamate, propylene glycol, and benzocaine; P < 0.05). Approximately one quarter of tested patients had at least 1 relevant allergic reaction to a non-NACDG allergen. Hypothetically, approximately one quarter of reactions detected by NACDG allergens would have been missed by TRUE TEST (SmartPractice Denmark, Hillerød, Denmark). These results affirm the value of patch testing with many allergens.


Is aircraft noise exposure associated with cardiovascular disease and hypertension? Results from a cohort study in Athens, Greece.
We followed up, in 2013, the subjects who lived near the Athens International Airport and had participated in the cross-sectional multicountry HYENA study in 2004-2006. To evaluate the association of exposure to aircraft and road traffic noise with the incidence of hypertension and other cardiovascular outcomes. From the 780 individuals who participated in the cross-sectional study, 537 were still living in the same area and 420 accepted to participate in the follow-up. Aircraft and road traffic noise exposure was based on the estimations conducted in 2004-2006, linking geocoded residential addresses of the participants to noise levels. We applied multiple logistic regression and Cox proportional hazards models, adjusting for potential confounders. The incidence of hypertension was significantly associated with higher aircraft noise exposure during the night. Specifically, the OR for hypertension per 10 dB increase in Lnight aircraft noise exposure was 2.63 (95% CI 1.21 to 5.71). Doctor-diagnosed cardiac arrhythmia was significantly associated with Lnight aircraft noise exposure, when prevalent and incident cases were considered with an OR of 2.09 (95% CI 1.07 to 4.08). Stroke risk was also increased with increasing noise exposure but the association was not significant. Twenty-four-hour road traffic noise associations with the outcomes considered were weaker and less consistent. In conclusion, our cohort study suggests that long-term exposure to aircraft noise, particularly during the night, is associated with incident hypertension and possibly, also, cardiovascular effects.


Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: a randomized double-blind placebo controlled trial.
Axonal sensory peripheral neuropathy is the major dose-limiting side effect of paclitaxel.Omega-3 fatty acids have beneficial effects on neurological disorders from their effects on neurons cells and inhibition of the formation of proinflammatory cytokines involved in peripheral neuropathy. This study was a randomized double blind placebo controlled trial to investigate the efficacy of omega-3 fatty acids in reducing incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN). Eligible patients with breast cancer randomly assigned to take omega-3 fatty acid pearls, 640 mg t.i.d during chemotherapy with paclitaxel and one month after the end of the treatment or placebo. Clinical and electrophysiological studies were performed before the onset of chemotherapy and one month after cessation of therapy to evaluate PIPN based on "reduced Total Neuropathy Score". Twenty one patients (70%) of the group taking omega-3 fatty acid supplement (n = 30) did not develop PN while it was 40.7%( 11 patients) in the placebo group(n = 27). A significant difference was seen in PN incidence (OR = 0.3, .95% CI = (0.10-0.88), p = 0.029). There was a non-significant trend for differences of PIPN severity between the two study groups but the frequencies of PN in all scoring categories were higher in the placebo group (0.95% CI = (-2.06 -0.02), p = 0.054). Omega-3 fatty acids may be an efficient neuroprotective agent for prophylaxis against PIPN. Patients with breast cancer have a longer disease free survival rate with the aid of therapeutical agents. Finding a way to solve the disabling effects of PIPN would significantly improve the patients' quality of life. This trial was registered at ClinicalTrials.gov (NCT01049295).


The Bioelectric Code: Reprogramming Cancer and Aging From the Interface of Mechanical and Chemical Microenvironments.
Cancer is a complex, heterogeneous group of diseases that can develop through many routes. Broad treatments such as chemotherapy destroy healthy cells in addition to cancerous ones, but more refined strategies that target specific pathways are usually only effective for a limited number of cancer types. This is largely due to the multitude of physiological variables that differ between cells and their surroundings. It is therefore important to understand how nature coordinates these variables into concerted regulation of growth at the tissue scale. The cellular microenvironment might then be manipulated to drive cells toward a desired outcome at the tissue level. One unexpected parameter, cellular membrane voltage (Vm), has been documented to exert control over cellular behavior both in culture and in vivo. Manipulating this fundamental cellular property influences a remarkable array of organism-wide patterning events, producing striking outcomes in both tumorigenesis as well as regeneration. These studies suggest that Vm is not only a key intrinsic cellular property, but also an integral part of the microenvironment that acts in both space and time to guide cellular behavior. As a result, there is considerable interest in manipulating Vm both to treat cancer as well as to regenerate organs damaged or deteriorated during aging. However, such manipulations have produced conflicting outcomes experimentally, which poses a substantial barrier to understanding the fundamentals of bioelectrical reprogramming. Here, we summarize these inconsistencies and discuss how the mechanical microenvironment may impact bioelectric regulation.


