Generalizing boundaries for triangular designs, and efficacy estimation at extended follow-ups.
Visceral leishmaniasis (VL) is a parasitic disease transmitted by sandflies and is fatal if left untreated. Phase II trials of new treatment regimens for VL are primarily carried out to evaluate safety and efficacy, while pharmacokinetic data are also important to inform future combination treatment regimens. The efficacy of VL treatments is evaluated at two time points, initial cure, when treatment is completed and definitive cure, commonly 6 months post end of treatment, to allow for slow response to treatment and detection of relapses. This paper investigates a generalization of the triangular design to impose a minimum sample size for pharmacokinetic or other analyses, and methods to estimate efficacy at extended follow-up accounting for the sequential design and changes in cure status during extended follow-up. We provided R functions that generalize the triangular design to impose a minimum sample size before allowing stopping for efficacy. For estimation of efficacy at a second, extended, follow-up time, the performance of a shrinkage estimator (SHE), a probability tree estimator (PTE) and the maximum likelihood estimator (MLE) for estimation was assessed by simulation. The SHE and PTE are viable approaches to estimate an extended follow-up although the SHE performed better than the PTE: the bias and root mean square error were lower and coverage probabilities higher. Generalization of the triangular design is simple to implement for adaptations to meet requirements for pharmacokinetic analyses. Using the simple MLE approach to estimate efficacy at extended follow-up will lead to biased results, generally over-estimating treatment success. The SHE is recommended in trials of two or more treatments. The PTE is an acceptable alternative for one-arm trials or where use of the SHE is not possible due to computational complexity. NCT01067443 , February 2010.


Predicting all-cause and lung cancer mortality using emphysema score progression rate between baseline and follow-up chest CT images: A comparison of risk model performances.
Normalized emphysema score is a protocol-robust CT biomarker of mortality. We aimed to improve mortality prediction by including the emphysema score progression rate-its change over time-into the models. CT scans from 6000 National Lung Screening Trial CT arm participants were included. Of these, 1810 died (445 lung cancer-specific). The remaining 4190 survivors were sampled with replacement up to 24432 to approximate the full cohort. Three overlapping subcohorts were formed which required participants to have images from specific screening rounds. Emphysema scores were obtained after resampling, normalization, and bullae cluster analysis of the original images. Base models contained solely the latest emphysema score. Progression models included emphysema score progression rate. Models were adjusted by including baseline age, sex, BMI, smoking status, smoking intensity, smoking duration, and previous COPD diagnosis. Cox proportional hazard models predicting all-cause and lung cancer mortality were compared by calculating the area under the curve per year follow-up. In the subcohort of participants with baseline and first annual follow-up scans, the analysis was performed on 4940 participants (23227 after resampling). Area under the curve for all-cause mortality predictions of the base and progression models 6 years after baseline were 0.564 (0.564 to 0.565) and 0.569 (0.568 to 0.569) when unadjusted, and 0.704 (0.703 to 0.704) to 0.705 (0.704 to 0.705) when adjusted. The respective performances predicting lung cancer mortality were 0.638 (0.637 to 0.639) and 0.643 (0.642 to 0.644) when unadjusted, and 0.724 (0.723 to 0.725) and 0.725 (0.725 to 0.726) when adjusted. Including emphysema score progression rate into risk models shows no clinically relevant improvement in mortality risk prediction. This is because scan normalization does not adjust for an overall change in lung density. Adjusting for changes in smoking behavior is likely required to make this a clinically useful measure of emphysema progression.


Role of Urinary Transforming Growth Factor Beta-B1 and Monocyte Chemotactic Protein-1 as Prognostic Biomarkers in Posterior Urethral Valve.
Posterior Urethral Valves (PUV) are the most common cause of congenital LUT obstruction in males. Biomarkers of glomerular or tubular injury may be of particular value in predicting the need for surgical intervention or in tracing progression of chronic kidney disease. Measurement of biomarker in urine is relatively easy. To evaluate the changes in values of urinary Transforming Growth Factor Beta 1(TGF-B1) and Monocyte Chemotactic Protein (MCP-1) before and after valve ablation and its prognostic value in Posterior urethral valve. This prospective study was conducted from September 2016 to August 2018. The study group included 20 consecutive male babies with the diagnosis of PUV treated and followed up versus equal numbers of age matched control without any renal or urinary tract disease. Pre-operative urine samples were collected in Operative room. Cystoscopy and valve ablation was done. Follow up was done clinically by urinary stream and radiologically with VCUG. Follow-up was planned at 1 month, 3 months and 6 months following cystoscopic valve ablation. All collected urine samples were centrifuged at 10,000 rpm for 20 minutes. Supernatant was collected and two divided aliquots were stored at -200c to be thawed on the day of assay. Optical density of each well was recorded at 450 nm and 540 nm A p-value of <0.05 was considered to be statistically significant. Out of 20 cases of PUV, 14 (70%) cases were 1st born males of their family. The median age at the time of valve ablation in PUV cases was 2.5 (1.20-3.87) years.. Most common symptoms are fever and UTI. The preoperative median serum creatinine level was 1.65 mg/dl(1.22-2.42) pre-ablation, and fall significantly after ablation. Median eGFR level (calculated) was 25.635 (16.38-35.40) and after 6 months was 71.490 (45.44-96.93). Preoperative median MCP1 in PUV cases was 147.2 (82.8-512.5) and significant difference was also found in 1st, 3rd and 6th months after surgery (p<0.001, p=0.004 and p=0.002).Preoperative median TGF-B1 level was 197.8 pg/ml (79.9-386.4). There was no statistically significant change in TGF-B1 level at preoperative to 1 month and preop to 3 months after surgery but at 6 months after surgery the median TGF-B1 level significantly decreased as compared with preoperative TGF-B1 level. TGF β1 and MCP1 can be considered as prognostic urinary biomarkers in patients of PUV and can be used to specify and counsel patient's attendant regarding possibility of ESRD and need for further intervention.


The role of colloidal and particulate organic compounds in denitrification and EBPR occurring in a full-scale activated sludge system.
The efficiencies of denitrification and enhanced biological phosphorus removal (EBPR) in biological nutrient removal (BNR) activated sludge systems are strongly dependent on the availability of appropriate carbon sources. Due to high costs of commercial compounds (such as methanol, ethanol, acetic acid etc.) and acclimation periods (usually) required, the effective use of internal carbon sources for denitrification is preferred. The aim of this study was to determine the immediate effects of slowly biodegradable substrates on the denitrification capability and phosphate release/uptake interactions for a full-scale biomass process from the "Wschod" wastewater treatment plant (WWTP) in Gdansk (Poland). Since it is hard to distinguish the slowly biodegradable substrate in a direct way, a novel procedure based on batch experiments was developed and implemented. The laboratory experiments were carried out in two parallel, fully automatic batch reactors with the settled wastewater without pretreatment and after coagulation-flocculation. The removal of colloidal and particulate fractions resulted in the reduced observed process rates, such as denitrification, phosphate release and phosphate uptake (under aerobic and anoxic conditions). The reduction ranged from approximately 14% for the anaerobic P release to approximately 46% for the anoxic P uptake.


Findings from an online behavioural weight management programme provided with or without a fortified diet beverage.
The present multi-centre randomised weight-loss trial evaluated the efficacy of a low-intensity 12-week online behavioural modification programme, with or without a fortified diet beverage using a 2 × 2 factorial design. A total of 572 participants were randomised to: (1) an online basic lifestyle information (OBLI) intervention, consisting of one online informational class about tips for weight management; (2) an online behavioural weight management (OBWM) intervention, entailing 12 weekly online classes focused on weight-loss behaviour modification; (3) an OBLI intervention plus a fortified diet cola beverage (BEV) containing green tea extract (total catechin 167 mg), soluble fibre dextrin (10 g) and caffeine (100 mg) (OBLI+BEV); (4) OBWM+BEV. Assessments included height, weight, dual-energy X-ray absorptiometry-derived body composition, and waist circumference (WC). Attrition was 15·7 %. Intention-to-treat (ITT) models demonstrated a main effect for type of Internet programme, with those assigned to the OBWM condition losing significantly more weight (F= 7·174; P= 0·008) and fat mass (F= 4·491; P= 0·035) than those assigned to the OBLI condition. However, there was no significant main effect for the OBWM condition on body fat percentage (F= 2·906; P= 0·089) or WC (F= 3·351; P= 0·068), and no significant main effect for beverage use or significant interactions between factors in ITT models. A 12-week, low-intensity behaviourally based online programme produced a greater weight loss than a basic information website. The addition of a fortified diet beverage had no additional impact.


Definitive Chemoradiation With Full-dose Gemcitabine for Unresectable Pancreatic Cancer: Efficacy of Involved-Field Radiotherapy.
Definitive chemoradiotherapy for unresectable pancreatic cancer has traditionally involved 5-fluorouracil-based chemotherapy. Our institution has a long history of combining gemcitabine and radiotherapy (RT), and performed a retrospective review of all patients treated in this manner. We reviewed the records of 180 patients treated from 1999 to 2012. Mean RT dose was 40.9 Gy in 2.2-Gy fractions, and targeted only radiographically apparent disease. Ninety-six percent of patients received full-dose gemcitabine-based chemotherapy with RT. Kaplan-Meier was used to analyze time-to-event endpoints, and Cox regression models were used to assess significant prognostic variables. Eighty-nine percent of patients completed RT without a toxicity-related treatment break. Median follow-up was 10.2 months. Twenty-nine percent of patients had a radiographic decrease in primary tumor size following treatment. Median overall survival was 11.8 months, time to distant metastasis (TDM) was 6.7 months, and time to local recurrence (TLR) was 8.3 months. On multivariate analysis, male sex, lower performance status, and higher posttreatment CA 19-9 level predicted for worse overall survival. Posttreatment, CA 19-9 was also associated with TDM and TLR, and radiographic tumor response was associated with better TLR. Definitive chemoradiation using full-dose gemcitabine is well tolerated and achieves survival outcomes comparable to reported trials in the literature.


