Reducing unnecessary biopsies while detecting clinically significant prostate cancer including cribriform growth with the ERSPC Rotterdam risk calculator and 4Kscore.
The use of risk calculators predicting clinically significant prostate cancer (csCaP) on biopsy reduces unnecessary biopsies and overdiagnosis of indolent disease compared to a Prostate Specific Antigen (PSA) strategy. Updating these tools using more specific outcome measures and contemporary predictors could potentially lead to further reductions. Our objective was to assess clinical impact of the 4 kallikrein (4K) score, the Rotterdam Prostate Cancer Risk Calculator (RPCRC), and the combination of both for predicting csCaP based on the latest International Society of Urological Pathology grading system and cribriform growth pattern. Our prospective cohort consisted of 2,872 men from the first screening round in the European Randomized Study of Screening for Prostate Cancer Rotterdam; biopsy indication PSA ≥ 3.0. The predictive performance of the 4Kscore, RPCRC, and the combination of RPCRC with 4Kscore were assessed with area under the receiver operator characteristic curve (AUC) and calibration plots. Decision curve analysis was used to evaluate the reduction of unnecessary biopsy and indolent CaP. The csCaP was present in 242 (8%) men, and indolent CaP in 578 (20%). The 4Kscore and RPCRC had similar high AUCs (0.88 vs. 0.87; P = 0.41). The 4Kscore-RPCRC combination improved AUC to 0.89 compared to 4Kscore (P < 0.01) and RPCRC (P < 0.01). The RPCRC and 4Kscore reduced the number of Bx with 42 and 44, respectively, per 100 men at risk compared to a ≥PSA 3.0 strategy without increasing missed csCaP. The RPCRC-4Kscore combination resulted in a slight additional net reduction of 3.3 biopsies per 100 men. The RPCRC and 4Kscore had similar reductions of unnecessary biopsies and overdiagnosis of indolent disease. Combination of both models slightly reduced unnecessary biopsies further. Gain in net benefit must, however, be weighed against additional costs and availability of tests.


Echocardiographic variables as prognostic indicators and therapeutic monitors in chronic congestive heart failure. Veterans Affairs cooperative studies V-HeFT I and II. V-HeFT VA Cooperative Studies Group.
Echocardiographic indexes of ventricular function have become indispensable in clinical cardiology but have not been tested as prognostic markers or therapeutic monitors in clinical trials. In two Veterans Administration trials on heart failure (Vasodilator-Heart Failure Trials I and II, V-HeFT I and II), echocardiographic variables were analyzed as predictors and monitors and were compared with other indicators of cardiac performance. Echocardiograms were recorded before randomization and at follow-up intervals. Baseline measurements of left ventricular internal diameters (LVIDd, LVIDs), wall thickness (THd, THs), radius to thickness ratios (Rd/THd, Rs/THs), and mitral E-point septal separation (EPSS) were evaluated as predictors of mortality individually, in multivariate regression models with each other, and with nonechocardiographic predictors. Within-subject changes were compared between treatment groups. Cumulative survival curves were compared between strata formed by cut-points of EPSS and Rs/THs data. In Cox regression analyses, EPSS, LVIDs, and Rs/THs were significant predictors of mortality. In V-HeFT I, Rd/THd was a predictor in the presence of ejection fraction and peak oxygen uptake. In patients with EPSS > or = 21, there was an 83% increase in mortality in the subgroup of patients with Rs/THs > or = 2.5 compared with Rs/THs < 2.5 (p = 0.003), whereas there was no statistical difference for EPSS < 21. EPSS showed improvement in patients treated with hydralazine-isosorbide dinitrate compared with placebo at 2 and 18 months and a trend toward deterioration between 36 and 66 months. In V-HeFT II, there were no differences between enalapril and hydralazine-isosorbide dinitrate groups at follow-up. Echocardiographic variables, EPSS, LVIDs, and Rs/THs were shown to be predictors of mortality and monitors of treatment for heart failure in clinical trials.


ECEIM consensus statement on equine metabolic syndrome.
Equine metabolic syndrome (EMS) is a widely recognized collection of risk factors for endocrinopathic laminitis. The most important of these risk factors is insulin dysregulation (ID). Clinicians and horse owners must recognize the presence of these risk factors so that they can be targeted and controlled to reduce the risk of laminitis attacks. Diagnosis of EMS is based partly on the horse's history and clinical examination findings, and partly on laboratory testing. Several choices of test exist which examine different facets of ID and other related metabolic disturbances. EMS is controlled mainly by dietary strategies and exercise programs that aim to improve insulin regulation and decrease obesity where present. In some cases, pharmacologic aids might be useful. Management of an EMS case is a long-term strategy requiring diligence and discipline by the horse's carer and support and guidance from their veterinarians.


Detection of bcr-abl fusion in chronic myelogeneous leukemia by in situ hybridization.
Chronic myelogeneous leukemia (CML) is genetically characterized by fusion of the bcr and abl genes on chromosomes 22 and 9, respectively. In most cases, the fusion involves a reciprocal translocation t(9;22)(q34;q11), which produces the cytogenetically distinctive Philadelphia chromosome (Ph1). Fusion can be detected by Southern (DNA) analysis or by in vitro amplification of the messenger RNA from the fusion gene with polymerase chain reaction (PCR). These techniques are sensitive but cannot be applied to single cells. Two-color fluorescence in situ hybridization (FISH) was used with probes from portions of the bcr and abl genes to detect the bcr-abl fusion in individual blood and bone marrow cells from six patients. The fusion event was detected in all samples analyzed, of which three were cytogenetically Ph1-negative. One of the Ph1-negative samples was also PCR-negative. This approach is fast and sensitive, and provides potential for determining the frequency of the abnormality in different cell lineages.


Biodisk: a new device for closure of patent foramen ovale: a feasibility study in swine.
To evaluate the feasibility, effectiveness, and safety of a porcine small intestinal submucosa (SIS)-covered Biodisk (BD) for the closure of patent foramen ovale (PFO) in swine. Twelve piglets (9-30 kg) with PFO ranging in size from 6 to 12 mm were used for the in vivo testing. The BD device consisted of two basic nitinol wire components covered with platinum coil, a flexible SIS-covered ring, and an anchor. The BD was advanced through an 8-Fr sheath from the femoral vein. Nine acute animals were used to test the BD for deployment, stability, immediate shunt closure, and device repositioning before or after its detachment. To assess retrievability, four devices were deployed and intentionally embolized into the RA (n = 2) and LA (n = 2). The effectiveness of the device was evaluated by angiocardiography. EKG was recorded before and after PFO closure for 3 hr. From the 12 animals, nine were acute and three were followed; one for 6 weeks, one for 12 weeks, and one for 16 weeks. Successful device implantation was achieved in all animals with no shunting of contrast media observed during follow-up in. One animal needed to have device repositioned for complete PFO occlusion because of suboptimal placement at the first attempt. The device was easily placed and retrieved before detachment in all nine animals in the acute study. None of the BDs spontaneously embolized during release or on follow-up. EKG did not demonstrate arrhythmias during or after treatment. Four intentionally embolized BDs were easily retrieved with an Amplatz goose neck snare. Macroscopic and histologic evaluation of the three long-term animals showed that devices were well incorporated in the atrial septum with complete shunt closure. The SIS showed progressive remodeling with the host cells. There was also progressive endothelization of the BD device. The BD device deployment is feasible, safe, and effective. Long-term studies are needed to evaluate its long-term effectiveness.


Noninvasive markers of fibrosis for longitudinal assessment of fibrosis in chronic liver disease: are they ready for prime time?
Over the past decade, there has been a renewed enthusiasm to develop noninvasive serum markers or tests to assess the presence and severity of fibrosis in chronic liver disease. Although a single marker or test has lacked the necessary accuracy to predict fibrosis, different combinations of these markers or tests have shown encouraging results. However, inter-laboratory variability and inconsistent results with liver diseases of varying etiologies have made it difficult to assess the reliability of these markers in clinical practice. In this issue of the journal, Poynard et al. describe the "histological" response to lamivudine in patients with chronic Hepatitis B Virus (HBV) over a 24-month period using surrogate serum biomarkers (Fibrotest-Actitest, FT-AT) without corroborating histological data. Investigators found improvement in fibrosis and inflammation in 85% and 91%, respectively, despite the emergence of YMDD mutation in 41.5% of patients. The higher improvement rates reported in this study should be interpreted with caution for a number of reasons including the absence of data on virological response rates, corroboratory histological data, and data on the validity of FT to evaluate fibrosis in a longitudinal manner. Although FT has been studied extensively by the authors of the current study, to date there are only few independent studies. In addition to significant inter-laboratory variations, these studies have shown that significant fibrosis could be missed, or conversely significant fibrosis diagnosed in the absence of minimal or no fibrosis in about 15% to 20% of patients. We may be approaching a time when serum biomarkers may become an integral part of the assessment of patients with chronic liver disease, but published evidence suggests that these markers are not yet ready for prime time.


The Quest for Selectivity in Hydrogen Atom Transfer Based Aliphatic C-H Bond Oxygenation.
Aliphatic C-H bond functionalization is at the frontline of research because it can provide straightforward access to simplified and cost-effective synthetic procedures. A number of these methodologies are based on hydrogen atom transfer (HAT), which, as a consequence of the inert character of C-H bonds, often represents the most challenging step of the overall process. Because the majority of organic molecules contain multiple nonequivalent C-H bonds that display similar chemical properties, differentiating between these bonds with high levels of selectivity represents one of the most challenging issues. Clarification of the factors that govern the relative reactivity of C-H bonds toward HAT reagents is thus of primary importance in order to develop selective functionalization procedures. In this Account we describe, through the combination of kinetic studies employing a genuine HAT reagent such as the cumyloxyl radical, along with oxidations performed with H2O2 and iron or manganese catalysts, our contribution toward the development of selective C-H functionalization methodologies. Despite the different nature of these reagents, an oxygen-centered radical and a metal-oxo species, congruent reactivity and selectivity patterns have emerged, providing strong evidence that both reactions proceed via HAT. Consequently, selectivity in this class of metal catalyzed C-H oxidations can be reasonably predicted and synthetically exploited. Amides have been identified as preferential functional groups for governing selectivity on the basis of electronic, steric, and stereoelectronic effects. Torsional effects have proven moreover to be particularly important C-H directing factors in the oxidation of cyclohexane scaffolds where a delicate balance of these effects, in synergistic combination with catalyst design, enables highly chemoselective and enantioselective oxidations. Medium effects have been also shown to govern the relative HAT reactivity of C-H bonds in proximity to polar, hydrogen bond acceptor (HBA) functional groups. By engaging in hydrogen bonding with these groups, fluorinated alcohols strongly deactivate proximal C-H bonds toward HAT-based oxidation. As a result, alcohols, ethers, amines, and amides, which are electron rich and effective proximal C-H activating groups toward HAT reagents in conventional solvents, become oxidatively robust deactivating functionalities that direct C-H oxidation toward remote positions. These deactivating effects enable moreover the accomplishment of product chemoselective methylenic hydroxylations. Overall, clarification of the factors that govern HAT-based reactions has served to provide unique examples of catalytic methodologies for chemoselective and enantioselective oxidation of nonactivated aliphatic C-H bonds of potential utility in organic synthesis.


