GAD antibodies in probands and their relatives in a cohort clinically selected for Type 2 diabetes.
A subset of patients who present as if they have Type 2 diabetes have positive pancreatic autoantibodies, and have been referred to as having latent autoimmune diabetes in adults (LADA). We assessed the prevalence and clinical characteristics of patients with glutamic acid decarboxylase antibodies (GADA) in a cohort clinically selected for Type 2 diabetes and determined the presence of diabetes and GADA in their first-degree relatives. GADA were measured in 2059 subjects, not known to be related, and clinically selected as having Type 2 diabetes for genetic studies. Clinical characteristics were compared in GADA positive and GADA negative subjects. Diabetes and GAD antibody status were compared in 208 first-degree relatives of GADA positive and GADA negative probands. Of the subjects, 136 (7%) were GADA positive. Compared with the GADA negative subjects, they were slimmer (P < 0.001), diagnosed at a younger age (P = 0.011) and progressed to insulin faster (P < 0.001). Thirty-three per cent of GADA positive subjects had a first-degree relative with diabetes compared with 42% of GADA negative subjects (P = 0.034). The overall prevalence of GADA was similar in the first-degree relatives of GADA positive and GADA negative probands (4 v 5%), and 19 of 22 (86%) diabetic relatives of GADA positive probands were GADA negative. Despite clinically selecting a Type 2 diabetes cohort, 7% were GADA positive with an altered phenotype. These GADA positive patients had a strong family history of non-autoimmune diabetes. This suggests that, in this subgroup of patients, autoimmune pancreatic beta-cell destruction occurs on a background of Type 2 diabetes genetic susceptibility.


Comparison of Dizziness Factors for Mild Traumatic Brain Injury Patients with and without Dizziness: A Factor Analysis and Propensity Score Model Study.
Traumatic brain injury (TBI) causes major socioeconomic problems worldwide. In the United States, nearly three-quarters of patients with TBI have mild TBI (mTBI). 32% of these patients may develop dizziness. In this study, we analyzed the factor structure of the traditional Chinese version of the DHI and evaluate the differences in DHI factors between dizziness and nondizziness groups. In total, 315 patients with mTBI, comprising 158 with self-reported dizziness and 157 without dizziness, were recruited from three hospitals. The responses for Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) demonstrated between-group differences. The Chinese DHI had internal validity and had four factors that differed from the English version (3 aspects). The group effects for the physical subscale remained significantly different even after adjustments in the propensity score model. For the Chinese version, two of four factors remained significantly different in the effects between self-reported dizziness and nondizziness groups. The factors of our Chinese DHI differed from those of the original English version of DHI. After adjustments using the propensity score model, the physical subscale demonstrated significant differences between the self-reported dizziness and nondizziness groups. Only two factors from our Chinese DHI were significantly different; moreover, it contained only three physical, five functional, and three emotional items.


Colocalization for super-resolution microscopy via optimal transport.
Super-resolution fluorescence microscopy is a widely used technique in cell biology. Stimulated emission depletion (STED) microscopy enables the recording of multiple-color images with subdiffraction resolution. The enhanced resolution leads to new challenges regarding colocalization analysis of macromolecule distributions. We demonstrate that well-established methods for the analysis of colocalization in diffraction-limited datasets and for coordinate-stochastic nanoscopy are not equally well suited for the analysis of high-resolution STED images. We propose optimal transport colocalization, which measures the minimal transporting cost below a given spatial scale to match two protein intensity distributions. Its validity on simulated data as well as on dual-color STED recordings of yeast and mammalian cells is demonstrated. We also extend the optimal transport colocalization methodology to coordinate-stochastic nanoscopy.


Primary brain tumors in adults.
Primary malignant brain tumors account for 2 percent of all cancers in U.S. adults. The most common malignant brain tumor is glioblastoma multiforme, and patients with this type of tumor have a poor prognosis. Previous exposure to high-dose ionizing radiation is the only proven environmental risk factor for a brain tumor. Primary brain tumors are classified based on their cellular origin and histologic appearance. Typical symptoms include persistent headache, seizures, nausea, vomiting, neurocognitive symptoms, and personality changes. A tumor can be identified using brain imaging, and the diagnosis is confirmed with histopathology. Any patient with chronic, persistent headache in association with protracted nausea, vomiting, seizures, change in headache pattern, neurologic symptoms, or positional worsening should be evaluated for a brain tumor. Magnetic resonance imaging is the preferred initial imaging study. A comprehensive neurosurgical evaluation is necessary to obtain tissue for diagnosis and for possible resection of the tumor. Primary brain tumors rarely metastasize outside the central nervous system, and there is no standard staging method. Surgical resection of the tumor is the mainstay of therapy. Postoperative radiation and chemotherapy have improved survival in patients with high-grade brain tumors. Recent developments in targeted chemotherapy provide novel treatment options for patients with tumor recurrence. Primary care physicians play an important role in the perioperative and supportive treatment of patients with primary brain tumors, including palliative care and symptom control.


