Effect of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evidence from randomized trials.
The effect of statin treatment on ventricular arrhythmic complications is uncertain. We sought to test whether statins reduce the risk of ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death. We searched MEDLINE, EMBASE, and CENTRAL up to October 2010. Randomized controlled trials comparing statin with no statin or comparing intensive vs. standard dose statin, with more than 100 participants and at least 6-month follow-up were considered for inclusion and relevant unpublished data obtained from the investigators. Twenty-nine trials of statin vs. control (113 568 participants) were included in the main analyses. In these trials, statin therapy did not significantly reduce the risk of ventricular tachyarrhythmia [212 vs. 209; odds ratio (OR) = 1.02, 95% confidence interval (CI) 0.84-1.25, P = 0.87] or of cardiac arrest (82 vs. 78; OR = 1.05, 95% CI 0.76-1.45, P = 0.84), but was associated with a significant 10% reduction in sudden cardiac death (1131 vs. 1252; OR = 0.90; 95% CI 0.82-0.97, P = 0.01). This compared with a 22% reduction in the risk of other 'non-sudden' (mostly atherosclerotic) cardiac deaths (1235 vs. 1553; OR = 0.78, 95% CI 0.71-0.87, P < 0.001). Results were not materially altered by inclusion of eight trials (involving 41 452 participants) of intensive vs. standard dose statin regimens. Statins have a modest beneficial effect on sudden cardiac death. However, previous suggestions of a substantial protective effect on ventricular arrhythmic events could not be supported.


Magnetic nanoparticle-enhanced surface plasmon resonance biosensor for extracellular vesicle analysis.
The sensitive analysis of small lipid extracellular vesicles (EVs) by using a grating-coupled surface plasmon resonance (GC-SPR) biosensor has been reported. In order to enable the analysis of trace amounts of EVs present in complex liquid samples, the target analyte is pre-concentrated on the sensor surface by using magnetic nanoparticles and its affinity binding is probed by wavelength interrogation of SPR. The GC-SPR has been demonstrated to allow for the implementation of efficient pulling of EVs to the sensor surface by using magnetic nanoparticles and an external magnetic field gradient applied through the sensor chip. This approach overcomes slow diffusion-limited mass transfer and greatly enhances the measured sensor response. The specific detection of different EV populations secreted from mesenchymal stem cells is achieved with a SPR sensor chip modified with antibodies against the surface marker CD81 and magnetic nanoparticles binding the vesicles via annexin V and cholera toxin B chain.


Impact of detailed informed consent on research subjects' participation: a prospective, randomized trial.
This study was undertaken to measure potential research subjects' participation in a survey research design, based on level and type of informed consent required before enrollment. In this prospective, randomized trial, 300 eligible Emergency Department participants were randomized to one of three groups: verbal consent (n = 100), limited written consent (n = 100), and detailed written consent with signature (n = 100). The consent was related to a self-administered patient satisfaction survey. The primary outcome was level of participation, where participation was categorized as full, limited, or refusal. Ninety-five percent confidence intervals (CI) constructed about proportions were used to assess differences in participation rates between the three consent groups. Among 300 participants, no demographic differences were found between groups for age or gender. Participants who were randomized to complete the detailed written consent had a significantly lower rate of full participation (72%) when compared to those randomized to verbal consent (85%; mean difference between groups 13%, 95% CI 2% to 24%) and to those with limited written consent (84%; mean difference between groups 12%, 95% CI 1% to 23%). Participants randomized to detailed written consent also had a significantly higher refusal rate (23%) when compared to those in the limited written group (12%; mean difference between groups -11%, 95% CI -21% to -1%). The length and type of informed consent required affected potential research subject participation in a survey research design. Participants who were asked to sign a detailed written informed consent document had a lower rate of participation compared to those with verbal or limited written consent.


Correlation between rhodamine 123 accumulation and azole sensitivity in Candida species: possible role for drug efflux in drug resistance.
A wide variety of prokaryotic and eukaryotic cells exhibit a multidrug resistance (MDR) phenotype, indicating that resistance to potentially toxic compounds is mediated by their active efflux from the cell. We have sought to determine whether resistance to azoles in some strains of Candida species may be due in part to active drug efflux. Rhodamine 123 (Rh123) is a fluorescent compound that is transported by a wide variety of MDR cell types. We have shown that certain azole-resistant strains of Candida albicans, C. glabrata, and C. krusei accumulate less Rh123 than azole-susceptible ones. In C. albicans, Rh123 accumulation was growth phase and temperature dependent and was increased by proton uncouplers and by reserpine, an MDR modulator. This is consistent with an energy-dependent efflux mechanism for Rh123, mediated by an MDR transporter. In C. glabrata, but not in C. albicans, there was competition between Rh123 and fluconazole for efflux. Thus, in C. glabrata, Rh123 and fluconazole appear to be transported via a common MDR-like transporter, whereas in C. albicans, the Rh123 transporter does not appear to transport azoles.


Auditory steady-state responses and speech feature discrimination in infants.
The aim of this study was to determine whether there was a correlation between auditory steady-state responses (ASSRs) for complex toneburst stimuli and speech feature discrimination (SFD) abilities in young infants. Seventeen infants (mean age = 9.4 months) and 21 adults (mean age = 27 years) with normal hearing had ASSR and SFD tests. The ASSR test employed an eight-component complex toneburst stimulus; threshold and input-output functions were determined as level was systematically varied. The SFD test utilized an observer-based, visual-reinforcement test procedure to determine the infant's ability to detect the speech feature change from /ba/ to /da/. The correlation of the group mean /ba/-/da/ discrimination performance (percent correct) with the group mean ASSR score (percent responses present) ranged from r = 0.64 for the 1500 Hz amplitude-modulated and frequency-modulated tone burst to 0.99 for ASSRs for all stimulus components; however, correlations between ASSRs and SFD scores for individual subjects were modest. The ASSR and SFD results appear to reflect the audibility of the stimuli.


Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT.
The clinical diagnosis of primary hyperparathyroidism is based largely on serum laboratory test results, as patients often are asymptomatic. Surgery, often with bilateral exploration of the neck, has been considered the definitive treatment for symptomatic disease. However, given that approximately 90% of cases are due to a single parathyroid adenoma, a better treatment may be the selective surgical excision of the hyperfunctioning parathyroid gland after its preoperative identification and localization at radiologic imaging. Scintigraphy and ultrasonography are the imaging modalities most often used for preoperative localization. Various scintigraphic protocols may be used in the clinical setting: Single-phase dual-isotope subtraction imaging, dual-phase single-isotope imaging, or a combination of the two may be used to obtain planar or tomographic views. Single photon emission computed tomography (SPECT) with the use of technetium-99m ((99m)Tc) sestamibi as the radiotracer, especially when combined with x-ray-based computed tomography (CT), is particularly helpful for preoperative localization: The three-dimensional functional information from SPECT is fused with the anatomic information obtained from CT. In addition, knowledge of the anatomy and embryologic development of the parathyroid glands and the pathophysiology of primary hyperparathyroidism aid in the identification and localization of hyperfunctioning glands.


Responding to intractable terminal suffering: the role of terminal sedation and voluntary refusal of food and fluids. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians-American Society of Internal Medicine.
When provided by a skilled, multidisciplinary team, palliative care is highly effective at addressing the physical, psychological, social, and spiritual needs of dying patients and their families. However, some patients who have witnessed harsh death want reassurance that they can escape if their suffering becomes intolerable. In addition, a small percentage of terminally ill patients receiving comprehensive care reach a point at which their suffering becomes severe and unacceptable despite unrestrained palliative efforts; some of these patients request that death be hastened. This paper presents terminal sedation and voluntary refusal of hydration and nutrition as potential last resorts that can be used to address the needs of such patients. These two practices allow clinicians to address a much wider range of intractable end-of-life suffering than physician-assisted suicide (even if it were legal) and can also provide alternatives for patients, families, and clinicians who are morally opposed to physician-assisted suicide. This paper will define the two practices, distinguish them from more standard palliative care interventions and from physician-assisted suicide, illustrate them with a real clinical scenario, provide potential guidelines and practicalities, and explore their moral and legal status. Although medicine cannot sanitize dying or provide perfect answers for all challenging end-of-life clinical problems, terminal sedation and voluntary refusal of hydration and nutrition substantially increase patients' choices at this inherently challenging time.


Is Chaalia/Pan Masala harmful for health? practices and knowledge of children of schools in Mahmoodabad and Chanesar Goth, Karachi.
To determine the practices and knowledge of harmful effects regarding use of Chaalia and Pan Masala in three schools of Mahmoodabad and Chanesar Goth, Jamshed Town, Karachi, Pakistan. To achieve the objective a cross-sectional design was used in three government schools of Mahmoodabad and Chanesar Goth, Jamshed Town, Karachi. Students of either gender drawn from these schools fulfilling the inclusion and exclusion criteria were interviewed using a pre-coded structured questionnaire. Along with demographic data, questions regarding frequency of Chaalia and Pan Masala use, practices of this habit in friends and family and place of procurement of these substances, were inquired. Knowledge was assessed about harmful effects and its source of information. In addition, practices in relation to that knowledge were assessed. A total of 370 students were interviewed over a period of six weeks, of which 205 (55.4%) were boys. The ages of the students were between 10 and 15 years. Thirty one percent of the fathers and 62% of the mothers were uneducated. The frequency of use of any brand of Chaalia was found to be 94% and that of Pan Masala was 73.8%. Eighty five percent of them were regular users. A large majority (88%) procured the substances themselves from near their homes. Ninety five percent of the children had friends with the same habits. Eighty four percent were using the substances in full knowledge of their families. Chaalia was considered harmful for health by 96% and Pan Masala by 60%. Good taste was cited as a reason for continuing the habit by 88.5% of the children and use by friends by 57%. Knowledge about established harmful effects was variable. Knowledge about harmful effects was high in both "daily" and "less than daily users". The frequency of habits of Chaalia and Pan Masala chewing, by school children in lower socio-economic areas is extremely high. The probable reasons for this high frequency are taste, the widespread use of these substances by family members and friends, low cost and easy availability.