Emerging therapy options in heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening thrombotic complication of heparin, which is the result of platelet activation by anti-PF4/heparin antibodies. With lepirudin and danaparoid no longer available in the US, treatment options are limited to argatroban, fondaparinux (off-label use) and bivalirudin (for patients undergoing percutaneous coronary intervention). Both argatroban and bivalirudin are parenteral drugs and require close monitoring and hospitalization. Fondaparinux is contraindicated in patients with significant renal impairment and is associated with a small risk of HIT. Anticoagulants approved for thromboprophylaxis and management of thromboembolic conditions such as rivaroxaban, dabigatran, and apixaban have fixed oral dose, rapid onset of action and does not require monitoring. These novel agents do not interact with anti-PF4/heparin antibody and offer attractive therapy options for HIT. Their utility in HIT has been supported by a few clinical reports, however, larger studies are needed before they can be utilized in clinical practice. Therapeutic plasma exchange has been utilized with some success in patients with HIT, who need heparin reexposure for cardiac surgery but their safety and efficacy needs further exploration. 2-O, 3-O desulfated heparin, which lacks any anticoagulant effect, has been shown to reduce the development of HIT in murine models. Finally, novel targets based on the molecular pathogenesis of HIT are being studied for therapeutic drug development. We hope that the availability of novel therapies in the future will expand the options available for the management of HIT.


Intakes and sources of dietary sugars and their association with metabolic and inflammatory markers.
Associations of dietary sugars with metabolic and inflammatory markers may vary according to the source of the sugars. The aim of this study was to examine the association of dietary sugars from different sources [beverages (liquids), foods (solids), extrinsic (free) or intrinsic (non-free)] with metabolic and inflammatory markers. Population-based cross-sectional study of adults in the East of England (n = 9678). Sugar intakes were estimated using food frequency questionnaires. Fasting glycated haemoglobin, glucose, insulin, and C-Reactive Protein (CRP) were measured and indices of metabolic risk were derived (homeostatic model of insulin resistance, HOMA-IR and metabolic risk z-score). In multiple linear regression analyses adjusted for potential confounders including BMI and TEI, sugars from liquids were positively associated with ln-CRP [b-coefficient (95%CI), 0.14 (0.05,0.22) per 10%TEI] and metabolic risk z-score [0.13 (0.07,0.18)]. Free sugars were positively associated with ln-HOMA-IR [0.05 (0.03,0.08)] and metabolic risk z-score [0.09 (0.06,0.12)]. Sugars from solids were not associated with any outcome. Among major dietary contributors to intakes (g/d), sugars in fruit, vegetables, dairy products/egg dishes, cakes/biscuits/confectionary and squash/juice drinks were not associated, but sugar added to tea, coffee, cereal was significantly positively associated with all outcomes. Sugars in 100% juice [0.16 (0.06,0.25) per 10%TEI] and other non-alcoholic beverages [0.13 (0.03,0.23)] were positively associated with metabolic risk z-score. Higher intakes of sugars from non-alcoholic beverages and sugar added to tea, coffee, cereal were associated with glycaemia and inflammatory markers. Sugars from solids were not associated, irrespective of whether they were intrinsic or extrinsic. Positive associations of free sugars were largely explained by contribution of beverages to intake.


Endotracheal tube cuff pressures - the worrying reality: a comparative audit of intra-operative versus emergency intubations.
The primary aim was to assess the need for objective cuff pressure monitoring in the theatre complex and trauma centre at Groote Schuur Hospital, Cape Town, South Africa. Secondary aims were to determine whether the tube size, tube make or place of intubation affected cuff pressure. Endotracheal tube cuff pressures of 91 patients in the trauma centre and 100 patients in the theatre complex were randomly measured using a Mallinckrodt cuff pressure gauge. The measurements were recorded on a standardised data sheet and transferred to an electronic database for analysis. There was a significant difference between cuff pressures in the trauma centre and those in the theatre complex (p<0.001), the means being 55 cmH2O and 25 cmH2O, respectively. The site of intubation had a significant (p=0.001) effect on cuff pressures, with mean pressures as follows: on scene - 71 cmH2O; referral hospital - 57 cmH2O; and Groote Schuur trauma centre - 42 cmH2O. Only 30% of cuff pressures measured in the trauma centre were below 30 cmH2O, and, alarmingly, 17% were between 91 and 120 cmH2O. In the theatre complex, 77% of cuff pressures were in the acceptable range. Digital balloon palpation corresponded poorly (correlation coefficient 0.47) with measured cuff pressure, and statistical analysis showed that it tended to underestimate the pressure at higher cuff pressures. The risk of a high cuff pressure is roughly two- to threefold higher in emergency patients than in theatre patients. These unacceptably high cuff pressures are especially concerning in view of the fact that many trauma patients are hypotensive and therefore more susceptible to mucosal ischaemia.


Search for supersymmetry with like-sign lepton-tau events at CDF.
We present a search for chargino-neutralino associated production using like electric charge dilepton events collected by the CDF II detector at the Fermilab Tevatron in proton-antiproton collisions at sqrt[s] = 1.96 TeV. One lepton is identified as the hadronic decay of a tau lepton, while the other is an electron or muon. In data corresponding to 6.0 fb(-1) of integrated luminosity, we obtain good agreement with standard model predictions and set limits on the chargino-neutralino production cross section for simplified gravity- and gauge-mediated models. As an example, assuming that the chargino and neutralino decays to taus dominate, in the simplified gauge-mediated model we exclude cross sections greater than 300 fb at 95% credibility level for chargino and neutralino masses of 225 GeV/c(2). This analysis is the first to extend the LHC searches for electroweak supersymmetric production of gauginos to high tanβ and slepton next-to-lightest supersymmetric particle scenarios.


Dynamic palmitoylation of lymphoma proprotein convertase prolongs its half-life, but is not essential for trans-Golgi network localization.
Proprotein convertases are responsible for the endoproteolytic activation of proproteins in the secretory pathway. The most recently discovered member of this family, lymphoma proprotein convertase (LPC), is a type-I transmembrane protein. Previously, we have demonstrated that its cytoplasmic tail is palmitoylated. In this study, we have identified the two most proximal cysteine residues in the cytoplasmic tail as palmitoylation sites. Substitution of either cysteine residue by alanine interfered with palmitoylation of the other. Palmitoylation of LPC was found to be sensitive to the protein palmitoyltransferase inhibitor tunicamycin but not cerulenin. It was also insensitive to the drugs brefeldin A, monensin and cycloheximide, indicating that the modification occurs in a late exocytic or endocytic compartment. Turnover of palmitoylated LPC is significantly faster (t(1/2) approximately 50 min) than that of the LPC polypeptide backbone (t(1/2) approximately 3 h), suggesting that palmitoylation is reversible. Abrogation of palmitoylation reduced the half-life of the LPC protein, but did not affect steady-state localization of LPC in the trans-Golgi network. Finally, LPC could not be detected in detergent-resistant membrane rafts. Taken together, these results suggest that dynamic palmitoylation of LPC is important for stability, but does not function as a dominant trafficking signal.


Dependence on endocytic receptor binding via a minimal binding motif underlies the differential prognostic profiles of SerpinE1 and SerpinB2 in cancer.
Tumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential. Conversely, tumor expression of uPA and another specific inhibitor, SerpinB2 (plasminogen activator inhibitor type-2), are associated with favorable outcome and relapse-free survival. It is not known how overexpression of these uPA inhibitors results in such disparate outcomes. A possible explanation may be related to the presence of a proposed low density lipoprotein receptor (LDLR)-binding motif in SerpinE1 responsible for mitogenic signaling via ERK that is absent in SerpinB2. We now show that complementation of such a LDLR-binding motif in SerpinB2 by mutagenesis of two key residues enabled high affinity binding to very LDLR (VLDLR). Furthermore, the VLDLR-binding SerpinB2 form behaved in a manner indistinguishable from SerpinE1 in terms of enhanced uPA-SerpinB2 complex endocytosis and subsequent ERK phosphorylation and cell proliferation; that is, the introduction of the LDLR-binding motif to SerpinB2 was necessary and sufficient to allow it to acquire characteristics of SerpinE1 associated with malignancy. In conclusion, this study defines the structural elements underlying the distinct interactions of SerpinE1 versus SerpinB2 with endocytic receptors and how differential VLDLR binding impacts on downstream cellular behavior. This has clear relevance to understanding the paradoxical disease outcomes associated with overexpression of these serpins in cancer.


Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia.
Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.


