Blood pressure control for diabetic retinopathy.
Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Simultaneous blood pressure control has been advocated for the same purpose, but findings reported from individual studies have supported varying conclusions regarding the ocular benefit of interventions on blood pressure. The primary aim of this review was to summarize the existing evidence regarding the effect of interventions to control or reduce blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs. A secondary aim was to compare classes of anti-hypertensive medications with respect to the same outcomes. We searched a number of electronic databases including CENTRAL as well as ongoing trial registries. We last searched the electronic databases on 25 April 2014. We also reviewed reference lists of review articles and trial reports selected for inclusion. In addition, we contacted investigators of trials with potentially pertinent data. We included in this review randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to intense versus less intense blood pressure control, to blood pressure control versus usual care or no intervention on blood pressure, or to different classes of anti-hypertensive agents versus placebo. Pairs of review authors independently reviewed titles and abstracts from electronic and manual searches and the full text of any document that appeared to be relevant. We assessed included trials independently for risk of bias with respect to outcomes reported in this review. We extracted data regarding trial characteristics, incidence and progression of retinopathy, visual acuity, quality of life, and cost-effectiveness at annual intervals after study entry whenever provided in published reports and other documents available from included trials. We included 15 RCTs, conducted primarily in North America and Europe, that had enrolled 4157 type 1 and 9512 type 2 diabetic participants, ranging from 16 to 2130 participants in individual trials. In 10 of the 15 RCTs, one group of participants was assigned to one or more anti-hypertensive agents and the control group received placebo. In three trials, intense blood pressure control was compared to less intense blood pressure control. In the remaining two trials, blood pressure control was compared with usual care. Five of the 15 trials enrolled type 1 diabetics, and 10 trials enrolled type 2 diabetics. Six trials were sponsored entirely by pharmaceutical companies, seven trials received partial support from pharmaceutical companies, and two studies received support from government-sponsored grants and institutional support.Study designs, populations, interventions, and lengths of follow-up (range one to nine years) varied among the included trials. Overall, the quality of the evidence for individual outcomes was low to moderate. For the primary outcomes, incidence and progression of retinopathy, the quality of evidence was downgraded due to inconsistency and imprecision of estimates from individual studies and differing characteristics of participants.For primary outcomes among type 1 diabetics, one of the five trials reported incidence of retinopathy and one trial reported progression of retinopathy after 4 to 5 years of treatment and follow-up; four of the five trials reported a combined outcome of incidence and progression over the same time interval. Among type 2 diabetics, 5 of the 10 trials reported incidence of diabetic retinopathy and 3 trials reported progression of retinopathy; one of the 10 trials reported a combined outcome of incidence and progression during a 4- to 5-year follow-up period. One trial in which type 2 diabetics participated had reported no primary (or secondary) outcome targeted for this review.The evidence from these trials supported a benefit of more intensive blood pressure control intervention with respect to 4- to 5-year incidence of diabetic retinopathy (estimated risk ratio (RR) 0.80; 95% confidence interval (CI) 0.71 to 0.92) and the combined outcome of incidence and progression (estimated RR 0.78; 95% CI 0.63 to 0.97). The available evidence provided less support for a benefit with respect to 4- to 5-year progression of diabetic retinopathy (point estimate was closer to 1 than point estimates for incidence and combined incidence and progression, and the CI overlapped 1; estimated RR 0.88; 95% CI 0.73 to 1.05). The available evidence regarding progression to proliferative diabetic retinopathy or clinically significant macular edema or moderate to severe loss of best-corrected visual acuity did not support a benefit of intervention on blood pressure: estimated RRs and 95% CIs 0.95 (0.83 to 1.09) and 1.06 (0.85 to 1.33), respectively, after 4 to 5 years of follow-up. Findings within subgroups of trial participants (type 1 and type 2 diabetics; participants with normal blood pressure levels at baseline and those with elevated levels) were similar to overall findings.The adverse event reported most often (7 of 15 trials) was death, yielding an estimated RR 0.86 (95% CI 0.64 to 1.14). Hypotension was reported from three trials; the estimated RR was 2.08 (95% CI 1.68 to 2.57). Other adverse ocular events were reported from single trials. Hypertension is a well-known risk factor for several chronic conditions in which lowering blood pressure has proven to be beneficial. The available evidence supports a beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to 4 to 5 years. However, the lack of evidence to support such intervention to slow progression of diabetic retinopathy or to prevent other outcomes considered in this review, along with the relatively modest support for the beneficial effect on incidence, weakens the conclusion regarding an overall benefit of intervening on blood pressure solely to prevent diabetic retinopathy.


Therapeutic effects of probiotics on neonatal jaundice.
To evaluate the therapeutic effects of probiotics on neonatal jaundice and the safety. Sixty-eight neonates with jaundice were divided into a control group and a treatment group (n=34) randomly, and treated by blue light phototherapy and that in combination with probiotics. The serum bilirubin levels were detected before and 1, 4, 7 days after treatment. The time when therapy showed effects and jaundice faded, clinical outcomes as well as adverse reactions were recorded. The categorical data were expressed as (±s) and compared by t test. The numerical data were expressed as (case, %) and compared by χ² test. P<0.05 was considered statistically significant. Serum bilirubin levels of the two groups were similar before treatment (P>0.05). The levels significantly decreased 1, 4 and 7 days after treatment (P<0.05), but there was no significant inter-group difference on the post-treatment 1st day (P>0.05). The treatment group underwent more significant decreases on the 4th and 7th days than the control group did (P=0.002, 0.001). In the treatment group, the therapy exerted effects on (1.0±0.5) d and jaundice faded on (3.8±1.7) d, which were (2.6±0.6) d and (5.3±2.1) d respectively in the control group (P=0.001, 0.002). The effective rate of the treatment group significantly exceeded that of the control group (P=0.002). There were no obvious adverse reactions in either group. Probiotics lowered the serum bilirubin levels of neonates with jaundice rapidly, safely and significantly, and accelerated jaundice fading as well. This method is worthy of application in clinical practice.


Comparative Proteomics of Marinobacter sp. TT1 Reveals Corexit Impacts on Hydrocarbon Metabolism, Chemotactic Motility, and Biofilm Formation.
The application of chemical dispersants during marine oil spills can affect the community composition and activity of marine microorganisms. Several studies have indicated that certain marine hydrocarbon-degrading bacteria, such as Marinobacter spp., can be inhibited by chemical dispersants, resulting in lower abundances and/or reduced biodegradation rates. However, a major knowledge gap exists regarding the mechanisms underlying these physiological effects. Here, we performed comparative proteomics of the Deepwater Horizon isolate Marinobacter sp. TT1 grown under different conditions. Strain TT1 received different carbon sources (pyruvate vs. n-hexadecane) with and without added dispersant (Corexit EC9500A). Additional treatments contained crude oil in the form of a water-accommodated fraction (WAF) or chemically-enhanced WAF (CEWAF; with Corexit). For the first time, we identified the proteins associated with alkane metabolism and alginate biosynthesis in strain TT1, report on its potential for aromatic hydrocarbon biodegradation and present a protein-based proposed metabolism of Corexit components as carbon substrates. Our findings revealed that Corexit exposure affects hydrocarbon metabolism, chemotactic motility, biofilm formation, and induces solvent tolerance mechanisms, like efflux pumps, in strain TT1. This study provides novel insights into dispersant impacts on microbial hydrocarbon degraders that should be taken into consideration for future oil spill response actions.


The acceptability of Internet-based treatment and characteristics of an adult sample with obsessive compulsive disorder: an Internet survey.
Obsessive-compulsive disorder (OCD) is a disabling anxiety disorder, but most individuals delay seeking treatment. Internet-based cognitive behavioural therapy (iCBT) is an innovative service delivery method that may help to improve access to care, but the acceptability to consumers of such programs has not yet been established. People with symptoms of OCD were invited to complete an online survey enquiring about demographic characteristics, symptom severity, and acceptability of Internet-based treatment. Demographic and symptom severity data were compared with people with OCD identified in a national epidemiological survey and with a sample of patients with OCD from a specialist outpatient anxiety clinic. 129 volunteers to an online Internet survey, 135 patients at a specialist anxiety disorders outpatient clinic, and 297 cases identified in a national epidemiological survey. Demographic characteristics, and severity of symptoms as measured by the Kessler 10-Item scale, the 12-item World Health Organisation Disability Assessment Schedule-Second Edition and the Yale Brown Obsessive Compulsive Scale-Self Report Version. The Internet sample was similar demographically but reported more severe symptoms than the comparison groups, although had similar severity of symptoms of OCD compared with other clinical samples reported in the literature. Participants reported Internet-based treatment for OCD would be highly acceptable. Internet-based treatment may reduce barriers to accessing treatment to people with OCD. Individuals in this study were similar demographically to other samples and had similar severity of symptoms as those identified in other clinical samples, suggesting that Internet-based treatment using techniques employed in face-to-face treatment may be effective in this group. Internet-based treatments for OCD need to be developed and evaluated.


Precipitation influences on uptake of a global pollutant by a coastal avian species.
Climatic variation, including precipitation amounts and timing, has been linked to abundance and breeding success of many avian species. Less studied, but also of significance, is the consequence of climatic variability on the exposure and uptake of nutrients and contaminants by wildlife. The authors examined mercury (Hg) concentrations in nestling wood stork feathers in a coastal setting over a 16-yr period to understand the influence of rainfall amounts on Hg transfer by parental provisioning relative to habitat use, assuming differential bioavailability of Hg within freshwater and saltwater habitat types. Coastal Hg uptake by stork nestlings was linked to freshwater habitat use, as indicated by stable carbon isotope (δ(13)C) analyses. Cumulative rainfall amounts exceeding 220 cm in the 23 mo preceding the breeding seasons resulted in greater use of freshwater wetlands as foraging habitat and greater Hg accumulation by nestling storks.