Complementary roles of different oscillatory activities in the subthalamic nucleus in coding motor effort in Parkinsonism.
The basal ganglia may play an important role in the control of motor scaling or effort. Recently local field potential (LFP) recordings from patients with deep brain stimulation electrodes in the basal ganglia have suggested that local increases in the synchronisation of neurons in the gamma frequency band may correlate with force or effort. Whether this feature uniquely codes for effort and whether such a coding mechanism holds true over a range of efforts is unclear. Here we investigated the relationship between frequency-specific oscillatory activities in the subthalamic nucleus (STN) and manual grips made with different efforts. The latter were self-rated using the 10 level Borg scale ranging from 0 (no effort) to 10 (maximal effort). STN LFP activities were recorded in patients with Parkinson's Disease (PD) who had undergone functional surgery. Patients were studied while motor performance was improved by dopaminergic medication. In line with previous studies we observed power increase in the theta/alpha band (4-12 Hz), power suppression in the beta band (13-30 Hz) and power increase in the gamma band (55-90 Hz) and high frequency band (101-375 Hz) during voluntary grips. Beta suppression deepened, and then reached a floor level as effort increased. Conversely, gamma and high frequency power increases were enhanced during grips made with greater effort. Multiple regression models incorporating the four different spectral changes confirmed that the modulation of power in the beta band was the only independent predictor of effort during grips made with efforts rated <5. In contrast, increases in gamma band activity were the only independent predictor of effort during grips made with efforts ≥5. Accordingly, the difference between power changes in the gamma and beta bands correlated with effort across all effort levels. These findings suggest complementary roles for changes in beta and gamma band activities in the STN in motor effort coding. The latter function is thought to be impaired in untreated PD where task-related reactivity in these two bands is deficient.


Introduction: Gonadotropin-releasing hormone agonist triggering of final follicular maturation for in vitro fertilization.
These Views and Reviews articles examine the use of GnRH agonist for triggering the final stage of follicular maturation in IVF, resulting in excellent follicle maturation. An advantage of the GnRH agonist trigger is the ability to retrieve oocytes in high responders, yet markedly reducing the risk of ovarian hyperstimulation syndrome (OHSS). However, the induction of early luteolysis after the GnRH agonist trigger requires the use of aggressive steroidal luteal support or low-dose hCG to allow successful fresh ET and live birth. With the enhanced effectiveness of vitrification, segmentation in GnRH agonist-triggered cycles with freezing all embryos for transfer in subsequent cycles may be the optimal strategy for eliminating OHSS.


Association between ferritin, high sensitivity C-reactive protein (hsCRP) and relative abundance of Hepcidin mRNA with the risk of type 2 diabetes in obese subjects.
Obesity and Type 2 diabetes mellitus share a strong pro-inflammatory profile. It has been observed that iron is a risk factor in the development of type 2 diabetes. The aim of this study was to evaluate the relationship between iron nutritional status and inflammation with the risk of type 2 diabetes development in obese subjects. We studied 30 obese men with type 2 diabetes (OBDM); 30 obese subjects without diabetes (OB) and 30 healthy subjects (Cn). We isolated peripheral mononuclear cells (PMCs) and challenged them with high Fe concentrations. Total mRNA was isolated and relative abundance of TNF-, IL-6 and hepcidin were determined by qPCR. Iron status, biochemical, inflammatory and oxidative stress parameters were also characterized. OBDM and OB patients showed increased hsCRP levels compared to the Cn group. OBDM subjects showed higher levels of ferritin than the Cn group. TNF-α and IL-6 mRNA relative abundances were increased in OBDM PMCs treated with high/Fe. Hepcidin mRNA was increased with basal and high iron concentration. We found that the highest quartile of ferritin was associated with an increased risk of type 2 diabetes when it was adjusted to BMI and HOMA-IR; this association was independent of the inflammatory status. The highest level of hepcidin gene expression also showed a trend of increased risk of diabetes, however it was not significant. Levels of hsCRP over 2 mg/L showed a significant trend of increasing the risk of diabetes. In conclusion, iron may stimulate the expression of pro-inflammatory genes (TNF-α and IL- 6), and both hepcidin and ferritin gene expression levels could be a risk factor for the development of type 2 diabetes. Subjects that have an increased cardiovascular risk also have a major risk to develop type 2 diabetes, which is independent of the BMI and insulin resistance state.


Direct health care costs after traumatic spinal cord injury.
The objective was to quantify direct health care costs attributable to traumatic spinal cord injury (SCI). This population-based cohort study followed individuals with SCI from date of injury to 6 years postinjury. SCI cases were matched to a comparison group randomly selected from the general population. Administrative data from a Canadian province with a universal publicly funded health care system and centralized health databases were used. Costs included hospitalizations, physician services, home care, and long-term care. Attributable costs in the first year were $121,600 (2002 $CDN) per person with a complete SCI, and $42,100 per person with an incomplete injury. In the subsequent 5 years, annual costs were $5,400 and $2,800 for persons with complete and incomplete SCIs, respectively. Direct costs in the first year after SCI are substantial. In the subsequent 5 years, individuals with SCI will continue to accrue greater costs than the general public.


How HIV affects health and service use for adults with intellectual and developmental disabilities.
Although rates of human immunodeficiency virus (HIV) are similar for individuals with and without intellectual and developmental disabilities (IDD), very little is known about the health needs and service use of those with IDD and HIV. Among a population with IDD, we compared the physical and mental health profiles, as well as general and mental health service use for those with and without HIV. Retrospective cohort study in Ontario, Canada using linked administrative health and social service databases. The prevalence of physical conditions and mental health disorders, and patterns of service use for any reason and service use for mental health issues were compared among Ontario adults with IDD and HIV (n = 107) and without HIV (n = 63 901) in log-binomial models adjusted for age, sex and neighbourhood income and rurality. Adults with IDD and HIV were more likely than those without HIV to have three types of mental health disorders: non-psychotic disorders [aRR: adjusted rate ratio (aRR): 1.22 (95% confidence interval (CI): 1.01-1.47)], psychotic disorders [aRR: 1.57 (1.09, 2.28)] and substance use disorders [aRR: 3.52 (2.53, 4.91)]. Adults with IDD and HIV were also more likely to have emergency department visits [aRR: 1.68 (1.42, 1.98)] and hospital admissions [aRR: 2.55 (1.74, 3.73)] for any reason, and to have mental health emergency department visits and/or admissions [aRR: 2.82 (1.90, 4.18)]. Adults with IDD and HIV have complex health profiles and greater health service use than HIV-negative adults with IDD. These findings call for closer integration of programs delivered by the HIV and disability sectors to optimise the health of this patient population.


Morphological and immunocytochemical characteristics indicate the yield of early progenitors and represent a quality control for human mesenchymal stem cell culturing.
Human mesenchymal stem cells (hMSC) are a heterogeneous cell population, which is reflected in varying morphological and biological properties. Three subpopulations with intrinsic characteristics can be distinguished: small rapidly self-renewing cells, spindle-shaped cells and large, flattened cells. Unfortunately, it has neither been possible to morphologically define these distinct cells consistently, nor to relate them to specific surface marker features. Here, the primary hMSC subpopulations of three donors are clearly defined by maximum cell diameter and area. Furthermore, these cells were stained for the putative hMSC surface markers CD105, CD90 as well as CD73, and evaluated by three-colour flow cytometry and simultaneous multicolour immunocytochemistry. Interestingly, cell cultures with a high rate of triple-positive hMSC featured a higher content of rapidly self-renewing cells. On the other hand, a higher fraction of flattened cells correlated with a loss of one or more hMSC surface markers. The expression of CD73 showed the highest heterogeneity. Immunocytochemistry further confirmed that flattened cells mainly lack CD73 expression, whereas rapidly self-renewing cells were steadily positive for all three hMSC markers. In the literature, hMSC properties are especially conceded to rapidly self-renewing cells, whereas flattened cells have been suggested to represent early stages of lineage-specific progenitors. We reveal that among the recently suggested surface markers, CD73 is the most sensitive, as it seems to be down-regulated in the early stages of differentiation. Our morphological and immunocytochemical characterization of hMSC subpopulations indicates the yield of early multipotent hMSC and thereby provides a quality control approach for hMSC culturing.


Using mobile phone data to predict the spatial spread of cholera.
Effective response to infectious disease epidemics requires focused control measures in areas predicted to be at high risk of new outbreaks. We aimed to test whether mobile operator data could predict the early spatial evolution of the 2010 Haiti cholera epidemic. Daily case data were analysed for 78 study areas from October 16 to December 16, 2010. Movements of 2.9 million anonymous mobile phone SIM cards were used to create a national mobility network. Two gravity models of population mobility were implemented for comparison. Both were optimized based on the complete retrospective epidemic data, available only after the end of the epidemic spread. Risk of an area experiencing an outbreak within seven days showed strong dose-response relationship with the mobile phone-based infectious pressure estimates. The mobile phone-based model performed better (AUC 0.79) than the retrospectively optimized gravity models (AUC 0.66 and 0.74, respectively). Infectious pressure at outbreak onset was significantly correlated with reported cholera cases during the first ten days of the epidemic (p < 0.05). Mobile operator data is a highly promising data source for improving preparedness and response efforts during cholera outbreaks. Findings may be particularly important for containment efforts of emerging infectious diseases, including high-mortality influenza strains.