Health-related quality of life after anterior cruciate ligament reconstruction: a systematic review.
Anterior cruciate ligament reconstructions (ACLRs) are frequently performed on young, active patients and can result in persistent knee symptoms and activity limitations that may affect health-related quality of life (HRQoL). To date, there has been no systematic review of HRQoL outcomes after ACLR. The objectives of this study were to report HRQoL ≥5 years after ACLR, compare HRQoL outcomes with available population norms, and describe factors that may affect HRQoL in this population. Systematic review. All studies reporting HRQoL ≥5 years after ACLR with hamstring or patellar tendon autografts were eligible for review. Common HRQoL outcomes were pooled using a random-effects meta-analysis and compared with published population norms. The Spearman rank correlation coefficient (ρ) was used to identify variables associated with HRQoL outcomes. Where insufficient data were available, outcomes were reported descriptively. Fourteen studies were eligible for review, and HRQoL was reported for 2493 patients at a mean of 9 years (range, 5-16 years) after ACLR. Pooling of knee-related quality of life outcomes (Knee injury and Osteoarthritis Outcome Score [KOOS]-QOL) found impairments after ACLR when compared with population norms. In comparison, studies using the Short Form-36 (SF-36) reported similar or better HRQoL compared with normative data. The KOOS-QOL subscores correlated strongly with KOOS-sport/recreation (ρ = .70, P = .04) and KOOS-pain (ρ = .85, P = .003) subscores. Severe radiographic osteoarthritis, meniscal injuries sustained after surgery, and revision ACLR were associated with poorer HRQoL outcomes at a minimum 5-year follow-up. The negative influence of concomitant meniscal surgery on HRQoL became apparent more than 10 years after ACLR. This review found that patients assessed using a knee-specific measure (KOOS-QOL) were more likely to report poorer HRQoL values, compared with population norms, than those assessed using a generic HRQoL measure (SF-36). Revision surgeries, meniscal injuries, and severe radiographic osteoarthritis were associated with poorer HRQoL outcomes after ACLR. However, these relationships should be interpreted with caution, as they were only investigated in a small number of studies. These results can be used by clinicians to educate patients about potential long-term outcomes after ACLR and to develop strategies for optimizing postoperative HRQoL.


Natural vegetation as a source or sink for atmospheric ammonia: a case study.
Measurements of gaseous ammonia above a montane-subalpine forest in the Colorado mountains show that the role of the forest as a source or sink depends on the atmospheric concentrations. The canopy appeared to be an ammonia source when exposed to air containing low concentrations, but a sink when exposed to air enriched by nearby agricultural sources. The forest-averaged compensation point was 0.8 part per billion by volume at 20 degrees C. The net burden of ammonia and other nitrogen species of anthropogenic origin at this site was much less than at forest sites in the eastern United States and Europe and may provide a valuable resource for this nitrogen-limited ecosystem.


The HSV-1 exonuclease, UL12, stimulates recombination by a single strand annealing mechanism.
Production of concatemeric DNA is an essential step during HSV infection, as the packaging machinery must recognize longer-than-unit-length concatemers; however, the mechanism by which they are formed is poorly understood. Although it has been proposed that the viral genome circularizes and rolling circle replication leads to the formation of concatemers, several lines of evidence suggest that HSV DNA replication involves recombination-dependent replication reminiscent of bacteriophages λ and T4. Similar to λ, HSV-1 encodes a 5'-to-3' exonuclease (UL12) and a single strand annealing protein [SSAP (ICP8)] that interact with each other and can perform strand exchange in vitro. By analogy with λ phage, HSV may utilize viral and/or cellular recombination proteins during DNA replication. At least four double strand break repair pathways are present in eukaryotic cells, and HSV-1 is known to manipulate several components of these pathways. Chromosomally integrated reporter assays were used to measure the repair of double strand breaks in HSV-infected cells. Single strand annealing (SSA) was increased in HSV-infected cells, while homologous recombination (HR), non-homologous end joining (NHEJ) and alternative non-homologous end joining (A-NHEJ) were decreased. The increase in SSA was abolished when cells were infected with a viral mutant lacking UL12. Moreover, expression of UL12 alone caused an increase in SSA, which was completely eliminated when a UL12 mutant lacking exonuclease activity was expressed. UL12-mediated stimulation of SSA was decreased in cells lacking the cellular SSAP, Rad52, and could be restored by coexpressing the viral SSAP, ICP8, indicating that an SSAP is also required. These results demonstrate that UL12 can specifically stimulate SSA and that either ICP8 or Rad52 can function as an SSAP. We suggest that SSA is the homology-mediated repair pathway utilized during HSV infection.


Are carbon nanotube effects on green algae caused by shading and agglomeration?
Due to growing production, carbon nanotubes (CNT) may soon be found in a broad range of products and thus in the environment. In this work, an algal growth test was developed to determine effects of pristine and oxidized CNT on the green algae Chlorella vulgaris and Pseudokirchneriella subcapitata. CNT suspensions were prepared in algal test medium and characterized taking into account the suspension age, the reduced light transmittance of nanoparticle suspensions defined as shading of CNT and quantified by UV/vis spectroscopy, and the agglomeration of the CNT and of the algal cells. Growth inhibition and photosynthetic activity were investigated as end points. Growth of C. vulgaris was inhibited with effect concentrations of 50% (EC(50)) values of 1.8 mg CNT/L and of 24 mg CNT/L in well dispersed and in agglomerated suspensions, respectively, and 20 mg CNT/L and 36 mg CNT/L for P. subcapitata, respectively. However, the photosynthetic activity was not affected. Growth inhibition was highly correlated with the shading of CNT and the agglomeration of algal cells. This suggests that the reduced algal growth might be caused mainly by indirect effects, i.e. by reduced availability of light and different growth conditions caused by the locally elevated algal concentration inside of CNT agglomerates.


Diagnosis and prognostication of ductal adenocarcinomas of the pancreas based on genome-wide DNA methylation profiling by bacterial artificial chromosome array-based methylated CpG island amplification.
To establish diagnostic criteria for ductal adenocarcinomas of the pancreas (PCs), bacterial artificial chromosome (BAC) array-based methylated CpG island amplification was performed using 139 tissue samples. Twelve BAC clones, for which DNA methylation status was able to discriminate cancerous tissue (T) from noncancerous pancreatic tissue in the learning cohort with a specificity of 100%, were identified. Using criteria that combined the 12 BAC clones, T-samples were diagnosed as cancers with 100% sensitivity and specificity in both the learning and validation cohorts. DNA methylation status on 11 of the BAC clones, which was able to discriminate patients showing early relapse from those with no relapse in the learning cohort with 100% specificity, was correlated with the recurrence-free and overall survival rates in the validation cohort and was an independent prognostic factor by multivariate analysis. Genome-wide DNA methylation profiling may provide optimal diagnostic markers and prognostic indicators for patients with PCs.


Chimpanzees' use of conspecific cues in matching-to-sample tasks: public information use in a fully automated testing environment.
Social animals have much to gain from observing and responding appropriately to the actions of their conspecific group members. This can in turn lead to the learning of novel behavior patterns (social learning) or to foraging, ranging, or social behavioral choices copied from fellow group members, which do not necessarily result in long-term learning, but at the time represent adaptive responses to environmental cues (public information use). In the current study, we developed a novel system for the study of public information use under fully automated conditions. We modified a classic single-subject laboratory paradigm--matching-to-sample (MTS)--and examined chimpanzees' ability to interpret and utilize cues provided by the behavior of a conspecific to solve the task. In Experiment 1, two subjects took turns on an identity MTS task, with one subject (the model) performing the first half of the trial and the other subject (the observer) completing the trial using the model's actions as discriminative cues. Both subjects performed above chance from the first session onwards. In Experiment 2, the subjects were tested on a symbolic version of the same MTS task, with one subject showing spontaneous transfer. Our study establishes a novel method for examining public information use within a highly controlled and automated setting.


Selective age-related changes in orientation perception.
Orientation perception is a fundamental property of the visual system and an important basic processing stage for visual scene perception. Neurophysiological studies have found broader tuning curves and increased noise in orientation-selective neurons of senescent monkeys and cats, results that suggest an age-related decline in orientation perception. However, behavioral studies in humans have found no evidence for such decline, with performance being comparable for younger and older participants in orientation detection and discrimination tasks. Crucially, previous behavioral studies assessed performance for cardinal orientation only, and it is well known that the human visual system prefers cardinal over oblique orientations, a phenomenon called the oblique effect. We hypothesized that age-related changes depend on the orientation tested. In two experiments, we investigated orientation discrimination and reproduction for a large range of cardinal and oblique orientations in younger and older adults. We found substantial age-related decline for oblique but not for cardinal orientations, thus demonstrating that orientation perception selectively declines for oblique orientations. Taken together, our results serve as the missing link between previous neurophysiological and human behavioral studies on orientation perception in healthy aging.


Neuropsychological heterogeneity in preschool ADHD: investigating the interplay between cognitive, affective and motivation-based forms of regulation.
There is a trend toward diagnosing ADHD prior to school entry. Despite this, there is a lack of studies investigating ADHD in the preschool years, at least studies including a large range of different neuropsychological functions. Our knowledge of the independent effects of different neuropsychological functions in relation to preschool ADHD is therefore limited. In order to address this issue, the present study investigated cognitive, affective, and motivation-based regulation in relation to ADHD symptoms in 104 preschool children (age M = 67.33 months, SD = 10.10; 65 % boys). Results showed that these regulatory processes were all significantly related to ADHD symptoms and that most of these relations remained after controlling for comorbid conduct problems. Most previous preschool studies have only included cognitive regulation, and to some extent motivation-based regulation. By also including affective regulation, we were able to explain a larger proportion of the variance in ADHD symptoms. However, it should be noted that the amount of variance explained was still small in comparison with what has been found in previous studies of school-aged children. This finding could be taken as an indication that further studies examining the nature of preschool ADHD are needed, and that it may be necessary to look beyond the neuropsychological factors that have been linked to the disorder in older children and adults.