5-Hydroxytryptamine does not reduce sympathetic nerve activity or neuroeffector function in the splanchnic circulation.
Infusion of 5-hydroxytryptamine (5-HT) in conscious rats results in a sustained (up to 30 days) fall in blood pressure. This is accompanied by an increase in splanchnic blood flow. Because the splanchnic circulation is regulated by the sympathetic nervous system, we hypothesized that 5-HT would: 1) directly reduce sympathetic nerve activity in the splanchnic region; and/or 2) inhibit sympathetic neuroeffector function in splanchnic blood vessels. Moreover, removal of the sympathetic innervation of the splanchnic circulation (celiac ganglionectomy) would reduce 5-HT-induced hypotension. In anaesthetized Sprague-Dawley rats, mean blood pressure was reduced from 101±4 to 63±3mm Hg during slow infusion of 5-HT (25μg/kg/min, i.v.). Pre- and postganglionic splanchnic sympathetic nerve activity were unaffected during 5-HT infusion. In superior mesenteric arterial rings prepared for electrical field stimulation, neither 5-HT (3, 10, 30nM), the 5-HT1B receptor agonist CP 93129 nor 5-HT1/7 receptor agonist 5-carboxamidotryptamine inhibited neurogenic contraction compared to vehicle. 5-HT did not inhibit neurogenic contraction in superior mesenteric venous rings. Finally, celiac ganglionectomy did not modify the magnitude of fall or time course of 5-HT-induced hypotension when compared to animals receiving sham ganglionectomy. We conclude it is unlikely 5-HT interacts with the sympathetic nervous system at the level of the splanchnic preganglionic or postganglionic nerve, as well as at the neuroeffector junction, to reduce blood pressure. These important studies allow us to rule out a direct interaction of 5-HT with the splanchnic sympathetic nervous system as a cause of the 5-HT-induced fall in blood pressure.


Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo.
Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer.


Effectiveness of the Indiana 4-H tractor program at instilling safe tractor operating behaviors and attitudes in youth.
The purpose of this research was to determine what impact the Indiana 4-H Tractor Program has had on safer tractor operating behavior and attitudes of participants and to provide recommendations for program improvement. To assess the impact, 108 non 4-H youth who reported they operated a tractor regularly were compared with 104 4-H Tractor Program participants. A single skilled evaluator observed each individual in the two groups as she/he operated a tractor through a standard tractor-operating course. Information on recent tractor-related injury history and attitudes toward tractor safety was gathered using a written survey. Results showed that the program has had both a perceived and demonstrable positive influence; however, a need for improvements was also shown. Most significant of the findings was that participants in the 4-H Tractor Program were observed to operate tractors in a safer and more skillful manner. Even though the 4-H Tractor Program participants reported substantially more exposure time to tractor operation, they did not report a significantly different injury experience in comparison to the non-participants. Responses from the 4-H program participants, however, indicated a trend toward having more tractor-related close call incidents. There was no significant difference between the two groups in their attitudes toward tractor safety. Program recommendations developed as a result of the study primarily related to the need for updating instructional material used in the 4-H Tractor Program and the need for additional training and resources for volunteer leaders.


Polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity.
The E157Q substitution in HIV-1 integrase (IN) is a relatively common natural polymorphism associated with HIV resistance to IN strand transfer inhibitors (INSTIs). Although R263K is the most common resistance substitution for the INSTI dolutegravir, an INSTI treatment-experienced individual recently failed dolutegravir-based therapy, with E157Q being the only resistance-associated change reported. Given that different resistance pathways can sometimes synergize to confer high levels of resistance to antiretroviral drugs, we studied the effects of E157Q in association with R263K. Because Glu157 is thought to lie within the binding site of HIV IN DNA binding inhibitors such as FZ41, we also evaluated DNA binding activity and resistance to IN inhibitors in the presence of E157Q. Purified recombinant IN proteins were assessed in cell-free assays for their strand transfer and DNA binding activities. NL4.3 viral stocks harbouring IN mutations were generated and characterized in the presence and absence of IN inhibitors in tissue culture. E157Q alone had little if any effect on the biochemical activity of IN, and partially restored the activity of R263K-containing IN. The E157Q/R263K double viral mutant displayed infectiousness in culture equivalent to WT, while increasing resistance to dolutegravir by 10-fold compared with lower-level resistance associated with R263K alone. None of the mutations tested showed significant resistance to either raltegravir or FZ41. This study shows that E157Q may act as a compensatory mutation for R263K. Since E157Q is a natural polymorphism present in 1%-10% of HIV-positive individuals, it may be of particular importance for patients receiving INSTI therapy.


Shift in ecological strategy helps marginal populations of shepherd's purse (Capsella bursa-pastoris) to overcome a high genetic load.
The outcome of species range expansion depends on the interplay of demographic, environmental and genetic factors. Self-fertilizing species usually show a higher invasive ability than outcrossers but selfing and bottlenecks during colonization also lead to an increased genetic load. The relationship between genomic and phenotypic characteristics of expanding populations has, hitherto, rarely been tested experimentally. We analysed how accessions of the shepherd's purse, Capsella bursa-pastoris, from the colonization front or from the core of the natural range performed under increasing density of competitors. First, accessions from the front showed a lower fitness than those from the core. Second, for all accessions, competitor density impacted negatively both vegetative growth and fruit production. However, despite their higher genetic load and lower absolute performances, accessions from the front were less affected by competition than accessions from the core. This seems to be due to phenotypic trade-offs and a shift in phenology that allow accessions from the front to avoid competition.


Mathematical modelling of the diurnal regulation of the MEP pathway in Arabidopsis.
Isoprenoid molecules are essential elements of plant metabolism. Many important plant isoprenoids, such as chlorophylls, carotenoids, tocopherols, prenylated quinones and hormones are synthesised in chloroplasts via the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. Here we develop a mathematical model of diurnal regulation of the MEP pathway in Arabidopsis thaliana. We used both experimental and theoretical approaches to integrate mechanisms potentially involved in the diurnal control of the pathway. Our data show that flux through the MEP pathway is accelerated in light due to the photosynthesis-dependent supply of metabolic substrates of the pathway and the transcriptional regulation of key biosynthetic genes by the circadian clock. We also demonstrate that feedback regulation of both the activity and the abundance of the first enzyme of the MEP pathway (1-deoxy-D-xylulose 5-phosphate synthase, DXS) by pathway products stabilizes the flux against changes in substrate supply and adjusts the flux according to product demand under normal growth conditions. These data illustrate the central relevance of photosynthesis, the circadian clock and feedback control of DXS for the diurnal regulation of the MEP pathway.


Comparison of cultured and uncultured keratinocytes seeded into a collagen-GAG matrix for skin replacements.
A well-characterised collagen-glycosaminoglycan (CG) matrix functions as an extracellular matrix analogue (ECMA) of dermis on full-thickness wounds. The epidermis can be reconstituted by seeding autologous uncultured keratinocytes into the matrix prior to grafting. We hypothesised that seeding the CG matrix with keratinocytes cultured to sub-confluence may provide the ECMA with more proliferating keratinocytes than with uncultured keratinocytes. Autologous cells were isolated from split-thickness skin grafts and cultured to sub-confluence. ECMAs were seeded by centrifuging cultured (n = 8) or uncultured (n = 8) autologous keratinocytes into a CG matrix at a density of 100,000 cells/cm2, then applied onto full-thickness wounds on Yorkshire pigs. Gross and histologic observations were made up to 21 days post-grafting. At 14 days, a fully differentiated epidermis was present on all graft sites, but the epidermis of the cultured-cell-seeded matrices was thicker, 180 (19) microns, than the uncultured-cell-seeded matrices, 110 (18) microns. The epidermis of cultured-cell-seeded matrices was acanthotic, containing 14 (4) cell layers, as compared to uncultured-cell-seeded matrices, 9 (1) cell layers. The number of subepithelial keratinocyte cysts/cm cross-section present in the neodermis was also greater in cultured-, 1.35 (0.37), than in uncultured-cell-seeded matrices, 0.47 (0.35). Epidermal confluence on day 14 was 96 (3)% on cultured-cell-seeded grafts and 50 (17)% on uncultured-cell-seeded grafts. These results are consistent with the hypothesis that the process of in vitro cell cultivation increases the proportion of dividing cells in preference to differentiated cells. This technology may be useful in reconstruction of specialised bilayer tissues with minimal donor sites.


In vivo molecular imaging of colorectal cancer using quantum dots targeted to vascular endothelial growth factor receptor 2 and optical coherence tomography/laser-induced fluorescence dual-modality imaging.
Optical coherence tomography/laser induced fluorescence (OCT/LIF) dual-modality imaging allows for minimally invasive, nondestructive endoscopic visualization of colorectal cancer in mice. This technology enables simultaneous longitudinal tracking of morphological (OCT) and biochemical (fluorescence) changes as colorectal cancer develops, compared to current methods of colorectal cancer screening in humans that rely on morphological changes alone. We have shown that QDot655 targeted to vascular endothelial growth factor receptor 2 (QD655-VEGFR2) can be applied to the colon of carcinogen-treated mice and provides significantly increased contrast between the diseased and undiseased tissue with high sensitivity and specificity ex vivo. QD655-VEGFR2 was used in a longitudinal in vivo study to investigate the ability to correlate fluorescence signal to tumor development. QD655-VEGFR2 was applied to the colon of azoxymethane (AOM-) or saline-treated control mice in vivo via lavage. OCT/LIF images of the distal colon were taken at five consecutive time points every three weeks after the final AOM injection. Difficulties in fully flushing unbound contrast agent from the colon led to variable background signal; however, a spatial correlation was found between tumors identified in OCT images, and high fluorescence intensity of the QD655 signal, demonstrating the ability to detect VEGFR2 expressing tumors in vivo.