Decreased alveolar oxygen induces lung inflammation.
Molecular mechanisms of the inflammatory reaction in hypoxia-induced lung injury are not well defined. Therefore, effects of alveolar hypoxia were studied in rat lungs, exposing rats to 10% oxygen over periods of 1, 2, 4, 6, and 8 h. An increase in the number of macrophages in bronchoalveolar lavage fluid of hypoxic animals was shown between 1 and 8 h. Extravasation of albumin was enhanced after 1 h and remained increased throughout the study period. NF-kappaB-binding activity as well as mRNA for TNF-alpha, macrophage inflammatory protein (MIP)-1beta, and monocyte chemoattractant protein (MCP)-1 were increased within the first 2 h of exposure to hypoxia. Hypoxia-inducible factor (HIF)-1alpha and intercellular adhesion molecule (ICAM)-1 mRNA were upregulated between 1 and 6 h. Elimination of alveolar macrophages by intratracheal application of liposome-encapsulated clodronate led to a decreased expression of NF-kappaB binding activity, HIF-1alpha, TNF-alpha, ICAM-1, and MIP-1beta. In summary, alveolar hypoxia induced macrophage recruitment, an increase in albumin leakage, and enhanced expression of inflammatory mediators, which were mainly macrophage dependent. Alveolar macrophages appear to have a prominent role in the inflammatory response in hypoxia-induced lung injury and the related upregulation of inflammatory mediators.


Long-term back problems and physical work exposures in the 1990 Ontario Health Survey.
This study sought to provide data on the relationship of work exposures to long-term back problems in a population survey. The Ontario Health Survey in 1990 used a representative population sample of the province. It included data on long-term back problems, occupational activity, and physical work exposures. The current study examined relationships between these variables. The prevalence of long-term back problems was 7.8% in working-age adults. It generally increased with age. Long-term back problems were more prevalent in blue-collar occupations and among those not working, as well as among people with less formal education, smokers, and those overweight. Physical work exposures--awkward working position, working with vibrating vehicles or equipment, and bending and lifting--were all associated with a greater risk of back problems. The number of simultaneous physical exposures was monotonically related to increased risk. Within the limitations of the data and assuming the relationship to be causal, about one quarter of the excess back pain morbidity in the working population could be explained by physical work exposures.


An active surveillance study of vancomycin-resistant Enterococcus in Queen Elizabeth Hospital, Hong Kong.
To assess the rate of faecal vancomycin-resistant Enterococcus colonisation in high-risk patients in a regional hospital. Prospective observational surveillance study. Queen Elizabeth Hospital, Hong Kong. From September 2001 to December 2002, stool samples from patients in the intensive care unit and patients in whom Clostridium difficile testing was requested were used for study using a broth enrichment method. Number of faecal vancomycin-resistant Enterococcus colonisation. A total of 2414 cultures from 1792 patients were tested for vancomycin-resistant Enterococcus using a broth enrichment method. Only one (0.06%) patient was found to harbour a vancomycin-resistant Enterococcus faecalis in the gastro-intestinal tract. Surveillance cultures from contacts of the case revealed another six with vancomycin-resistant Enterococcus faecalis. Vancomycin-resistant Enterococcus faecalis was also later reported from a clinical specimen (catheterized urine) of another patient. They were all epidemiologically linked to the index case. Mean inhibitory concentrations of vancomycin and teicoplanin were determined to be higher than 256 and 0.5 microgram/mL, respectively by E-test for all the vancomycin-resistant Enterococcus isolates. Polymerase chain reaction analysis confirmed the presence of vanB genes and the result was in line with the phenotype. Pulsed-field gel electrophoresis confirmed a monoclonal vancomycin-resistant Enterococcus outbreak. Strict infection control measures recommended by the Centers for Disease Control and Prevention were followed and the outbreak was successfully controlled. Vancomycin-resistant Enterococcus colonisation is rare, but present among high-risk patients in our hospital. A routine surveillance programme should be implemented that will enable early case detection and prompt initiation of infection control measures to prevent the emergence of an endemic situation.


UK Neovascular Age-Related Macular Degeneration Database. Report 6: time to retreatment after a pause in therapy. Outcomes from 92 976 intravitreal ranibizumab injections.
To study the time to retreatment in eyes with neovascular age-related macular degeneration (nAMD) that had been treatment-free for intervals of 3 months, 6 months, 9 months and 12 months during the maintenance phase of ranibizumab therapy within the UK National Health Service. In this multicentre national nAMD database study, structured data were collected from 14 centres (involving 12 951 eyes receiving 92 976 ranibizumab injections). Patients were treated with three fixed, monthly injections in a loading phase of treatment, followed by a pro re nata retreatment regimen in a maintenance phase. Eyes with a treatment-free interval (TFI) of 3 months, 6 months, 9 months or 12 months in the maintenance phase were identified and the time to retreatment after these TFIs was determined. The time to retreatment for the 20th and 50th centiles was 0.58/2.54 months after a 3-month TFI, 2.07/9.62 months after a 6-month TFI, 3.69/15.84 months after a 9-month TFI and 5.90/22.49 months after a 12-month TFI. Following a TFI of 3 months, 6 months, 9 months and 12 months, 68%, 44%, 31% and 21% of eyes required retreatments after an additional 6 months of follow-up, respectively. Similarly, after 12 months of follow-up, 77%, 56%, 43% and 34% of these eyes required retreatment. This study provides times to retreatment in eyes with nAMD that have been treatment-free for intervals of 3-12 months and demonstrates the likelihood of repeat therapy within the next year, even after a TFI of 12 months. These outcomes can help plan appropriate follow-up intervals for patients who have been treatment-free for intervals of up to 12 months.