Novel prodrug-like fusion toxin with protease-sensitive bioorthogonal PEGylation for tumor targeting.
Highly potent biotoxins like Pseudomonas exotoxin A (ETA) are attractive payloads for tumor targeting. However, despite replacement of the natural cell-binding domain of ETA by tumor-selective antibodies or alternative binding proteins like designed ankyrin repeat proteins (DARPins) the therapeutic window of such fusion toxins is still limited by target-independent cellular uptake, resulting in toxicity in normal tissues. Furthermore, the strong immunogenicity of the bacterial toxin precludes repeated administration in most patients. Site-specific modification to convert ETA into a prodrug-like toxin which is reactivated specifically in the tumor, and at the same time has a longer circulation half-life and is less immunogenic, is therefore appealing. To engineer a prodrug-like fusion toxin consisting of the anti-EpCAM DARPin Ec1 and a domain I-deleted variant of ETA (ETA″), we used strain-promoted azide alkyne cycloaddition for bioorthogonal conjugation of linear or branched polyethylene glycol (PEG) polymers at defined positions within the toxin moiety. Reversibility of the shielding was provided by a designed peptide linker containing the cleavage site for the rhinovirus 3C model protease. We identified two distinct sites, one within the catalytic domain and one close to the C-terminal KDEL sequence of Ec1-ETA″, simultaneous PEGylation of which resulted in up to 1000-fold lower cytotoxicity in EpCAM-positive tumor cells. Importantly, the potency of the fusion toxin was fully restored by proteolytic unveiling. Upon systemic administration in mice, PEGylated Ec1-ETA″ was much better tolerated than Ec1-ETA″; it showed a longer circulation half-life and an almost 10-fold increased area under the curve (AUC). Our strategy of engineering prodrug-like fusion toxins by bioorthogonal veiling opens new possibilities for targeting tumors with more specificity and efficacy.


Thermodynamic Hydricity of Transition Metal Hydrides.
Transition metal hydrides play a critical role in stoichiometric and catalytic transformations. Knowledge of free energies for cleaving metal hydride bonds enables the prediction of chemical reactivity, such as for the bond-forming and bond-breaking events that occur in a catalytic reaction. Thermodynamic hydricity is the free energy required to cleave an M-H bond to generate a hydride ion (H(-)). Three primary methods have been developed for hydricity determination: the hydride transfer method establishes hydride transfer equilibrium with a hydride donor/acceptor pair of known hydricity, the H2 heterolysis method involves measuring the equilibrium of heterolytic cleavage of H2 in the presence of a base, and the potential-pKa method considers stepwise transfer of a proton and two electrons to give a net hydride transfer. Using these methods, over 100 thermodynamic hydricity values for transition metal hydrides have been determined in acetonitrile or water. In acetonitrile, the hydricity of metal hydrides spans a range of more than 50 kcal/mol. Methods for using hydricity values to predict chemical reactivity are also discussed, including organic transformations, the reduction of CO2, and the production and oxidation of hydrogen.


Nutrition prescription to achieve positive outcomes in chronic kidney disease: a systematic review.
In Chronic Kidney Disease (CKD), management of diet is important in prevention of disease progression and symptom management, however evidence on nutrition prescription is limited. Recent international CKD guidelines and literature was reviewed to address the following question "What is the appropriate nutrition prescription to achieve positive outcomes in adult patients with chronic kidney disease?" Databases included in the search were Medline and CINAHL using EBSCOhost search engine, Embase and the Cochrane Database of Systematic Reviews published from 2000 to 2009. International guidelines pertaining to nutrition prescription in CKD were also reviewed from 2000 to 2013. Three hundred and eleven papers and eight guidelines were reviewed by three reviewers. Evidence was graded as per the National Health and Medical Research Council of Australia criteria. The evidence from thirty six papers was tabulated under the following headings: protein, weight loss, enteral support, vitamin D, sodium, fat, fibre, oral nutrition supplements, nutrition counselling, including protein and phosphate, nutrients in peritoneal dialysis solution and intradialytic parenteral nutrition, and was compared to international guidelines. While more evidence based studies are warranted, the customary nutrition prescription remains satisfactory with the exception of Vitamin D and phosphate. In these two areas, additional research is urgently needed given the potential of adverse outcomes for the CKD patient.


Relationships between bone geometry, volumetric bone mineral density and bone microarchitecture of the distal radius and tibia with alcohol consumption.
Chronic heavy alcohol consumption is associated with bone density loss and increased fracture risk, while low levels of alcohol consumption have been reported as beneficial in some studies. However, studies relating alcohol consumption to bone geometry, volumetric bone mineral density (vBMD) and bone microarchitecture, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), are lacking. Here we report an analysis from the Hertfordshire Cohort Study, in which we studied associations between HR-pQCT measures at the distal radius and tibia and alcohol consumption in 376 participants (198 men and 178 women) aged 72.1-81.4 years. A total of 30 (15.2%), 90 (45.5%) and 78 (39.4%) men drank minimal/none (<1 unit/week), low (≥1 unit/week and <11 units/week) and moderate/high (≥11 units/week) amounts of alcohol respectively. These figures were 74 (41.8%), 80 (45.2%) and 23 (13.0%) respectively in women for minimal/none (<1 unit/week), low (≥1 unit/week and <8 units/week) and moderate/high (≥8 units/week). At the distal radius, after adjustment for confounding factors (age, BMI, smoking status, dietary calcium intake, physical activity and socioeconomic status and years since menopause and HRT use for women), men that drank low alcohol had lower cortical thickness (p=0.038), cortical vBMD (p=0.033), and trabecular vBMD (p=0.028) and higher trabecular separation (p=0.043) than those that drank none/minimal alcohol. Similar differences were shown between minimal/none and moderate/high alcohol although these only reached statistical significance for the cortical parameters. Interestingly, after similar adjustment, women showed similar differences in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia. However, women that drank moderate/high alcohol had significantly higher trabecular vBMD (p=0.007), trabecular thickness (p=0.026), and trabecular number (p=0.042) and higher trabecular separation (p=0.026) at the distal radius than those that drank low alcohol. Our results suggest that alcohol consumption (low and moderate/high) may have a detrimental impact on bone health in men in both the cortical and trabecular compartments at the distal radius with similar results in women in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia suggesting that avoidance of alcohol may be beneficial for bone health.


Connexin Signaling Is Involved in the Reactivation of a Latent Stem Cell Niche after Spinal Cord Injury.
The ependyma of the adult spinal cord is a latent stem cell niche that is reactivated by spinal cord injury contributing new cells to the glial scar. The cellular events taking place in the early stages of the reaction of the ependyma to injury remain little understood. Ependymal cells are functionally heterogeneous with a mitotically active subpopulation lining the lateral domains of the central canal (CC) that are coupled via gap junctions. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. Thus, we hypothesized that communication via connexins in the CC is developmentally regulated and may play a part in the reactivation of this latent stem cell niche after injury. To test these possibilities, we combined patch-clamp recordings of ependymal cells with immunohistochemistry for various connexins in the neonatal and the adult (P > 90) normal and injured spinal cord of male and female mice. We find that coupling among ependymal cells is downregulated as postnatal development proceeds but increases after injury, resembling the immature CC. The increase in gap junction coupling in the adult CC was paralleled by upregulation of connexin 26, which correlated with the resumption of proliferation and a reduction of connexin hemichannel activity. Connexin blockade reduced the injury-induced proliferation of ependymal cells. Our findings suggest that connexins are involved in the early reaction of ependymal cells to injury, representing a potential target to improve the contribution of the CC stem cell niche to repair.SIGNIFICANCE STATEMENT Ependymal cells in the adult spinal cord are latent progenitors that react to injury to support some degree of endogenous repair. Understanding the mechanisms by which these progenitor-like cells are regulated in the aftermath of spinal cord injury is critical to design future manipulations aimed at improving healing and functional recovery. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. We find here that connexin signaling in the ependyma changes after injury of the adult spinal cord, functionally resembling the immature active-stem cell niche of neonatal animals. Our findings suggest that connexins in ependymal cells are potential targets to improve self-repair of the spinal cord.


Magnetic resonance imaging localization with cod liver oil capsules for the minimally invasive approach to small intradural extramedullary tumors of the thoracolumbar spine.
Accurate intraoperative localization of small intradural extramedullary thoracolumbar (T-1 to L-3 level) spinal cord tumors is vital when minimally invasive techniques, such as hemilaminectomy, are used to excise these lesions. In this study, the authors describe a simple and effective method of preoperative MRI localization of small intradural extramedullary tumors using cod liver oil capsules. Thirty-five patients with intradural tumors underwent preoperative MRI localization the evening prior to surgery. Patients were positioned prone in the MRI gantry, mimicking the intraoperative position. Nine capsules were placed in 3 rows to cover the lesion. This localization was used to guide the level for a minimally invasive approach using a hemilaminectomy to excise these tumors. The mean patient age was 51.5 ± 14.3 years, and the mean body mass index was 24.1 ± 3.5 kg/m(2). Twenty-two tumors involved the thoracic spine, and 13 involved the upper lumbar spine from L-1 to L-3. The mean tumor size was 2.2 ± 1.0 cm. Localization was accurate in 34 patients (97.1%). Accurate localization with the described method is quick, safe, cost-effective, and noninvasive with no exposure to radiation. It also reduces operating time by eliminating the need for intraoperative fluoroscopy.