Synchronization measurement of multiple neuronal populations.
The purpose of the present paper is to develop a method, based on equal-time correlation, correlation matrix analysis and surrogate resampling, that is able to quantify and describe properties of synchronization of population neuronal activity recorded simultaneously from multiple sites. Initially, Lorenz-type oscillators were used to model multiple time series with different patterns of synchronization. Eigenvalue and eigenvector decomposition was then applied to identify "clusters" of locally synchronized activity and to calculate a "global synchronization index." This method was then applied to multichannel data recorded from an in vitro model of epileptic seizures. The results demonstrate that this novel method can be successfully used to analyze synchronization between multiple neuronal population series.


Cdk1-dependent phosphoinhibition of a formin-F-BAR interaction opposes cytokinetic contractile ring formation.
In Schizosaccharomyces pombe, cytokinesis requires the assembly and constriction of an actomyosin-based contractile ring (CR). A single essential formin, Cdc12, localizes to the cell middle upon mitotic onset and nucleates the F-actin of the CR. Cdc12 medial recruitment is mediated in part by its direct binding to the F-BAR scaffold Cdc15. Given that Cdc12 is hyperphosphorylated in M phase, we explored whether Cdc12 phosphoregulation impacts its association with Cdc15 during mitosis. We found that Cdk1, a major mitotic kinase, phosphorylates Cdc12 on six N-terminal residues near the Cdc15-binding site, and phosphorylation on these sites inhibits its interaction with the Cdc15 F-BAR domain. Consistent with this finding, a cdc12 mutant with all six Cdk1 sites changed to phosphomimetic residues (cdc12-6D) displays phenotypes similar to cdc12-P31A, in which the Cdc15-binding motif is disrupted; both show reduced Cdc12 at the CR and delayed CR formation. Together, these results indicate that Cdk1 phosphorylation of formin Cdc12 antagonizes its interaction with Cdc15 and thereby opposes Cdc12's CR localization. These results are consistent with a general role for Cdk1 in inhibiting cytokinesis until chromosome segregation is complete.


Three-dimensional magnetic resonance imaging of the phakic crystalline lens during accommodation.
To quantify changes in crystalline lens curvature, thickness, equatorial diameter, surface area, and volume during accommodation using a novel two-dimensional magnetic resonance imaging (MRI) paradigm to generate a complete three-dimensional crystalline lens surface model. Nineteen volunteers, aged 19 to 30 years, were recruited. T(2)-weighted MRIs, optimized to show fluid-filled chambers of the eye, were acquired using an eight-channel radio frequency head coil. Twenty-four oblique-axial slices of 0.8 mm thickness, with no interslice gaps, were acquired to visualize the crystalline lens. Three Maltese cross-type accommodative stimuli (at 0.17, 4.0, and 8.0 D) were presented randomly to the subjects in the MRI to examine lenticular changes with accommodation. MRIs were analyzed to generate a three-dimensional surface model. During accommodation, mean crystalline lens thickness increased (F = 33.39, P < 0.001), whereas lens equatorial diameter (F = 24.00, P < 0.001) and surface radii both decreased (anterior surface, F = 21.78, P < 0.001; posterior surface, F = 13.81, P < 0.001). Over the same stimulus range, mean crystalline lens surface area decreased (F = 7.04, P < 0.005) with a corresponding increase in lens volume (F = 6.06, P = 0.005). These biometric changes represent a 1.82% decrease and 2.30% increase in crystalline lens surface area and volume, respectively. CONCLUSIONS; The results indicate that the capsular bag undergoes elastic deformation during accommodation, causing reduced surface area, and the observed volumetric changes oppose the theory that the lens is incompressible.


Cardiopulmonary response during whole-body vibration training in patients with severe COPD.
Several studies in patients with chronic obstructive pulmonary disease (COPD) have shown that whole-body vibration training (WBVT) has beneficial effects on exercise capacity. However, the acute cardiopulmonary demand during WBVT remains unknown and was therefore investigated in this study. Ten patients with severe COPD (forced expiratory volume in 1 s: 38±8% predicted) were examined on two consecutive days. On day one, symptom-limited cardiopulmonary exercise testing was performed on a cycle ergometer. The next day, six bouts of repeated squat exercises were performed in random order for one, two or three minutes either with or without WBVT while metabolic demands were simultaneously measured. Squat exercises with or without WBVT induced comparable ventilatory efficiency (minute ventilation (VE)/carbon dioxide production (V'CO2 ): 38.0±4.4 with WBVT versus 37.4±4.1 without, p=0.236). Oxygen uptake after 3 min of squat exercises increased from 339±40 mL·min-1 to 1060±160 mL·min-1 with WBVT and 988±124 mL min-1 without WBV (p=0.093). However, there were no significant differences between squat exercises with and without WBVT in oxygen saturation (90±4% versus 90±4%, p=0.068), heart rate (109±13 bpm versus 110±15 bpm, p=0.513) or dyspnoea (Borg scale 5±2 versus 5±2, p=0.279). Combining squat exercises with WBVT induced a similar cardiopulmonary response in patients with severe COPD compared to squat exercises without WBVT. Bearing in mind the small sample size, WBVT might be a feasible and safe exercise modality even in patients with severe COPD.


Peripherally inserted central catheters (PICCs) in cancer patients under chemotherapy: A prospective study on the incidence of complications and overall failures.
The increasing use of peripherally inserted central venous catheters (PICCs) for chemotherapy has led to the observation of an elevated risk of complications and failures. This study investigates PICC failures in cancer patients. A prospective study was conducted at a single cancer institution on 291 PICC placement for chemotherapy. The primary study outcome was PICC failure. Median follow-up was 119 days. PICC complications occurred in 72 patients (24.7%) and failures with removal in 44 (15.1%). Reasons for failures were upper extremity deep venous thrombosis (UEDVT) 12 (4.1%), central line associate bloodstream infection (CLABSI) 5 (1.7%) with an infection rate of 0.95 per 1,000 catheter days, exit site infection 9 (3.1%) with a rate of 1.46 per 1,000 catheter days, catheter dislodgment 11 (3.8%), and occlusion 7 (2.4%). Statistically significant risk factors were previous DVT (HR 2.95, 95%CI 1.33-6.53), reason for PICC implant (HR 3.65, 95%CI 1.12-10.34) and 5-fluorouracil, oxaliplatin and bevacizumab based chemotherapy (HR 3.11, 95%CI 1.17-8.26). PICC is a safe venous device for chemotherapy delivery. Nevertheless, a 15% rate of failure has to be taken in account when planning PICC insertion for chemotherapy purposes. J. Surg. Oncol. 2016;113:708-714. © 2016 Wiley Periodicals, Inc.


Spindle fusion requires dynein-mediated sliding of oppositely oriented microtubules.
Bipolar spindle assembly is critical for achieving accurate segregation of chromosomes. In the absence of centrosomes, meiotic spindles achieve bipolarity by a combination of chromosome-initiated microtubule nucleation and stabilization and motor-driven organization of microtubules. Once assembled, the spindle structure is maintained on a relatively long time scale despite the high turnover of the microtubules that comprise it. To study the underlying mechanisms responsible for spindle assembly and steady-state maintenance, we used microneedle manipulation of preassembled spindles in Xenopus egg extracts. When two meiotic spindles were brought close enough together, they interacted, creating an interconnected microtubule structure with supernumerary poles. Without exception, the perturbed system eventually re-established bipolarity, forming a single spindle of normal shape and size. Bipolar spindle fusion was blocked when cytoplasmic dynein function was perturbed, suggesting a critical role for the motor in this process. The fusion of Eg5-inhibited monopoles also required dynein function but only occurred if the initial interpolar separation was less than twice the microtubule radius of a typical monopole. Our experiments uniquely illustrate the architectural plasticity of the spindle and reveal a robust ability of the system to attain a bipolar morphology. We hypothesize that a major mechanism driving spindle fusion is dynein-mediated sliding of oppositely oriented microtubules, a novel function for the motor, and posit that this same mechanism might also be involved in normal spindle assembly and homeostasis.


Probabilistic language models in cognitive neuroscience: Promises and pitfalls.
Cognitive neuroscientists of language comprehension study how neural computations relate to cognitive computations during comprehension. On the cognitive part of the equation, it is important that the computations and processing complexity are explicitly defined. Probabilistic language models can be used to give a computationally explicit account of language complexity during comprehension. Whereas such models have so far predominantly been evaluated against behavioral data, only recently have the models been used to explain neurobiological signals. Measures obtained from these models emphasize the probabilistic, information-processing view of language understanding and provide a set of tools that can be used for testing neural hypotheses about language comprehension. Here, we provide a cursory review of the theoretical foundations and example neuroimaging studies employing probabilistic language models. We highlight the advantages and potential pitfalls of this approach and indicate avenues for future research.