HIV-1 phenotypic reverse transcriptase inhibitor drug resistance test interpretation is not dependent on the subtype of the virus backbone.
To date, the majority of HIV-1 phenotypic resistance testing has been performed with subtype B virus backbones (e.g. HXB2). However, the relevance of using this backbone to determine resistance in non-subtype B HIV-1 viruses still needs to be assessed. From 114 HIV-1 subtype C clinical samples (36 ARV-naïve, 78 ARV-exposed), pol amplicons were produced and analyzed for phenotypic resistance using both a subtype B- and C-backbone in which the pol fragment was deleted. Phenotypic resistance was assessed in resulting recombinant virus stocks (RVS) for a series of antiretroviral drugs (ARV's) and expressed as fold change (FC), yielding 1660 FC comparisons. These Antivirogram® derived FC values were categorized as having resistant or sensitive susceptibility based on biological cut-off values (BCOs). The concordance between resistance calls obtained for the same clinical sample but derived from two different backbones (i.e. B and C) accounted for 86.1% (1429/1660) of the FC comparisons. However, when taking the assay variability into account, 95.8% (1590/1660) of the phenotypic data could be considered as being concordant with respect to their resistance call. No difference in the capacity to detect resistance associated with M184V, K103N and V106M mutations was noted between the two backbones. The following was concluded: (i) A high level of concordance was shown between the two backbone phenotypic resistance profiles; (ii) Assay variability is largely responsible for discordant results (i.e. for FC values close to BCO); (iii) Confidence intervals should be given around the BCO's, when assessing resistance in HIV-1 subtype C; (iv) No systematic resistance under- or overcalling of subtype C amplicons in the B-backbone was observed; (v) Virus backbone subtype sequence variability outside the pol region does not contribute to phenotypic FC values. In conclusion the HXB2 virus backbone remains an acceptable vector for phenotyping HIV-1 subtype C pol amplicons.


Prospective international cohort study demonstrates inability of interim PET to predict treatment failure in diffuse large B-cell lymphoma.
The International Atomic Energy Agency sponsored a large, multinational, prospective study to further define PET for risk stratification of diffuse large B-cell lymphoma and to test the hypothesis that international biological diversity or diversity of healthcare systems may influence the kinetics of treatment response as assessed by interim PET (I-PET). Cancer centers in Brazil, Chile, Hungary, India, Italy, the Philippines, South Korea, and Thailand followed a common protocol based on treatment with R-CHOP (cyclophosphamide, hydroxyadriamycin, vincristine, prednisolone with rituximab), with I-PET after 2-3 cycles of chemotherapy and at the end of chemotherapy scored visually. Two-year survivals for all 327 patients (median follow-up, 35 mo) were 79% (95% confidence interval [CI], 74%-83%) for event-free survival (EFS) and 86% (95% CI, 81%-89%) for overall survival (OS). Two hundred ten patients (64%) were I-PET-negative, and 117 (36%) were I-PET-positive. Two-year EFS was 90% (95% CI, 85%-93%) for I-PET-negative and 58% (95% CI, 48%-66%) for I-PET-positive, with a hazard ratio of 5.31 (95% CI, 3.29-8.56). Two-year OS was 93% (95% CI, 88%-96%) for I-PET-negative and 72% (95% CI, 63%-80%) for I-PET-positive, with a hazard ratio of 3.86 (95% CI, 2.12-7.03). On sequential monitoring, 192 of 312 (62%) patients had complete response at both I-PET and end-of-chemotherapy PET, with an EFS of 97% (95% CI, 92%-98%); 110 of these with favorable clinical indicators had an EFS of 98% (95% CI, 92%-100%). In contrast, the 107 I-PET-positive cases segregated into 2 groups: 58 (54%) achieved PET-negative complete remission at the end of chemotherapy (EFS, 86%; 95% CI, 73%-93%); 46% remained PET-positive (EFS, 35%; 95% CI, 22%-48%). Heterogeneity analysis found no significant difference between countries for outcomes stratified by I-PET. This large international cohort delivers 3 novel findings: treatment response assessed by I-PET is comparable across disparate healthcare systems, secondly a negative I-PET findings together with good clinical status identifies a group with an EFS of 98%, and thirdly a single I-PET scan does not differentiate chemoresistant lymphoma from complete response and cannot be used to guide risk-adapted therapy.