Phosphorylation of TET proteins is regulated via O-GlcNAcylation by the O-linked N-acetylglucosamine transferase (OGT).
TET proteins oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine and thus provide a possible means for active DNA demethylation in mammals. Although their catalytic mechanism is well characterized and the catalytic dioxygenase domain is highly conserved, the function of the regulatory regions (the N terminus and the low-complexity insert between the two parts of the dioxygenase domains) is only poorly understood. Here, we demonstrate that TET proteins are subject to a variety of post-translational modifications that mostly occur at these regulatory regions. We mapped TET modification sites at amino acid resolution and show for the first time that TET1, TET2, and TET3 are highly phosphorylated. The O-linked GlcNAc transferase, which we identified as a strong interactor with all three TET proteins, catalyzes the addition of a GlcNAc group to serine and threonine residues of TET proteins and thereby decreases both the number of phosphorylation sites and site occupancy. Interestingly, the different TET proteins display unique post-translational modification patterns, and some modifications occur in distinct combinations. In summary, our results provide a novel potential mechanism for TET protein regulation based on a dynamic interplay of phosphorylation and O-GlcNAcylation at the N terminus and the low-complexity insert region. Our data suggest strong cross-talk between the modification sites that could allow rapid adaption of TET protein localization, activity, or targeting due to changing environmental conditions as well as in response to external stimuli.


Differential roles of the Leloir pathway enzymes and metabolites in defining galactose sensitivity in yeast.
The metabolism of galactose via enzymes of the Leloir pathway: galactokinase, galactose-1-P uridylyltransferase, and UDP galactose-4'-epimerase, is a process that has been conserved from Escherichia coli through humans. Impairment of this pathway in patients results in the disease galactosemia. Despite decades of study, the underlying pathophysiology in galactosemia remains unknown. Here we have defined the functional and metabolic implications of impaired galactose metabolism in yeast, by asking two questions: (1) What is the impact of loss of each of the three Leloir enzymes on the ability of cells to metabolize galactose, and on their sensitivity to galactose, and (2) what is the relationship between gal-1P and galactose-sensitivity in yeast? Our results demonstrate that only transferase-null cells are able to deplete their medium of galactose; deletion of kinase or epimerase halts this process. In contrast, only kinase-null cultures grow well in glycerol/ethanol medium despite the addition of galactose; both transferase and epimerase-null yeast arrest growth under these conditions. Indeed, epimerase-null yeast arrest growth at galactose concentrations 10-fold lower than do their transferase-null counterparts. Secondary deletion of kinase relieves growth arrest in both strains. Finally, rather than a continuous relationship between gal-1P and growth arrest, we observed a threshold level of gal-1P (approximately 10 nmol/mg cell DM) above which both transferase-null and epimerase-null cultures could not grow. These results both confirm and significantly extend prior knowledge of galactose metabolism in yeast, and set the stage for future studies into the mediators and mechanism of Leloir-impaired galactose sensitivity in eukaryotes.


Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure.
The mechanisms underlying the progression of diabetes mellitus and heart failure are closely intertwined, such that worsening of one condition is frequently accompanied by worsening of the other; the degree of clinical acceleration is marked when the 2 coexist. Activation of the sodium-hydrogen exchanger in the heart and vasculature (NHE1 isoform) and the kidneys (NHE3 isoform) may serve as a common mechanism that links both disorders and may underlie their interplay. Insulin insensitivity and adipokine abnormalities (the hallmarks of type 2 diabetes mellitus) are characteristic features of heart failure; conversely, neurohormonal systems activated in heart failure (norepinephrine, angiotensin II, aldosterone, and neprilysin) impair insulin sensitivity and contribute to microvascular disease in diabetes mellitus. Each of these neurohormonal derangements may act through increased activity of both NHE1 and NHE3. Drugs used to treat diabetes mellitus may favorably affect the pathophysiological mechanisms of heart failure by inhibiting either or both NHE isoforms, and drugs used to treat heart failure may have beneficial effects on glucose tolerance and the complications of diabetes mellitus by interfering with the actions of NHE1 and NHE3. The efficacy of NHE inhibitors on the risk of cardiovascular events may be enhanced when heart failure and glucose intolerance coexist and may be attenuated when drugs with NHE inhibitory actions are given concomitantly. Therefore, the sodium-hydrogen exchanger may play a central role in the interplay of diabetes mellitus and heart failure, contribute to the physiological and clinical progression of both diseases, and explain certain drug-drug and drug-disease interactions that have been reported in large-scale randomized clinical trials.