Novel expression of the tyrosine hydroxylase gene requires both acidic fibroblast growth factor and an activator.
Substances found in the soluble extract of muscle can alter the differentiative fate of certain brain neurons in culture by triggering novel expression of the gene for the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) (Iacovitti et al., 1989; Iacovitt, 1991). In this study, we demonstrate that TH induction in cultured noncatecholamine neurons from the mouse striatum requires the cooperative interaction of at least two substances found in muscle. Purification studies, combined with biological assay, revealed that one necessary component is acidic fibroblast growth factor (aFGF), and the other, an unidentified molecule(s) of < 10 kDa molecular weight that activated aFGF. Thus, muscle-derived aFGF, if incubated in the presence but not the absence of the < 10 kDa fraction of muscle, induced a dose-dependent increase in the number of striatal neurons that novelly express TH. This expression was blocked by prior incubation and protein A precipitation of the factor with polyclonal antibodies to aFGF (1:200-1:1000). Similar to muscle-purified aFGF, commercial preparations of native bovine and human recombinant aFGF (0.1-100 ng/ml) were potent inducers of TH when coincubated with the < 10 kDa activator. In contrast, basic FGF produced little and FGF-7 no induction of TH. Unlike the unidentified activating agent in muscle, heparin (20-500 mU), a known activator of aFGF, did not potentiate the factor's TH-inducing activity. Nonetheless, heparatinase (100 mU) prevented TH induction by aFGF and its activator, indicating that binding of heparan sulfated proteoglycans is necessary for the effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence and clinical characteristics of adult polymyositis and dermatomyositis; data from a large and unselected Norwegian cohort.
The occurrence of polymyositis (PM) and dermatomyositis (DM) in the general population is largely unknown and unbiased data on clinical and laboratory features in PM/DM are missing. Here, we aim to identify and characterise every PM/DM patient living in southeast Norway (denominator population 2.64 million), 2003-2012. Due to the structure of the Norwegian health system, all patients with PM/DM are followed at public hospitals. Hence, all public hospital databases in southeast Norway were screened for patients having ICD-10 codes compatible with myositis. Manual chart review was then performed to identify all cases meeting the Peter & Bohan and/or Targoff classification criteria for PM/DM. The ICD-10 search identified 3160 potential myositis patients, but only 208/3160 patients met the Peter & Bohan criteria and 230 the Targoff criteria (100 PM, 130 DM). With 56 deaths during the observation period, point prevalence of PM/DM was calculated to 8.7/100 000. Estimated annual incidences ranged from 6 to 10 /1 000 000, with peak incidences at 50-59 (DM) and 60-69 years (PM). Myositis specific antibodies (Jo-1, PL-7, PL-12, signal recognition particle (SRP) and Mi-2) were present in 53% (109/204), while 137/163 (87%) had pathological muscle MRI. Frequent clinical features included myalgia (75%), arthritis (41%) dyspnoea (62%) and dysphagia (58%). Positive anti-Jo-1, present in 39% of DM and 22% of PM cases, was associated with dyspnoea, arthritis and mechanic hands. Our data indicate that the population prevalence of PM/DM in Caucasians is quite low, but underscores the complexity and severity of the disorders.


Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate.
The abuse of methylenedioxymethamphetamine (MDMA), flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate (GHB) is discussed. Club drugs are chemical substances used recreationally in social settings. Use is increasingly frequent among young people, especially during all-night dance parties. All four agents have been classified as controlled substances. MDMA ("ecstasy") is available as a tablet, a capsule, and a powder; formulations may contain many adulterants. MDMA increases the release of neurotransmitters. The desired effects are euphoria, a feeling of intimacy, altered visual perception, enhanced libido, and increased energy. The most common adverse effects are agitation, anxiety, tachycardia, and hypertension. More serious adverse effects include arrhythmias, hyperthermia, and rhabdomyolysis. Flunitrazepam is a potent benzodiazepine. At higher doses, the drug can cause lack of muscle control and loss of consciousness. Other adverse effects are hypotension, dizziness, confusion, and occasional aggression. Ketamine is a dissociative anesthetic used primarily in veterinary practice. It may be injected, swallowed, snorted, or smoked. Like phencyclidine, ketamine interacts with the N-methyl-D-aspartate channel. Analgesic effects occur at lower doses and amnestic effects at higher doses. Cardiovascular and respiratory toxicity may occur, as well as confusion, hostility, and delirium. GHB, a naturally occurring fatty acid derivative of gamma-aminobutyric acid, was introduced as a dietary supplement. Increasing doses progressively produce amnesia, drowsiness, dizziness, euphoria, seizures, coma, and death. Flunitrazepam, ketamine, and GHB have been used to facilitate sexual assault. Supportive care is indicated for most cases of club drug intoxication. The increasing abuse of MDMA, flunitrazepam, ketamine hydrochloride, and GHB, particularly by young people in social settings such as clubs, should put health care professionals on guard to recognize and manage serious reactions.


The role of blood-brain barrier transporters in pathophysiology and pharmacotherapy of stroke.
Cerebral ischemia is one of the major causes of disability worldwide. In cerebral ischemic stroke, occlusion of a major cerebral artery by an embolus or local thrombosis can result in transient or permanent reduction of cerebral blood flow to a portion of the brain, resulting in deprivation of glucose and oxygen. Since the brain relies on a continuous supply of nutrients and ions via mostly carrier mediated processes across the blood-brain barrier (BBB), any irregularity in these transport mechanisms dramatically affects neuronal function and outcome after acute and chronic stroke. Despite numerous encouraging breakthroughs in preclinical stroke studies that evaluate monotherapies and a prevailing neurocentric approach that has yielded disappointing clinical translation, preclinical stroke studies investigating additional therapeutic targets might be used more effectively in combination with thrombolysis. In this context, this current review discusses the current understanding of dysfunctionional BBB nutrient and ion transport mechanisms involved in stroke pathophsyiology as novel therapeutic approaches. Recognition of the important role of the neurovascular unit in pathophysiology of stroke will provide new opportunities to treat ischemic brain injury, and maintenance of nutrient and ionic homeostasis should facilitate brain repair after stroke.


Local dynamics of heart rate: detection and prognostic implications.
The original observation that reduced heart rate variability (HRV) confers poor prognosis after myocardial infarction has been followed by many studies of heart rate dynamics. We tested the hypothesis that an entropy-based local dynamics measure gave prognostic information in ambulatory patients undergoing 24-h electrocardiography. In this context, entropy is the probability that short templates will find matches in the time series. We studied RR interval time series from 24-h Holter monitors of 1564 consecutive patients over age 39. We generated histograms of the count of templates as a function of the number of templates matches in short RR interval time series, and found characteristic appearance of histograms for atrial fibrillation, sinus rhythm with normal HRV, and sinus rhythm with reduced HRV and premature ventricular contractions (PVCs). We developed statistical models to detect the abnormal dynamic phenotype of reduced HRV with PVCs and fashioned a local dynamics score (LDs) that, after controlling for age, added more prognostic information than other standard risk factors and common HRV metrics, including, to our surprise, the PVC count and the HRV of normal-to-normal intervals. Addition of the LDs to a predictive model using standard risk factors significantly increased the ROC area and the net reclassification improvement was 27%. We conclude that abnormal local dynamics of heart rate confer adverse prognosis in patients undergoing 24-h ambulatory electrocardiography.


To freeze or not to freeze: decision regret and satisfaction following elective oocyte cryopreservation.
To characterize the degree of decision regret following elective oocyte cryopreservation (EOC) for social indications, and identify factors associated with regret. Retrospective cohort survey study. Academic center. Two hundred one women who underwent EOC for fertility preservation between 2012 and 2016. None. Decision Regret Scale (DRS) score, from 0-100, with a cut-off >25 indicative of moderate to severe regret; and attitudes regarding decision satisfaction. Median DRS score was 0 (interquartile range 0-15) and the mean was 10 (range 0-90). Thirty-three women (16%) experienced moderate to severe decision regret. Factors associated with decision regret included: number of eggs frozen, perceived adequacy of information prior to EOC, adequacy of emotional support during EOC, and patient-estimated probability of achieving a live birth using their banked eggs. In a multivariate logistic model, increased perceived adequacy of information (adjusted odds ratio 0.63, 95% confidence interval 0.42-0.97) and patient-estimated probability of achieving a live birth (adjusted odds ratio 0.80, 95% confidence interval 0.67-0.96) were associated with reduced odds of regret. One hundred sixty-seven women (88%) reported increased control over reproductive planning following EOC. One hundred eighty-three (89%) affirmed they will be happy they froze eggs, even if they never use them. The risk of decision regret following EOC is non-negligible. Low number of mature oocytes cryopreserved is a risk factor for increased regret, while perceptions of adequate information and emotional support, and increased patient-estimates of achieving a live birth using banked eggs are associated with reduced risk of regret.


Using molecular rotors to probe gelation.
A series of fluorescent probes, including a number of molecular rotors, have been used to follow the self-assembly of dipeptide-based low molecular weight gelators. We show that these probes can be used to gain an insight into the assembly process. Thioflavin T, a commonly used stain for β-sheets, appears to act as a molecular rotor in these gelling systems, with the fluorescence data closely matching that of other rotors. The molecular rotor was incorporated into an assay system with glucose oxidase to enable glucose-concentration specific gelation and hence generating a fluorescent output. Applying this system to urine from patients with various levels of glycosuria (a symptom of diabetes), it was found to provide excellent correlation with different clinical assessments of diabetes. This demonstrates a new concept in gelation-linked biosensing for a real clinical problem.