Prognosis and Survival of Older Patients With Dizziness in Primary Care: A 10-Year Prospective Cohort Study.
The prognosis of older patients with dizziness in primary care is unknown. Our objective was to determine the prognosis and survival of patients with different subtypes and causes of dizziness. In a primary care prospective cohort study, 417 older adults with dizziness (mean age 79 years) received a full diagnostic workup in 2006-2008. A panel of physicians classified the subtype and primary cause of dizziness. Main outcome measures were mortality and dizziness-related impairment assessed at 10-year follow-up. At 10-year follow-up 169 patients (40.5%) had died. Presyncope was the most common dizziness subtype (69.1%), followed by vertigo (41.0%), disequilibrium (39.8%), and other dizziness (1.7%). The most common primary causes of dizziness were cardiovascular disease (56.8%) and peripheral vestibular disease (14.4%). Multivariable adjusted Cox models showed a lower mortality rate for patients with the subtype vertigo compared with other subtypes (hazard ratio [HR] = 0.62; 95% CI, 0.40-0.96), and for peripheral vestibular disease vs cardiovascular disease as primary cause of dizziness (HR = 0.46; 95% CI, 0.25-0.84). After 10 years, 47.7% of patients who filled out the follow-up measurement experienced substantial dizziness-related impairment. No significant difference in substantial impairment was seen between different subtypes and primary causes of dizziness. The 10-year mortality rate was lower for the dizziness subtype vertigo compared with other subtypes. Patients with dizziness primarily caused by peripheral vestibular disease had a lower mortality rate than patients with cardiovascular disease. Substantial dizziness-related impairment in older patients with dizziness 10 years later is high, and indicates that current treatment strategies by family physicians may be suboptimal.


Mechanism and substrate recognition of human holo ACP synthase.
Mammals utilize a single phosphopantetheinyl transferase for the posttranslational modification of at least three different apoproteins: the carrier protein components of cytosolic and mitochondrial fatty acid synthases and the aminoadipate semialdehyde reductase involved in lysine degradation. We determined the crystal structure of the human phosphopantetheinyl transferase, a eukaryotic phosphopantetheinyl transferase characterized, complexed with CoA and Mg(2+), and in ternary complex with CoA and ACP. The involvement of key residues in ligand binding and catalysis was confirmed by mutagenesis and kinetic analysis. Human phosphopantetheinyl transferase exhibits an alpha/beta fold and 2-fold pseudosymmetry similar to the Sfp phosphopantetheinyl transferase from Bacillus subtilis. Although the bound ACP exhibits a typical four-helix structure, its binding is unusual in that it is facilitated predominantly by hydrophobic interactions. A detailed mechanism is proposed describing the substrate binding and catalytic process.


Cigarette smoking and second-hand smoking exposure in adolescents with chronic kidney disease: a study from the Midwest Pediatric Nephrology Consortium.
Smoking and second-hand smoking [SHS] cause significant cardiovascular mortality and morbidity. In healthy individuals and adults with chronic kidney disease [CKD], cigarette smoking is associated with albuminuria, increased risk for CKD, increased graft loss and progression of renal insufficiency. In children, SHS has been associated with higher blood pressure variability, blood pressure load, elevated C-reactive protein and decreased cognitive function. Using a survey document and urine cotinine, we sought to investigate prevalence of cigarette use and SHS in adolescents with CKD. A cross-sectional study was conducted in which adolescents aged 13 to 18 years with CKD were asked to complete a single anonymous self-administered survey. In addition, a single freshly voided urine sample for cotinine measurement was obtained from eligible subjects. Of 182 subjects, 60 (34%), 25 (14%) and 93 (52%) were transplant recipients, were dialysis dependent and had a glomerulopathy, respectively. Renal status was lacking in four. Twenty-four per cent (24%) had smoked at some point in their lives, and 13% had smoked within the last 30 days of taking the survey. Fifty-two per cent (52%) of all respondents reported living with an adult who smoked, and 54% reported having friends that smoked. Forty-seven per cent (47%) and 44% of those who had never smoked lived with an adult and had friends that smoked, respectively. There was a discrepancy rate of 7% between self-reported non-smokers and urine cotinine, suggesting smoking rates were higher. The highest cotinine/creatinine levels among the non-smokers were observed in those who lived with a smoker and had friends that smoked. Among adolescents with CKD, cigarette smoking and SHS exposure are prevalent and may be important variables to consider when evaluating renal and cardiovascular risk factors and outcomes in children with CKD.


Sequence-specific interaction between HIV-1 matrix protein and viral genomic RNA revealed by in vitro genetic selection.
The human immunodeficiency virus type-1 matrix protein (HIV-1 MA) is a multifunctional structural protein synthesized as part of the Pr55 gag polyprotein. We have used in vitro genetic selection to identify an RNA consensus sequence that specifically interacts with MA (Kd = 5 x 10(-7) M). This 13-nt MA binding consensus sequence bears a high degree of homology (77%) to a region (nt 1433-1446) within the POL open reading frame of the HIV-1 genome (consensus sequence from 38 HIV-1 strains). Chemical interference experiments identified the nucleotides within the MA binding consensus sequence involved in direct contact with MA. We further demonstrate that this RNA-protein interaction is mediated through a stretch of basic amino acids within MA. Mutations that disrupt the interaction between MA and its RNA binding site within the HIV-1 genome resulted in a measurable decrease in viral replication.


Development and Validation of an Esophageal Squamous Cell Carcinoma Detection Model by Large-Scale MicroRNA Profiling.
Patients with late-stage esophageal squamous cell carcinoma (ESCC) have a poor prognosis. Noninvasive screening tests using serum microRNAs (miRNAs) to accurately detect early-stage ESCC are needed to improve mortality. To establish a model using serum miRNAs to distinguish patients with ESCC from noncancer controls. In this case-control study, serum miRNA expression profiles of patients with ESCC (n = 566) and control patients without cancer (n = 4965) were retrospectively analyzed to establish a diagnostic model, which was tested in a training set and confirmed in a validation set. Patients histologically diagnosed as having ESCC who did not receive prior therapy or have a past or concurrent cancer other than ESCC were enrolled from the National Cancer Center Hospital in Tokyo, Japan. Between October 2010 and November 2015, control samples were collected from the National Cancer Center Biobank, the Biobank of the National Center for Geriatrics and Gerontology, and the general population undergoing routine health examination. Data analysis was performed between August 2015 and October 2018. Serum samples were randomly divided into discovery and validation sets. The expression of 2565 miRNAs was assessed in each sample. The discriminant model (named the EC index) was evaluated in the training set using Fisher linear discriminant analysis with a greedy algorithm. Receiver operating characteristic curve analysis evaluated the diagnostic ability of the model in the validation set. In the training set, 283 patients with esophageal cancer (median age, 67 years [range, 37-90 years]; 83.4% male) were compared with 283 control patients (median age, 54 years [range, 22-100 years]; 43.1% male), and the EC index was constructed using 6 miRNAs (miR-8073, miR-6820-5p, miR-6794-5p, miR-3196, miR-744-5p, and miR-6799-5p). The area under the receiver operating characteristic curve was 1.00, with sensitivity of 1.00 and specificity of 0.98. The validation set included 283 patients (median age, 66 years [range, 42-87 years]; 83.0% male) and 4682 control patients (median age, 68 years [range, 20-98 years]; 44.7% male), and the area under the receiver operating characteristic curve for the EC index was 1.00, with sensitivity of 0.96 and specificity of 0.98. What appears to be novel serum miRNA discriminant model was developed for the diagnosis of ESCC. A multicenter prospective study is ongoing to confirm the present observations.


Early allelic selection in maize as revealed by ancient DNA.
Maize was domesticated from teosinte, a wild grass, by approximately 6300 years ago in Mexico. After initial domestication, early farmers continued to select for advantageous morphological and biochemical traits in this important crop. However, the timing and sequence of character selection are, thus far, known only for morphological features discernible in corn cobs. We have analyzed three genes involved in the control of plant architecture, storage protein synthesis, and starch production from archaeological maize samples from Mexico and the southwestern United States. The results reveal that the alleles typical of contemporary maize were present in Mexican maize by 4400 years ago. However, as recently as 2000 years ago, allelic selection at one of the genes may not yet have been complete.


Increased cellular triglyceride levels in human monocytic and rat smooth muscle cells after lovastatin.
Beta-hydroxy-beta-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors reduce plasma LDL cholesterol by upregulating hepatic LDL receptors. However, their effects on lipid metabolism in extrahepatic cells may also contribute to their therapeutic benefit. We examined the effects of lovastatin (LOV) on cellular lipid levels in the human monocytic Mono Mac 6sr and cultured rat smooth muscle cells. In both cell types, LOV produced a dose-dependent increase in cellular triglycerides. This increase was observed in cells grown in the absence of exogenous lipids in the culture medium, but was more pronounced after additions of oleic acid (50 to 200 microM) and VLDL (50 to 200 microg ml-1). In Mono Mac 6sr cells grown in medium containing 10% delipidated FCS for the last 16 h, the LOV-induced rise in triglyceride levels was completely reversed by 2 mM mevalonic acid and was associated with a decrease in cellular cholesterol. However, when cells were maintained in lipoprotein-replete medium, the LOV-induced rise in triglycerides did not correlate with cellular cholesterol. LOV also reduced cellular cholesterol esterification and increased the synthesis of fatty acids and their incorporation into triglycerides and phospholipids. Increased triglyceride levels were also seen in Mono Mac 6sr cells treated with the lanosterol demethylase inhibitor RS-21607 and the acylcoenzyme A:cholesterol acyltransferase inhibitor SaH 58035. Our findings suggest that the LOV-induced triglyceride accumulation involves changes in intracellular cholesterol pools regulating cellular fatty acid concentrations. Although decreased cholesterol levels in cells participating in plaque formation are beneficial, the impact of the herein described shift in intracellular neutral lipid metabolism on other cellular functions warrants further investigation.