The inhibition of the estrogenic effects of pesticides and environmental chemicals by curcumin and isoflavonoids.
Many environmental chemicals and pesticides have been found to be estrogenic and have been shown to stimulate the growth of estrogen receptor-positive (ER-positive) human breast cancer cells. Since it is difficult to avoid human exposure to environmental estrogens, a potentially important area of research is the development of dietary strategies to prevent the stimulated growth of breast tumors by environmental estrogens. In this context, the inhibitory action of curcumin and a combination of curcumin and isoflavonoids were studied in ER-positive human breast cancer cells (MCF-7 and T47D) and ER-negative MDA-MB-231 cells induced by the pesticide o,p'-DDT and the environmental pollutants 4-nonylphenol and 4-octylphenol. The median inhibitory concentration (IC50) for curcumin in T47D cells was 10 microM when measured at either a 48-hr or a 6-day incubation time. The IC50 value for curcumin was within the 8-10 microM range for inhibiting the growth of T47D cells induced by a 10- microM concentration each of 4-nonylphenol, 4-octylphenol, and o, p'-DDT. The IC50 for curcumin in MCF-7 cells induced by 10 microM of either o,p'-DDT, 4-octylphenol, or 4-nonylphenol were 9, 39, and >50 microM, respectively. A combination of curcumin and isoflavonoids was able to inhibit the induced growth of ER-positive cells up to 95%. For MDA-MB-231 cells, the IC50 for curcumin was 17 microM, which was reduced to 11 microM in the presence of 25 microM genistein. Curcumin and genistein induce drastic changes in the morphological shape of both ER-positive and ER-negative cells. Data presented here indicate that a mixture of curcumin and isoflavonoids is the most potent inhibitor against the growth of human breast tumor cells. These data suggest that combinations of natural plant compounds may have preventive and therapeutic applications against the growth of breast tumors induced by environmental estrogens.


Peri-operative glycaemic control regimens for preventing surgical site infections in adults.
Surgical site infections (SSIs) are associated with significant morbidity, mortality, and resource utilization and are potentially preventable. Peri-operative hyperglycaemia has been associated with increased SSIs and previous recommendations have been to treat glucose levels above 200 mg/dL. However, recent studies have questioned the optimal glycaemic control regimen to prevent SSIs. Whether the benefits of strict or intensive glycaemic control with insulin infusion as compared to conventional management outweigh the risks remains controversial. To summarise the evidence for the impact of glycaemic control in the peri-operative period on the incidence of surgical site infections, hypoglycaemia, level of glycaemic control, all-cause and infection-related mortality, and hospital length of stay and to investigate for differences of effect between different levels of glycaemic control. A search strategy was developed to search the following databases: Cochrane Wounds Group Specialised Register (searched 25 March 2009), The Cochrane Central Register of Controlled Trials, The Cochrane Library 2009, Issue 1; Ovid MEDLINE (1950 to March Week 2 2009); Ovid EMBASE (1980 to 2009 Week 12) and EBSCO CINAHL (1982 to March Week 3 2009). The search was not limited by language or publication status. Randomised controlled trials (RCTs) were eligible for inclusion if they evaluated two (or more) glycaemic control regimens in the peri-operative period (within one week pre-, intra-, and/or post-operative) and reported surgical site infections as an outcome. The standard method for conducting a systematic review in accordance with the Cochrane Wounds Group was used. Two review authors independently reviewed the results from the database searches and identified relevant studies. Two review authors extracted study data and outcomes from each study and reviewed each study for methodological quality. Any disagreement was resolved by discussion or by referral to a third review author. Five RCTs met the pre-specified inclusion criteria for this review. No trials evaluated strict glycaemic control in the immediate pre-operative period or outside the intensive care unit. Due to heterogeneity in patient populations, peri-operative period, glycaemic target, route of insulin administration, and definitions of outcome measures, combination of the results of the five included trials into a meta-analysis was not appropriate. The methodological quality of the trials was variable. In terms of outcomes, only one trial demonstrated a significant reduction in SSIs with strict glycaemic control, but the quality of this trial was difficult to assess as a result of poor reporting; furthermore the baseline rate of SSIs was high (30%). The other trials were either underpowered to detect a difference in SSIs, due to a low baseline rate (less than or equal to 5%), or did not report SSIs as a single outcome but as part of a composite. Of the three trials reporting hypoglycaemia (which was not consistently defined) all had a higher rate in the strict glycaemic control group but none attributed significant morbidity to the hypoglycaemia. Adequacy of glucose control between groups was measured differently among studies. Studies could not be compared due to differences in target ranges, and were susceptible to measurement bias due to differences in frequency of measurement and lack of blinding by the providers following the glycaemic protocols. Infection-related mortality was not reported in any of the trials, and no trials demonstrated a significant difference in all-cause mortality. Length of hospital stay was significantly reduced in the strict glycaemic control groups in only one trial. There is insufficient evidence to support strict glycaemic control versus conventional management (maintenance of glucose < 200 mg/dL) for the prevention of SSIs. No trials were found that evaluated strict glycaemic control in the immediate pre-operative period or outside the setting of an intensive care unit. The trials were limited by small sample size, inconsistencies in the definitions of the outcome measures and methodological quality. Further large randomised trials are required to address this question and may be most appropriately performed in patients at high risk for SSIs.