Involvement of heterotrimeric GTP-binding protein and rho protein, but not protein kinase C, in agonist-induced Ca2+ sensitization of skinned muscle of guinea pig vas deferens.
We studied the involvement of protein kinase C (PKC) and a small GTP-binding protein (G-protein), rho, in receptor-mediated Ca2+ sensitization of the contractile apparatus of smooth muscle of guinea pig vas deferens. In beta-escin-permeabilized smooth muscle strips, norepinephrine (NE) in the presence of GTP caused further contraction of the preparations at a constant Ca2+ level (Ca2+ sensitization). Prazosin and GDP beta S, a nonhydrolyzable GDP analogue, inhibited NE-induced Ca2+ sensitization, indicating an alpha-1 adrenoceptor/G-protein mediated response. GTP alone (> 10 microM) and GTP gamma S, a non-hydrolyzable GTP analogue, also induced Ca2+ sensitization. Pretreatment of preparations with C3 exoenzyme of Clostridium botulinum, which is known to ADP-ribosylate rho family proteins, with NAD resulted in complete inhibition of NE- and GTP (GTP gamma S)-induced Ca2+ sensitization. AIF4-, which activates heterotrimeric G-, but not small G-protein also induced Ca2+ sensitization. Interestingly, AIF4(-)-induced Ca2+ sensitization was inhibited by not only GDP beta S but also C3-treatment, suggesting that activation of heterotrimeric GTP-binding protein precedes activation of rho protein. On the other hand, phorbol 12,13-dibutyrate, like NE, also induced Ca2+ sensitization. The sensitization was inhibited by PKC(19-31), a PKC inhibitor peptide. However, PKC(19-31) did not have any effect on NE- or AIF4(-)-induced Ca2+ sensitization.(ABSTRACT TRUNCATED AT 250 WORDS)


Anatomically asymmetrical runners move more asymmetrically at the same metabolic cost.
We hypothesized that, as occurring in cars, body structural asymmetries could generate asymmetry in the kinematics/dynamics of locomotion, ending up in a higher metabolic cost of transport, i.e. more 'fuel' needed to travel a given distance. Previous studies found the asymmetries in horses' body negatively correlated with galloping performance. In this investigation, we analyzed anatomical differences between the left and right lower limbs as a whole by performing 3D cross-correlation of Magnetic Resonance Images of 19 male runners, clustered as Untrained Runners, Occasional Runners and Skilled Runners. Running kinematics of their body centre of mass were obtained from the body segments coordinates measured by a 3D motion capture system at incremental running velocities on a treadmill. A recent mathematical procedure quantified the asymmetry of the body centre of mass trajectory between the left and right steps. During the same sessions, runners' metabolic consumption was measured and the cost of transport was calculated. No correlations were found between anatomical/kinematic variables and the metabolic cost of transport, regardless of the training experience. However, anatomical symmetry significant correlated to the kinematic symmetry, and the most trained subjects showed the highest level of kinematic symmetry during running. Results suggest that despite the significant effects of anatomical asymmetry on kinematics, either those changes are too small to affect economy or some plastic compensation in the locomotor system mitigates the hypothesized change in energy expenditure of running.


A preliminary study of multidimensional pain inventory profile differences in predicting treatment outcome in a heterogeneous cohort of patients with chronic pain.
The objective was to evaluate whether the Multidimensional Pain Inventory (MPI) is effective for predicting response to interdisciplinary treatment in a heterogeneous group of patients with chronic pain. Changes in patients' profiles to a predominantly adaptive coping status after treatment also were assessed. A prospective study was conducted of patients with an array of pain conditions. A standard evaluation battery, including measures of self-reported pain and disability, psychosocial functioning, helpfulness of the program, and medication use, was used for all patients before and after treatment. The MPI status of patients was evaluated and differential response to treatment was assessed. Sixty-five consecutive patients with chronic pain were evaluated before and immediately after participation in an interdisciplinary pain treatment program. This heterogeneous pain-condition cohort was also differentiated on the basis of the MPI to evaluate potential differential response to treatment. Results revealed significant improvement among these patients with chronic pain when a comprehensive interdisciplinary pain-management program was administered. This improvement was seen across the variety of outcomes evaluated, including narcotic medication use. Most important, the MPI subgroup classification did not significantly predict the degree of positive treatment outcome; all subgroups improved. Although there were major differences in psychosocial functioning before treatment, the MPI was not found to significantly predict response to interdisciplinary treatment in a heterogeneous group of patients with chronic pain. Thus, a comprehensive interdisciplinary treatment program may achieve its full effectiveness across a wide array of pain/disability-related outcome variables, regardless of initial MPI profile categorization.


Cohort patterns in mortality trends among the elderly in seven European countries, 1950-99.
Secular trends in old-age mortality are of crucial importance to population ageing. For the understanding and prediction of these trends, it is important to determine whether birth cohort effects, i.e. long-lasting effects of exposures earlier in life, are important in determining mortality trends up to old age. This study aimed to identify and describe cohort patterns in trends in mortality among the elderly (>60 years of age) in seven European countries. A standard age-period-cohort analysis was applied to all-cause and cause-specific mortality data by 5-year age groups and sex, for Denmark, England and Wales, Finland, France, The Netherlands, Norway, and Sweden, in the period 1950-99. Cohort patterns were identified in all countries, for both the sexes and virtually all causes of death. They strongly influenced the trends in all-cause mortality among Danish, Dutch, and Norwegian men, and the trends in mortality from infectious diseases, lung cancer (men only), prostate cancer, breast cancer, and chronic obstructive pulmonary disease (COPD). All-cause mortality decline stagnated among Danish, Dutch, and Norwegian male birth cohorts born between 1890 and 1915, among French men born after 1920, and among women from all countries born after 1920. Where all-cause mortality decline stagnated, cohort patterns in mortality from lung cancer, COPD, and to a lesser extent ischaemic heart diseases, were unfavourable as well. For infectious diseases, stomach cancer, and cerebrovascular diseases, mortality increased among cohorts born before 1890, and decreased strongly thereafter. Cohort effects related to factors such as living conditions in childhood and smoking in adulthood were important in determining the recent trends in mortality among the elderly in seven European countries.


Growth in semisolid agar of prostate cancer cells obtained from bone marrow aspirates.
Thirty-one bone marrow aspirations were performed on patients with prostatic carcinoma metastatic to bone. After separation over a Ficoll-Hypaque gradient viable nucleated cells were cultured in semisolid agar. Colony formation occurred in 14 of 27 (52%) nonbacterially contaminated cultures. Characterization of cells from the colonies showed them to be consistent with malignant prostate cells. After staining, these cells were periodic acid-Schiff positive, prostatic acid phosphatase positive, and prostatic specific antigen positive. Other studies demonstrated the cells to be karyotypically abnormal, ultrastructurally similar to epithelial cells, and capable of secondary colony formation. Three bone marrow aspirate specimens did not have metastatic prostatic carcinoma detected by standard methods but did demonstrate colony formation. However, colony formation was most frequently seen when a radionuclide scan was positive at the aspiration site and when tumor cells were microscopically detectable by Wright staining of a smeared aspirate. The potential utility of colony forming cultures in prostate cancer is discussed. In working with bone marrow aspirates, additional cell separation procedures may be required to calculate and maximize plating efficiencies.


Mode of action of closthioamide: the first member of the polythioamide class of bacterial DNA gyrase inhibitors.
The spread of MDR bacteria represents a serious threat to human society and novel antibiotic drugs, preferably from new chemical classes, are urgently needed. Closthioamide was isolated from the strictly anaerobic bacterium Clostridium cellulolyticum and belongs to a new class of natural products, the polythioamides. Here, we investigated the antimicrobial activity and mechanism of action of closthioamide. For assessing the antimicrobial activity of closthioamide, MIC values and killing kinetics were determined. To identify its target pathway, whole-cell-based assays were used including analysis of macromolecular synthesis and recording the susceptibility profile of a library of clones with down-regulated potential target genes. Subsequently, the inhibitory effect of closthioamide on the activity of isolated target enzymes, e.g. DNA gyrase and topoisomerase IV, was evaluated. Closthioamide had broad-spectrum activity against Gram-positive bacteria. Notably, closthioamide was very potent against MRSA and VRE strains. Closthioamide impaired DNA replication and inhibited DNA gyrase activity, in particular the ATPase function of gyrase and of topoisomerase IV, whereas there was little effect on the cleavage-rejoining function. Closthioamide also inhibited the relaxation activity of DNA gyrase, which does not require ATP hydrolysis, and thus may allosterically rather than directly interfere with the ATPase activity of gyrase. Cross-resistance to ciprofloxacin and novobiocin could not be detected in experimental mutants and clinical isolates. Closthioamide, a member of an unprecedented class of antibiotics, is a potent inhibitor of bacterial DNA gyrase; however, its molecular mechanism differs from that of the quinolones and aminocoumarins.


Computational high-throughput screening of fluid permeability in heterogeneous fiber materials.
We explore computational high-throughput screening as a design strategy for heterogeneous, isotropic fiber materials. Fluid permeability, a key property in the design of soft porous materials, is systematically studied using a multi-scale lattice Boltzmann framework. After characterizing microscopic permeability as a function of solid volume fraction in the microstructure, we perform high-throughput computational screening of in excess of 35 000 macrostructures consisting of a continuous bulk interrupted by spherical/elliptical domains with either lower or higher microscopic permeability (hence with two distinct microscopic solid volume fractions and therefore two distinct microscopic permeabilities) to assess which parameters determine macroscopic permeability for a fixed average solid volume fraction. We conclude that the fractions of bulk and domains and the distribution of solid volume fraction between them are the primary determinants of macroscopic permeability, and that a substantial increase in permeability compared to the corresponding homogenous material is attainable.