Management of uncomplicated malaria in febrile under five-year-old children by community health workers in Madagascar: reliability of malaria rapid diagnostic tests.
Early diagnosis, as well as prompt and effective treatment of uncomplicated malaria, are essential components of the anti-malaria strategy in Madagascar to prevent severe malaria, reduce mortality and limit malaria transmission. The purpose of this study was to assess the performance of the malaria rapid diagnostic tests (RDTs) used by community health workers (CHWs) by comparing RDT results with two reference methods (microscopy and Polymerase Chain Reaction, PCR). Eight CHWs in two districts, each with a different level of endemic malaria transmission, were trained to use RDTs in the management of febrile children under five years of age. RDTs were performed by CHWs in all febrile children who consulted for fever. In parallel, retrospective parasitological diagnoses were made by microscopy and PCR. The results of these different diagnostic methods were analysed to evaluate the diagnostic performance of the RDTs administered by the CHWs. The stability of the RDTs stored by CHWs was also evaluated. Among 190 febrile children with suspected malaria who visited CHWs between February 2009 and February 2010, 89.5% were found to be positive for malaria parasites by PCR, 51.6% were positive by microscopy and 55.8% were positive by RDT. The performance accuracy of the RDTs used by CHWs in terms of sensitivity, specificity, positive and negative predictive values was greater than 85%. Concordance between microscopy and RDT, estimated by the Kappa value was 0.83 (95% CI: 0.75-0.91). RDTs stored by CHWs for 24 months were capable of detecting Plasmodium falciparum in blood at a level of 200 parasites/μl. Introduction of easy-to-use diagnostic tools, such as RDTs, at the community level appears to be an effective strategy for improving febrile patient management and for reducing excessive use of anti-malarial drugs.


Type specimens on deposit in the United States department of agriculture nematode collection, beltsville, Maryland.
A list of the deposited type specimens with references, a detailed historical background, importance, and maintenance procedures are given for the type collection of the United States Department of Agriculture Nematode Collection (USDANC). The type specimen section is considered one of the largest and most valuable in existence. It contains 1,430 species mounted and preserved on 5,177 metal and glass slides and 404 vials. Also, a brief description of the other constituent divisions of the collection is given, which, including the type collection, consists of 34,000 permanent slides and vials and 19,500 species entries. The list of deposited types is a type specimen location reference only and should not be used for the status of type species. The generic and specific names are arranged in alphabetical order and are given as indicated by the author(s) or depositor(s) when the types were deposited in the type section of the USDANC. The complete title of the reference is not given for each species, only the author's date, and source and slide number(s). Also, included are authors of designated types other than those of the original type series, e.g. paralectotype, allolectotype, neotype.


Decoupling of the minority PhD talent pool and assistant professor hiring in medical school basic science departments in the US.
Faculty diversity is a longstanding challenge in the US. However, we lack a quantitative and systemic understanding of how the career transitions into assistant professor positions of PhD scientists from underrepresented minority (URM) and well-represented (WR) racial/ethnic backgrounds compare. Between 1980 and 2013, the number of PhD graduates from URM backgrounds increased by a factor of 9.3, compared with a 2.6-fold increase in the number of PhD graduates from WR groups. However, the number of scientists from URM backgrounds hired as assistant professors in medical school basic science departments was not related to the number of potential candidates (R2=0.12, p>0.07), whereas there was a strong correlation between these two numbers for scientists from WR backgrounds (R2=0.48, p<0.0001). We built and validated a conceptual system dynamics model based on these data that explained 79% of the variance in the hiring of assistant professors and posited no hiring discrimination. Simulations show that, given current transition rates of scientists from URM backgrounds to faculty positions, faculty diversity would not increase significantly through the year 2080 even in the context of an exponential growth in the population of PhD graduates from URM backgrounds, or significant increases in the number of faculty positions. Instead, the simulations showed that diversity increased as more postdoctoral candidates from URM backgrounds transitioned onto the market and were hired.


Crystal structure of a heterodimeric ABC transporter in its inward-facing conformation.
ATP-binding cassette (ABC) transporters shuttle a wide variety of molecules across cell membranes by alternating between inward- and outward-facing conformations, harnessing the energy of ATP binding and hydrolysis at their nucleotide binding domains (NBDs). Here we present the 2.9-Å crystal structure of the heterodimeric ABC transporter TM287-TM288 (TM287/288) from Thermotoga maritima in its inward-facing state. In contrast to previous studies, we found that the NBDs only partially separate, remaining in contact through an interface involving conserved motifs that connect the two ATP hydrolysis sites. We observed AMP-PNP binding to the degenerate catalytic site, which deviates from the consensus sequence in the same positions as the eukaryotic homologs CFTR and TAP1-TAP2 (TAP1/2). The TM287/288 structure provides unprecedented insights into the mechanism of heterodimeric ABC exporters and will enable future studies on this large transporter superfamily.


A multicentre randomized controlled trial of expectant management versus IVF in women with Fallopian tube patency.
Although observational studies suggest that IVF is more effective than no treatment for women with Fallopian tube patency, this has not been tested rigorously in a randomized controlled trial (RCT). Eligible consenting couples planning their first treatment cycle in five Canadian fertility clinics received either IVF, within 90 days of randomization, or a period of 90 days with no treatment. Random allocation was stratified by female age and sperm quality, and administered using numbered, opaque, sealed envelopes. Follow-up assessed live birth and associated morbidity. Sixty-eight couples were randomized to a first cycle of IVF and 71 couples had 3 months without treatment. The live birth rates were 20/68 (29%) and 1/71 (1%), respectively. The single delivery in the untreated group was of twins, as were six of the 20 IVF deliveries (30%). An average of 2.0 embryos were transferred and no triplet pregnancies resulted. The relative likelihood of delivery after allocation to IVF was 20.9-fold higher than after allocation to no treatment [95% confidence interval (CI) 2.8-155]. The presence of abnormal sperm did not reduce this likelihood. Treating four women (95% CI 3-6) with one cycle of IVF is required to achieve a single additional birth. This study provides a valid and up-to-date comparison for policy makers and patients as they make choices around IVF, accurately measuring and confirming a major benefit from treatment.


Changes in foetal liver T2* measurements by MRI in response to maternal oxygen breathing: application to diagnosing foetal growth restriction.
The motivation of the project was to investigate the use of oxygen-challenge magnetic resonance imaging (OC-MRI) as a method of diagnosing foetal growth restriction. Foetal growth restriction is associated with restricted foetal oxygen supply and is also associated with increased risks of perinatal mortality and morbidity, and a number of serious and chronic health problems. Measurements of T2* relaxation time, an MRI parameter which increases with blood oxygenation, were made in the right lobe of the foetal liver in 80 singleton pregnancies, before and after the mother breathed oxygen. The groups consisted of 41 foetuses with normal growth and 39 with apparent growth restriction. The mean +/- SD gestational age at scanning was 35 +/- 3 weeks. Changes in foetal liver T2* on maternal oxygen breathing showed no significant difference between the groups therefore the OC-MRI protocol used in this study has no value in the diagnosis of foetal growth restriction. A secondary finding was that a significant positive correlation of T2* change with gestational age was observed. Future studies on the use of oxygen-challenge MRI to investigate foetal growth restriction may therefore need to control for gestational age at the time of MR scanning in order to observe any underlying foetal growth-related effects.


Cardiac testing to manage cardiovascular risk in cancer patients.
Cardiovascular toxicity is one of the most feared complications of cancer treatment. Recent advances in oncologic therapies have resulted in improved cancer outcomes but also a new set of cardiovascular adverse effects. Common toxicities include left ventricular dysfunction/heart failure, hypertension, and myocardial ischemia. Accurate risk stratification allows avoidance of potentially harmful treatments in those patients at greatest risk while maintaining the ability to deliver high doses of effective therapies to the lower-risk population. Cardiac investigations, including echocardiography, nuclear imaging, magnetic resonance imaging, biomarker measurement, blood pressure monitoring, electrocardiography, stress testing, and invasive angiography, can help to risk-stratify selected patients. In this review, common complications are discussed in terms of the factors used to identify patients with elevated risk, the monitoring strategies available, and selected interventions that have been used to modify outcomes in patients identified as being at high risk for cardiac complications of cancer treatment.


First Report of Cochliobolus sativus Causing Leaf Spot on Paper Mulberry in China.
Paper mulberry, Broussonetia papyrifera (L.) Vent., is a highly adaptable, fast-growing tree that is native to eastern Asia. Its ability to absorb pollutants makes it ideal for ornamental landscapes, especially in industrial and mining areas. During the summer of 2010, brown lesions were observed on leaves of paper mulberry in Baiwangshan Forest Park, Beijing, China. These lesions were ovoid to fusiform and 4 to 9 × 2 to 4 mm with dark brown centers and light brown irregular edges. Spots on severely infected leaves sometimes coalesced to form long stripes with gray centers. To isolate the causal agent of the lesions, 4-mm2 pieces of diseased leaf tissue from 12 leaves were collected at the lesion margins and surface disinfected in 0.5% NaOCl for 3 min, rinsed three times with sterile water, plated on water agar, and incubated at 25°C with a 12-h photoperiod. After 5 days, the cultures, which became dark brown to black, were observed. Conidiophores (120 to 220 × 4 to 7 μm) were solitary or in groups of two to five, straight or flexuous with swollen bases, and light or dark brown. Conidia were dark olive brown, spindle- or oval-shaped with truncated ends (60 to 120 × 15 to 30 μm), slightly curved, and containing 3 to 12 distoseptate (mostly 6 to 10). Pseudothecia, produced after 14 days in culture, were dark brown to black and flask shaped (420 to 530 μm in diameter with 85 to 100 × 75 to 90 μm ostiolar beaks). Asci were cylindrical (100 to 220 × 30 to 40 μm) and contained eight ascospores. Ascospores were filiform, (150 to 360 × 6 to 9 μm), hyaline, with 6 to 11 septations. Isolates were identified as Cochliobolus sativus (Ito & Kurib.) Drechsler & Dastur (anamorph Bipolaris sorokiniana (Sacc. & Sorok.) Shoem.) on the basis of culture color and dimensions and colors of pseudothecia, asci, ascospores, conidiophores, and conidia (2,3). The identity of one isolate was confirmed by ITS1-5.8S-ITS2 rDNA sequence (GenBank Accession No. HQ 654781) analysis that showed 100% homology to C. sativus listed in Berbee et al. (1). Koch's postulates were performed with six potted 3-month-old paper mulberry plants. An isolate was grown on potato dextrose agar for 14 days to obtain conidia for a conidial suspension (3 × 104 conidia/ml). Three of the potted plants were sprayed with the conidial suspension and three were sprayed with sterile water as controls. Each plant was covered with a plastic bag for 24 h to maintain high humidity and incubated at 25°C with a 12-h photoperiod. After 7 days, the inoculated plants showed leaf symptoms identical to those previously observed on paper mulberry trees in the Baiwangshan Forest Park, while control trees remained symptom free. Reisolation of the fungus from the inoculated plants confirmed that the causal agent was C. sativus. C. sativus is widely distributed worldwide causing a variety of cereal diseases. Wheat and barley are the most economically important hosts. To our knowledge, this is the first report of C. sativus as a pathogen causing leaf spot of paper mulberry in China. References: (1) M. L. Berbee et al. Mycologia 91:964, 1999. (2) M. B. Ellis. Dematiaceous Hyphomycetes. CABI, Oxon, UK, 1971. (3) A. Sivanesan et al. No.701 in: Descriptions of Pathogenic Fungi and Bacteria. CAB, Kew, Surrey, U.K., 1981.