Anticonvulsant effects of the BK-channel antagonist paxilline.
Mutations that enhance currents through the Ca(2+)- and voltage-gated K(+) channel BK (Slo, maxiK, KCNMA1) have been associated with seizure disorders in both rodent models and humans. Previously we have found that seizures themselves induce a gain-of-function in BK channels that is associated with elevated excitability in neocortical neurons. In this study, we sought to examine whether administration of BK-channel antagonists possess anticonvulsant activity in vivo. Seizures were induced in animals by intraperitoneal (i.p.) injection of the gamma-aminobutyric acid (GABA)(A) antagonists picrotoxin or pentylenetetrazole. Twenty-four hours following induction of the initial seizure episode, animals were reinjected with chemoconvulsant in the presence of the BK-channel antagonist paxilline or saline. The presence and duration of tonic-clonic seizures were evaluated. Intraperitoneal injection of paxilline was sufficient to eliminate tonic-clonic seizures in picrotoxin-treated animals. Paxilline reduced seizure duration and intensity in pentylenetetrazole-injected animals. The BK-channel antagonist paxilline possesses significant anticonvulsant activity in both picrotoxin and pentylenetetrazole seizure models, an effect that may be related to the seizure-dependent gain-of-function in BK channel previously observed in neocortical neurons in vitro.


Risk of tooth loss after cigarette smoking cessation.
Little is known about the effect of cigarette smoking cessation on risk of tooth loss. We examined how risk of tooth loss changed with longer periods of smoking abstinence in a prospective study of oral health in men. Research subjects were 789 men who participated in the Veterans Administration Dental Longitudinal Study from 1968 to 2004. Tooth status and smoking status were determined at examinations performed every 3 years, for a maximum follow-up time of 35 years. Risk of tooth loss subsequent to smoking cessation was assessed sequentially at 1-year intervals with multivariate proportional hazards regression models. Men who never smoked cigarettes, cigars, or pipes formed the reference group. Hazard ratios were adjusted for age, education, total pack-years of cigarette exposure, frequency of brushing, and use of floss. The hazard ratio for tooth loss was 2.1 (95% confidence interval [CI], 1.5-3.1) among men who smoked cigarettes during all or part of follow-up. Risk of tooth loss among men who quit smoking declined as time after smoking cessation increased, from 2.0 (95% CI, 1.4-2.9) after 1 year of abstinence to 1.0 (95% CI, 0.5-2.2) after 15 years of abstinence. The risk remained significantly elevated for the first 9 years of abstinence but eventually dropped to the level of men who never smoked after 13 or more years. These results indicate that smoking cessation is beneficial for tooth retention, but long-term abstinence is required to reduce the risk to the level of people who have never smoked.


Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells.
Information on the regulation of steroid hormone receptors and their distinct functions within the human endometrial epithelium is largely unavailable. We have immortalized human primary endometrial epithelial cells (EECs) isolated from a normal proliferative phase endometrium by stably transfecting the catalytic subunit (hTERT) of the human telomerase complex and cultured these hTERT-EECs now for over 350 population doublings. Active hTERT was detected in hTERT-EECs employing the telomerase repeat amplification assay protocol. hTERT-EECs revealed a polarized, non-invasive epithelial phenotype with apical microvilli and production of a basal lamina when grown on a three-dimensional collagen-fibroblast lattice. Employing atomic force microscopy, living hTERT-EECs were shown to produce extracellular matrix (ECM) components and ECM secretion was modified by estrogen and progesterone (P4). hTERT-EECs expressed inducible and functional endogenous estrogen receptor-alpha (ER-alpha) as demonstrated by estrogen response element reporter assays and induction of P4 receptor (PR). P4 treatment down-regulated PR expression, induced MUC-1 gene activity and resulted in increased ER-beta transcriptional activity. Gene activities of cytokines and their receptors interleukin (IL)-6, leukemia inhibitory factor (LIF), IL-11 and IL-6 receptor (IL6-R), LIF receptor and gp130 relevant to implantation revealed a 17 beta-estradiol (E2)-mediated up-regulation of IL-6 and an E2- and P4-mediated up-regulation of IL6-R in hTERT-EECs. Thus, hTERT-EECs may be regarded as a novel in vitro model to investigate the role of human EECs in steroid hormone-dependent normal physiology and pathologies, including implantation failure, endometriosis and endometrial cancer.