Protein Folding Modulation in Cells Subject to Differentiation and Stress.
Cytomimetic media are used to mimic the physicochemical properties of the cellular milieu in an in vitro experiment. The motivation is that compared to entire cells, they can be used efficiently in combination with a broad range of experimental techniques. However, the development and use of cytomimetic media is hampered by the lack of in-cell data that could be used as a hallmark to directly evaluate and improve the performance of cytomimetic media in different applications. Such data must include the study of specific biomolecular reactions in different cell types, different compartments of a single cells and different cellular conditions. In previous studies, model systems such as cancer cell lines, bacteria or oocytes were used. Here we studied how the environment of cells that undergo neuronal differentiation or proteostasis stress modulates the protein folding equilibrium. We found that NGF induced differentiation leads to a decrease of the melting temperature and a change of the folding mechanism. Proteomic changes that occur upon differentiation could explain this effect, however, we found that the crowding effect remained unchanged. Using MG132, a common proteasome inhibitor and inducer of the unfolded protein response, we show that changes to the quality control machinery modulate the folding equilibrium, leading to protein destabilization at prolonged stress exposure. Our study explores the range of protein folding modulation within cells subject to differentiation or stress that must be encountered in the development of cytomimetic media.


Dopamine, time, and impulsivity in humans.
Disordered dopamine neurotransmission is implicated in mediating impulsiveness across a range of behaviors and disorders including addiction, compulsive gambling, attention-deficit/hyperactivity disorder, and dopamine dysregulation syndrome. Whereas existing theories of dopamine function highlight mechanisms based on aberrant reward learning or behavioral disinhibition, they do not offer an adequate account of the pathological hypersensitivity to temporal delay that forms a crucial behavioral phenotype seen in these disorders. Here we provide evidence that a role for dopamine in controlling the relationship between the timing of future rewards and their subjective value can bridge this explanatory gap. Using an intertemporal choice task, we demonstrate that pharmacologically enhancing dopamine activity increases impulsivity by enhancing the diminutive influence of increasing delay on reward value (temporal discounting) and its corresponding neural representation in the striatum. This leads to a state of excessive discounting of temporally distant, relative to sooner, rewards. Thus our findings reveal a novel mechanism by which dopamine influences human decision-making that can account for behavioral aberrations associated with a hyperfunctioning dopamine system.


Patient selection in outpatient and short-stay total knee arthroplasty.
The purpose of the current study is to identify patients who are at high risk for rehospitalization, revision, complications, and mortality after outpatient and short-stay total knee arthroplasty (TKA). The Medicare 5% limited data set sample was used to identify patients with a TKA procedure who were treated in an outpatient setting or who were discharged within 1 or 2 days in the hospital setting. Rehospitalization risk increased with higher Charlson score (i.e., poorer health status), older patients, inpatients (vs. outpatients), patients not receiving a femoral nerve block, earlier (vs. recent) year of surgery, and those with a recent history of heart failure. The findings of this study suggest that existing comorbidities, particularly heart failure, have the greatest effect on event risk after outpatient and short-stay TKA. The information obtained from this study should assist with patient selection for TKA performed on an outpatient basis.


Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel.
Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.


The SOBANE risk management strategy and the Déparis method for the participatory screening of the risks.
The first section of the document describes a risk-prevention strategy, called SOBANE, in four levels: screening, observation, analysis and expertise. The aim is to make risk prevention faster, more cost effective, and more effective in coordinating the contributions of the workers themselves, their management, the internal and external occupational health (OH) practitioners and the experts. These four levels are: screening, where the risk factors are detected by the workers and their management, and obvious solutions are implemented; observation, where the remaining problems are studied in more detail, one by one, and the reasons and the solutions are discussed in detail; analysis, where, when necessary, an OH practitioner is called upon to carry out appropriate measurements to develop specific solutions; expertise, where, in very sophisticated and rare cases, the assistance of an expert is called upon to solve a particular problem. The method for the participatory screening of the risks (in French: Dépistage Participatif des Risques), Déparis, is proposed for the first level screening of the SOBANE strategy. The work situation is systematically reviewed and all the aspects conditioning the easiness, the effectiveness and the satisfaction at work are discussed, in search of practical prevention measures. The points to be studied more in detail at level 2, observation, are identified. The method is carried out during a meeting of key workers and technical staff. The method proves to be simple, sparing in time and means and playing a significant role in the development of a dynamic plan of risk management and of a culture of dialogue in the company.


Plastic diagnostics: The remaking of disease and evidence in personalized medicine.
Politically authorized reports on personalized and precision medicine stress an urgent need for finer-grained disease categories and faster taxonomic revision, through integration of genomic and phenotypic data. Developing a data-driven taxonomy is, however, not as simple as it sounds. It is often assumed that an integrated data infrastructure is relatively easy to implement in countries that already have highly centralized and digitalized health care systems. Our analysis of initiatives associated with the Danish National Genome Center, recently launched to bring Denmark to the forefront of personalized medicine, tells a different story. Through a "meta-taxonomy" of taxonomic revisions, we discuss what a genomics-based disease taxonomy entails, epistemically as well as organizationally. Whereas policy reports promote a vision of seamless data integration and standardization, we highlight how the envisioned strategy imposes significant changes on the organization of health care systems. Our analysis shows how persistent tensions in medicine between variation and standardization, and between change and continuity, remain obstacles for the production as well as the evaluation of genomics-based taxonomies of difference. We identify inherent conflicts between the ideal of dynamic revision and existing regulatory functions of disease categories in, for example, the organization and management of health care systems. Moreover, we raise concerns about shifts in the regulatory regime of evidence standards, where clinical care increasingly becomes a vehicle for biomedical research.


Repeat stereotactic body radiation therapy for patients with pulmonary malignancies who had previously received SBRT to the same or an adjacent tumor site.
Retrospective analysis of patients with recurrences at or closely adjacent to the site of prior lung stereotactic body radiation therapy (SBRT) who received repeat SBRT. Nine patients with non-small cell lung cancer (n = 8) or oligometastatic colonic adenocarcinoma (n = 1) were treated with image-guided lung SBRT to a median of 60 Gy (range, 30-60) in a median of 3 fractions (3-5). Patients developed in-field relapse (n = 3) or recurrence adjacent (≤ 3.5 cm away) to the previous tumor location (n = 6) and received 2 nd lung SBRT to a median of 60 Gy. Median follow-up after 2 nd SBRT was 22 months (4-40). All completed prescribed course of repeat SBRT and acute toxicity was limited. There was no grade >3 late toxicity. 3 (33.3%) patients developed Grade 3 late reactions: 2 pulmonary and 1 chest wall pain. Late pulmonary toxicity included 2 (22.2%) patients with Grade 3 and 3 (33.3%) with Grade 2. One patient (11.1%) had late Grade 3 and 1 (11.1%) Grade 2 chest wall pain. 1 (11.1%) developed Grade 2 late brachial plexopathy. No myelopathy was observed. Two patients developed progression of tumors treated by 2 nd SBRT. Local recurrence free survival and overall survival was 75% and 68.6%, respectively at 2 years. Relative volume of ipsilateral lung receiving 5 Gy (V5) and V10 were lower for 2 nd SBRT. Repeat image-guided SBRT for patients with small peripheral recurrences was feasible and severe toxicity was not observed. Additional studies are needed to evaluate the safety and efficacy of lung reirradiation using 2 nd SBRT.


The effect of sodium valproate on chronic daily headache and its subgroups.
The objective of the study was to assess the efficacy and tolerability of sodium valproate (VPA) on chronic daily headache (CDH) in a prospective, double-blind, randomized, placebo-controlled trial. Seventy patients were included in the study. Twenty-nine had chronic migraine (CM) and 41 had chronic tension-type headache (CTTH). VPA and placebo were applied for 3 months to 40 and 30 patients, respectively. Visual analog scale (VAS) and pain frequency (PF) were used for evaluation. VPA decreased the maximum pain VAS levels (MaxVAS) and PF at the end of the study (P = 0.028 and P = 0.000, respectively), but did not change general pain VAS (GnVAS) levels (P = 0.198). In CM patients, the decreases in MaxVAS, GnVAS and PF parameters were more in VPA treated patients (P = 0.006, P = 0.03, and P = 0.000, respectively). VPA treatment caused more reduction in PF than placebo in the CTTH subgroup (P = 0.000). VPA is effective in the prophylactic treatment of CDH by reducing MaxVAS levels and PF. It was more effective in CM than in CTTH.


Long-Term in Vivo Performance of Low-Temperature 3D-Printed Bioceramics in an Equine Model.
Bone has great self-healing capacity, but above a certain critical size, bone defects will not heal spontaneously, requiring intervention to achieve full healing. Among the synthetic calcium phosphate (CaP) bone replacement materials, brushite (CaHPO4·2H2O)-based materials are of particular interest because of their degree of solubility and the related high potential to promote bone regeneration after dissolution. They can be produced tailor-made using modern three-dimensional (3D) printing technology. Although this type of implant has been widely tested in vitro, there are only limited in vivo data and less so in a relevant large animal model. In this study, material properties of a 3D-printed brushite-based scaffold are characterized, after which the material is tested by in vivo orthotopic implantation in the equine tuber coxae for 6 months. The implantation procedure was easy to perform and was well tolerated by the animals, which showed no detectable signs of discomfort. In vitro tests showed that compressive strength along the vertical axis of densely printed material was around 13 MPa, which was reduced to approximately 8 MPa in the cylindrical porous implant. In vivo, approximately 40% of the visible volume of the implants was degraded after 6 months and replaced by bone, showing the capacity to stimulate new bone formation. Histologically, ample bone ingrowth was observed. In contrast, empty defects were filled with fibrous tissue only, confirming the material's osteoconductive capacity. It is concluded that this study provides proof that the 3D-printed brushite implants were able to promote new bone growth after 6 months' implantation in a large animal model and that the new equine tuber coxae bone model that was used is a promising tool for bone regeneration studies.