Prevalence of low back pain in the community: implications for service provision in Bradford, UK.
To assist a purchasing district in the planning of services for low back pain by assessing the prevalence of symptoms and the current involvement of primary, secondary, and complementary care in the treatment of low back pain. In the light of these findings, to assess further the potential impact of a new system of open access to physical therapy, as recommended by the British Clinical Standards Advisory Group (CSAG). A two-stage cross sectional survey approach using postal questionnaires. Altogether 1437 men and 1747 women aged 25-64 years, randomly selected from the family health services association register in Bradford. An annual incidence of 4.7% for low back pain was found, with lifetime, 12 month period, and point prevalences of 59%, 39%, and 19% respectively. Over a one year period, 50.3% of episodes were acute (< 2 weeks), 21% were subacute (2 weeks-3 months), and 26% were chronic (over 3 months) in duration. Altogether 17.8% of the population in this age range experienced referred pain, numbness, or tingling, and 6.4% took time off work as a result of low back pain. In the same year, 20% of the population in the same age range consulted no-one about their pain, 13.7% were treated at the primary care level, 4% received secondary care, and 3% visited a complementary therapist. One fifth of those who did not consult a professional experienced severe pain during episodes. Prevalence estimates indicate that an emphasis on early intervention and primary care management of simple low back pain as recommended by the CSAG could generate a 131% surge in demand for physical therapy. Local prevalence estimates may allow purchasers to estimate the potential effects of a shift in management policy for low back pain and to highlight areas of unmet need in terms of resources and patient education.


The genetics of Caenorhabditis elegans.
Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C. elegans are large.


Twenty-four-hour blood pressure profiles in normotensive sons of hypertensive parents.
We investigated whether blood pressures are higher in normotensive offspring of hypertensive parents than in normotensive offspring of normotensive parents outside the physician's office and, if so, whether these higher blood pressures are dependent on the level of dietary sodium intake. We compared 24-hour ambulatory blood pressure profiles between 11 normotensive sons of two hypertensive parents and 11 normotensive sons of two normotensive parents; profiles were recorded after 1 week of a low sodium diet (10 meq/day) and after 1 week of a high sodium diet (200 meq/day). The sons of hypertensive parents were on average 6 years older than the sons of normotensive parents (47 +/- 5 [SD] versus 41 +/- 4 years, p < 0.05). The shift from low to high sodium diet did not significantly change the magnitude of differences in office or ambulatory blood pressures between the groups (i.e., no group-by-diet interaction); thus, we assessed group effects by contrasting blood pressure means for each group pooled across diets. Age-adjusted office blood pressure was higher in sons of hypertensive parents than in sons of normotensive parents (116 +/- 7/80 +/- 6 versus 111 +/- 7/75 +/- 6 mm Hg; p = 0.020 for systolic and p = 0.003 for diastolic blood pressure).(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluating Robotic Surgical Skills Performance Under Distractive Environment Using Objective and Subjective Measures.
Distractions are recognized as a significant factor affecting performance in safety critical domains. Although operating rooms are generally full of distractions, the effect of distractions on robot-assisted surgical (RAS) performance is unclear. Our aim was to investigate the effect of distractions on RAS performance using both objective and subjective measures. Fifteen participants performed a knot-tying task using the da Vinci Surgical System and were exposed to 3 distractions: (1) passive distraction entailed listening to noise with a constant heart rate, (2) active distraction included listening to noise and acknowledging a change of random heart rate from 60 to 120 bpm, and (3) interactive distraction consisted of answering math questions. The objective kinematics of the surgical instrument tips were used to evaluate performance. Electromyography (EMG) of the forearm and hand muscles of the participants were collected. The median EMG frequency (EMG(fmed)) and the EMG envelope (EMG(env)) were analyzed. NASA Task Load Index and Fundamentals of Laparoscopic Surgery score were used to evaluate the subjective performance. One-way repeated analysis of variance was applied to examine the effects of distraction on skills performance. Spearman's correlations were conducted to compare objective and subjective measures. Significant distraction effect was found for all objective kinematics measures (P < .05). There were significant distraction effects for EMG measures (EMG(env), P < .004; EMG(fmed), P = .031). Significant distraction effects were also found for subjective measurements. Distraction impairs surgical skills performance and increases muscle work. Understanding how the surgeons cope with distractions is important in developing surgical education.


[Insomnia in children and adolescents. A consensus document].
Insomnia is very common during childhood (30% of children under 5), and causes a serious cognitive and emotional consequence in learning, as well as significant medical comorbidity. It also affects the quality of life, not only of the child, but also of the whole family. Paediatrician training in its diagnosis and treatment is usually poor. For this reason a consensus document is presented on the management of insomnia in children and adolescents. This has been developed by members of the Spanish Paediatrics Association, the Spanish Sleep Society, the Spanish Society of Paediatric Outpatient and Primary Care, the Spanish Adolescent Medicine Society, the Spanish Child and Adolescent Society, and the Spanish Paediatric Neurology Society. The group suggests that diagnosis must be clinical and complementary tests will only be required in doubtful cases or when a differential diagnosis is needed. Likewise, treatment should be mainly based on cognitive-behavioural therapy and the modification of sleeping habits. Using medicines and other substances to make the sleep easier is currently quite common, even although there are no clinical guidelines to support this.


Terminal maturation of resting B cells by proliferation-independent B cells differentiation factors.
Using response to four different BCDF preparations as a model of B cell maturation, we have shown that induction of B cell proliferation abrogates terminal maturation of these cells. In fact, response to some BCDFs can occur in the presence of inhibitors of DNA replication, suggesting that there are proliferation-independent as well as proliferation-dependent BCDFs. These findings cannot be explained by changes in the kinetics of the BCDF response, nor can they be reversed by repletion of media or changing cell densities. Proliferation-independent BCDFs appear to exert their effects on dense, resting 4F2- B cells rather than more activated B cells. This is in contrast to B cell differentiation signals of IL-2 alone or SAC and IL-2 in concert. These data suggest that the current models of B cell activation and maturation may require some reorganization, relegating the proliferative phase of B cell maturation to a lesser role. In addition, evidence is provided for the fact that the resting B cell may have the full complement of receptors for BCDF as well as BCGF and BCPF and may help account for the inherent nonspecificity of the immune response.


Phorbol esters, protein phosphorylation and the regulation of neuronal ion channels.
Protein kinase C is an enzyme whose activity is modulated by its lipid environment and which is fully activated by diacylglycerol in the presence of phosphatidyl serine and calcium ions. This kinase is highly enriched in the nervous systems of both vertebrates and invertebrates. The activity of protein kinase C can be stimulated in intact cells by certain synthetic diacylglycerols as well as by phorbol esters which substitute for endogenous diacylglycerol. The effects of such activators on the endogenous electrical properties of neurones, as well as on synaptic transmission, have recently been investigated in several vertebrate and invertebrate preparations of neurones. One example is that of the bag cell neurones of Aplysia which, in response to brief stimulation, generate a prolonged discharge during which the height of their action potentials is increased. Exposure of isolated bag cell neurones to activators of protein kinase C results in the enhancement of their action potentials through an increase in the amplitude of their voltage-dependent calcium current. This is caused by the unmasking of a previously inactive species of calcium channel in the plasma membrane.


Journal peer review in context: A qualitative study of the social and subjective dimensions of manuscript review in biomedical publishing.
Peer- and editorial review of research submitted to biomedical journals ('manuscript review') is frequently argued to be essential for ensuring scientific quality and the dissemination of important ideas, but there is also broad agreement that manuscript review is often unsuccessful in achieving its goals. Problems with manuscript review are frequently attributed to the social and subjective dimensions of the process (e.g., bias and conflict of interest). While there have been numerous efforts to improve the process, these have had limited success. This may be because these efforts do not account sufficiently for all of the social and subjective dimensions of the process. We set out, therefore, to characterise the most salient social and subjective dimensions of the manuscript review process, from the perspective of practising reviewers and editors. Open-ended interviews were carried out with 35 journal editors, and peer reviewers in the U.K., U.S.A. and Australia. It emerged from these interviews that reviewers and editors were conscious of a number of social and subjective influences on the review process including: a wide variety of motivations for participation, complex relations of power, epistemic authority and moral responsibility, and unavoidable prejudice and intuition. Importantly, these social and subjective influences were often viewed positively and were seen as expressions of, rather than threats to, editors' and reviewers' epistemic authority and expertise. From this we conclude that the social and subjective dimensions of biomedical manuscript review should be made more explicit, accommodated and even encouraged, not only because these dimensions of human relationships and judgements are unavoidable, but because their explicit presence is likely to enrich, rather than threaten the manuscript review process. We suggest a 'dialectical' model which can simultaneously accommodate, and embrace, all dimensions of the manuscript review process.


Does Reassessment Improve Prediction? A Prospective Study of the Sexual Offender Treatment Intervention and Progress Scale (SOTIPS).
This prospective study examined the predictive validity of the Sex Offender Treatment Intervention and Progress Scale (SOTIPS; McGrath et al., 2012), a sexual recidivism risk/need tool designed to identify dynamic (changeable) risk factors relevant to supervision and treatment. The SOTIPS risk tool was scored by probation officers at two sites (n = 565) for three time points: near the start of community supervision, at 6 months, and then at 12 months. Given that conventions for analyzing dynamic prediction studies have yet to be established, one of the goals of the current paper was to demonstrate promising statistical approaches for the analysis of longitudinal studies in corrections. In most analyses, static SOTIPS scores predicted all types of recidivism (sexual, violent, and general [any]). Dynamic SOTIPS scores, however, only improved the prediction of general recidivism, and only when the analyses with the greatest statistical power were used (Cox regression with time dependent covariates).


Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.
Considering that elevated blood levels of homocyst(e)ine represent a known independent risk factor for macrovascular disease, we assessed the link between hyperhomocyst(e)inemia and diabetic microvascular complications. Homocyst(e)ine and thrombomodulin plasma levels, a marker of endothelial cell damage, were measured before and 3 h after oral methionine loading in 75 patients with stable, well-controlled IDDM and 40 healthy control subjects matched for sex and age. Exclusion criteria were hyperlipidemia, hypertension, smoking, or positive family history for cardiovascular disease. IDDM patients had higher pre- and postload homocyst(e)ine plasma levels than did healthy control subjects (12.0 vs. 7.7 mumol/l and 27.6 vs. 16.0 mumol/l; P < 0.001). Of 75 IDDM patients, 26 had homocyst(e)ine plasma levels above the normal range (defined as mean +2 SD of values obtained in the control group). The IDDM patients with hyperhomocyst(e)inemia had higher thrombomodulin plasma levels (62.2 vs. 38.2 ng/ml; P < 0.001), higher albumin excretion rates (485 vs. 115 mg/l; P < 0.005), and a higher prevalence of late diabetic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs. 51%; neuropathy, 57 vs. 41%; macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells show an increased release of thrombomodulin into the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might contribute to vascular complications of patients with diabetes. Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.


Mimicking surface plasmons with structured surfaces.
Metals such as silver support surface plasmons: electromagnetic surface excitations localized near the surface that originate from the free electrons of the metal. Surface modes are also observed on highly conducting surfaces perforated by holes. We establish a close connection between the two, showing that electromagnetic waves in both materials are governed by an effective permittivity of the same plasma form. The size and spacing of holes can readily be controlled on all relevant length scales, which allows the creation of designer surface plasmons with almost arbitrary dispersion in frequency and in space, opening new vistas in surface plasmon optics.


Long Non-Coding RNA Reprogramming (ROR) Promotes Cell Proliferation in Colorectal Cancer via Affecting P53.
BACKGROUND Colorectal cancer (CRC) remains one of the most common lethal malignant tumors worldwide. The correlation between lncRNAs expression and CRC development has not been well identified in the recent literature. This study focused on the role of lncRNA-ROR on CRC progression and development. MATERIAL AND METHODS Quantitative real-time PCR (qRT-PCR) assay was conducted to identify the expression level of lncRNA-ROR. Cell proliferation and viability were examined by MTT assay and colony formation assay. Cell cycle distribution and apoptosis were detected by flow cytometry. Expressions of p53, p21, and FAS protein levels were assessed by Western blotting. CRC cells transfected with lncRNA-shRNA were injection into nude mice to identify the function of lncRNA-ROR on tumorigenesis in vivo. RESULTS The expression level of lncRNA-ROR was elevated in CRC tissues when compared to adjacent tissues (n=78). lncRNA-ROR knockdown significantly suppressed cell proliferation and viability, while lncRNA-ROR overexpression had the opposite effect. Decreased lncRNA-ROR expression enhanced cell apoptosis and triggered cell cycle arrest in G0/G1 phase, while elevated lncRNA-ROR expression presented the opposite effect. Protein levels of p53 and p53 target genes were affected by lncRNA-ROR in vitro, and downregulation of lncRNA-ROR impeded tumorigenesis in vivo. CONCLUSIONS Our study demonstrates that lncRNA-ROR participates in controlling CRC proliferation, viability, and apoptosis, partially by modulating p53, which provides potential and prospective therapeutic targets for CRC.


A Model To Estimate Carbon Dioxide Injectivity and Storage Capacity for Geological Sequestration in Shale Gas Wells.
Recent studies suggest the possibility of CO2 sequestration in depleted shale gas formations, motivated by large storage capacity estimates in these formations. Questions remain regarding the dynamic response and practicality of injection of large amounts of CO2 into shale gas wells. A two-component (CO2 and CH4) model of gas flow in a shale gas formation including adsorption effects provides the basis to investigate the dynamics of CO2 injection. History-matching of gas production data allows for formation parameter estimation. Application to three shale gas-producing regions shows that CO2 can only be injected at low rates into individual wells and that individual well capacity is relatively small, despite significant capacity variation between shale plays. The estimated total capacity of an average Marcellus Shale well in Pennsylvania is 0.5 million metric tonnes (Mt) of CO2, compared with 0.15 Mt in an average Barnett Shale well. Applying the individual well estimates to the total number of existing and permitted planned wells (as of March, 2015) in each play yields a current estimated capacity of 7200-9600 Mt in the Marcellus Shale in Pennsylvania and 2100-3100 Mt in the Barnett Shale.


Boiling and Frying Peanuts Decreases Soluble Peanut (Arachis Hypogaea) Allergens Ara h 1 and Ara h 2 But Does Not Generate Hypoallergenic Peanuts.
Peanut allergy continues to be a problem in most developed countries of the world. We sought a processing method that would alter allergenic peanut proteins, such that allergen recognition by IgE from allergic individuals would be significantly reduced or eliminated. Such a method would render accidental exposures to trace amounts of peanuts safer. A combination of boiling and frying decreased recovery of Ara h 1 and Ara h 2 at their expected MWs. In contrast, treatment with high pressures under varying temperatures had no effect on protein extraction profiles. Antibodies specific for Ara h 1, Ara h 2, and Ara h 6 bound proteins extracted from raw samples but not in boiled/fried samples. However, pre-incubation of serum with boiled/fried extract removed most raw peanut-reactive IgE from solution, including IgE directed to Ara h 1 and 2. Thus, this method of processing is unlikely to generate a peanut product tolerated by peanut allergic patients. Importantly, variability in individual patients' IgE repertoires may mean that some patients' IgE would bind fewer polypeptides in the sequentially processed seed.


Helicobacter pylori bab Paralog Distribution and Association with cagA, vacA, and homA/B Genotypes in American and South Korean Clinical Isolates.
Helicobacter pylori genetic variation is a crucial component of colonization and persistence within the inhospitable niche of the gastric mucosa. As such, numerous H. pylori genes have been shown to vary in terms of presence and genomic location within this pathogen. Among the variable factors, the Bab family of outer membrane proteins (OMPs) has been shown to differ within subsets of strains. To better understand genetic variation among the bab genes and to determine whether this variation differed among isolates obtained from different geographic locations, we characterized the distribution of the Bab family members in 80 American H. pylori clinical isolates (AH) and 80 South Korean H. pylori clinical isolates (KH). Overall, we identified 23 different bab genotypes (19 in AH and 11 in KH), but only 5 occurred in greater than 5 isolates. Regardless of strain origin, a strain in which locus A and locus B were both occupied by a bab gene was the most common (85%); locus C was only occupied in those isolates that carried bab paralog at locus A and B. While the babA/babB/- genotype predominated in the KH (78.8%), no single genotype could account for greater than 40% in the AH collection. In addition to basic genotyping, we also identified associations between bab genotype and well known virulence factors cagA and vacA. Specifically, significant associations between babA at locus A and the cagA EPIYA-ABD motif (P<0.0001) and the vacA s1/i1/m1 allele (P<0.0001) were identified. Log-linear modeling further revealed a three-way association between bab carried at locus A, vacA, and number of OMPs from the HOM family (P<0.002). En masse this study provides a detailed characterization of the bab genotypes from two distinct populations. Our analysis suggests greater variability in the AH, perhaps due to adaptation to a more diverse host population. Furthermore, when considering the presence or absence of both the bab and homA/B paralogs at their given loci and the vacA genotype, an association was observed. Our results highlight the multifactorial nature of H. pylori mediated disease and the importance of considering how the specific combinations of H. pylori virulence genes and their multiple interactions with the host will collectively impact disease progression.


Novel fungi from an ancient niche: cercosporoid and related sexual morphs on ferns.
The fern flora of the world (Pteridophyta) has direct evolutionary links with the earliest vascular plants that appeared in the late Devonian. Knowing the mycobiota associated to this group of plants is critical for a full understanding of the Fungi. Nevertheless, perhaps because of the minor economic significance of ferns, this niche remains relatively neglected by mycologists. Cercosporoid fungi represent a large assemblage of fungi belonging to the Mycosphaerellaceae and Teratosphaeriaceae (Ascomycota) having cercospora-like asexual morphs. They are well-known pathogens of many important crops, occurring on a wide host range. Here, the results of a taxonomic study of cercosporoid fungi collected on ferns in Brazil are presented. Specimens were obtained from most Brazilian regions and collected over a 7-yr period (2009-2015). Forty-three isolates of cercosporoid and mycosphaerella-like species, collected from 18 host species, representing 201 localities, were studied. This resulted in a total of 21 frond-spotting taxa, which were identified based on morphology, ecology and sequence data of five genomic loci (actin, calmodulin, ITS, LSU and partial translation elongation factor 1-α). One novel genus (Clypeosphaerella) and 15 novel species (Cercospora samambaiae, Clypeosphaerella sticheri, Neoceratosperma alsophilae, N. cyatheae, Paramycosphaerella blechni, Pa. cyatheae, Pa. dicranopteridis-flexuosae, Pa. sticheri, Phaeophleospora pteridivora, Pseudocercospora brackenicola, Ps. paranaensis, Ps. serpocaulonicola, Ps. trichogena, Xenomycosphaerella diplazii and Zasmidium cyatheae) are introduced. Furthermore, 11 new combinations (Clypeosphaerella quasiparkii, Neoceratosperma yunnanensis, Paramycosphaerella aerohyalinosporum, Pa. dicranopteridis, Pa. gleicheniae, Pa. irregularis, Pa. madeirensis, Pa. nabiacense, Pa. parkii, Pa. pseudomarksii and Pa. vietnamensis) are proposed. Finally, nine new host associations are recorded for the following known fungal species: Cercospora coniogrammes, Cercospora sp. Q, Ps. abacopteridicola, Ps. lygodiicola and Ps. thelypteridis.