Changes in dietary intake after diagnosis of breast cancer.
To quantify change in intake of kilocalories, macronutrients, and fruit and vegetable servings after diagnosis of breast cancer, and to correlate these changes with subject characteristics and with self-reported global change in dietary patterns. Food frequency questionnaires were completed by women newly diagnosed with breast cancer shortly after diagnosis. They were asked to recall intake 1 year before diagnosis. Two years after the initial interview another food frequency questionnaire was completed recalling intake during the previous year. At the 2-year follow-up interview women were also asked if they had changed their intake of fruit, vegetables, and fat since diagnosis. Two hundred sixty New Mexico women with newly diagnosed breast cancer between July 1997 and March 1999. Two-year change scores for kilocalories, macronutrients, and fruit and vegetable servings were calculated and tested for difference from zero using paired t tests or Wilcoxon signed rank tests. Subjects' characteristics were related to change in kilocalories and linear regression was used to determine the relative importance of these characteristics. Amount of change in fruit and vegetable servings and fat intake were calculated using food frequency data for women who reported increasing their intake of fruits and vegetables or decreasing their intake of fat after diagnosis. Small but significant decreases in intake of total energy and macronutrients were found 2 years postdiagnosis, with younger women reporting the greatest decreases. Fat as a percentage of diet increased over this period. There was no change in mean intake of fruit and vegetable servings. There is agreement between change as measured by food frequency questionnaire and change reported by more global questions on dietary habits; however, the amount of change measured was small. Women reporting an increase in fruit and vegetable intake postdiagnosis described an increase of one-quarter serving of fruit and one-third serving of vegetables per day. Breast cancer diagnosis results in modest dietary changes. Small changes in fruit and vegetable consumption suggest that efforts are needed to encourage increased consumption of these foods.


Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins.
In every established species, protein-protein interactions have evolved such that they are fit for purpose. However, the molecular details of the evolution of new protein-protein interactions are poorly understood. We have used nuclear magnetic resonance spectroscopy to investigate the changes in structure and dynamics during the evolution of a protein-protein interaction involving the intrinsically disordered CREBBP (CREB-binding protein) interaction domain (CID) and nuclear coactivator binding domain (NCBD) from the transcriptional coregulators NCOA (nuclear receptor coactivator) and CREBBP/p300, respectively. The most ancient low-affinity "Cambrian-like" [540 to 600 million years (Ma) ago] CID/NCBD complex contained less secondary structure and was more dynamic than the complexes from an evolutionarily younger "Ordovician-Silurian" fish ancestor (ca. 440 Ma ago) and extant human. The most ancient Cambrian-like CID/NCBD complex lacked one helix and several interdomain interactions, resulting in a larger solvent-accessible surface area. Furthermore, the most ancient complex had a high degree of millisecond-to-microsecond dynamics distributed along the entire sequences of both CID and NCBD. These motions were reduced in the Ordovician-Silurian CID/NCBD complex and further redistributed in the extant human CID/NCBD complex. Isothermal calorimetry experiments show that complex formation is enthalpically favorable and that affinity is modulated by a largely unfavorable entropic contribution to binding. Our data demonstrate how changes in structure and motion conspire to shape affinity during the evolution of a protein-protein complex and provide direct evidence for the role of structural, dynamic, and frustrational plasticity in the evolution of interactions between intrinsically disordered proteins.


Risk Factors for Transformation to Higher-Grade Lymphoma and Its Impact on Survival in a Large Cohort of Patients With Marginal Zone Lymphoma From a Single Institution.
Given the paucity of data on higher-grade transformation (HGT) to aggressive lymphoma in patients with marginal zone lymphoma (MZL), we report on a large cohort of patients, identify risk factors, and determine HGT impact on overall survival (OS). We analyzed 453 patients with biopsy-proven MZL seen at our institution between 1995 and 2016. Kaplan-Meier, Cox proportional hazards regression, and competing risk methods were used in analyses of time-to-event outcomes. Thirty-four patients (7.5%) had biopsy-proven HGT to diffuse large B-cell lymphoma, including seven (21%) diagnosed at the time of initial MZL diagnosis. Among 27 incident patients, median time to HGT was 29 months (range, 1.3 to 135 months). Higher risk of HGT was observed in those with nodal/splenic MZL (subdistribution hazard ratio [SHR], 2.60; P = .023). On multivariable competing risk analysis, elevated lactate dehydrogenase (SHR, 2.71), more than four nodal sites (SHR, 2.97), and failure to achieve complete remission (CR) after initial treatment (SHR, 3.76) conveyed significantly higher risk for HGT ( P < .02). International Prognostic Index (IPI), Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were only significant predictors of HGT univariably. Patients with HGT had shorter OS (5-year rate, 65% v 86%; P < .001). Patients who presented with HGT within 12 months since MZL diagnosis had shorter OS than those with HGT at MZL diagnosis combined with those with HGT more than 12 months later (4-year rate, 43% v 81%, P < .001). Non-CR and higher scores of IPI, Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were the main significant predictors for shorter progression-free survival and OS. Failure to achieve CR after initial treatment, elevated lactate dehydrogenase, and more than four nodal sites at the time of MZL diagnosis are the main predictors of increased risk of HGT. Patients with HGT have shorter OS.