Predictive value of neutrophil to lymphocyte ratio in patients with acute exacerbation of chronic obstructive pulmonary disease.
This study aimed to determine the predictive value of the neutrophil to lymphocyte ratio (NLR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). A retrospective study was conducted from March 2012 to May 2016 in Fuxing Hospital, Capital University of Medical Science. We collected 906 cases (525 males, 381 females, mean age 81.86±9.75 years) diagnosed with AECOPD. The NLR was calculated from their white blood cell (WBC), neutrophil (NEU), and lymphocyte (LYM) counts, which were obtained at laboratory examination. After treatment, 698 patients with AECOPD improved. The NLR was higher at admission (6.89±6.82) than after treatment (4.19±5.11) (P = 0.000). The area under the receiver operating characteristic curve (AUC) of the NLR for predicting the 28-day mortality rate was 0.737. Using 8.130 as the critical NLR value, the sensitivity was 60.5%, and the specificity was 74.8%. The AUC of the NLR for predicting the frequency of the need for invasive mechanical ventilation was 0.732. Using 10.345 as the critical NLR value, the sensitivity was 54.3%, and the specificity was 84.8%. The AUC of WBC, NEU and LYM for predicting 28-day mortality and the need for invasive mechanical ventilation in these patients were all less than 0.7. An increased NLR was an independent risk factor for 28-day mortality (OR = 1.067, 95% CI = 1.039 to 1.095, P = 0.000), intensive care unit occupancy (OR = 1.046, 95% CI = 1.023 to 1.068, P = 0.000), and the need for invasive mechanical ventilation (OR = 1.042, 95% CI = 1.019 to 1.066, P = 0.000). Compared with those patients without comorbidities, patients with renal dysfunction or upper gastrointestinal bleeding had an increased risk of death within 28 days (OR = 3.102, 95% CI = 1.525 to 6.312; OR = 4.598, 95% CI = 1.825 to 11.583, respectively), ICU admission (OR = 2.228, 95% CI = 1.286 to 3.860; OR = 3.103, 95% CI = 1.402 to 6.866, respectively), and the need for invasive mechanical ventilation (OR = 3.572, 95% CI = 1.822 to 7.000; OR = 4.279, 95% CI = 1.823 to 10.045, respectively). In patients with AECOPD, the accuracy of the NLR for predicting the 28-day mortality rate and frequency of the need for mechanical ventilation was significantly higher than the accuracy of WBC, NEU and LYM counts. AECOPD patients with an NLR≥8.130 had higher 28-day mortality rate, while those with an NLR ≥10.345 were more likely to need invasive mechanical ventilation.


A sparse Ising model with covariates.
There has been a lot of work fitting Ising models to multivariate binary data in order to understand the conditional dependency relationships between the variables. However, additional covariates are frequently recorded together with the binary data, and may influence the dependence relationships. Motivated by such a dataset on genomic instability collected from tumor samples of several types, we propose a sparse covariate dependent Ising model to study both the conditional dependency within the binary data and its relationship with the additional covariates. This results in subject-specific Ising models, where the subject's covariates influence the strength of association between the genes. As in all exploratory data analysis, interpretability of results is important, and we use ℓ1 penalties to induce sparsity in the fitted graphs and in the number of selected covariates. Two algorithms to fit the model are proposed and compared on a set of simulated data, and asymptotic results are established. The results on the tumor dataset and their biological significance are discussed in detail.


The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?
Some patients treated with ondansetron for postoperative nausea and vomiting do not respond to therapy. One possible mechanism for this failure is ultrarapid drug metabolism via the cytochrome P-450 system, specifically the enzyme 2D6 (CYP2D6). Ultrarapid metabolism is seen in patients with multiple functional copies (>/= 3) of the CYP2D6 allele. This study was designed to determine whether patients who were given prophylactic ondansetron and had multiple CYP2D6 alleles had an increased rate of postoperative nausea and vomiting. Two hundred fifty female patients undergoing standardized general anesthesia were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting. DNA was extracted from blood in all patients and was analyzed by using a gene-specific probe to determine the CYP2D6 gene copy number and genotyped by polymerase chain reaction amplification with a custom oligonucleotide microarray to determine the specific CYP2D6 genotypes. Eighty-eight patients experienced nausea, and 37 of those patients also had vomiting. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27%), 27 in 198 (14%), and 7 in 23 (30%), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8%), 5 in 30 (17%), 26 in 176 (15%), and 5 in 11 (45%), respectively (P < 0.01 vs. all other groups). There were no differences between groups in the incidence of nausea based on CYP2D6 copy number or genotype. Patients with three copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolism, or both have an increased incidence of ondansetron failure for the prevention of postoperative vomiting but not nausea.


Combined inhibition of PI3Kβ and PI3Kγ reduces fat mass by enhancing α-MSH-dependent sympathetic drive.
Obesity is defined as an abnormal increase in white adipose tissue and has become a major medical burden worldwide. Signals from the brain control not only appetite but also energy expenditure, both of which contribute to body weight. We showed that genetic or pharmacological inhibition of two phosphatidylinositol 3-kinases (PI3Kβ and PI3Kγ) in mice reduced fat mass by promoting increased energy expenditure. This effect was accompanied by stimulation of lipolysis and the acquisition of the energy-burning characteristics of brown adipocytes by white adipocytes, a process referred to as "browning." The browning of the white adipocytes involved increased norepinephrine release from the sympathetic nervous system. We found that PI3Kβ and PI3Kγ together promoted a negative feedback loop downstream of the melanocortin 4 receptor in the central nervous system, which controls appetite and energy expenditure in the periphery. Analysis of mice with drug-induced sympathetic denervation suggested that these kinases controlled the sympathetic drive in the brain. Administration of inhibitors of both PI3Kβ and PI3Kγ to mice by intracerebroventricular delivery induced a 10% reduction in fat mass as quickly as 10 days. These results suggest that combined inhibition of PI3Kβ and PI3Kγ might represent a promising treatment for obesity.


Oral zinc sulfate in the treatment of Behcet's disease: a double blind cross-over study.
This was a randomized, controlled, double-blind trial of zinc sulfate in the treatment of Behcet's disease. Patients with Behcet's disease were recruited in this study between November 2001 and February 2003. A clinical manifestations index (CMI) was calculated for each patient. Serum zinc was estimated in all patients both at the beginning and monthly throughout the trial. Serum zinc levels were estimated from 30 healthy normal subjects matched for age and sex as a control group. Patients were randomly allocated to receive either 100 mg zinc sulfate or identical placebo tablet three times daily in a double-blind manner. After 3 months of starting treatment, patients were crossed over, that is, patients on placebo received zinc sulfate and vice versa. Mean serum zinc level in Behcet's disease patients was statistically significantly lower than mean serum zinc levels in healthy the control. In group A (started with zinc sulfate), the mean CMI started to decline directly after the first month of therapy with zinc sulfate to significantly lower levels. After shifting to placebo treatment in the fourth month, the mean of CMI started to rise again gradually but remained significantly lower than levels before therapy for the fourth and fifth months. In group B (started with placebo), the mean of CMI remained high for the first 3 months. After crossing over to zinc sulfate in the fourth month, the mean of CMI started to decrease after the fourth month. An inverse correlation between CMI and serum zinc level was found. No side-effects were seen in either group. In conclusion, zinc sulfate was found to be a good option in the treatment of Behcet's disease.


Increased Dose of Inhaled Corticosteroid versus Add-On Long-acting β-Agonist for Step-Up Therapy in Asthma.
Guidelines advocate adding long-acting β-agonist (LABA) to inhaled corticosteroid as the preferred step-up therapy to increasing inhaled corticosteroid dose for patients with uncontrolled asthma on inhaled corticosteroid monotherapy. However, less than 5% of patients with asthma qualify for the randomized controlled trials on which guidelines are based. Thus, real-world data are needed to complement the results of randomized trials with narrow entry criteria. To compare the effectiveness of stepping up asthma therapy with an increased dose of various types of inhaled corticosteroid as compared with add-on LABA. We performed a historical matched cohort study using large primary care databases to compare asthma step-up therapy with small- and standard size-particle inhaled corticosteroid versus added LABA for patients 12-80 years old. As outcomes, we examined a composite of asthma control and rates of severe exacerbations. The odds of asthma control and rates of severe exacerbations over one outcome year were comparable with increased inhaled corticosteroid dose versus added LABA. The adjusted odds ratios (95% confidence interval) for achieving asthma control with increased inhaled corticosteroid dose versus inhaled corticosteroid/LABA were 0.99 (0.88-1.12) for small-particle inhaled corticosteroid (n = 3,036 per cohort) and 0.85 (0.67-1.07) for standard size-particle inhaled corticosteroid (n = 809 per cohort). The adjusted rate ratios (95% confidence interval) for severe exacerbations, compared with inhaled corticosteroid/LABA combination inhaler, were 1.04 (0.91-1.20) and 1.18 (0.92-1.54), respectively. The results were not affected by smoking status. When applied to a broad primary care population, antiinflammatory therapy using increased doses of small- or standard size-particle inhaled corticosteroid is as effective as adding LABA, as measured by outcomes important to both patients and providers. Real-world populations and outcomes need to be taken into consideration when formulating treatment recommendations.


Iatrogenic retinal breaks in ultrahigh-speed 25-gauge vitrectomy: a prospective study of elective cases.
To evaluate the incidence of intraoperative retinal breaks in the ultrahigh-speed (UHS) 25-gauge vitrectomy system in elective vitreous-retina surgery cases. A prospective series of 1676 eyes of 1306 consecutive patients. All eyes underwent an UHS 25-gauge transconjunctival sutureless pars plana vitrectomy for elective cases such as idiopathic epiretinal membrane (586 cases), floaters (153), macular hole (385), vitreous macular traction syndrome (119), dropped nucleus or intraocular lens (84) and vitreous bleeding (82). Patients were followed up for a minimum of 6 months. There were 1409 eyes involved in this study. Iatrogenic retinal breaks were found in 25 eyes (1.8%) during surgery. The majority were detected in cases where posterior vitreous detachment was induced during surgery (21 eyes; 2.8% of the patients), and in only four eyes (0.6%) with an already detached vitreous. In nine cases, rhegmatogenous retinal detachment developed during the follow-up. Patients who showed intraoperative retinal breaks were not in this group. Other complications during the follow-up included two cases of vitreous haemorrhage (0.1%), two cases of dislocated intraocular lens (0.1%), and 23 eyes with hypotony without any further complications. UHS 25-gauge transconjunctival sutureless vitrectomy is a safe procedure for treatment of elective vitreous-retina cases. The risk of developing iatrogenic breaks seems to be correlated with adhesion of the posterior vitreous hyaloid. Other complications, such as rhegmatogenous retinal detachment or hypotony, were similar to previous reports. No correlation was found between iatrogenic retina breaks and other complications.