Comparison of chlorine and peroxyacetic-based disinfectant to inactivate Feline calicivirus, Murine norovirus and Hepatitis A virus on lettuce.
In recent years, raw fruits and vegetables have frequently been involved in foodborne transmission to humans of enteric viruses, particularly noroviruses and hepatitis A virus (HAV). Although viral contamination can occur during all steps of food processing, primary production is a critical stage on which prevention measures must be focused to minimize the risk of infection to consumers. Postharvest sanitation may be a valid technological solution for decreasing the bacterial load on fresh raw material, but there is a lack of data concerning the effectiveness of this process on enteric viruses. In this study, we compared the survival of two human norovirus surrogates, the feline calicivirus (FCV), and the murine norovirus (MNV-1), and of HAV on lettuce after water washing with bubbles and with or without ultrasound, and washing with bubbles in the presence of active chlorine (15 ppm) or peroxyacetic acid-based disinfectant (100 ppm). Cell culture and quantitative RT-PCR assays were used to detect and quantify the viruses on the surface of the lettuce after the sanitizing treatments. Levels of viral inactivation on the lettuce leaves were not significantly different between washing with bubbles and washing with bubbles plus ultrasound and were not dependant on the quantification method. A simple washing without disinfectant resulted in a decrease of approximately 0.7 log units in the quantity of virus detected for HAV and FCV and of 1.0 log unit for MNV-1. In the experimental set-up including a washing step (with or without ultrasound) followed by washing for 2 min in the presence of disinfectants, 15 ppm of active chlorine was found more effective for inactivating FCV (2.9 log units) than HAV and MNV-1 (1.9 log units and 1.4 log units, respectively) whereas 100 ppm of peroxyacetic-based biocide was found effective for inactivating FCV (3.2 log units) and MNV-1 (2.3 log units), but not HAV (0.7 log units). Quantitative RT-PCR results indicated that the presence of viral RNA did not correlate with the presence of infectious viruses on disinfected lettuce, except for MNV-1 processed with chlorine (15 ppm). In comparison with water washing, a substantial additional decrease of genomic FCV titer (1.1 log units) but no significant reduction of the genomic titers of HAV and MNV-1 were found on lettuce treated with chlorine (15 ppm). No significant effect of the disinfection step of lettuce with peroxyacetic-based biocide (100 ppm peracetic acid) was found by qRT-PCR on all genomic viral titers tested. This study illustrates the necessity of determining the effectiveness of technological processes against enteric viruses, using a relevant reference such as HAV, in order to reduce the risk of hepatitis and gastroenteritis by exposure to vegetables.


Multigene DNA priming-boosting vaccines protect macaques from acute CD4+-T-cell depletion after simian-human immunodeficiency virus SHIV89.6P mucosal challenge.
We evaluated four priming-boosting vaccine regimens for the highly pathogenic simian human immunodeficiency virus SHIV89.6P in Macaca nemestrina. Each regimen included gene gun delivery of a DNA vaccine expressing all SHIV89.6 genes plus Env gp160 of SHIV89.6P. Additional components were two recombinant vaccinia viruses, expressing SHIV89.6 Gag-Pol or Env gp160, and inactivated SHIV89.6 virus. We compared (i) DNA priming/DNA boosting, (ii) DNA priming/inactivated virus boosting, (iii) DNA priming/vaccinia virus boosting, and (iv) vaccinia virus priming/DNA boosting versus sham vaccines in groups of 6 macaques. Prechallenge antibody responses to Env and Gag were strongest in the groups that received vaccinia virus priming or boosting. Cellular immunity to SHIV89.6 peptides was measured by enzyme-linked immunospot assay; strong responses to Gag and Env were found in 9 of 12 vaccinia virus vaccinees and 1 of 6 DNA-primed/inactivated-virus-boosted animals. Vaccinated macaques were challenged intrarectally with 50 50% animal infectious doses of SHIV89.6P 3 weeks after the last immunization. All animals became infected. Five of six DNA-vaccinated and 5 of 6 DNA-primed/particle-boosted animals, as well as all 6 controls, experienced severe CD4(+)-T-cell loss in the first 3 weeks after infection. In contrast, DNA priming/vaccinia virus boosting and vaccinia virus priming/DNA boosting vaccines both protected animals from disease: 11 of 12 macaques had no loss of CD4(+) T cells or moderate declines. Virus loads in plasma at the set point were significantly lower in vaccinia virus-primed/DNA-boosted animals versus controls (P = 0.03). We conclude that multigene vaccines delivered by a combination of vaccinia virus and gene gun-delivered DNA were effective against SHIV89.6P viral challenge in M. nemestrina.


Cognitive Behavioral Therapy vs. Eye Movement Desensitization and Reprocessing for Treating Panic Disorder: A Randomized Controlled Trial.
Objective: Cognitive Behavioral Therapy (CBT) is an effective intervention for patients with panic disorder (PD). From a theoretical perspective, Eye Movement Desensitization and Reprocessing (EMDR) therapy could also be useful in the treatment of PD because: (1) panic attacks can be experienced as life threatening; (2) panic memories specific to PD resemble traumatic memories as seen in posttraumatic stress disorder (PTSD); and (3) PD often develops following a distressing life event. The primary objective of this Randomized Controlled Trial (RCT), was to compare EMDR therapy with CBT for PD and determine whether EMDR is not worse than CBT in reducing panic symptoms and improving Quality Of Life (QOL). Methods: Two-arm (CBT and EMDR) parallel RCT in patients with PD (N = 84). Patients were measured at baseline (T1), directly after the last therapy session (T2), and 3 months after ending therapy (T3). Non-inferiority testing (linear mixed model with intention-to-treat analysis) was applied. Patients were randomly assigned to 13 weekly 60-min sessions of CBT (N = 42) or EMDR therapy (N = 42). Standard protocols were used. The primary outcome measure was severity of PD at T3, as measured with the Agoraphobic Cognitions Questionnaire (ACQ), the Body Sensations Questionnaire (BSQ), and the Mobility Inventory (MI). The secondary outcome measure was QOL, as measured with the World Health Organization Quality of Life short version (WHOQOL-Bref), at T3. Results: The severity of PD variables ACQ and BSQ showed non-inferiority of EMDR to CBT, while MI was inconclusive (adjusted analyses). Overall QOL and general health, Psychological health, Social relationships, and Environment showed non-inferiority of EMDR to CBT, while Physical health was inconclusive. Conclusion: EMDR therapy proved to be as effective as CBT for treating PD patients. Trial Registration: Dutch Trial Register, Nr. 3134 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3134.


Gender Differences in Publication Productivity, Academic Rank, and Career Duration Among U.S. Academic Gastroenterology Faculty.
Female representation in academic medicine is increasing without proportional increases in female representation at senior ranks. The purpose of this study is to describe the gender representation in academic gastroenterology (GI) and compare publication productivity, academic rank, and career duration between male and female gastroenterologists. In 2014, the authors collected data including number of publications, career duration, h-index, and m-index for faculty members at 114 U.S. academic GI programs. Of 2,440 academic faculty, 1,859 (76%) were men and 581 (24%) were women. Half (50%) of men held senior faculty position compared with 29% of women (P < .001). Compared with female faculty, male faculty had significantly (P < .001) longer careers (20 vs. 11 years), more publications (median 24 [0-949] vs. 9 [0-438]), and higher h-indices (8 vs. 4). Higher h-index correlated with higher academic rank (P < .001). The authors detected no difference in the h-index between men and women at the same rank for professor, associate professor, and instructor, nor any difference in the m-index between men and women (0.5 vs. 0.46, respectively, P = .214). A gender gap exists in the number and proportion of women in academic GI; however, after correcting for career duration, productivity measures that consider quantity and impact are similar for male and female faculty. Women holding senior faculty positions are equally productive as their male counterparts. Early and continued career mentorship will likely lead to continued increases in the rise of women in academic rank.


Bilateral somatosensory evoked potentials following intermittent theta-burst repetitive transcranial magnetic stimulation.
Intermittent theta-burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation that may alter cortical excitability in the primary somatosensory cortex (SI). The present study investigated the effects of iTBS on subcortical and early cortical somatosensory evoked potentials (SEPs) recorded over left, iTBS stimulated SI and the right-hemisphere non-stimulated SI. SEPs were recorded before and at 5, 15, and 25 minutes following iTBS. Compared to pre-iTBS, the amplitude of cortical potential N20/P25 was significantly increased for 5 minutes from non-stimulated SI and for 15 to 25 minutes from stimulated SI. Subcortical potentials recorded bilaterally remained unaltered following iTBS. We conclude that iTBS increases the cortical excitability of SI bilaterally and does not alter thalamocortical afferent input to SI. ITBS may provide one avenue to induce cortical plasticity in the somatosensory cortex.


Soil-water potential: direct measurement by a new technique.
Current methods of measuring the potential of water in soil are inadequate. It is proposed to depress the reference free energy of water by a predetermined amount from the standard level of pure free water at atmospheric pressure by use of a solute. The specific free-energy difference of soil water from the depressed reference can be measured as a pressure.


Alveolar mechanics in the acutely injured lung: role of alveolar instability in the pathogenesis of ventilator-induced lung injury.
With patients who have acute lung injury, respiratory function is routinely evaluated and the treatment may entail choices from various ventilatory strategies. The ventilatory strategies that have been used over the years are being replaced by newer protocols that represent improvements in patient treatment. However, the rationales for the various ventilatory strategies are largely empirical, because the physiology and mechanics of lung inflation are poorly understood. Researchers have proposed competing and contradictory mechanisms of lung inflation at the alveolar level, based on assessments of lung function and discordant descriptions of histological changes during ventilation. We have researched alveolar histophysiology with animal experiments that combined a conventional histological approach with in vivo microscopy to assess alveolar dynamics during normal and disease-state ventilation. Our video and computer analyses document real-time changes of alveolar size and function, often in the same animal and in adjacent areas of the same lung. Our research indicates that, instead of supporting one theory of alveolar mechanics or another, the various behaviors reportedly exhibited by alveoli may be consistent and represent a continuum between normal alveolar function and the alveolar mechanics of acute lung injury.


How the U.S.-Mexico border influences adolescent substance use: Youth participatory action research using photovoice.
The purpose of this study is to use Youth Participatory Action Research (YPAR) methods and Photovoice to identify the perceived environmental factors that influence substance use among adolescents living at the U.S.-Mexico border. One academic and a local youth health coalition engaged in Youth Participatory Action Research (YPAR) using Photovoice and qualitative methods to examine the perceived factors influencing adolescent substance use in their border community. Identified novel risk factors for adolescent substance use on the border included the normalization of drug trafficking, normalization of substance use, and cross-border access to substances. Novel protective factors included living in a close-knit binational community and having strong binational family and social support systems. The findings also illustrate a nexus of 'factors' wherein risk and protective elements overlap. This study contributes to the broader literature on international border health and how living in a border space influences adolescent substance use. The examination of influential border-bound factors provides a more complete understanding of the experiences of youth living on the U.S.-Mexico border, and informs the field of the importance of considering the border experience for future prevention and risk reduction efforts with border adolescents.