Epidemiology of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell malignancies with significant morbidity and high mortality. The incidence of MDS increases markedly with age, and the disease is most prevalent in individuals who are white and male. It is conservatively estimated that >10,000 new cases of MDS occur in the United States annually, and that ≥ 60,000 individuals with MDS currently reside in the country. With an aging population and an improving awareness of the disease, the documented disease burden is expected to escalate in the near future. Recent studies have identified new or inconsistent etiologic factors that warrant further research. Given the poor survival of individuals with MDS, it is important to identify prognostic factors to better risk-stratify patients for more effective treatment. The relevance of different comorbidities to MDS prognosis and the potential interaction between various comorbidities represents an interesting area of research.


Involvement of palliative care in euthanasia practice in a context of legalized euthanasia: A population-based mortality follow-back study.
In the international debate about assisted dying, it is commonly stated that euthanasia is incompatible with palliative care. In Belgium, where euthanasia was legalized in 2002, the Federation for Palliative Care Flanders has endorsed the viewpoint that euthanasia can be embedded in palliative care. To examine the involvement of palliative care services in euthanasia practice in a context of legalized euthanasia. Population-based mortality follow-back survey. Physicians attending a random sample of 6871 deaths in Flanders, Belgium, in 2013. People requesting euthanasia were more likely to have received palliative care (70.9%) than other people dying non-suddenly (45.2%) (odds ratio = 2.1 (95% confidence interval, 1.5-2.9)). The most frequently indicated reasons for non-referral to a palliative care service in those requesting euthanasia were that existing care already sufficiently addressed the patient's palliative and supportive care needs (56.5%) and that the patient did not want to be referred (26.1%). The likelihood of a request being granted did not differ between cases with or without palliative care involvement. Palliative care professionals were involved in the decision-making process and/or performance of euthanasia in 59.8% of all euthanasia deaths; this involvement was higher in hospitals (76.0%) than at home (47.0%) or in nursing homes (49.5%). In Flanders, in a context of legalized euthanasia, euthanasia and palliative care do not seem to be contradictory practices. A substantial proportion of people who make a euthanasia request are seen by palliative care services, and for a majority of these, the request is granted.


The Healthcare Systems Research Network (HCSRN) as an Environment for Dissemination and Implementation Research: A Case Study of Developing a Multi-Site Research Study in Precision Medicine.
In existence for nearly 25 years, the Healthcare Systems Research Network (HCSRN) is an established and sustainable network of health care systems that serves as a "real world" laboratory to enable the integration of research findings into practice. The objective of this paper is to demonstrate how the HCSRN serves as an ideal environment for studying dissemination and implementation of evidence-based practices into health care systems through the example of developing a multi-site study on the implementation of evidence-based precision medicine practices. The "Implementing Universal Lynch Syndrome Screening (IMPULSS)" study (NIH R01CA211723) involves seven HCSRN health care systems and two external health care systems. The IMPULSS study will describe and explain organizational variability around Lynch syndrome (LS) screening to identify which factors in different organizational contexts are important for successful implementation of LS screening programs and will create a toolkit to facilitate organizational decision making around implementation and improvement of precision medicine programs in health care systems. The strengths of the HCSRN that facilitate D&I research include: 1) a culture of collaboration, 2) standardization of data and processes across systems, and 3) researchers embedded in diverse health care systems. We describe how these strengths contributed to developing the IMPULSS study. Given the importance of conducting research in real world settings to improve patient outcomes, the unique strengths of the HCSRN are of vital importance. The IMPULSS study is one case example of how the strengths of the HCSRN make it an excellent environment for research on implementing evidence-based precision medicine practices in health care systems.