Self-reported data from patients with bipolar disorder: frequency of brief depression.
Patients with bipolar disorder often report depressive symptoms that do not meet the DSM-IV criteria for an episode. Using daily self-reported mood ratings, we studied how changing the length requirement to that typical of recurrent brief depression (2-4 days) would impact the number of depressed episodes. 203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software on a home computer (30,348 total days; mean 150 days). Episodes of depression and days of depression outside of episodes were determined. Symptom intensity (mild versus moderate or severe) was investigated within and outside of depressive episodes. Decreasing the minimum duration criterion for an episode of depression to 2 days increased the number of patients with a depressed episode two and a half times (52 to 131), and quadrupled both the number of depressed episodes per patient (0.62 to 2.88) and the number of depressed episodes for all patients (125 to 584). With a 2-day episode length, 34% of days of depression remained outside an episode. The ratio of days with severe symptoms within episodes remained consistent (about 25%) in spite of decreasing the episode length to 2 days. Considering only days with severe symptoms, about 25% remained outside of episodes even with a 2-day length. None of the results distinguished bipolar I from bipolar II disorder. Self-reported data, computer access required, relatively short study length, no control group. Brief depressive episodes and single days of depression outside of episodes occur frequently in both bipolar I and bipolar II disorder. Moderate or severe symptoms occur during brief episodes at a ratio similar to that for episodes that meet the DSM-IV criteria.


Science in the Making: Right Hand, Left Hand. I: A BBC television programme broadcast in 1953.
In August 1953, the BBC broadcast a television science programme entitled Science in the Making: Right Hand, Left Hand. The programme was broadcast live, being presented by Dr Jacob Bronowski in collaboration with Dr Kenneth Smith, and produced by George Noordhof. It not only presented a popular account of current ideas about right- and left-handedness, by using a group of celebrities (and a chimpanzee) in the studio, but also asked viewers to complete a brief questionnaire on handedness, which was printed in the Radio Times. Recently 6,336 of the returned questionnaires, which were said to have been analysed by Sir Cyril Burt and a colleague, were found in the archive of the Psychology Department of University College London. The present paper describes what we have discovered about the programme from various sources, including the producer and the son of Dr Kenneth Smith, and also presents basic descriptions of the postcards and the response to the programme. In two subsequent papers we will describe our analysis of the data from the postcards, which represents an unusual, large-scale survey of handedness in the mid-twentieth century.


Understanding the mechanisms of trace organic contaminant removal by high retention membrane bioreactors: a critical review.
High retention membrane bioreactors (HR-MBR) combine a high retention membrane separation process such as membrane distillation, forward osmosis, or nanofiltration with a conventional activated sludge (CAS) process. Depending on the physicochemical properties of the trace organic contaminants (TrOCs) as well as the selected high retention membrane process, HR-MBR can achieve effective removal (80-99%) of a broad spectrum of TrOCs. An in-depth assessment of the available literature on HR-MBR performance suggests that compared to CAS and conventional MBRs (using micro- or ultra-filtration membrane), aqueous phase removal of TrOCs in HR-MBR is significantly better. Conceptually, longer retention time may significantly improve TrOC biodegradation, but there are insufficient data in the literature to evaluate the extent of TrOC biodegradation improvement by HR-MBR. The accumulation of hardly biodegradable TrOCs within the bioreactor of an HR-MBR system may complicate further treatment and beneficial reuse of sludge. In addition to TrOCs, accumulation of salts gradually increases the salinity in bioreactor and can adversely affect microbial activities. Strategies to mitigate these limitations are discussed. A qualitative framework is proposed to predict the contribution of the different key mechanisms of TrOC removal (i.e., membrane retention, biodegradation, and sorption) in HR-MBR.


Feature- versus rule-based generalization in rats, pigeons and humans.
Humans can spontaneously create rules that allow them to efficiently generalize what they have learned to novel situations. An enduring question is whether rule-based generalization is uniquely human or whether other animals can also abstract rules and apply them to novel situations. In recent years, there have been a number of high-profile claims that animals such as rats can learn rules. Most of those claims are quite weak because it is possible to demonstrate that simple associative systems (which do not learn rules) can account for the behavior in those tasks. Using a procedure that allows us to clearly distinguish feature-based from rule-based generalization (the Shanks-Darby procedure), we demonstrate that adult humans show rule-based generalization in this task, while generalization in rats and pigeons was based on featural overlap between stimuli. In brief, when learning that a stimulus made of two components ("AB") predicts a different outcome than its elements ("A" and "B"), people spontaneously abstract an opposites rule and apply it to new stimuli (e.g., knowing that "C" and "D" predict one outcome, they will predict that "CD" predicts the opposite outcome). Rats and pigeons show the reverse behavior-they generalize what they have learned, but on the basis of similarity (e.g., "CD" is similar to "C" and "D", so the same outcome is predicted for the compound stimulus as for the components). Genuinely rule-based behavior is observed in humans, but not in rats and pigeons, in the current procedure.


Disjunctive Normal Shape and Appearance Priors with Applications to Image Segmentation.
The use of appearance and shape priors in image segmentation is known to improve accuracy; however, existing techniques have several drawbacks. Active shape and appearance models require landmark points and assume unimodal shape and appearance distributions. Level set based shape priors are limited to global shape similarity. In this paper, we present a novel shape and appearance priors for image segmentation based on an implicit parametric shape representation called disjunctive normal shape model (DNSM). DNSM is formed by disjunction of conjunctions of half-spaces defined by discriminants. We learn shape and appearance statistics at varying spatial scales using nonparametric density estimation. Our method can generate a rich set of shape variations by locally combining training shapes. Additionally, by studying the intensity and texture statistics around each discriminant of our shape model, we construct a local appearance probability map. Experiments carried out on both medical and natural image datasets show the potential of the proposed method.


PPARγ as a molecular target of EPA anti-inflammatory activity during TNF-α-impaired skeletal muscle cell differentiation.
Activated skeletal muscle satellite cells facilitate muscle repair or growth through proliferation, differentiation and fusion into new or existing myotubes. Elevated levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) impair this process and are documented to have significant roles in muscle pathology. Recent evidence shows that the ω-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) can block TNF-mediated suppression of progenitor cell differentiation, but the nature of this activity and its significance for local regulation of inflammation are not known. In the current study, we examined differentiation of the C2C12 myoblast line during treatment with TNF-α and EPA and measured the expression, activation and inhibition of peroxisome proliferator-activated receptor-γ (PPARγ), as several studies have shown its involvement in mediating EPA activity and the inhibition of nuclear factor (NF)-κB inflammatory gene activation. We found that TNF-α treatment increased NF-κB activity and reduced expression and activation of PPARγ, resulting in impaired myotube formation. EPA treatment attenuated these effects of TNF-α and was associated with up-regulation of PPARγ. Furthermore, EPA inhibited TNF-α-mediated transcription and secretion of interleukin (IL)-6, a key target gene of TNF-mediated NF-κB transcriptional activity. Pretreatment with a PPARγ selective antagonist inhibited some of the actions of EPA but was only partially effective in reversing inhibition of IL-6 production. These results show that EPA activity was associated with altered expression and activation of PPARγ, but exerted through both PPARγ-dependent and PPARγ-independent pathways leading to suppression of the proinflammatory cellular microenvironment.


Changes in Choroidal Thickness follow the RNFL Changes in Leber's Hereditary Optic Neuropathy.
Leber's hereditary optic neuropathy (LHON) is typically characterized by vascular alterations in the acute phase. The aim of this study was to evaluate choroidal changes occurring in asymptomatic, acute and chronic stages of LHON. We enrolled 49 patients with LHON, 19 with Dominant Optic Atrophy (DOA) and 22 healthy controls. Spectral Domain-Optical Coherence Tomography (SD-OCT) scans of macular and peripapillary regions were performed in all subjects, to evaluate macular and peripapillary choroidal thickness, and retinal nerve fiber layer (RNFL) thicknes. Macular and peripapillary choroidal thicknesses were significantly increased in the acute LHON stage. On the contrary, macular choroidal thickness was significantly reduced in the chronic stage. Furthermore, peripapillary choroidal thickness was decreased in chronic LHON and in DOA. Both RNFL and choroid had the same trend (increased thickness, followed by thinning), but RNFL changes preceded those affecting the choroid. In conclusion, our study quantitatively demonstrated the involvement of the choroid in LHON pathology. The increase in choroidal thickness is a feature of the LHON acute stage, which follows the thickening of RNFL. Conversely, thinning of the choroid is the common outcome in chronic LHON and in DOA.


Word Learning by Preschool-Age Children With Developmental Language Disorder: Impaired Encoding and Robust Consolidation During Slow Mapping.
Purpose Learning novel words, including the specific phonemes that make up word forms, is a struggle for many individuals with developmental language disorder (DLD). Building robust representations of words includes encoding during periods of input and consolidation between periods of input. The primary purpose of the current study is to determine differences between children with DLD and with typical development (TD) in the encoding and consolidation of word forms during the slow mapping process. Method Preschool-age children (DLD = 9, TD = 9) were trained on nine form-referent pairs across multiple consecutive training days. Children's ability to name referents at the end of training days indicated their ability to encode forms. Children's ability to name referents at the beginning of training days after a period of overnight sleep indicated their ability to consolidate forms. Word learning was assessed 1 month after training to determine long-term retention of forms. Results Throughout training, children with DLD produced fewer forms correctly and produced forms with less phonological precision than children with TD. Thus, children with DLD demonstrated impaired encoding. However, children with and without DLD demonstrated a similar ability to consolidate forms between training days and to retain forms across a 1-month delay. Conclusions Difficulties with word form learning are primarily driven by deficits in encoding for children with DLD. Clinicians and educators can support encoding by providing children with adequate exposures to target words via robust training that occurs across multiple sessions. Supplemental Material https://doi.org/10.23641/asha.16746454.