A survey into the respiratory effects of prolonged exposure to pulverised fuel ash.
Previous studies of respiratory disorders in workers exposed to pulverised fuel ash (PFA) have been confined to radiological effects that were found to be minimal. The present survey included 268 men (88% of the defined population) with a history of more than 10 years exposure to PFA in six power stations in the south east of England. Respiratory questionnaires with full occupational histories were obtained from all of these subjects, of whom 207 were actively employed and 61 had retired; 243 had lung function tests and 208 had chest x ray examinations. The men were grouped, using their occupational histories, into high, medium, and low exposure categories. Dust concentrations were obtained by personal sampling on a representative sample of men from the three exposure categories. Lung function tests showed that a modest effect on forced vital capacity, vital capacity, forced expiratory volume in one second, peak flow, and gas transfer (DCO) was associated with prolonged heavy exposure to PFA. The men with prolonged heavy exposure also showed higher prevalences of respiratory symptoms. No definite relation between exposure and x ray changes was established. The results of this cross sectional survey indicate that exposures to PFA should not exceed the limits recommended by the Health and Safety Executive for low toxicity dusts.


Indicators of hearing protection use: self-report and researcher observation.
Hearing protection devices (HPD) are commonly used to prevent occupational noise-induced hearing loss. There is a large body of research on hearing protection use in industry, and much of it relies on workers' self-reported use of hearing protection. Based on previous studies in fixed industry, worker self-report has been accepted as an adequate and reliable tool to measure this behavior among workers in many industrial sectors. However, recent research indicates self-reported hearing protection use may not accurately reflect subject behavior in industries with variable noise exposure. This study compares workers' self-reported use of hearing protection with their observed use in three workplaces with two types of noise environments: one construction site and one fixed industry facility with a variable noise environment, and one fixed industry facility with a steady noise environment. Subjects reported their use of hearing protection on self-administered surveys and activity cards, which were validated using researcher observations. The primary outcome of interest in the study was the difference between the self-reported use of hearing protection in high noise on the activity card and survey: (1) over one workday, and (2) over a 2-week period. The primary hypotheses for the study were that subjects in workplaces with variable noise environments would report their use of HPDs less accurately than subjects in the stable noise environment, and that reporting would be less accurate over 2 weeks than over 1 day. In addition to noise variability, other personal and workplace factors thought to affect the accuracy of self-reported hearing protection use were also analyzed. This study found good agreement between subjects' self-reported HPD use and researcher observations. Workers in the steady noise environment self-reported hearing protection use more accurately on the surveys than workers in variable noise environments. The findings demonstrate the potential importance of noise exposure variability as a factor influencing reporting accuracy.


Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0.
Constraint-based reconstruction and analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental molecular systems biology data and quantitative prediction of physicochemically and biochemically feasible phenotypic states. The COBRA Toolbox is a comprehensive desktop software suite of interoperable COBRA methods. It has found widespread application in biology, biomedicine, and biotechnology because its functions can be flexibly combined to implement tailored COBRA protocols for any biochemical network. This protocol is an update to the COBRA Toolbox v.1.0 and v.2.0. Version 3.0 includes new methods for quality-controlled reconstruction, modeling, topological analysis, strain and experimental design, and network visualization, as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data. New multi-lingual code integration also enables an expansion in COBRA application scope via high-precision, high-performance, and nonlinear numerical optimization solvers for multi-scale, multi-cellular, and reaction kinetic modeling, respectively. This protocol provides an overview of all these new features and can be adapted to generate and analyze constraint-based models in a wide variety of scenarios. The COBRA Toolbox v.3.0 provides an unparalleled depth of COBRA methods.


Percutaneous coronary intervention for obstructive bifurcation lesions: the 14th consensus document from the European Bifurcation Club.
The European Bifurcation Club recommends an approach to a bifurcation stenosis which involves careful assessment, planning and a sequential provisional approach. In the minority of lesions where two stents are required, careful deployment and optimal expansion are essential to achieve a long-term result.


Binding of neuroligins to PSD-95.
PSD-95 is a component of postsynaptic densities in central synapses. It contains three PDZ domains that localize N-methyl-D-aspartate receptor subunit 2 (NMDA2 receptor) and K+ channels to synapses. In mouse forebrain, PSD-95 bound to the cytoplasmic COOH-termini of neuroligins, which are neuronal cell adhesion molecules that interact with beta-neurexins and form intercellular junctions. Neuroligins bind to the third PDZ domain of PSD-95, whereas NMDA2 receptors and K+ channels interact with the first and second PDZ domains. Thus different PDZ domains of PSD-95 are specialized for distinct functions. PSD-95 may recruit ion channels and neurotransmitter receptors to intercellular junctions formed between neurons by neuroligins and beta-neurexins.


Numerical Taxonomy Helps Identification of Merliniidae and Telotylenchidae (Nematoda: Tylenchoidea) from Iran.
Numerical taxonomy was used for identification and grouping of the genera, species, and populations in the families Merliniidae and Telotylenchidae. The variability of each of 44 morphometric characters was evaluated by calculation of the coefficient of variability (CV) and the ratio of extremes (max/min) in the range of 1,020 measured females. Also correlation and regression analyses were made between characters to find potential collinearities. Hierarchical cluster analysis (HCA) was used for (i) grouping 21 genera in the superfamily Dolichodoroidea based on literature data coded for states of 18 diagnostic characters, and (ii) for grouping Iranian populations belonging to selected genera. Furthermore, STEPDISC analysis was used for (i) grouping 11 genera of Merliniidae and Telotylenchidae based on the measurements of 35 characters from 1,007 Iranian female specimens, and (ii) grouping measured females of eight species of Amplimerlinius and Pratylenchoides. The multivariate data analysis approach showed robust enough to summarize relationship between morphometric characters and group genera, species, and populations of the nematodes and in particular help to identify the genera and species of Amplimerlinius and Pratylenchoides.


Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures.
We have previously hypothesized that the pro-inflammatory cytokine TNF alpha has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by cross-linking surface p55 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF alpha soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metallo-proteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF alpha-mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced approximately 15-fold in the presence of BB-2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF alpha (P < 0.006), p55 sTNF-R (P < 0.006), and p75 sTNF-R (P < 0.004). Paradoxically, despite the reduction in soluble TNF alpha levels, the production of IL-1 beta, IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of neutralizing anti-TNF alpha antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exits between the enzyme(s) which process membrane-bound TNF alpha, and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF alpha secretion and TNF-R cleavage may not modulate down-stream effects of TNA alpha, and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases.


Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease.
Estimates of the diagnostic performance of serologic testing and HLA-DQ typing for detecting celiac disease have mainly come from case-control studies. To define the performance of serologic testing and HLA-DQ typing prospectively. Prospective cohort study. University hospital. Patients referred for small-bowel biopsy for the diagnosis of celiac disease. Celiac serologic testing (antigliadin antibodies [AGA], antitransglutaminase antibodies [TGA], and antiendomysium antibodies [EMA]) and HLA-DQ typing. Diagnostic performance of serologic testing and HLA-DQ typing compared with a reference standard of abnormal histologic findings and clinical resolution after a gluten-free diet. Sixteen of 463 participants had celiac disease (prevalence, 3.46% [95% CI, 1.99% to 5.55%]). A positive result on both TGA and EMA testing had a sensitivity of 81% (CI, 54% to 95.9%), specificity of 99.3% (CI, 98.0% to 99.9%), and negative predictive value of 99.3% (CI, 98.0% to 99.9%). Testing positive for either HLA-DQ type maximized sensitivity (100% [CI, 79% to 100%]) and negative predictive value (100% [CI, 98.6% to 100%]), whereas testing negative for both minimized the negative likelihood ratio (0.00 [CI, 0.00 to 0.40]) and posttest probability (0% [CI, 0% to 1.4%]). The addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, did not change test performance compared with either testing strategy alone. Few cases of celiac disease precluded meaningful comparisons of testing strategies. In a patient population referred for symptoms and signs of celiac disease with a prevalence of celiac disease of 3.46%, TGA and EMA testing were the most sensitive serum antibody tests and a negative HLA-DQ type excluded the diagnosis. However, the addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, provided the same measures of test performance as either testing strategy alone.


Measurement of hemoglobin A1c by a new liquid-chromatographic assay: methodology, clinical utility, and relation to glucose tolerance evaluated.
A chromatographic method for determining glycated hemoglobin (Hb A1c) by use of a new monodisperse cation-exchanger has been investigated. Hb A1c was separated from other "minor hemoglobins": Hb F, Hb A3 (the glutathione adduct), and the acetaldehyde adduct in alcoholics. The method was fully automated and a single column could be used for more than 1000 runs. The normal reference interval was 4.0-5.2%; the interval for diabetic outpatients was 5.6-12.4%. Within-run and the between-run CVs were less than 0.9% and 1.7%, respectively. Carbamylation in uremic patients who were undergoing hemodialysis increased the proportion of Hb A1c to 1%. Hb A1c results were compared with results from glucose tolerance tests. In our study, Hb A1c less than 5.5% excluded diabetes: subjects with Hb A1c greater than 6.2% showed diabetes. If blood sampled during fasting had been screened with determinations of glucose and Hb A1c, only 20% of referred subjects would have needed an oral glucose tolerance test for diagnosis of diabetes.