Human ovarian reserve from conception to the menopause.
The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50-51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained r2 correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve (r2 = 0.81). When restricted to ages up to 25 years, the ADC curve has r2 = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments.


Effects of fragrance inhalation on sympathetic activity in normal adults.
We investigated the effects of fragrance inhalation on sympathetic activity in normal adult subjects using both power spectral analysis of blood pressure fluctuations and measurement of plasma catecholamine levels. Fragrance inhalation of essential oils, such as pepper oil, estragon oil, fennel oil or grapefruit oil, resulted in 1.5- to 2.5-fold increase in relative sympathetic activity, representing low frequency amplitude of systolic blood pressure (SBP-LF amplitude), compared with inhalation of an odorless solvent, triethyl citrate (P<0.05, each). In contrast, fragrance inhalation of rose oil or patchouli oil caused a 40% decrease in relative sympathetic activity (P<0.01, each). Fragrance inhalation of pepper oil induced a 1.7-fold increase in plasma adrenaline concentration compared with the resting state (P = 0.06), while fragrance inhalation of rose oil caused a 30% decrease in adrenaline concentration (P<0.01). Our results indicate that fragrance inhalation of essential oils may modulate sympathetic activity in normal adults.


Comparison of methods for monitoring bacterial transport in the subsurface.
The purpose of this study was to compare in a laboratory experiment, a suite of methods developed to track viable bacteria during field transport experiments. The criteria for development and selection of these methods included: (1) the ability to track bacteria within the environment from which they were isolated; (2) the lack of any effect upon the viability or the transport characteristics of the strain; (3) low detection limits; (4) a quantification range that covered several orders of magnitude; and (5) an analytical cost and turnover time commensurate with the analysis of several thousands of samples in a few months. The approaches developed included: enumeration of bacteria labeled with a vital fluorescent stain (CFDA/SE) using microplate spectrofluorometry, flow cytometry, and ferrographic (immunomagnetic) capture; enumeration of highly (13)C-enriched bacteria using combustion-IRMS; and quantitative PCR. These methods were compared to direct microscopic enumeration and plate counts during a bacterial transport experiment performed in an intact sediment core and designed to simulate the field experiment. Four of the seven methods had equivalent recoveries for the breakthrough of a pulse of bacteria eluting from a 50-cm long sediment core, and all of the methods detected the arrival of cells in the effluent prior to the conservative tracer. Combustion IRMS and ferrographic enumeration had the lowest quantification limits (approximately 2 to 20 cells/ml), whereas microplate spectrofluorometry had the highest quantification limit (approximately 10(5) cells/ml). These methods have the potential for numerous applications beyond tracking bacteria injected into the subsurface.


Gliomas: application of cumulative histogram analysis of normalized cerebral blood volume on 3 T MRI to tumor grading.
Glioma grading assumes significant importance in that low- and high-grade gliomas display different prognoses and are treated with dissimilar therapeutic strategies. The objective of our study was to retrospectively assess the usefulness of a cumulative normalized cerebral blood volume (nCBV) histogram for glioma grading based on 3 T MRI. From February 2010 to April 2012, 63 patients with astrocytic tumors underwent 3 T MRI with dynamic susceptibility contrast perfusion-weighted imaging. Regions of interest containing the entire tumor volume were drawn on every section of the co-registered relative CBV (rCBV) maps and T2-weighted images. The percentile values from the cumulative nCBV histograms and the other histogram parameters were correlated with tumor grades. Cochran's Q test and the McNemar test were used to compare the diagnostic accuracies of the histogram parameters after the receiver operating characteristic curve analysis. Using the parameter offering the highest diagnostic accuracy, a validation process was performed with an independent test set of nine patients. The 99th percentile of the cumulative nCBV histogram (nCBV C99), mean and peak height differed significantly between low- and high-grade gliomas (P = <0.001, 0.014 and <0.001, respectively) and between grade III and IV gliomas (P = <0.001, 0.001 and <0.001, respectively). The diagnostic accuracy of nCBV C99 was significantly higher than that of the mean nCBV (P = 0.016) in distinguishing high- from low-grade gliomas and was comparable to that of the peak height (P = 1.000). Validation using the two cutoff values of nCBV C99 achieved a diagnostic accuracy of 66.7% (6/9) for the separation of all three glioma grades. Cumulative histogram analysis of nCBV using 3 T MRI can be a useful method for preoperative glioma grading. The nCBV C99 value is helpful in distinguishing high- from low-grade gliomas and grade IV from III gliomas.


Electrochemical biosensing platform based on complex biantennary N-glycan for detecting enzymatic sialylation processes.
Sialylated glycans and glycoproteins are involved in cellular communication and are crucial for distinguishing between signal pathways. Sialylation levels and patterns modulate recognition events and are regulated by the enzymatic activity of sialyltransferases and neuraminidases. Abnormal activity of these enzymes is related to diseases such as cancer and viral infection. Monitoring these enzymatic activities offers valuable diagnostic tools. This work presents an impedimetric biosensing platform for following and detecting sialylation and desialylation processes. This platform is based on a native biantennary N-glycan substrate attached to a glassy carbon electrode. Changes in the molecular layer, as a result of enzymatic reactions, were detected by electrochemical impedance spectroscopy, displaying high sensitivity to the enzymatic surface reactions. Increase in the molecular layer roughness in response to the sialylation was visualized using atomic force microscopy. After enzymatic sialylation, the presence of sialic acid was confirmed using cyclic voltammetry by coupling of the redox active marker aminoferrocene. The sialylation showed selectivity toward the N-glycan compared to another glycan substrate. A time dependent sialylation was followed by electrochemical impedance spectroscopy, proving that the new system can be applied to evaluate the enzymatic kinetics. Our findings suggest that analyzing sialylation processes using this platform can become a useful tool for the detection of pathological states and pathogen invasion.


Catalyst-free nanowires with axial InxGa1-xAs/GaAs heterostructures.
Self-catalyzed growth of axial In(x)Ga(1-x)As/GaAs heterostructures has been realized by molecular beam epitaxy. The growth of the wires is achieved from gallium/indium alloy droplets that are nucleated in situ. By variation of the In/Ga beam flux during the growth it was possible to vary the effective indium content up to x = 5%, as deduced from photoluminescence measurements. We have analyzed the dependence of the alloy concentration on the growth conditions and present a simple model for the growth. The heterostructures grown with the method presented were spatially mapped along the wires with confocal microphotoluminescence and cathodoluminescence. It was found as expected that the emission of GaAs/In(x)Ga(1-x)As/GaAs heterostructures is localized. This work is important for the use of an external catalyst-free growth of complex axial heterostructures and related opto-electronic devices that facilitates its possible integration in the device or system fabrication processes.


Controversial issues in the management of older adults with early breast cancer.
It is well recognized that the incidence of breast cancer increases significantly with age. Despite this, older people remain under-represented in many clinical trials and their management relies on extrapolation of data from younger patients. Providing an aggressive intervention can be challenging, particularly in less fit older patients where a conservative approach is commonly perceived to be more appropriate. The optimal management of this population is unknown and treatment decision should be personalized. This review article will discuss several controversial issues in managing older adults with early breast cancer in a multidisciplinary setting, including the role of surgical treatment of the axilla in clinically node negative disease, radiotherapy after breast conservation surgery in low-risk tumours, personalizing adjuvant systemic therapy, and geriatric assessments in breast cancer treatment decisions.


Faces and objects in macaque cerebral cortex.
How are different object categories organized by the visual system? Current evidence indicates that monkeys and humans process object categories in fundamentally different ways. Functional magnetic resonance imaging (fMRI) studies suggest that humans have a ventral temporal face area, but such evidence is lacking in macaques. Instead, face-responsive neurons in macaques seem to be scattered throughout temporal cortex, with some relative concentration in the superior temporal sulcus (STS). Here, using fMRI in alert fixating macaque monkeys and humans, we found that macaques do have discrete face-selective patches, similar in relative size and number to face patches in humans. The face patches were embedded within a large swath of object-selective cortex extending from V4 to rostral TE. This large region responded better to pictures of intact objects compared to scrambled objects, with different object categories eliciting different patterns of activity, as in the human. Overall, our results suggest that humans and macaques share a similar brain architecture for visual object processing.