Gene expression markers of tendon fibroblasts in normal and diseased tissue compared to monolayer and three dimensional culture systems.
There is a paucity of data regarding molecular markers that identify the phenotype of the tendon cell. This study aims to quantify gene expression markers that distinguish between tendon fibroblasts and other mesenchymal cells which may be used to investigate tenogenesis. Expression levels for 12 genes representative of musculoskeletal tissues, including the proposed tendon progenitor marker scleraxis, relative to validated reference genes, were evaluated in matched samples of equine tendon (harvested from the superficial digital flexor tendon), cartilage and bone using quantitative PCR (qPCR). Expression levels of genes associated with tendon phenotype were then evaluated in healthy, including developmental, and diseased equine tendon tissue and in tendon fibroblasts maintained in both monolayer culture and in three dimensional (3D) collagen gels. Significantly increased expression of scleraxis was found in tendon compared with bone (P = 0.002) but not compared to cartilage. High levels of COL1A2 and scleraxis and low levels of tenascin-C were found to be most representative of adult tensional tendon phenotype. While, relative expression of scleraxis in developing mid-gestational tendon or in acute or chronically diseased tendon did not differ significantly from normal adult tendon, tenascin-C message was significantly upregulated in acutely injured equine tendon (P = 0.001). Relative scleraxis gene expression levels in tendon cell monolayer and 3D cultures were significantly lower than in normal adult tendon (P = 0.002, P = 0.02 respectively). The findings of this study indicate that high expression of both COL1A2 and scleraxis, and low expression of tenascin-C is representative of a tensional tendon phenotype. The in vitro culture methods used in these experiments however, may not recapitulate the phenotype of normal tensional tendon fibroblasts in tissues as evidenced by gene expression.


NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs.
Natural killer (NK) cells are sentinel components of the innate response to pathogens, but the cell types, pathogen recognition receptors, and cytokines required for their activation in vivo are poorly defined. Here, we investigated the role of plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs), Toll-like receptors (TLRs), and of NK cell stimulatory cytokines for the induction of an NK cell response to the protozoan parasite Leishmania infantum. In vitro, pDCs did not endocytose Leishmania promastigotes but nevertheless released interferon (IFN)-alpha/beta and interleukin (IL)-12 in a TLR9-dependent manner. mDCs rapidly internalized Leishmania and, in the presence of TLR9, produced IL-12, but not IFN-alpha/beta. Depletion of pDCs did not impair the activation of NK cells in L. infantum-infected mice. In contrast, L. infantum-induced NK cell cytotoxicity and IFN-gamma production were abolished in mDC-depleted mice. The same phenotype was observed in TLR9(-/-) mice, which lacked IL-12 expression by mDCs, and in IL-12(-/-) mice, whereas IFN-alpha/beta receptor(-/-) mice showed only a minor reduction of NK cell IFN-gamma expression. This study provides the first direct evidence that mDCs are essential for eliciting NK cell cytotoxicity and IFN-gamma release in vivo and demonstrates that TLR9, mDCs, and IL-12 are functionally linked to the activation of NK cells in visceral leishmaniasis.


Unveiling the species-rank abundance distribution by generalizing the Good-Turing sample coverage theory.
Based on a sample of individuals, we focus on inferring the vector of species relative abundance of an entire assemblage and propose a novel estimator of the complete species-rank abundance distribution (RAD). Nearly all previous estimators of the RAD use the conventional "plug-in" estimator Pi (sample relative abundance) of the true relative abundance pi of species i. Because most biodiversity samples are incomplete, the plug-in estimators are applied only to the subset of species that are detected in the sample. Using the concept of sample coverage and its generalization, we propose a new statistical framework to estimate the complete RAD by separately adjusting the sample relative abundances for the set of species detected in the sample and estimating the relative abundances for the set of species undetected in the sample but inferred to be present in the assemblage. We first show that P, is a positively biased estimator of pi for species detected in the sample, and that the degree of bias increases with increasing relative rarity of each species. We next derive a method to adjust the sample relative abundance to reduce the positive bias inherent in j. The adjustment method provides a nonparametric resolution to the longstanding challenge of characterizing the relationship between the true relative abundance in the entire assemblage and the observed relative abundance in a sample. Finally, we propose a method to estimate the true relative abundances of the undetected species based on a lower bound of the number of undetected species. We then combine the adjusted RAD for the detected species and the estimated RAD for the undetected species to obtain the complete RAD estimator. Simulation results show that the proposed RAD curve can unveil the true RAD and is more accurate than the empirical RAD. We also extend our method to incidence data. Our formulas and estimators are illustrated using empirical data sets from surveys of forest spiders (for abundance data) and soil ciliates (for incidence data). The proposed RAD estimator is also applicable to estimating various diversity measures and should be widely useful to analyses of biodiversity and community structure.


HLA-A*02-B*46 haplotype: an adverse prognostic factor in Han patients with nasopharyngeal carcinoma.
Epidemiological studies have shown that human leukocyte antigen (HLA) allelic polymorphisms are closely correlated to susceptibility to nasopharyngeal carcinoma (NPC), and in a previous study, we showed that HLA-B*46 and HLA-A*02-B*46 haplotypes were strongly associated with NPC susceptibility. In this retrospective study, we investigated the phenotype of the HLA-A and HLA-B alleles and haplotypes and correlated these data to the clinical and pathological parameters of NPC to understand the role of HLA alleles and haplotypes in NPC prognosis. The cohort comprised 117 NPC patients from a Han population in Xinjiang. The local recurrence-free survival (LRFS), distant metastasis- free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were analyzed. The 5-year DMFS of the HLA-A*02-B*46 haplotype carriers and non-carriers was 66.4% and 90.3%, respectively. In addition, age was found to be a prognostic factor for LRFS, DFS, and OS (P=0.032, 0.040, and 0.013, respectively). We found that the HLA-A*02-B*46 haplotype might be a prognostic marker in addition to the traditional TNM staging in patients with NPC.


[Association between fasting blood glucose levels and perioperative morbimortality: retrospective study in surgical elderly patients.].
The relationship between altered blood glucose levels and perioperative complications in elderly patients undergoing surgeries are not known. The objective of this study was to evaluate the association between fasting blood glucose levels and perioperative morbimortality in elderly surgical patients. Medical records of patients older than 60 years undergoing several surgical procedures during a 6-month period were analyzed and divided, according to fasting blood glucose levels, in three groups: < 100 mg.dL-1, between 100 and 125 mg.dL-1, and > 126 mg.dL-1. Age, physical status (ASA), history of diabetes mellitus (DM), and treatment and perioperative surgery-specific cardiologic risk were analyzed. Using univariate analysis and a model of multivariate logistic regression, the relationship among the outcome (frequency of postoperative complications [POC] and death) and the following variables: fasting blood glucose, history of DM, physical status (ASA), and cardiac risk, was evaluated. A statistical association was demonstrated only among the three groups and physical status and history of DM. All parameters studied demonstrated a statistical relationship regarding the higher frequency of POC and death, except for the parameter history of DM, which did not demonstrate any relationship with deaths. In the multivariate logistic regression model, there was an association between cardiac risk and blood glucose levels with POC, while only physical status and cardiac risk demonstrated a statistical association with death. This retrospective study demonstrated a significant association among blood glucose levels above 100 mg.dL-1 and postoperative morbimortality in the elderly.


Review of the epidemiologic literature on EMF and Health.
Exposures to extremely low-frequency electric and magnetic fields (EMF) emanating from the generation, transmission, and use of electricity are a ubiquitous part of modern life. Concern about potential adverse health effects was initially brought to prominence by an epidemiologic report two decades ago from Denver on childhood cancer. We reviewed the now voluminous epidemiologic literature on EMF and risks of chronic disease and conclude the following: a) The quality of epidemiologic studies on this topic has improved over time and several of the recent studies on childhood leukemia and on cancer associated with occupational exposure are close to the limit of what can realistically be achieved in terms of size of study and methodological rigor. b) Exposure assessment is a particular difficulty of EMF epidemiology, in several respects: i) The exposure is imperceptible, ubiquitous, has multiple sources, and can vary greatly over time and short distances. ii) The exposure period of relevance is before the date at which measurements can realistically be obtained and of unknown duration and induction period. iii) The appropriate exposure metric is not known and there are no biological data from which to impute it. c) In the absence of experimental evidence and given the methodological uncertainties in the epidemiologic literature, there is no chronic disease for which an etiological relation to EMF can be regarded as established. d) There has been a large body of high quality data for childhood cancer, and also for adult leukemia and brain tumor in relation to occupational exposure. Among all the outcomes evaluated in epidemiologic studies of EMF, childhood leukemia in relation to postnatal exposures above 0.4 microT is the one for which there is most evidence of an association. The relative risk has been estimated at 2.0 (95% confidence limit: 1.27-3.13) in a large pooled analysis. This is unlikely to be due to chance but, may be, in part, due to bias. This is difficult to interpret in the absence of a known mechanism or reproducible experimental support. In the large pooled analysis only 0.8% of all children were exposed above 0.4 microT. Further studies need to be designed to test specific hypotheses such as aspects of selection bias or exposure. On the basis of epidemiologic findings, evidence shows an association of amyotrophic lateral sclerosis with occupational EMF exposure although confounding is a potential explanation. Breast cancer, cardiovascular disease, and suicide and depression remain unresolved.