'Being appropriately unusual': a challenge for nurses in health-promoting conversations with families.
This study describes the theoretical assumptions and the application for health-promoting conversations, as a communication tool for nurses when talking to patients and their families. The conversations can be used on a promotional, preventive and healing level when working with family-focused nursing. They are based on a multiverse, salutogenetic, relational and reflecting approach, and acknowledge each person's experience as equally valid, and focus on families' resources, and the relationship between the family and its environment. By posing reflective questions, reflection is made possible for both the family and the nurses. Family members are invited to tell their story, and they can listen to and learn from each other. Nurses are challenged to build a co-creating partnership with families in order to acknowledge them as experts on how to lead their lives and to use their own expert knowledge in order to facilitate new meanings to surface. In this way, family health can be enhanced.


Afferent Visual Pathway Affection in Patients with PMP22 Deletion-Related Hereditary Neuropathy with Liability to Pressure Palsies.
The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute's 39-item Visual Functioning Questionnaire (NEI-VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. PMP22 deletion leads to functional, metabolic and macro-structural alterations in the afferent visual system of HNPP patients. Our data suggest a functional relevance of these changes for peripheral vision, which warrants further investigation and confirmation.


Investigation of skin vasoreactivity and blood flow oscillations in hypertensive patients: effect of short-term antihypertensive treatment.
In order to evaluate whether arterial hypertension (AH) affects skin microcirculation, 46 newly diagnosed, never-treated, hypertensive patients and 20 healthy normotensive controls underwent a forearm skin postocclusive reactive hyperaemia (PORH) test, using laser-Doppler flowmetry (LDF). Their resting skin blood flow oscillations (SBFOs) were also investigated using wavelet spectral analyses of skin LDF tracings within six frequency subintervals in the 0.005-2 Hz spectral range. To evaluate whether antihypertensive treatment affects skin microcirculation, the same measurements were repeated in 22 of the recruited hypertensive patients after 8 ± 2 weeks of antihypertensive treatment. Significantly reduced PORH, together with significantly higher spectral amplitudes within the majority of the investigated SBFO subintervals, was found in untreated hypertensive patients compared with controls. In the 22 hypertensive patients who completed the follow-up, there was a significant increase in PORH after antihypertensive treatment compared with before (357 ± 178 vs. 284 ± 214%, respectively, P < 0.05). Following antihypertensive treatment, the same 22 hypertensive patients did not differ significantly from controls either in PORH or in the majority of the investigated SBFO frequency subintervals. This study showed reduced skin vasoreactivity in the hypertensive patients, confirming that antihypertensive treatment negatively affects skin microcirculation. The short period of efficacious antihypertensive treatment resulted in normalization of skin vasoreactivity in hypertensive patients who completed the follow-up, suggesting that antihypertensive treatment affects positively skin microcirculation in AH. The SBFO increase in untreated hypertensive patients, and its almost complete normalization in treated hypertensive patients, suggests that SBFO enhancement in untreated hypertensive patients could be an adaptive reversible response to AH.


Effect of intra-abdominally induced pressure on the urethral pressure profiles of healthy and incontinent bitches.
To determine whether reduced pressure transmission is of importance in the pathophysiologic mechanism of urinary incontinence in bitches. 20 sexually intact, continent bitches and 21 spayed, incontinent bitches. Urethral pressure profiles before (resting) and after (stressed) insufflation of gas in the abdominal cavity were recorded in bitches under general anesthesia. Differences (stressed minus resting) were calculated for all variables. On the basis of these values, the pressure transmission ratio was determined. Resting pressure profiles of incontinent bitches indicated significantly (P < 0.05) lower maximal closure pressure (4.5 +/- 3.0 cm of H2O) than did those of continent bitches (11.2 +/- 7.2 cm of H2O). The intra-abdominal pressure increase lead to a shortening of total profile length, which was equal in both groups and caused an increase in maximal urethral pressure. The change in maximal urethral pressure was significantly (P < 0.05) greater in incontinent bitches (12.4 +/- 4.1 cm of H2O) than in continent bitches (8.8 +/- 4.5 cm of H2O). The profile areas and the pressure transmission ratios did not differ significantly (P < 0.05) between the 2 groups. The effect of decreased pressure transmission on the urethra is not a factor in the pathophysiologic mechanism of urinary incontinence attributable to urethral incompetence in bitches.


Expression of the murine Dlx-1 homeobox gene during facial, ocular and limb development.
We have analysed the expression pattern of the mouse homeobox containing gene Dlx-1. This gene harbors a homeodomain related to that found in the Drosophila distal-less (dll) gene. In addition to its expression in the developing forebrain, Dlx-1 is transcribed in several structures containing cells of neural crest origin such as the facial mesenchyme and various elements of the peripheral nervous system. Dlx-1 transcripts are also detected in the differentiating retina and during limb morphogenesis, in the apical ectodermal ridge. The possible involvement of Dlx-1 during facial, ocular and limb development is discussed.


How Does Time Spent Working in Custody Influence Health and Fitness Characteristics of Law Enforcement Officers?
This study investigated the influence of time spent working in custody on the health and fitness of law enforcement officers (LEOs). Retrospective analysis was conducted on data from 48 male and 12 female LEOs, divided into groups based upon time spent working custody: LEO ≤ 24 (≤24 months; n = 15); LEO 2547 (25-47 months; n = 24); and LEO 48+ (≥48 months; n = 21). The following were measured: body mass index (BMI); fat mass percentage; waist-to-hip ratio (WHR); resting heart rate (RHR); blood pressure; grip strength; sit-and-reach; push-ups; sit-ups; and YMCA step test recovery heart rate (HR). A univariate ANCOVA (controlling for sex and age) with Bonferroni post hoc determined significant between-group differences. Select assessments were compared to normative data. The LEO 48+ group completed fewer sit-ups than the LEO 2547 group (p = 0.006); there were no other significant between-group differences. Forty-nine LEOs were overweight or obese according to BMI; 52 were fatter than average or above; 27 had a WHR that increased cardiovascular disease risk. Forty-three LEOs had very poor RHR; 52 had elevated blood pressure. Forty-eight LEOs had average-to-very poor step test recovery HR. Irrespective of time spent working in custody, personnel should be physically active to maintain health and fitness and, where possible, engage in formal strength training and conditioning.


Refractory childhood epilepsy and factors related to refractoriness.
To clarify the characteristics of refractory childhood epilepsy, we compared recent refractory cases and those of approximately 15 years ago, all of which were seen at the Okayama University Hospital. We also analyzed predictive factors related to refractoriness in the recent refractory cases. Among the recent refractory cases, the proportion of localization-related epilepsies increased, and the proportion of generalized epilepsies decreased compared to historical cases. In generalized epilepsies, the proportion of cases with Lennox-Gastaut syndrome decreased to less than half. In localization-related epilepsies, the proportion of cases with frontal lobe epilepsy increased. The proportion of cases with unknown causes decreased to less than half. Of the cases with known causes, postencephalitis/postencephalopathy and focal cortical malformation, including tuberous sclerosis, accounted for most of the cases. More of the recent refractory cases were treated with high-dose AED monotherapy, compared to more polytherapy in the cases of 15 years earlier. The following factors were related to future refractoriness: less than 1 year of age at onset of seizures, the presence of underlying pathology, status epilepticus. changes in type of epilepsy during the clinical course, and neonatal seizures. Regarding EEG findings of cases that had localization-related epilepsies at the end of follow-up, focal spike-waves associated with diffuse spike-waves on the first EEGs indicated future refractoriness.


A study of bone turnover markers in gestational diabetes mellitus.
Gestational diabetes is defined as carbohydrate intolerance resulting in hyperglycemia of variable severity with the first recognition during pregnancy. Established risk factors for gestational diabetes mellitus (GDM) are maternal age, obesity, family history of diabetes, etc. Vitamin D, parathyroid hormone (PTH), and various other hormones are known for their function in maintaining calcium and phosphorous homeostatic. Furthermore, Vitamin D, PTH serum ionized calcium, and alkaline phosphatase (ALP) have been reported to be altered with glucose homeostasis. The present study compares the bone markers in pregnant women with and without gestational diabetes. This cross-sectional study was conducted at outpatient antenatal check-up clinic and outpatient diabetic clinics at J. N. Medical College and Hospital, Aligarh. One hundred pregnant females, of which fifty with GDM and fifty without GDM, were included in the study from January 2014 to November 2015. Detailed history, physical examination, and anthropometric measurement were done. Bone turnover markers in the form of Vitamin D, parathyroid hormone, serum ionized calcium, and serum ALP were measured in pregnant women who had gestational diabetes which was compared with normal pregnant women. In our study, the mean age of participate of GDM group was 28.2 ± 3 years, while the mean age group in non-GDM group was 25.44 ± 2.78 years. Ionized calcium in GDM was found to be 4.606 ± 0.354 mEq/L, while in non-GDM, it was 4.548 ± 0.384 mEq/L, P = 0.430. Vitamin D came out to be 21.80 ± 9.48 ng/ml, while it was 32.346 ± 8.37 ng/ml in non-GDM group. Serum PTH in GDM group was 71.436 ± 36.189 pg/ml and 37.168 ± 8.128 pg/ml in nondiabetic gestational group. Serum ALP in GDM group was 9.1 ± 4.56 KA U/dl and 6.98 ± 2.2 KA U/dl in nondiabetic gestational group, P - 0.0038. In GDM group, there was a significant negative linear correlation between PTH and 25-hydroxyvitamin D with research correlation coefficient r = -0.9073, P = 0; there was a significant positive linear correlation coefficient between PTH and ALP with Persian correlation coefficient r = 0.6597, P = 0; there was no statistically significant correlation between PTH and ionized calcium r = 0.1416, P = 0.3267. All GDM subjects should ideally be screened for serum calcium, vitamin D, PTH, ALP. If found impaired should immediately be corrected in order to prevent its adverse effects on maternal and fetal outcome. Vitamin D supplementation should ideally be initiated in all GDM females even if the above parameters are not investigated in Indian setup.