Ultrasonography for diagnosis and management of nephrolithiasis: state of the art and new perspectives
The correct management of patients with kidney stones is a crucial issue for nephrologists. In recent years, the incidence and prevalence rates of nephrolithiasis have maintained a growing trend worldwide, showing a strong correlation with other systemic disease such as diabetes mellitus, hypertension, obesity, metabolic syndrome and chronic kidney disease. International guidelines indicate computed tomography as the first choice for all adult patients with suspected acute symptoms for obstructive nephrolithiasis. Intravenous pyelogram is more useful in the follow-up of patients with relapsing nephrolithiasis and known stone composition, while the high costs and the long image acquisition times limit the routine use of magnetic resonance. Recent innovative tools have improved the accuracy of kidney stone localization and measuring with B-Mode and color Doppler imaging, thereby reducing the gap between ultrasonography and computer tomography. The aim of this review is to report the latest evidence on risk factors and on the pathophysiology of nephrolithiasis, and to compare the utility of the available imaging techniques in the management of patients with kidney stones, focusing on the role of ultrasonography and the present and future strategies to improve its accuracy.


Neurosurgeon transition to retirement: results of the 2007 Congress of Neurological Surgeons Consensus Conference.
Recent studies of age-related effects on cognition and performance have raised concerns about the appropriate timing and regulatory surveillance of retirement for surgeons. Little is known about the practice patterns and retirement plans of aging neurosurgeons. Analyses of informed opinions on possible regulatory options are also lacking. During a consensus development workshop conducted at the 2007 Annual Meeting of the Congress of Neurological Surgeons, participants collected data regarding neurosurgeons' retirement plans, reviewed expert background information, and assessed opinions. Participants submitted data and discussion points throughout the session using digital handheld devices. These data were then statistically analyzed, with particular attention to shifts in opinion and emergence of consensus after the presentation of expert material and discussion. Neurosurgeons strongly oppose government regulation of retirement using uniform retirement age regulations. The most favored policy option, initially, particularly among older neurosurgeons, was status quo. After consensus development, the most favored policy option was local regulation by hospital privileging bodies. Neurosurgeon age, but not perceived ability to reach financial retirement goals, significantly influenced opinions. Retirement age is an area of active government regulation in other professions. Neurosurgeons seem to favor a flexible system of regulation based on local and quality standards, rather than national age-based thresholds. The Congress of Neurological Surgeons Consensus Conference process offers a viable methodology for initiating discussion of important policy issues facing organized neurosurgery, engaging the informed input of practicing neurosurgeons, and formulating preliminary strategies for pursuit by stakeholder neurosurgical policy organizations.


A tool-kit for cDNA microarray and promoter analysis.
We describe two sets of programs for expediting routine tasks in analysis of cDNA microarray data and promoter sequences. The first set permits bad data points to be flagged with respect to a number of parameters and performs normalization in three different ways. It allows combining of result files into comprehensive data sets, evaluation of the quality of both technical and biological replicates and row and/or column standardization of data matrices. The second set supports mapping ESTs in the genome, identifying the corresponding genes and recovering their promoters, analyzing promoters for transcription factor binding sites, and visual representation of the results. The programs are designed primarily for Arabidopsis thaliana researchers, but can be adapted readily for other model systems. Availability and Supplementary information: http://www.personal.psu.edu/nhs109/Programs/


Establishing a panel of chemo-resistant mesothelioma models for investigating chemo-resistance and identifying new treatments for mesothelioma.
Mesothelioma is inherently chemo-resistant with only 50% of patients responding to the standard of care treatments, and consequently it has a very grim prognosis. The aim of this study was to establish a panel of chemo-resistant mesothelioma models with clinically relevant levels of resistance as tools for investigating chemo-resistance and identifying new treatments for mesothelioma. Chemo-resistant cell lines were established in vitro and characterized in vivo using syngeneic Fischer rats. Tumors derived from all chemo-resistant cell lines were immunohistochemically classified as mesothelioma. Homozygous deletion of p16(INK4A)/p14(ARF) and increased expression of several ATP-binding cassette transporters were demonstrated, consistent with findings in human mesothelioma. Further, the acquisition of chemo-resistance in vitro resulted in changes to tumor morphology and overall survival. In conclusion, these models display many features corresponding with the human disease, and provide the first series of matched parental and chemo-resistant models for in vitro and in vivo mesothelioma studies.


Effects of bovine lactoferrin in surgically created bone defects on bone regeneration around implants.
The aim of this experimental study was to evaluate the effect of bovine lactoferrin (bLF)-loaded gelatin microspheres (GM) used in combination with anorganic bovine bone on bone regeneration in surgically created bone defects around tooth implants. Twenty-four uniform bone defects were created in the frontal bone via an extraoral approach in 12 domestic pigs. Twenty-four implants were placed at the center of the defects. In eight animals one of these defects was filled with 0.3 mL anorganic bovine bone while the other was left empty. In four animals, all defects were filled with 3 mg/defect bLF-loaded GM and anorganic bovine bone. All the defects were covered with collagen membranes. All animals were sacrificed after 10 weeks of healing, and the implants with the surrounding bone defects were removed en bloc. Undecalcified sections were prepared for histomorphometric analysis. The mean total area of hard tissue was 26.9 ± 6.0% in the empty defect group, 31.8 ± 8.4% in the graft group, and 47.6 ± 5.0% in the lactoferrin group (P < 0.001). The mean area of newly formed bone was 26.9 ± 6.0% in the empty defect group, 22.4 ± 8.2% in the graft group, and 46.1 ± 5.1% in the lactoferrin group (P < 0.001). The mean residual graft area was 9.4 ± 3.2% in the graft group and 1.5 ± 0.6% in the lactoferrin group (P < 0.001). The mean proportion of bone-implant contact in the defect region was 21.9 ± 8.4% in the empty defect group, 26.9 ± 10.1% in the graft group and 29.9 ± 10.3% in the lactoferrin group (P = 0.143). These data indicate that a combination of 3 mg bLF-loaded GM and bovine-derived HA promotes bone regeneration in defects around implants.


Alpha-tocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits.
The composition of atherosclerotic plaques, not just macroscopical lesion size, has been implicated in their susceptibility to rupture and the risk of thrombus formation. By focusing on the quality of lipids, macrophages, apoptosis, collagen, metalloproteinase expression and plaque integrity, we evaluated the possible anti-atherosclerotic effect of the antioxidants alpha-tocopherol and astaxanthin in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one WHHL rabbits were divided into three groups and were fed a standard diet, as controls (N =10), or a standard diet with the addition of 500 mg alpha-tocopherol per kg feed (N =11) or 100 mg astaxanthin per kg feed (N =10) for 24 weeks. We found that both antioxidants, particularly astaxanthin, significantly decreased macrophage infiltration in the plaques although they did not affect lipid accumulation. All lesions in the astaxanthin-treated rabbits were classified as early plaques according to the distribution of collagen and smooth muscle cells. Both antioxidants also improved plaque stability and significantly diminished apoptosis, which mainly occurred in macrophages, matrix metalloproteinase three expressions and plaque ruptures. Although neither antioxidant altered the positive correlations between the lesion size and lipid accumulation, the lesion size and apoptosis were only positively correlated in the control group. Astaxanthin and alpha-tocopherol may improve plaque stability by decreasing macrophage infiltration and apoptosis in this atherosclerotic setting. Apoptosis reduction by alpha-tocopherol and astaxanthin may be a new anti-atherogenic property of these antioxidants.


Thyroid eye disease with choroidal folds.
Purpose: To determine the clinical course of patients with chorioretinal folds (CRF) in thyroid eye disease (TED).Methods: A multi-center retrospective case series of patients with TED who developed CRF.Results: Ten patients (17 eyes) with CRF related to TED were identified. The mean age of presentation was 59.3 ± 8.3 years old. The majority of patients were male (70%), hyperthyroid (70%), hyperopic (53%), had a history of radioactive iodine (60%), and currently on methimazole treatment (30%). Three patients (3 eyes) had unilateral involvement of CRF with bilateral TED. The average clinical activity score was 3.6 ± 2.1 at the time of presentation. The most commonly enlarged extraocular muscles were medial (76%), inferior (64%), superior (64%) and lateral rectus (35%). Compressive optic neuropathy was seen in 47% of eyes. Treatment included oral prednisone (70%), orbital decompression (59%), thyroidectomy (20%) and tocilizumab (10%). The CRF did not resolve over a follow up period of 24.7 ± 23.7 months in 70% of eyes. There was no significant difference in average axial length (25.7 ± 4.9 mm) and optic nerve to optic strut distance (37.8 ± 3.9 mm) between patients with CRF and the eight age-and sex-matched TED control patients without CRF (p = 0.81 and 0.65 respectively). A univariable and multivariable analysis found an enlarged inferior rectus as a factor in TED patients with persistent CRF.Conclusions: CRF are often an indicator of visually threatening situations and often do not resolve despite treatment of TED.


Pregnancy, autonomy and paternalism.
Modern medicine is increasingly aware of the significance of patient autonomy in making treatment choices. This would seem to be particularly important where the therapy requested was "voluntary" as in fertility treatment or cosmetic surgery. However, the Hippocratic doctrine "Primum non nocere", seems especially relevant where the treatment sought may have a low chance of a successful outcome or even be life-threatening. Mrs A's case demonstrates the difficulty faced by the physician who wants to maximise her patient's autonomy, but "Above all, do no harm".


Sleep-related gastroesophageal reflux.
Although we spend approximately one third of our lives sleeping, rarely do we consider that sleep may contribute to medical conditions. For gastroesophageal reflux, sleep or physiologic changes associated with the sleep state often promote or increase the likelihood of reflux and aspiration. These changes include the assumption of the supine position, a decrease in the arousal threshold, mechanical effects of the abdomen, and disorders associated with sleep. Of the sleep disorders, obstructive sleep apnea is associated with a high frequency of gastroesophageal reflux, probably due to the generation of negative intrathoracic pressures and obesity associated with the disease. Obstructive sleep apnea in patients with gastroesophageal reflux can lead to difficult-to-treat or refractory gastroesophageal reflux, predominantly nocturnal or early-morning symptoms, and unusual or uncommon manifestations that do not appear to reflect the underlying pathologic process. Under most circumstances, aggressive treatment regimens must be instituted for both disorders in order to effectively control symptoms. This article reviews the major information that is currently available on the relationship between obstructive sleep apnea and gastroesophageal reflux.