The Adapted Lifestyle-Integrated Functional Exercise Program for Preventing Functional Decline in Young Seniors: Development and Initial Evaluation.
The Lifestyle-integrated Functional Exercise (LiFE) program is an intervention integrating balance and strength activities into daily life, effective at reducing falls in at-risk people ≥70 years. There is potential for LiFE to be adapted to young seniors in order to prevent age-related functional decline. We aimed to (1) develop an intervention by adapting Lifestyle-integrated Functional Exercise (aLiFE) to be more challenging and suitable for preventing functional decline in young seniors in their 60s and (2) perform an initial feasibility evaluation of the program. Pre-post changes in balance, mobility, and physical activity (PA) were also explored. Based on a conceptual framework, a multidisciplinary expert group developed an initial aLiFE version, including activities for improving strength, neuromotor performances, and PA. Proof-of-concept was evaluated in a 4-week pre-post intervention study measuring (1) feasibility including adherence, frequency of practice, adverse events, acceptability (i.e., perceived helpfulness, adaptability, level of difficulty of single activities), and safety, and (2) changes in balance/mobility (Community Balance and Mobility Scale) and PA (1 week activity monitoring). The program was refined based on the study results. To test the initial aLiFE version, 31 young seniors were enrolled and 30 completed the study (mean age 66.4 ± 2.7 years, 60% women). Of a maximum possible 16 activities, participants implemented on average 12.1 ± 1.8 activities during the intervention, corresponding to mean adherence of 76%. Implemented activities were practiced 3.6-6.1 days/week and 1.8-7.8 times/day, depending on the activity type. One noninjurious fall occurred during practice, although the participant continued the intervention. The majority found the activities helpful, adaptable to individual lifestyle, appropriately difficult, and safe. CMBS score increased with medium effect size (d = 0.72, p = 0.001). Increase in daily walking time (d = 0.36) and decrease in sedentary time (d = -0.10) were nonsignificant. Refinements included further increasing the task challenge of some strength activities and defining the most preferred activities in the trainer's manual to facilitate uptake of the program. aLiFE has the potential to engage young seniors in regular lifestyle-integrated activities. Effectiveness needs to be evaluated in a randomized controlled trial.


Nonmalignant respiratory disease among hematite mine workers in China.
The mortality risk of nonmalignant respiratory disease among hematite workers in the Longyan and Taochong mines of China was investigated in a retrospective cohort study covering the period 1970-1982. The cohort was limited to men and consisted of 5406 underground miners, of whom 1335 (25%) were diagnosed as having silicosis. Among those with silicosis, 560 (42%) were diagnosed as having silicotuberculosis. Among the 490 underground miners who died, 278 (57%) died of nonmalignant respiratory disease. The relative risk for death due to nonmalignant respiratory disease for stage III silicotics compared to nonsilicotics was almost 100-fold. High dust exposure was associated with a statistically significant increase in risk of death due to nonmalignant respiratory disease (relative risk 5.3). The relative risk associated with jobs with high dust exposure before the introduction of industrial hygiene controls was 7.7, and the corresponding value for after their introduction was 2.3. There is a need for continued close monitoring of industrial hygiene in these mines.


Induction of protein citrullination and auto-antibodies production in murine exposed to nickel nanomaterials.
Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity.


Facial Contouring by Targeted Restoration of Facial Fat Compartment Volume: The Midface.
Recent anatomical findings have suggested that facial fat distribution is complex and changes with age. Here, the authors developed a grafting technique based on the physiologic distribution and volume changes of facial fat compartments to achieve a youthful and natural-appearing face. Forty cadaveric hemifaces were used for the dissection of fat compartments and neurovascular structures in the midface area. Seventy-eight patients were treated for cheek atrophy using the authors' targeted restoration of midface fat compartment volume. The outcome was evaluated by a two-dimensional assessment, malar lipoatrophy assessment, and a satisfaction survey. The medial and lateral parts of the deep medial cheek fat compartment were separated by a septum arising from the lateral border of the levator anguli oris muscle. The angular vein traveled between the deep medial cheek fat compartment and the buccal fat pad, 12 mm from the maxilla. A total volume of 29.3 ml of fat was grafted per cheek for each patient. A 12-month follow-up revealed an average volume augmentation rate of 27.1 percent. Pleasing and elevated anterior projection of the cheek and ameliorated nasolabial groove were still obvious by 12 months after the procedure. In total, 95.2 percent of the patients were satisfied with their results. The present study provides the anatomical and clinical basis for the concept of compartmentally based fat grafting. It allows for the restoration of facial fat volume close to the physiologic state. With this procedure, a natural and youthful facial contour could be rebuilt with a high satisfaction rate. Therapeutic, IV.


Protective Effects of Black Cumin (Nigella sativa) and Its Bioactive Constituent, Thymoquinone against Kidney Injury: An Aspect on Pharmacological Insights.
The prevalence of chronic kidney disease (CKD) is increasing worldwide, and a close association between acute kidney injury (AKI) and CKD has recently been identified. Black cumin (Nigella sativa) has been shown to be effective in treating various kidney diseases. Accumulating evidence shows that black cumin and its vital compound, thymoquinone (TQ), can protect against kidney injury caused by various xenobiotics, namely chemotherapeutic agents, heavy metals, pesticides, and other environmental chemicals. Black cumin can also protect the kidneys from ischemic shock. The mechanisms underlying the kidney protective potential of black cumin and TQ include antioxidation, anti-inflammation, anti-apoptosis, and antifibrosis which are manifested in their regulatory role in the antioxidant defense system, NF-κB signaling, caspase pathways, and TGF-β signaling. In clinical trials, black seed oil was shown to normalize blood and urine parameters and improve disease outcomes in advanced CKD patients. While black cumin and its products have shown promising kidney protective effects, information on nanoparticle-guided targeted delivery into kidney is still lacking. Moreover, the clinical evidence on this natural product is not sufficient to recommend it to CKD patients. This review provides insightful information on the pharmacological benefits of black cumin and TQ against kidney damage.


Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual hsp70 chaperones.
Hsp70 is a central molecular chaperone that passively prevents protein aggregation and uses the energy of ATP hydrolysis to solubilize, translocate, and mediate the proper refolding of proteins in the cell. Yet, the molecular mechanism by which the active Hsp70 chaperone functions are achieved remains unclear. Here, we show that the bacterial Hsp70 (DnaK) can actively unfold misfolded structures in aggregated polypeptides, leading to gradual disaggregation. We found that the specific unfolding and disaggregation activities of individual DnaK molecules were optimal for large aggregates but dramatically decreased for small aggregates. The active unfolding of the smallest aggregates, leading to proper global refolding, required the cooperative action of several DnaK molecules per misfolded polypeptide. This finding suggests that the unique ATP-fueled locking/unlocking mechanism of the Hsp70 chaperones can recruit random chaperone motions to locally unfold misfolded structures and gradually disentangle stable aggregates into refoldable proteins.


Bacterial biofilms on gold grains-implications for geomicrobial transformations of gold.
The biogeochemical cycling of gold (Au), i.e. its solubilization, transport and re-precipitation, leading to the (trans)formation of Au grains and nuggets has been demonstrated under a range of environmental conditions. Biogenic (trans)formations of Au grains are driven by (geo)biochemical processes mediated by distinct biofilm consortia living on these grains. This review summarizes the current knowledge concerning the composition and functional capabilities of Au-grain communities, and identifies contributions of key-species involved in Au-cycling. To date, community data are available from grains collected at 10 sites in Australia, New Zealand and South America. The majority of detected operational taxonomic units detected belong to the α-, β- and γ-Proteobacteria and the Actinobacteria. A range of organisms appears to contribute predominantly to biofilm establishment and nutrient cycling, some affect the mobilization of Au via excretion of Au-complexing ligands, e.g. organic acids, thiosulfate and cyanide, while a range of resident Proteobacteria, especially Cupriavidus metallidurans and Delftia acidovorans, have developed Au-specific biochemical responses to deal with Au-toxicity and reductively precipitate mobile Au-complexes. This leads to the biomineralization of secondary Au and drives the environmental cycle of Au.


Implications of silver nanoparticle induced cell apoptosis for in vitro gene therapy.
The impact of manufactured nanomaterials on human health and the environment is a major concern for commercial use of nanotechnology based products. A judicious choice of selective usage, lower nanomaterial concentration and use in combination with conventional therapeutic materials may provide the best solution. For example, silver nanoparticles (Ag NPs) are known to be bactericidal and also cytotoxic to mammalian cells. Herein, we investigate the molecular mechanism of Ag NP mediated cytotoxicity in both cancer and non-cancer cells and find that optimum particle concentration leads to programmed cell death in vitro. Also, the benefit of the cytotoxic effects of Ag NPs was tested for therapeutic use in conjunction with conventional gene therapy. The synergistic effect of Ag NPs on the uracil phosphoribosyltransferase expression system sensitized the cells more towards treatment with the drug 5-fluorouracil. Induction of the apoptotic pathway makes Ag NPs a representative of a new chemosensitization strategy for future application in gene therapy.


Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy.
Fabry disease is an X-linked deficiency of alpha-galactosidase A, resulting in lysosomal deposition of globotriaosylceramide in nearly all tissues. The disease frequently causes diarrhea and abdominal pain, which are assumed to arise from malfunction of enteric neurons and which mimic diarrhea-predominant irritable bowel syndrome (IBS). There are limited data about the prevalence and nature of gastrointestinal symptoms in patients with Fabry disease and the response to enzyme replacement therapy (ERT) in large cohorts. The aims of this study were to evaluate the nature and prevalence of gastrointestinal symptoms and their impact on health-related quality of life (HRQoL) in patients with Fabry disease and to analyze changes after 12 and 24 months of treatment with agalsidase alfa. Information about gastrointestinal symptoms was obtained from regular interviews before and during the time of ERT. Data on HRQoL were collected by using the EQ-5D questionnaire. The overall prevalence of gastrointestinal symptoms was 52%, with abdominal pain and diarrhea being most frequent. Female patients were more frequently affected than male patients, and there was a high prevalence in children (abdominal pain, 49.3%; diarrhea 25.4%). ERT with agalsidase alfa reduced the prevalence of abdominal pain, with a statistically significant decrease in male patients and in children after 12 months of treatment. The gastrointestinal symptomatology of Fabry disease is very similar to diarrhea-predominant IBS; however, pathophysiologic similarities remain to be elucidated. ERT reduced the prevalence of gastrointestinal symptoms in Fabry disease, particularly in children and male patients.