Calibration of the Andersen cascade impactor for the characterization of nasal products.
Current cascade impactor protocols do not completely rule out nasal preparations entering the lower respiratory tract. A modified cascade impactor (MCI) was developed to characterize the particle size fraction capable of deposition in the lower respiratory tract. This is an important measure of the potential for delivery to a site which is not the route of administration, and which could lead to potential toxicity. Monodisperse aerosols were utilized to calibrate the Stage -2 and Stage -0 of an Andersen Mk II nonviable cascade impactor at 15 L per minute flow rate. While these sampling conditions are beyond the normal working range of impactor theory in practice the instrument was shown to discriminate the designated particle sizes sampled. This novel setup extended the upper limit of the range of particle sizes that the cascade impactor can characterize from 8.7 to 16.5 microm.


Stem cell transplantation with chemoradiotherapy myeloablation and interleukin-2.
Interleukin 2 (IL-2) stimulates the proliferation of T-cells both in vitro and in vivo. When murine or human peripheral blood (PB) or bone marrow (BM) mononuclear cells are incubated with IL-2 in vitro for 24 hours, cytotoxic T-cells are generated. If these activated cells are infused into mice, the enhanced cytotoxicity continues if low dose IL-2 is administered. This combination of administering activated cells with the subsequent low dose IL-2 infusion results in enhanced tumor cell destruction and improved survival rates in mice with acute myeloid leukemia. The encouraging results of these laboratory experiments prompted the initiation of phase I clinical trials in patients with refractory/relapsed hematologic malignancies and patients with breast cancer (Stages II-IV). Results from these trials demonstrate that stem cell transplantation with IL-2 activated stem cells (either PB or BM) with or without parenteral administration of IL-2 results in hematopoietic reconstitution with mild-to-moderate toxicities. This regimen also generates cutaneous and visceral autologous graft versus host disease (AuGVHD). The majority of our patients with relapsed/refractory hematologic malignancies or breast cancer developed either clinical and/or histological evidence of AuGVHD. Further studies are being conducted to determine if patients who develop AuGVHD experience improved disease-free survival from a possible autologous graft versus tumor (GVT) effect. Current laboratory evaluations include the elucidation of the pathogenesis of AuGVHD and molecular evaluation of the purging efficacy of IL-2.


Comprehensive interactome of Otx2 in the adult mouse neural retina.
The Otx2 homeodomain transcription factor exerts multiple functions in specific developmental contexts, probably through the regulation of different sets of genes. Protein partners of Otx2 have been shown to modulate its activity. Therefore, the Otx2 interactome may play a key role in selecting a precise target-gene repertoire, hence determining its function in a specific tissue. To address the nature of Otx2 interactome, we generated a new recombinant Otx2(CTAP-tag) mouse line, designed for protein complexes purification. We validated this mouse line by establishing the Otx2 interactome in the adult neural retina. In this tissue, Otx2 is thought to have overlapping function with its paralog Crx. Our analysis revealed that, in contrary to Crx, Otx2 did not develop interactions with proteins that are known to regulate phototransduction genes but showed specific partnership with factors associated with retinal development. The relationship between Otx2 and Crx in the neural retina should therefore be considered as complementarity rather than redundancy. Furthermore, study of the Otx2 interactome revealed strong associations with RNA processing and translation machineries, suggesting unexpected roles for Otx2 in the regulation of selected target genes all along the transcription/translation pathway. The Otx2(CTAP-tag) line, therefore, appears suitable for a systematic approach to Otx2 protein-protein interactions. genesis 53:685-694, 2015. © 2015 Wiley Periodicals, Inc.


Fast left ventricular mass and volume assessment in mice with three-dimensional guide-point modeling.
To investigate the accuracy (vs. standard manual analysis) and precision (scan-rescan reproducibility) of three-dimensional guide-point modeling (GPM) for the assessment of left ventricular (LV) function in mice. Six male wildtype C57/Bl6 mice (weight 26.2 +/- 1.1 g) were scanned twice, 3 days apart. Each scan was performed twice, at 0.2 mm/pixel with one average and at 0.1 mm/pixel with two averages. The 24 studies were anonymized and analyzed in blinded fashion using GPM and standard manual slice summation. The average error between GPM and standard analysis was 2.3 +/- 5.8 mg in mass, 1.7 +/- 3.2 microL in end-diastolic volume, 2.3 +/- 3.1 microL in end-systolic volume, -2.7 +/- 4.3% in ejection fraction, -0.6 +/- 3.3 microL in stroke volume, and -0.31 +/- 1.56 ml . min(-1) in cardiac output (mean difference +/- SD of differences, n = 24). The average time taken was 8.0 +/- 2.5 minutes for 3D GPM and 48.5 +/- 8.9 minutes for standard analysis (n = 24). Scan-rescan reproducibility results were similar to the standard analysis. No significant differences were found using linear mixed effects modeling in either accuracy or precision between scan resolutions or analysis method. 3D GPM enables fast analysis of mouse LV function, with similar accuracy and reproducibility to standard analysis. An image resolution of 0.2 mm/pixel with one average is adequate for LV function studies.


Hyperbaric oxygen therapy improves neurocognitive functions of post-stroke patients - a retrospective analysis.
Previous studies have shown that hyperbaric oxygen therapy (HBOT) can improve the motor functions and memory of post-stroke patients in the chronic stage. The aim of this study is to evaluate the effects of HBOT on overall cognitive functions of post-stroke patients in the chronic stage. The nature, type and location of the stroke were investigated as possible modifiers. A retrospective analysis was conducted on patients who were treated with HBOT for chronic stroke (>3 months) between 2008-2018. Participants were treated in a multi-place hyperbaric chamber with the following protocols: 40 to 60 daily sessions, 5 days per week, each session included 90 min of 100% oxygen at 2 ATA with 5 min air brakes every 20 minutes. Clinically significant improvements (CSI) were defined as > 0.5 standard deviation (SD). The study included 162 patients (75.3% males) with a mean age of 60.75±12.91. Of them, 77(47.53%) had cortical strokes, 87(53.7%) strokes were located in the left hemisphere and 121 suffered ischemic strokes (74.6%).HBOT induced a significant increase in all the cognitive function domains (p < 0.05), with 86% of the stroke victims achieving CSI. There were no significant differences post-HBOT of cortical strokes compared to sub-cortical strokes (p > 0.05). Hemorrhagic strokes had a significantly higher improvement in information processing speed post-HBOT (p < 0.05). Left hemisphere strokes had a higher increase in the motor domain (p < 0.05). In all cognitive domains, the baseline cognitive function was a significant predictor of CSI (p < 0.05), while stroke type, location and side were not significant predictors. HBOT induces significant improvements in all cognitive domains even in the late chronic stage. The selection of post-stroke patients for HBOT should be based on functional analysis and baseline cognitive scores rather than the stroke type, location or side of lesion.


Structure and function of the symbiosis partners of the lung lichen (Lobaria pulmonaria L. Hoffm.) analyzed by metaproteomics.
Environmental proteomics, also referred to as metaproteomics, is an emerging technology to study the structure and function of microbial communities. Here, we applied semi-quantitative label-free proteomics using one-dimensional gel electrophoresis combined with LC-MS/MS and normalized spectral counting together with fluorescence in situ hybridization and confocal laser scanning microscopy to characterize the metaproteome of the lung lichen symbiosis Lobaria pulmonaria. In addition to the myco- and photobiont, L. pulmonaria harbors proteins from a highly diverse prokaryotic community, which is dominated by Proteobacteria and including also Archaea. While fungal proteins are most dominant (75.4% of all assigned spectra), about the same amount of spectra were assigned to prokaryotic proteins (10%) and to the green algal photobiont (9%). While the latter proteins were found to be mainly associated with energy and carbohydrate metabolism, a major proportion of fungal and bacterial proteins appeared to be involved in PTMs and protein turnover and other diverse functions.


Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy.
Immunogenic cell death (ICD) occurs when apoptotic tumor cell elicits a specific immune response, which may trigger an anti-tumor effect, via the release of immunostimulatory damage-associated molecular patterns (DAMPs). Hypothesizing that nanomedicines may impact ICD due to their proven advantages in delivery of chemotherapeutics, we encapsulated oxaliplatin (OXA) or gemcitabine (GEM), an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer nanoparticles. Neither GEM nor nanoparticle-encapsulated GEM (NP-GEM) induced ICD, while both OXA and nanoparticle-encapsulated OXA (NP-OXA) induced ICD. Interestingly, NP-OXA treated tumor cells released more DAMPs and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. Furthermore, OXA and NP-OXA exhibited stronger therapeutic effects in immunocompetent mice than in immunodeficient mice, and the enhancement of therapeutic efficacy was significantly higher in the NP-OXA group than the OXA group. Moreover, NP-OXA treatment induced a higher proportion of tumor infiltrating activated cytotoxic T-lymphocytes than OXA treatment. This general trend of enhanced ICD by nanoparticle delivery was corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin and 5-fluorouracil. In conclusion, although nanoparticle encapsulation did not endow a non-ICD inducer with ICD-mediated anti-tumor capacity, treatment with a nanoparticle-encapsulated ICD inducer led to significantly enhanced ICD and consequently improved anti-tumor effects than the free ICD inducer. The proposed nanomedicine approach may impact cancer immunotherapy via the novel cell death mechanism of ICD.


The role of sociodemographic risk and maternal behavior in the prediction of infant attachment disorganization.
Predictors of infant attachment disorganization were examined among 203 primiparous mothers (52% European American, 48% African American) and their infants (104 female). The Strange Situation Procedure was administered at one year. Global maternal insensitivity and overtly negative maternal behavior were observed during distress-eliciting tasks when infants were six months and one year old. Mothers reported on their demographics to yield a measure of sociodemographic risk (i.e., age, education, income-to-needs). Overtly negative maternal behavior was positively associated with the infant attachment disorganization rating scale score, but did not predict being classified as disorganized. Global maternal insensitivity was associated with higher attachment disorganization, both the rating and the classification, when sociodemographic risk was high but not when sociodemographic risk was low. The pattern of results did not vary by maternal race. The results provide some support for the view that negative maternal behavior and the combination of sociodemographic risk and global maternal insensitivity play a role in the development of infant attachment disorganization.