Comparison of three in vitro implant leakage testing methods.
To assess the accuracy and sensitivity in detecting implants leakage with a gas-enhanced permeation test (GEPT) and to compare with a molecular- and a bacterial-based leakage tests. Three implants systems were tested (n = 20 per group): Nobel Biocare (NB), Astra Tech (AT) and Biomet 3i (B3i). Implants were mounted in PVC disks and were first tested for gas pressure change and infiltrated saline volume over 40 min. The same implants were then subjected to a molecular leakage evaluation using fluorescent Dextran for 28 days. After cleaning and sterilization, bacterial permeation (E. faecalis) was evaluated by selective media turbidity for another 28 days. Slopes in the pressure change and the perfused saline rate were used as a measure of leakage in the GEPT model and the times of positive events, that is, color change, after molecular and bacterial tests were recorded. Data were analyzed using Kolmogorov-Smirnov/Shapiro-Wilk, Kruskal-Wallis H and Spearman's Rho tests (P < 0.05). The gas and saline (ml) leakage values accounted for 0.85 ± 0.71 and 0.56 ± 0.50 ml (AT), 0.23 ± 0.030 and 0.12 ± 0.20 ml (NB) and 0.01 ± 0.01 and 0 ± 0 ml (B3i), respectively, and were significantly different from each other (P < 0.001). Slope in the pressure change over time showed a significant positive correlation with the collected saline solution (r = 0.91; P < 0.001). Molecular and bacterial leakage was positive at the same implants, which also showed increased leakage values in the GEPT setup. The development of positive events in the timeline of the bacterial leakage evaluation corresponded well to the GEPT leakage model. The GEPT proved to be a reliable method to quantify leakage. The B3i showed the best sealing among the tested systems.


A double-blind, placebo-controlled trial of topiramate for pathological gambling.
Pathological gambling (PG) is an impulse control disorder characterized by recurrent gambling thoughts and behaviours that impair social functioning. Earlier studies suggested that topiramate may be effective in treating some impulse control disorders. We conducted the first randomized, controlled trial of topiramate in PG. PG patients were randomized to topiramate (N = 20) or placebo (N = 22) in this 14-week, double-blind, placebo-controlled, parallel-group trial. The primary outcome measure was change in the obsessions subscale of the Yale-Brown Obsessive-Compulsive Scale Modified for Pathological Gambling. Mixed regression models (time [weeks] × treatment) revealed no significant treatment effect of topiramate on the primary or secondary outcome measures. The most statistically robust findings involved reducing the Barratt Impulsiveness Scale (BIS) total score and Motor and Non-Planning subscale scores, for which topiramate outperformed placebo at merely a trend level (P < 0.1). The observed trend in BIS score reductions may warrant further investigation to study whether topiramate reduces clinically important impulsivity in PG. Treatment studies with larger samples and less stringent exclusion criteria are needed to produce results that can be generalized to pathological gamblers in the community.


Evaluation of the periodontal status of palatally impacted maxillary canines after exposure using a modified window technique.
To evaluate the periodontal status of surgically exposed maxillary canines after their alignment. Twenty consecutive patients with one palatally impacted maxillary canine and one fully erupted synergist were selected. The impacted canines were surgically exposed with a modified window technique, an attachment was bonded, and the teeth were extruded and aligned. Six months after therapy, the periodontal status of both canines was evaluated by registering the following parameters: (1) keratinized gingiva level, (2) attached gingiva level, (3) sulcus probing depth, (4) length of clinical crown, (5) quality of marginal tissue, (6) bleeding on probing, and (7) height of alveolar bone. The data were analyzed with the Mann-Whitney test. There was no significant difference between the periodontal status of the two canine groups concerning the keratinized gingival level, the attached gingival level, the sulcus probing depth, and the length of the clinical crown. The quality of marginal tissue and bleeding on probing were acceptable. However, the level of alveolar bone was significantly lower in the surgically exposed group. The periodontal health of impacted maxillary canines that were exposed using a modified window technique and subsequently orthodontically aligned is acceptable. The only concern is a somewhat reduced alveolar bone level.


Modeling of intraluminal heating of biological tissue: implications for treatment of benign prostatic hyperplasia.
A computer model for predicting the thermal response of a biological tissue to different intraluminal heating modalities is presented. A practical application of the model is to calculate the temperature distributions during thermal coagulation of prostate by contact heating and radiative heating. The model uses a two-dimensional axisymmetric diffusion approximation method to calculate the light distribution during radiative heating. The traditional Pennes' bio-heat equation is used to calculate the temperatures in the presence of blood flow. An implicit finite difference scheme with nonuniform grid spacings is used to solve the diffusion equation for light distribution and the bio-heat equation. Model results indicate that the radiative heating of prostate by Nd:YAG (1064 mm) and diode (810 mm) lasers can be a more effective and efficient means of coagulating a large volume of prostate, as compared to contact heating of the tissue. Blood perfusion is shown to provide a considerable heat sink as the laser exposure time is increased. Surface cooling by irrigation during the laser irradiation of tissue is shown to be an effective method for delaying tissue explosion and obtaining a large volume of coagulated tissue. The model also shows that the volume of the coagulated tissue is appreciably altered by a change in the rate of energy deposition.


Chemokine (C-C motif) Ligand 2 is a potential biomarker of inflammation & physical fitness in obese children: a cross-sectional study.
Obesity is a global epidemic that is impacting children around the world. Obesity is a chronic inflammatory state with enhanced production of multiple cytokines and chemokines. Chemokine (C-C motif) Ligand 2 (CCL2) is produced by immune and metabolic cells and attracts immune cells into liver, muscle and adipose tissue, resulting in initiation and propagation of the inflammatory response in obesity. How obesity and fitness affect the production of this chemokine in children is unknown.This study tested the hypotheses that CCL2 levels are higher in obese children when compared to lean controls, and that fitness modulates CCL2 levels allowing its use as a biomarker of fitness. This was a cross sectional case-control study conducted in a Pediatric Tertiary care center in Hamilton, Ontario, Canada. Controls were recruited from the community. This study recruited overweight/obese children (BMI ≥ 85th percentile, n = 18, 9 female, mean age 14.0 ± 2.6 years) and lean controls (BMI < 85th percentile, n = 18, 8 female, mean age 14.0 ± 2.6 years) matched for age, sex and biological maturation.Aerobic fitness test was done using a cycle ergometer performing the McMaster All-Out Progressive Continuous Cycling test to exhaustion to determine peak oxygen uptake. Fasting CCL2 samples were taken prior to test. Categorical variables including subject categorization into different aerobic fitness levels in overweight/obese and lean children was reported based on the median split in each group. Obese participants had significantly higher CCL2 levels when compared to lean group (150.4 ± 61.85 pg/ml versus 112.7 ± 38 pg/ml, p-value 0.034).To establish if CCL2 is a biomarker of fitness, we divided the groups based on their fitness levels. There was a main effect for group (F (3,32) = 3.2, p = 0.036). Obese high fitness group were similar to lean unfit and fit participants. Post-hoc analysis revealed that the overweight/obese low fitness group had significantly higher level of CCL2 compared to the lean low fitness group when adjusted to age, sex and maturity offset (F (3,29) = 3.1, p = 0.04). CCL2 serves a dual role as a potential biomarker of inflammation and fitness in obese children.


Antitumor Effects of Freeze-Dried Robusta Coffee (Coffea canephora) Extracts on Breast Cancer Cell Lines.
Coffee consumption is believed to have chemopreventive and chemotherapeutic effects and to contribute to preventing the development and progression of cancer. However, there is still controversy around these claims. As indicated in our previous works, diet can influence the risk of breast cancer. Intake of coffee is hypothesized to reduce this risk, but current scientific evidence is not conclusive. This work is aimed at studying the effects of Robusta coffee bean extract on cell viability, proliferation, and apoptosis of different human cancers, especially breast cancer cell lines. To this end, cell viability was evaluated by Alamar Blue in 2D and 3D models, the cell cycle by PI, apoptosis by annexin V, mitochondrial morphology, and functionality by mitoTracker, and colony formation capacity by the clonogenic assay. Green and dark coffee extract significantly reduced viability in human breast, colorectal, brain, and bone cancer cells. Coffee anticancer activity was clearly evidenced in MDA-MB-231 (ER-) and MCF-7 (ER+) breast cancer cells but not in the normal breast cell line. In addition, coffee extract induces an increase S phase and a decrease G2/M population in breast cancer cells, affected the mitochondrial morphology, and triggered apoptosis. MDA-MB-231 breast cancer cells lost their clonogenic capacity after treatment. The antitumor activity was demonstrated in both 2D and 3D culture cell models.


Collision effects of wind-power generators and other obstacles on birds.
There is extensive literature on avian mortality due to collision with man-made structures, including wind turbines, communication masts, tall buildings and windows, power lines, and fences. Many studies describe the consequences of bird-strike rather than address the causes, and there is little data based on long-term, standardized, and systematic assessments. Despite these limitations, it is apparent that bird-strike is a significant cause of mortality. It is therefore important to understand the effects of this mortality on bird populations. The factors which determine avian collision risk are described, including location, structural attributes, such as height and the use of lighting, weather conditions, and bird morphology and behavior. The results of incidental and more systematic observations of bird-strike due to a range of structures are presented and the implications of collision mortality for bird populations, particularly those of scarce and threatened species susceptible to collisions, are discussed. Existing measures for reducing collision mortality are described, both generally and specifically for each type of structure. It is concluded that, in some circumstances, collision mortality can adversely affect bird populations, and that greater effort is needed to derive accurate estimates of mortality levels locally, regionally, and nationally to better assess impacts on avian populations. Priority areas for future work are suggested, including further development of remote technology to monitor collisions, research into the causes of bird-strike, and the design of new, effective mitigation measures.


Highly transparent and conductive films of densely aligned ultrathin Au nanowire monolayers.
The combination of low electrical resistance and high optical transparency in a single material is very uncommon. Developing these systems is a scientific challenge and a technological need, to replace ITO in flexible electronic components and other highly demanding applications. Here we report a facile method to prepare single layers of densely aligned ultrathin Au-nanowires, homogeneous over cm(2) areas. The as-deposited films show an electrical/optical performance competitive with ITO and graphene-based electrodes. Moreover, the Au-films show a good stability under ambient conditions, and the large aspect ratio of the ultrathin nanowires makes them perfect for deposition in flexible substrates.