Successional, spatial, and seasonal changes in seed rain in the Atlantic forest of southern Bahia, Brazil.
Seed arrival is a limiting factor for the regeneration of diverse tropical forests and may be an important mechanism that drives patterns of tree species' distribution. Here we quantify spatial and seasonal variation in seed rain of secondary forests in southern Bahia, Brazil. We also examine whether secondary forest age enhances seed dispersal and whether seed rain density and diversity in secondary forests decay with distance from mature forest. Across a chronosequence of 15 pairs of mature and secondary forests, 105 seed traps were installed and monitored for one year. We tested the effects of secondary forest age, distance from mature forest, and seasonality on monthly seed rain density, diversity, seed dispersal mode, and diaspore size. We found that secondary forest age had strong, positive effects on the diversity of seed rain, which was generally higher during the wet season. Moreover, contrasting patterns among diversity indices revealed that seeds of rare species occurred more often in 40 yr old secondary forests and mature forests. While the proportion of biotically and abiotically dispersed seeds did not change significantly with distance from mature forest across all forest age classes, we found that biotically dispersed seeds contributed disproportionately more to seed rain diversity. Our results emphasize the importance of biotic dispersal to enhance diversity during secondary succession and suggest that changes in secondary forest structure have the potential to enhance the diversity of tropical secondary forests, principally by increasing dispersal of rare species.


The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.
Protein lysine methyltransferases (PKMTs) regulate diverse physiological processes including transcription and the maintenance of genomic integrity. Genetic studies suggest that the PKMTs SUV420H1 and SUV420H2 facilitate proficient nonhomologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation (me2 and me3, respectively) of lysine 20 on histone 4 (H4K20). Here we report the identification of A-196, a potent and selective inhibitor of SUV420H1 and SUV420H2. Biochemical and co-crystallization analyses demonstrate that A-196 is a substrate-competitive inhibitor of both SUV4-20 enzymes. In cells, A-196 induced a global decrease in H4K20me2 and H4K20me3 and a concomitant increase in H4K20me1. A-196 inhibited 53BP1 foci formation upon ionizing radiation and reduced NHEJ-mediated DNA-break repair but did not affect homology-directed repair. These results demonstrate the role of SUV4-20 enzymatic activity in H4K20 methylation and DNA repair. A-196 represents a first-in-class chemical probe of SUV4-20 to investigate the role of histone methyltransferases in genomic integrity.


Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.
Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene. Acute attacks of abdominal pain begin early in life and the disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types of chronic pancreatitis, the frequency of pancreatic cancer in the inherited type of pancreatitis is uncertain. The aim of this study was to assess the frequency of pancreatic cancer and other tumors in patients with hereditary form of pancreatitis. To determine the natural history of hereditary pancreatitis, we invited all members of the American Pancreatic Association and the International Association of Pancreatology to participate in a longitudinal study of this rare form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (< or = 30 years) at onset of symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries contributed medical records of 246 (125 males and 121 females) patients thought to have hereditary pancreatitis as the most likely diagnosis. This group included 218 patients where the diagnosis appeared to be highly probable and 28 additional patients where the diagnosis of hereditary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients with onset of disease before age 30 years but with an uncertain family history. We reviewed all causes of death and compared the observed to the expected frequency of cancer in this historical cohort of patients with hereditary pancreatitis. The strength of the association between pancreatitis and pancreatic cancer was estimated by the standardized incidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the background population, adjusted for age, sex, and country. The mean age (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, eight pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years of follow-up, yielding an SIR of 53 (95% confidence interval [CI] = 23-105). The frequency of other tumors was not increased: SIR = 0.7 (95% CI = 0.3-1.6). Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort have already been tested for the defective hereditary pancreatitis gene: all 30 carry a mutated copy of the trypsinogen gene. The transmission pattern of hereditary pancreatitis was known for 168 of 238 patients without pancreatic cancer and six of eight with pancreatic cancer. Ninety-nine of the 238 patients without pancreatic cancer and six of the patients with pancreatic cancer inherited the disease through the paternal side of the family. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approaches 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. Patients with hereditary pancreatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern increases the probability of developing pancreatic cancer.


Cancer chronomics I. Origins of timed cancer treatment: early marker rhythm-guided individualized chronochemotherapy.
A 21-year old patient who presented in 1973 with a rare and highly malignant ovarian endodermal sinus tumor with spillage into the peritoneal cavity is alive and well today after receiving chronochemotherapy. During the first four courses of treatment, medications were given at different circadian stages. Complete blood counts and marker variables such as mood, vigor, nausea, and temperature were monitored around the clock and analyzed by cosinor to seek times of highest tolerance. Remaining treatment courses were administered at a time corresponding to the patient's best drug tolerance, rather than extrapolating the timing of optimal cyclophosphamide administration from also-implemented parallel laboratory studies on mice. Notwithstanding remaining hurdles in bringing chronochemotherapy to the clinic for routine care, merits of marker rhythm-guided chronotherapy documented in this and other case reports have led to the doubling of the two-year disease-free survival of patients with large perioral tumors in a clinical trial.


Phosphorylation of a high molecular weight DNA polymerase alpha.
Anti-human DNA polymerase alpha murine IgG SJK-287-38 [Tanaka, S., Hu, S.-Z., Wang, T. S.-F. & Korn, D. (1982) J. Biol. Chem. 257, 8386-8390] neutralized DNA polymerase alpha activity from rat embryonic fibroblasts infected with a temperature-sensitive transformation mutant of Rous sarcoma virus (tsLA24). After centrifugation of a crude cytosol fraction from log-phase cells in a 5-20% linear sucrose gradient, polypeptides of Mr approximately equal to 185,000 and 220,000 were immunoprecipitated only from gradient fractions containing DNA polymerase alpha activity. When similar cultures were incubated in medium containing [32P]orthophosphate, it was found that the Mr 220,000 protein was phosphorylated but that the other peptides specific for polymerase alpha activity did not contain detectable amounts of phosphate. Phospho amino acid analysis of the high molecular weight immunoprecipitable proteins indicated that the labeled amino acid was phosphoserine. Incubation of 2.5 units of crude DNA polymerase alpha with 4 units of agarose-immobilized alkaline phosphatase resulted in a nearly complete inhibition of DNA polymerase alpha activity. Subsequent incubation of this preparation with 5 or 50 microM ATP, but not the nonhydrolyzable analog adenosine 5'-[gamma-thio]triphosphate, restored the in vitro DNA polymerizing activity. These results demonstrate that a high molecular weight DNA polymerase alpha (Mr approximately equal to 220,000) is phosphorylated in cultured cells and that this protein is a substrate for a serine kinase rather than the tyrosine-specific protein kinase of Rous sarcoma virus. The results suggest that phosphorylation/dephosphorylation reactions modulate the activity of this polymerase.


Knowledge about complications and practice of abortion among female undergraduates in the university of ibadan, Nigeria.
Unwanted pregnancies and unsafe abortion pose major health risks to women in the reproductive age group. Female undergraduates are particularly exposed to these risks. This study was carried out to assess the knowledge about complications and practice of abortion among female undergraduates of the University of Ibadan. A cross-sectional study was conducted using structured, self-administered questionnaires, to collect data on respondents' socio-demographic characteristics, sexual behaviour, knowledge about various complications of abortion and practice of abortion. Data was analyzed using SPSS version 14. A total of 425 students were interviewed, mean age of the undergraduates was 21.5± 2.8 years. Overall, 122 (29%) of the respondents had ever had sexual intercourse. Twenty five percent of those who were sexually active had ever been pregnant and 90% had terminated the pregnancy. The most common reason given for termination was that pregnancy was unplanned for. Most of the respondents 354 (83.3%) had a good knowledge about complications of abortion and mean knowledge score was 4.01±1.58 (range 0-5). This group of students were aware of the risks associated with unsafe abortion; however, the abortion rate was still high. Sexual reproductive health interventions are needed on campus in order to equip female undergraduates with comprehensive knowledge and skills to reduce the likelihood of unplanned pregnancies.


Human leukocyte antigen-DR15, low infant sibling exposure and multiple sclerosis: gene-environment interaction.
The risk for development of multiple sclerosis has been associated with human leukocyte antigen-DRB1*1501-DQB1*0602 (HLA-DR15) genotype, low infant sibling exposure, and high Epstein-Barr nuclear antigen IgG levels. In a population-based case-control study (Tasmania, Australia), we found that the combined effect of HLA-DR15 positivity and low infant sibling exposure on multiple sclerosis (odds ratio, 7.88; 95% confidence interval, 3.43-18.11) was 3.9-fold greater than expected (test for interaction, p = 0.019) This interaction was observed irrespective of Epstein-Barr nuclear antigen IgG levels. This suggests that immune mechanisms involving HLA class II molecules are susceptible to modulation in early life. Ann Neurol 2009;66:261-265 ANN NEUROL 2010;67:259-263.


PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism.
Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.2+/-5.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.2+/-9.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G>A), and two patients had known Parkin mutations (heterozygous c.734A>T and c.924C>T; heterozygous c.924C>T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A>T) and four novel PINK1 changes of unknown pathogenic significance (-21G/A; IVS1+97A/G; IVS3+38_40delTTT; c.852C>T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.