Predictors of visual outcome following surgical resection of medial sphenoid wing meningiomas.
Objective Medial sphenoid wing meningiomas (SWMs) are relatively common tumors that are associated with significant morbidity and mortality, primarily from their anatomic proximity to many critical neurological and vascular structures. A major complication is visual deterioration. This study aimed to identify predictors of visual outcome following medial SWM resection. Design Retrospective, stepwise multivariate proportional hazards regression analysis. Setting Johns Hopkins Hospital. Participants All patients who underwent medial SWM resection from 1998 to 2009. Main Outcome Measures Visual function. Results Sixty-five medial SWM resections were performed. After multivariate proportional hazards regression analysis, preoperative visual decline (relative risk [RR] 95% confidence interval [CI]; 13.431 [2.601 to 46.077], p = 0.006), subtotal resection (RR [95% CI]; 3.717 [1.204 to 13.889], p = 0.02), and repeat surgery (RR [95% CI]; 5.681 [1.278 to 19.802], p = 0.03) were found to be independent predictors of visual decline at last follow-up. Tumor recurrence and postoperative radiation therapy trended toward, but did not reach statistical significance. Conclusion These findings advocate for early and aggressive surgical intervention for patients with medial SWMs to maximize the likelihood of subsequent visual preservation. This may provide patients and physicians with prognostic information that may guide medical and surgical therapy for patients with medial SWMs.


Participative approach to elicit water quality monitoring needs from stakeholder groups - An application of integrated watershed management.
Water quality monitoring programs (WQMPs) must be based on monitoring objectives originating from the real knowledge needs of all stakeholders in a watershed and users of the resource. This paper proposes a participative approach to elicit knowledge needs and preferred modes of communication from citizens and representatives of organized stakeholders (ROS) on water quality and quantity issues. The participative approach includes six steps and is adaptable and transferable to different types of watersheds. These steps are: (1) perform a stakeholder analysis; (2) conduct an adaptable survey accompanied by a user-friendly public participation geographical information system (PPGIS); (3) hold workshops to meet with ROS to inform them of the results of the survey and PPGIS; discuss attainment of past monitoring objectives; exchange views on new knowledge needs and concerns on water quality and quantity; (4) meet with citizens to obtain the same type of input (as from ROS); (5) analyze the data and information collected to identify new knowledge needs and modes of communication and (6) identify, in collaboration with the individuals in charge of the WQMPs, the short-, medium- and long-term monitoring objectives and communication strategies to be pursued. The participative approach was tested on two distinct watersheds in the province of Quebec, Canada. It resulted in a series of optimization objectives of the existing WQMPs, new monitoring objectives and recommendations regarding communication strategies of the WQMPs' results. The results of this study show that the proposed methodology is appreciated by all parties and that the outcomes and monitoring objectives are acceptable. We also conclude that successful integrated watershed management is a question of scale, and that every aspect of integrated watershed management needs to be adapted to the surface watershed, the groundwater watershed (aquifers) and the human catchment area.


Bright-field in situ hybridization for HER2 gene amplification in breast cancer using tissue microarrays: correlation between chromogenic (CISH) and automated silver-enhanced (SISH) methods with patient outcome.
HER2 gene amplification or overexpression occurs in 15% to 25% of breast cancers and has implications for treatment and prognosis. The most commonly used methods for HER2 testing are fluorescence in situ hybridization (FISH) and immunohistochemistry. FISH is considered to be the reference standard and more accurately predicts response to trastuzumab, but is technically demanding, expensive, and requires specialized equipment. In situ hybridization is required to be eligible for adjuvant treatment with trastuzumab in Australia. Bright-field in situ hybridization is an alternative to FISH and uses a combination of in situ methodology and a peroxidase-mediated chromogenic substrate such as diaminobenzidine [chromogenic in situ hybridization (CISH)] or multimer technology coupled with enzyme metallography [silver-enhanced in situ hybridization (SISH)] to create a marker visible under bright-field microscopy. CISH was introduced into diagnostic testing in Australia in October 2006. SISH methodology is a more recent introduction into the testing repertoire. An evaluation of CISH and SISH performance to assess patient outcome were performed using tissue microarrays. Tissue microarrays were constructed in duplicate using material from 593 patients with invasive breast carcinoma and assessed using CISH and SISH. Gene amplification was assessed using the American Society of Clinical Oncology/College of American Pathologists guideline and Australian HER2 Advisory Board criteria (single probe: diploid, 1 to 2.5 copies/nucleus; polysomy >2.5 to 4 copies/nucleus; equivocal, >4 to 6 copies/nucleus; low-level amplification, >6 to 10 copies/nucleus and high-level amplification >10 copies/nucleus; dual probe HER2/CHR17 ratio: nonamplified <1.8, equivocal 1.8 to 2.2, amplified >2.2). Results were informative for 337 tissue cores comprising 230 patient samples. Concordance rates were 96% for HER2 single probe CISH and SISH and 95.5% for single probe CISH and dual probe HER2/CHR17 SISH. Both bright-field methods correlated with immunohistochemistry results and with breast cancer-specific survival. HER2 SISH testing combines the advantages of automation and bright-field microscopy to facilitate workflow within the laboratory, improves turnaround time, and correlates with patient outcome.