Computational modeling of the catalytic mechanism of hydroxymethylbilane synthase.
Hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthesis pathway, catalyzes the formation of 1-hydroxymethylbilane (HMB) by a stepwise polymerization of four molecules of porphobilinogen (PBG) using the dipyrromethane (DPM) cofactor. The mechanism by which HMBS polymerizes four units of PBG has not been elucidated to date. In vitro and in silico studies on HMBS have suggested certain residues with catalytic importance, but their specific role in the catalysis is unclear. To understand the catalytic mechanism of HMBS, quantum mechanical (QM) calculations were performed on model systems obtained from the active site of the human HMBS enzyme. The addition of one molecule of PBG to the DPM cofactor is carried out in four steps: (1) protonation of the substrate, PBG; (2) deamination of PBG; (3) electrophilic addition of the deaminated substrate to the terminal pyrrole ring of the enzyme-bound DPM cofactor and (4) deprotonation of the carbon atom at the α-position of the second ring of DPM. Based on the energy profiles from the QM calculations on cluster models, R26 is proposed to be the best suitable proton donor to the PBG moiety, which aids in the deamination of the substrate. During the electrophilic addition step, the intermediate formed is stabilized by the carboxylate side chain of the D99 residue. In the final deprotonation step, an extra proton from the second ring of DPM is transferred to R26 via the carboxylate side chain of D99, thus completing one cycle of the catalytic mechanism. The residues in the cluster model seem to play an important role in obtaining accurate energy barriers. All the stationary points along the reaction pathway have been characterized using QM calculations. The rate limiting step for the complete mechanism is found to be the deamination of the PBG moiety. The results of this study provide a detailed understanding of the catalytic mechanism and would help design future studies aimed at modulating the activity of HMBS.


Inhibition of phosphatidylinositol 3-kinase activity blocks depolarization- and insulin-like growth factor I-mediated survival of cerebellar granule cells.
Depolarizing concentrations of potassium promote the survival of many neuronal cell types including cerebellar granule cells. To begin to understand the intracellular mediators of neuronal survival, we have tested whether the survival-promoting effect of potassium depolarization on cerebellar granule cells is dependent on either mitogen-activated protein (MAP) kinase or phosphatidylinositol 3-kinase (PI-3-K) activity. In 7-day cerebellar granule cell cultures, potassium depolarization activated both MAP kinase and PI-3-K. Preventing the activation of MAP kinase with the MEK1 inhibitor PD98059 did not affect potassium saving. In contrast, the survival-promoting effect of 25 mM potassium was negated by the addition of 30 microM LY 294002 or 1 microM wortmannin, two distinct inhibitors of PI-3-K. The cell death induced by PI-3-K inhibition was indistinguishable from the cell death caused by potassium deprivation; LY 294002-induced death included nuclear condensation, was blocked by cycloheximide, and had the same time course as potassium deprivation-induced cell death. Cerebellar granule cells can also be maintained in serum-free medium containing either 100 ng/ml insulin-like growth factor I (IGF-I) or 800 microM cAMP. PI-3-K inhibition completely blocked the survival-promoting activity of IGF-I, but had no effect on cAMP-mediated survival. These data indicate that the survival-promoting effects of depolarization and IGF-I, but not cAMP, require PI-3-K activity.


Selective attention and multisensory integration: multiple phases of effects on the evoked brain activity.
We used event-related potentials (ERPs) to evaluate the role of attention in the integration of visual and auditory features of multisensory objects. This was done by contrasting the ERPs to multisensory stimuli (AV) to the sum of the ERPs to the corresponding auditory-only (A) and visual-only (V) stimuli [i.e., AV vs. (A + V)]. V, A, and VA stimuli were presented in random order to the left and right hemispaces. Subjects attended to a designated side to detect infrequent target stimuli in either modality there. The focus of this report is on the ERPs to the standard (i.e., nontarget) stimuli. We used rapid variable stimulus onset asynchronies (350-650 msec) to mitigate anticipatory activity and included "no-stim" trials to estimate and remove ERP overlap from residual anticipatory processes and from adjacent stimuli in the sequence. Spatial attention effects on the processing of the unisensory stimuli consisted of a modulation of visual P1 and N1 components (at 90-130 msec and 160-200 msec, respectively) and of the auditory N1 and processing negativity (100-200 msec). Attended versus unattended multisensory ERPs elicited a combination of these effects. Multisensory integration effects consisted of an initial frontal positivity around 100 msec that was larger for attended stimuli. This was followed by three phases of centro-medially distributed effects of integration and/or attention beginning at around 160 msec, and peaking at 190 (scalp positivity), 250 (negativity), and 300-500 msec (positivity) after stimulus onset. These integration effects were larger in amplitude for attended than for unattended stimuli, providing neural evidence that attention can modulate multisensory-integration processes at multiple stages.


Comparison of Unenhanced and Gadolinium-Enhanced Imaging in Multiple Sclerosis: Is Contrast Needed for Routine Follow-Up MRI?
Gadolinium enhanced MRI is routinely used for follow-up of patients with multiple sclerosis. Our aim was to evaluate whether enhancing multiple sclerosis lesions on follow-up MR imaging can be detected by visual assessment of unenhanced double inversion recovery and FLAIR sequences. A total of 252 consecutive MRIs in 172 adult patients with a known diagnosis of multiple sclerosis were reviewed. The co-presence or absence of associated double inversion recovery and FLAIR signal abnormality within contrast-enhancing lesions was recorded by 3 neuroradiologists. In a subset of patients with prior comparisons, the number of progressive lesions on each of the 3 sequences was assessed. A total of 34 of 252 MRIs (13%) demonstrated 55 enhancing lesions, of which 52 (95%) had corresponding hyperintensity on double inversion recovery and FLAIR. All lesions were concordant between double inversion recovery and FLAIR, and the 3 enhancing lesions not visible on either sequence were small (<2 mm) and cortical/subcortical (n = 2) or periventricular (n = 1). A total of 17 (22%) of the 76 MRIs with a prior comparison had imaging evidence of disease progression: Ten (59%) of these showed new lesions on double inversion recovery or FLAIR only, 6 (35%) showed progression on all sequences, and 1 (6%) was detectable only on postcontrast T1, being located in a region of confluent double inversion recovery and FLAIR abnormality. There was a high concordance between enhancing lesions and hyperintensity on either double inversion recovery or FLAIR. Serial follow-up using double inversion recovery or FLAIR alone may capture most imaging progression, but isolated enhancing lesions in confluent areas of white matter abnormality could present a pitfall for this approach.


Cis-regulatory control of the nuclear receptor Coup-TF gene in the sea urchin Paracentrotus lividus embryo.
Coup-TF, an orphan member of the nuclear receptor super family, has a fundamental role in the development of metazoan embryos. The study of the gene's regulatory circuit in the sea urchin embryo will facilitate the placement of this transcription factor in the well-studied embryonic Gene Regulatory Network (GRN). The Paracentrotus lividus Coup-TF gene (PlCoup-TF) is expressed throughout embryonic development preferentially in the oral ectoderm of the gastrula and the ciliary band of the pluteus stage. Two overlapping λ genomic clones, containing three exons and upstream sequences of PlCoup-TF, were isolated from a genomic library. The transcription initiation site was determined and 5' deletions and individual segments of a 1930 bp upstream region were placed ahead of a GFP reporter cassette and injected into fertilized P.lividus eggs. Module a (-532 to -232), was necessary and sufficient to confer ciliary band expression to the reporter. Comparison of P.lividus and Strongylocentrotus purpuratus upstream Coup-TF sequences, revealed considerable conservation, but none within module a. 5' and internal deletions into module a, defined a smaller region that confers ciliary band specific expression. Putative regulatory cis-acting elements (RE1, RE2 and RE3) within module a, were specifically bound by proteins in sea urchin embryonic nuclear extracts. Site-specific mutagenesis of these elements resulted in loss of reporter activity (RE1) or ectopic expression (RE2, RE3). It is proposed that sea urchin transcription factors, which bind these three regulatory sites, are necessary for spatial and quantitative regulation of the PlCoup-TF gene at pluteus stage sea urchin embryos. These findings lead to the future identification of these factors and to the hierarchical positioning of PlCoup-TF within the embryonic GRN.


NUP82 is an essential yeast nucleoporin required for poly(A)+ RNA export.
We have isolated and characterized the gene encoding a novel essential nucleoporin of 82 kD, termed NUP82. Indirect immunofluorescence of cells containing an epitope tagged copy of the NUP82 localized it to the nuclear pore complex (NPC). Primary structure analysis indicates that the COOH-terminal 195 amino acids contain a putative coiled-coil domain. Deletion of the COOH-terminal 87 amino acids of this domain causes slower cell growth; deletion of the COOH-terminal 108 amino acids results in slower growth at 30 degrees C and lethality at 37 degrees C. Cells in which the last 108 amino acids of NUP82 have been deleted, when shifted to 37 degrees C, do not display any gross morphological defects in their nuclear pore complexes or nuclear envelopes. They do, however, accumulate poly(A)+ RNA in their nuclei at 37 degrees C. We propose that NUP82 acts as a linker to tether nucleoporins directly involved in nuclear transport to pore scaffolding via its coiled-coil domain.