Impact of sub-optimal HIV viral control on activated T cells.
HIV viral load (VL) monitoring is generally conducted 6-12 monthly in low- and middle-income countries, risking relatively prolonged periods of poor viral control. We explored the effects of different levels of loss of viral control on immune reconstitution and activation. Two hundred and eight participants starting protease inhibitor (PI)-based second-line therapy in the EARNEST trial (ISRCTN37737787) in Uganda and Zimbabwe were enrolled and CD38 + /HLA-DR + immunophenotyping performed (CD8-FITC/CD38-PE/CD3-PerCP/HLA-DR-APC; centrally gated) in real-time at 0, 12, 48, 96 and 144 weeks from randomization. VL was assayed retrospectively on samples collected every 12-16 weeks and classified as continuous suppression (<40 copies/ml throughout); suppression with transient blips; low-level rebound (two or more consecutive VL >40, <5000 copies/ml); high-level rebound/nonresponse (two or more consecutive VL >5000 copies/ml). Immunophenotype reconstitution varied between that defined by numbers of cells and that defined by cell percentages. Furthermore, VL dynamics were associated with substantial differences in expression of CD4 + and CD8 + cell activation markers, with only individuals with high-level rebound/nonresponse (>5000 copies/ml) experiencing significantly greater activation and impaired reconstitution. There was little difference between participants who suppressed consistently and who exhibited transient blips or even low-level rebound by 144 weeks ( P > 0.2 vs. suppressed consistently). Detectable viral load below the threshold at which WHO guidelines recommend that treatment can be maintained without switching (1000 copies/ml) appear to have at most, small effects on reconstitution and activation, for patients taking a PI-based second-line regimen.


Self-Tracking, Social Media and Personal Health Records for Patient Empowered Self-Care. Contribution of the IMIA Social Media Working Group.
This paper explores the range of self-tracking devices and social media platforms used by the self-tracking community, and examines the implications of widespread adoption of these tools for scientific progress in health informatics. A literature review was performed to investigate the use of social media and self-tracking technologies in the health sector. An environmental scan identified a range of products and services which were used to exemplify three levels of self-tracking: self-experimentation, social sharing of data and patient controlled electronic health records. There appears to be an increase in the use of self-tracking tools, particularly in the health and fitness sector, but also used in the management of chronic diseases. Evidence of efficacy and effectiveness is limited to date, primarily due to the health and fitness focus of current solutions as opposed to their use in disease management. Several key technologies are converging to produce a trend of increased personal health surveillance and monitoring, social connectedness and sharing, and integration of regional and national health information systems. These trends are enabling new applications of scientific techniques, from personal experimentation to e-epidemiology, as data gathered by individuals are aggregated and shared across increasingly connected healthcare networks. These trends also raise significant new ethical and scientific issues that will need to be addressed, both by health informatics researchers and the communities of self-trackers themselves.


Brain energy metabolism measured by (13)C magnetic resonance spectroscopy in vivo upon infusion of [3-(13)C]lactate.
The brain uses lactate produced by glycolysis as an energy source. How lactate originated from the blood stream is used to fuel brain metabolism is not clear. The current study measures brain metabolic fluxes and estimates the amount of pyruvate that becomes labeled in glial and neuronal compartments upon infusion of [3-(13)C]lactate. For that, labeling incorporation into carbons of glutamate and glutamine was measured by (13)C magnetic resonance spectroscopy at 14.1 T and analyzed with a two-compartment model of brain metabolism to estimate rates of mitochondrial oxidation, glial pyruvate carboxylation, and the glutamate-glutamine cycle as well as pyruvate fractional enrichments. Extracerebral lactate at supraphysiological levels contributes at least two-fold more to replenish the neuronal than the glial pyruvate pools. The rates of mitochondrial oxidation in neurons and glia, pyruvate carboxylase, and glutamate-glutamine cycles were similar to those estimated by administration of (13)C-enriched glucose, the main fuel of brain energy metabolism. These results are in agreement with primary utilization of exogenous lactate in neurons rather than astrocytes.


Functional assessment of a skin care system in patients on chemotherapy.
Cancer patients undergoing chemotherapy frequently experience skin problems such as xerosis. The aim of this study was to verify whether a concomitant treatment with an acidic washing and an acidic emollient (both pH 5.5) can significantly improve the quality of the skin in such patients. 30 adult patients on chemotherapy experiencing dry and sensitive skin were included in a controlled, monocentric, 3-week treatment trial. One forearm served as a test site, the other one remained untreated. Noninvasive biophysical measurements were performed at baseline, on days 7, 14 and 21, along with clinical evaluation of the skin symptoms. After a 3-week treatment, a significant increase in stratum corneum hydration was recorded in the treated site (p < 0.001). Reduced transepidermal water loss values, consistent with a restored barrier function, were obtained (p < 0.001). Casual sebum levels as measured by sebumetry showed a significant increase (p < 0.03). All skin symptoms investigated revealed a considerable improvement over 3 weeks. Controlled and regular use of a skin care system, especially an acidic one, improved skin physiology in patients undergoing chemotherapy.


Whole-Genome Sequence of Monascus purpureus GB-01, an Industrial Strain for Food Colorant Production.
We report the draft genome sequence of Monascus purpureus GB-01, an industrial strain used as a food colorant. De novo assembly of long reads resulted in 121 chromosomal contigs and 1 mitochondrial contig, and sequencing errors were corrected by paired-end short reads. This genome sequence will provide useful information for azaphilone pigments and mycotoxin citrinin biosynthesis.


Ethnic background has minimal impact on the etiology of nephrolithiasis.
Nephrolithiasis disproportionately affects white patients. However, recent studies propose an increase in the incidence of stone disease in nonwhite populations. We compared the metabolic risk factors of ethnically disparate stone formers from the same geographic region. A retrospective review of 1,141 patients identified 98 (9%) nonwhite stone formers. Of these individuals 60 underwent a comprehensive metabolic evaluation, comprising 44 black, 8 Asian and 8 Hispanic patients. A similar sex and age matched group of 66 white stone forming patients were also identified for comparative analysis. Stone analyses were recorded when available. Urinary metabolic abnormalities were defined as low urine volume-urine volume less than 2,000 cc, gouty diathesis-pH 5.5 or less (normal level 5.5 to 6.5), hypercalciuria-calcium greater than 200 mg, hyperoxaluria-oxalate greater than 45 mg, hyperuricosuria-uric acid greater than 600 mg, hypocitraturia-citrate less than 600 mg and purine gluttony-sulfate greater than 20 mg. The incidence of metabolic abnormalities was surprisingly similar between the white and nonwhite stone formers. Whites have a higher prevalence of hypercalciuria compared with nonwhites (67% vs 25%, respectively, p <0.01). This comparison persisted when the white group was compared with individual ethnic groups (25% in each group). Whites also displayed a higher mean urinary calcium level (233 mg) than their nonwhite counterparts overall (146 mg), specifically with respect to blacks (146 mg, p <0.01). Asians had higher urine volumes with respect to whites and blacks (p <0.01) and, therefore, a decreased prevalence of low urine volumes (37.5% vs 74.2% and 79.5%, respectively). Hypocitraturia, hyperuricosuria, hyperoxaluria, gouty diathesis and high sulfate levels were equally represented among all ethnic groups. Although there appears to be a predominance of stone disease among whites, all racial groups demonstrated a remarkable similarity in the incidence of underlying metabolic abnormalities. These results suggest that dietary and environmental factors may be as important as ethnicity in the etiology of stone disease.


A randomized phase II trial of interleukin-2 and interferon-α plus bevacizumab versus interleukin-2 and interferon-α in metastatic renal-cell carcinoma (mRCC): results from the Danish Renal Cancer Group (DaRenCa) study-1.
Interleukin-2 (IL2)-based immunotherapy is curative for a small subset of patients with metastatic renal-cell carcinoma (mRCC). Preclinical data suggests that bevacizumab (BEV), a humanized anti-VEGF monoclonal antibody, has potential immunomodulatory effects by permitting efficient natural killer (NK) cell-mediated killing and by reverting immune suppression. We performed a randomized phase II study comparing IL2/IFN (interferon)/BEV with IL2/IFN in favourable/intermediate-risk mRCC patients. One hundred and eighteen patients received IFN 3 MIU subcutaneously (sc) daily and IL2 2.4 MIU/m2 sc twice daily, 5 days per week for two consecutive weeks every 28-day-cycle, for 9 months; or supplemented with BEV 10 mg/kg, every 2 weeks intravenously (iv) until progression, unacceptable toxicity, or 1 year following no evidence of disease (NED). Primary end point was progression-free survival (PFS). Baseline characteristics were well-balanced between the two arms; metastasis-free interval <1 year (75 versus 76%); prior nephrectomy (85 versus 86%); MSKCC favourable/intermediate-risk group (51/49 versus 52%/48%); three or more disease sites (41 versus 44%), respectively. The median PFS was 8.0 mo (95% CI, 4.2-11.9) with IL2/IFN/BEV and 8.1 mo (95% CI, 5.1-11.0) with IL2/IFN, p = .73. There was no difference in secondary endpoints, IL2/IFN/BEV versus IL2/IFN; median time-to-treatment failure (7.4 versus 5.6 mo, p = .54), response rate (44.1 versus 28.8%, p = .13), surgery of residual disease (17.0 versus 17.0%, p = 1.0), patients achieving NED (3.4 versus 8.5%, p = .44), and median overall survival (30.3 versus 34.1 mo, p = .39), respectively. TKI post progression was well-balanced (85 versus 78%). No new/unexpected toxicity was observed. Most common Grade 3/4 adverse events for IL2/IFN/BEV and IL2/IFN were fatigue (64 versus 61%), flu-like symptoms (37 versus 41%) and thrombosis (6.8 versus 18.6%, p = .01), respectively. The addition of BEV to IL-2/IFN did not add efficacy in mRCC. (ClinicalTrials.gov, NCT01274273.).