Back to work? Socioeconomic status after kidney transplantation.
Employment after kidney transplantation is an important marker of health recovery. The study addresses the impact of successful kidney transplantation on socioeconomic factors and employment in a Swiss cohort. Patients who received a kidney allograft at the University Hospital of Basel between 2000 and 2011 were investigated. A standardised survey was used to obtain information on socioeconomic factors 1 year before and after successful transplantation. A total of 610 patients were contacted; 354 (58%) answered the survey. The median age of respondents was 53.5 (interquartile range 42-61) years at the time of transplantation, 31.2% were females. Overall, 201 out of 282 working-age patients (71.3%) were working 1 year after transplantation: 102 full-time, 55 part-time, 30 patients part-time with additional disability pension, and 14 housework. Seventy-two patients (25.3%) did not work 1 year after transplantation: 63 patients had a full or partial disability pension, and nine patients were unemployed. Thirty out of 282 working-age patients (10.6%) had improved working ability after transplantation. Employment after transplantation was favoured by: living donor transplantation (p <0.0001), pre-emptive transplantation (p <0.0001), dialysis duration ≤1 year (p <0.0001), preserved employment before transplantation (p <0.0001), and higher education (p = 0.003), whereas age above 50 years (p = 0.006), and dialysis duration > 1 year (p <0.0001) had a negative impact. The employment rate in this Swiss cohort before and after successful kidney transplantation is high compared with the literature. A high number of living donors, of pre-emptive transplantations, and short dialysis vintages contribute to this observation.


Carambola optics for recycling of light.
Recycling of light allows the luminance (radiance) emitted by a light source to be increased at the cost of reducing the total luminous flux (radiant power). Recycling of light means returning part of the emitted light to the source, where part of it will escape absorption. An optical design that is suitable for multiple and controlled recycling is described. Carambola optics is named for its resemblance to star fruit. Several pairs of mirrors or prisms redirect light repeatedly onto the source, thus achieving multiple transits of the light through the source. This recycled light exits the carambola in the same phase space as light directly emitted and not recycled.


Mixed-mode pattern in Doublefoot mutant mouse limb--Turing reaction-diffusion model on a growing domain during limb development.
It has been suggested that the Turing reaction-diffusion model on a growing domain is applicable during limb development, but experimental evidence for this hypothesis has been lacking. In the present study, we found that in Doublefoot mutant mice, which have supernumerary digits due to overexpansion of the limb bud, thin digits exist in the proximal part of the hand or foot, which sometimes become normal abruptly at the distal part. We found that exactly the same behaviour can be reproduced by numerical simulation of the simplest possible Turing reaction-diffusion model on a growing domain. We analytically showed that this pattern is related to the saturation of activator kinetics in the model. Furthermore, we showed that a number of experimentally observed phenomena in this system can be explained within the context of a Turing reaction-diffusion model. Finally, we make some experimentally testable predictions.


Factors that affect proportional glomerular filtration rate after minimally invasive partial nephrectomy.
Several factors have been shown to impact the overall glomerular filtration (GFR) rate after partial nephrectomy. Change in overall GFR, however, does not necessarily reflect the impact of these factors on the operated kidney. Using preoperative and postoperative renal scintigraphy, we sought to assess the impact of patient, tumor, and operative factors on GFR of the affected kidney (proportional GFR). We identified 73 patients who underwent minimally invasive partial nephrectomy with preoperative and postoperative renal scans from two institutions. Patient, tumor, and operative characteristics were recorded. We used multiple linear regression to determine the patient and clinical factors predictive of postoperative proportional GFR in the operated kidney. We tested for an interaction between preoperative proportional GFR and nephrometry score and ischemia. We further fitted two separate linear models to compare the proportion of variance (R(2)) explained by ischemia time in change in renal function in the operated kidney with the change in renal function in both kidneys. Surgical parameters (procedure approach, ischemia time, and estimated blood loss) and preoperative proportional GFR were significantly associated with postoperative proportional GFR. Preoperative proportional GFR (β=5.93, 95% confidence interval [CI]: 3.88, 7.97, P<0.0005) and procedure approach (β=8.67, 95% CI: 4.50, 12.80, P<0.0005) were strongly associated with outcome while ischemia time (β=-1.80, 95% CI: -3.48, -0.11, P=0.04) and estimated blood loss (β=-1.15, 95% CI: -0.29, -0.01, P=0.04) just reached statistical significance. The interaction term between preoperative proportional GFR and nephrometry score or ischemia time was not statistically significant (nephrometry, P=0.2 continuous or P=0.6 categorical, and ischemia, P=0.7, respectively). Lower preoperative proportional GFR, longer ischemia times, and higher blood loss all negatively impact postoperative proportional GFR while tumor complexity as gauged by morphometry scoring does not. Larger studies are needed to determine whether renal scintigraphy is a more accurate method of measuring the impact of the ischemia time on postoperative proportional GFR.


3D fibre deposition and stereolithography techniques for the design of multifunctional nanocomposite magnetic scaffolds.
Magnetic nanocomposite scaffolds based on poly(ε-caprolactone) and poly(ethylene glycol) were fabricated by 3D fibre deposition modelling (FDM) and stereolithography techniques. In addition, hybrid coaxial and bilayer magnetic scaffolds were produced by combining such techniques. The aim of the current research was to analyse some structural and functional features of 3D magnetic scaffolds obtained by the 3D fibre deposition technique and by stereolithography as well as features of multimaterial scaffolds in the form of coaxial and bilayer structures obtained by the proper integration of such methods. The compressive mechanical behaviour of these scaffolds was investigated in a wet environment at 37 °C, and the morphological features were analysed through scanning electron microscopy (SEM) and X-ray micro-computed tomography. The capability of a magnetic scaffold to absorb magnetic nanoparticles (MNPs) in water solution was also assessed. confocal laser scanning microscopy was used to assess the in vitro biological behaviour of human mesenchymal stem cells (hMSCs) seeded on 3D structures. Results showed that a wide range of mechanical properties, covering those spanning hard and soft tissues, can be obtained by 3D FDM and stereolithography techniques. 3D virtual reconstruction and SEM showed the precision with which the scaffolds were fabricated, and a good-quality interface between poly(ε-caprolactone) and poly(ethylene glycol) based scaffolds was observed for bilayer and coaxial scaffolds. Magnetised scaffolds are capable of absorbing water solution of MNPs, and a preliminary information on cell adhesion and spreading of hMSCs was obtained without the application of an external magnetic field.


Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain.
Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na(v)s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na(v)1.7-specific inhibitor, ProTxII, allowed the isolation of Na(v)1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na(v)1.7 and Na(v)1.8 currents. The redistribution of Na(v)1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L(-/-)). SNS-Nedd4L(-/-) mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na(v)1.7 and Na(v)1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na(v)s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.


A 3-Year Prospective Study on Radiographic Marginal Bone Evaluation Around Platform-Shifting Implants with Internal Conical Connections.
To evaluate marginal bone level changes over 3 years around platform-shifting implants with internal conical connections, and to identify the factors relating to bone level changes. Systemically healthy patients who lost one tooth or two consecutive teeth were enrolled in the study. The subjects received one or two implants with platform-shifting and internal conical connections in healed bone in a submerged manner. Digital standardized periapical radiographs were obtained at the time of implant placement, at prosthesis delivery, at 1 year, and at 3 years after the definitive restorations. Marginal bone level changes were measured at the mesial and distal aspects of each implant. Spearman correlation coefficients were calculated to examine the correlation between marginal bone level changes and clinical factors (age, vertical mucosal thickness, implant length and diameter, insertion torque value, and vertical implant position). Twenty-five patients with 30 implants (8 men and 17 women, mean age: 61.24 ± 13.18 years) were followed up to 3 years after the definitive restorations. The implant survival rate was 100%, and no remarkable complications were found. Mean peri-implant marginal bone level changes were -0.41 ± 0.61 mm (from placement to prosthesis delivery: C1); -0.08 ± 0.54 mm (from prosthesis delivery to 1 year: C2); -0.04 ± 0.95 mm (from prosthesis delivery to 3 years: C3); and 0.04 ± 0.60 mm (from 1 year to 3 years: C4), respectively. Statistically significant differences in bone level changes were observed between C1 and C3, and C1 and C4. Significant correlations of marginal bone level changes with implant diameter in C1 and with vertical implant position in C2 and C3 were observed. Within the limitations of this study, platform-shifting implants with internal conical connections appeared to prevent marginal bone resorption, especially after delivery of definitive prostheses, although marginal bone resorption attributed to the reestablishment of biologic width following subcrestal placement might be unavoidable.


Clinical outcomes of bortezomib-based therapy in myeloma.
Bortezomib, a first generation proteasome inhibitor, is used in both newly diagnosed and relapsed myeloma settings. Considerable differences exist in the usage of bortezomib therapy in the clinical practice setting in comparison to clinical trial setting as well manufacturer's recommendations. These differences include route of administration (intravenous (iv) vs. subcutaneous (sc)), frequency from twice to once weekly, choice of alkylating agent used in combination with bortezomib (melphalan or cyclophosphamide), and choice of glucocorticoids (dexamethasone or prednisolone). We reviewed data from 272 consecutive bortezomib-treated myeloma patients, who received therapy within the regional Thames Valley Cancer Network for both newly diagnosed myeloma (NDMM, n = 120) and relapsed MM (RMM, n = 152). We investigated the influence of age, sex, transplant, bortezomib combinations (doublet vs. triplet), cumulative bortezomib dose per treatment line (<50mg vs. ≥50mg), and route of administration (iv vs. sc) on time to next treatment (TTNT) and on overall survival (OS). Route of bortezomib administration (iv vs. sc) influenced neither OS (41 vs 35 months, p = 0.5), nor TTNT (14 vs. 19 months, p = 0.052). Our study showed a statistically significant improvement in median OS in patients receiving a cumulative dose ≥50mg compared to <50mg (42 vs. 33months, p = 0.003), although presence of confounders need to be taken into account, such as disease stage, performance status, genetic changes and prior therapies. Median OS was longer using triplet therapies compared to a doublet in the RMM cohort (37 vs. 29 months, p = 0.06), although this did not reach statistical significance. Multivariate Cox Regression analysis showed that cumulative bortezomib dose ≥50mg (p = 0.002, HR = 1.83, 95% CI 1.25-2.67) and autologous transplant (p = 0.002, HR = 2.6, 95% CI 1.41-3.98) were both significant factors associated with improved OS. Our data argues in favour of continuing bortezomib for the recommended duration as per Summary of Product Characteristics (SPC), subject to good tolerability, in order to deepen response or extend the duration of best response.