Use of a new proximity assay (NanoBRET) to investigate the ligand-binding characteristics of three fluorescent ligands to the human β1-adrenoceptor expressed in HEK-293 cells.
Previous research has indicated that allosteric interactions across the dimer interface of β1-adrenoceptors may be responsible for a secondary low affinity binding conformation. Here we have investigated the potential for probe dependence, in the determination of antagonist pKi values at the human β1-adenoceptor, which may result from such allosterism interactions. Three fluorescent β1-adrenoceptor ligands were used to investigate this using bioluminescence energy transfer (BRET) between the receptor-bound fluorescent ligand and the N-terminal NanoLuc tag of a human β1-adrenoceptor expressed in HEK 293 cells (NanoBRET). This proximity assay showed high-affinity-specific binding to the NanoLuc- β1-adrenoceptor with each of the three fluorescent ligands yielding KD values of 87.1 ± 10 nmol/L (n = 8), 38.1 ± 12 nmol/L (n = 7), 13.4 ± 2 nmol/L (n = 14) for propranolol-Peg8-BY630, propranolol- β(Ala-Ala)-BY630 and CGP-12177-TMR, respectively. Parallel radioligand-binding studies with 3H-CGP12177 and TIRF microscopy, to monitor NanoLuc bioluminescence, confirmed a high cell surface expression of the NanoLuc- β1-adrenoceptor in HEK 293 cells (circa 1500 fmol.mg protein-1). Following a 1 h incubation with fluorescent ligands and β1-adrenoceptor competing antagonists, there were significant differences (P < 0.001) in the pKi values obtained for CGP20712a and CGP 12177 with the different fluorescent ligands and 3H-CGP 12177. However, increasing the incubation time to 2 h removed these significant differences. The data obtained show that the NanoBRET assay can be applied successfully to study ligand-receptor interactions at the human β1-adrenoceptor. However, the study also emphasizes the importance of ensuring that both the fluorescent and competing ligands are in true equilibrium before interpretations regarding probe dependence can be made.


Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder.
The objective of this study was to evaluate short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder who were manifesting behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these. This 8-week, double-blind, randomized, placebo-controlled, parallel-group study was conducted of children and adolescents (aged 6-17 years) with autistic disorder. Patients were randomly assigned (1:1) to flexibly dosed aripiprazole (target dosage: 5, 10, or 15 mg/day) or placebo. Efficacy outcome measures included the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression-Improvement score (CGI-I). Safety and tolerability were also assessed. Ninety-eight patients were randomly assigned to receive placebo (n = 51) or aripiprazole (n = 47). Mean improvement in Aberrant Behavior Checklist irritability subscale score was significantly greater with aripiprazole than with placebo from week 1 through week 8. Aripiprazole demonstrated significantly greater global improvements than placebo, as assessed by the mean CGI-I score from week 1 through week 8; however, clinically significant residual symptoms may still persist for some patients. Discontinuation rates as a result of adverse events (AEs) were 10.6% for aripiprazole and 5.9% for placebo. Extrapyramidal symptom-related AE rates were 14.9% for aripiprazole and 8.0% for placebo. No serious AEs were reported. Mean weight gain was 2.0 kg on aripiprazole and 0.8 kg on placebo at week 8. Aripiprazole was efficacious in children and adolescents with irritability associated with autistic disorder and was generally safe and well tolerated.


Co-localization of nestin and insulin and expression of islet cell markers in long-term human pancreatic nestin-positive cell cultures.
Strategies to differentiate progenitor cells into beta cells in vitro have been considered as an alternative to increase beta cell availability prior to transplantation. It has recently been suggested that nestin-positive cells could be multipotential stem cells capable of expressing endocrine markers upon specific stimulation; however, this issue still remains controversial. Here, we characterized short- and long-term islet cell cultures derived from three different human islet preparations, with respect to expression of nestin and islet cell markers, using confocal microscopy and semi-quantitative RT-PCR. The number of nestin-positive cells was found to be strikingly high in long-term cultures. In addition, a large proportion (49.7%) of these nestin-positive cells, present in long-term culture, are shown to be proliferative, as judged by BrdU incorporation. The proportion of insulin-positive cells was found to be high in short-term (up to 28 days) cultures and declined thereafter, when cells were maintained in the presence of 10% serum, concomitantly with the decrease in insulin and PDX-1 expression. Interestingly, insulin and nestin co-expression was observed as a rare event in a small proportion of cells present in freshly isolated human islets as well as in purified islet cells cultured in vitro for long periods of time. In addition, upon long-term subculturing of nestin-positive cells in 10% serum, we observed reappearance of insulin expression at the mRNA level; when these cultures were shifted to 1% serum for a month, expression of insulin, glucagon and somatostatin was also detected, indicating that manipulating the culture conditions can be used to modulate the nestin-positive cell's fate. Attempts to induce cell differentiation by plating nestin-positive cells onto Matrigel revealed that these cells tend to aggregate to form islet-like clusters, but this is not sufficient to increase insulin expression upon short-term culture. Our data corroborate previous findings indicating that, at least in vitro, nestin-positive cells may undergo the early stages of differentiation to an islet cell phenotype and that long-term cultures of nestin-positive human islet cells may be considered as a potential source of precursor cells to generate fully differentiated/ functional beta cells.


Multiple plastic versus fully covered metal stents for managing post-liver transplantation anastomotic biliary strictures: a meta-analysis of randomized controlled trials.
Anastomotic biliary strictures (ABS) following liver transplantation (LT) are one of the most common complications, occurring in 4.5-32% of patients. Multiple plastic stenting (MPS) requires multiple sessions, with the associated risk, cost and patient discomfort. Fully covered self-expandable metal stents (FC-SEMS) have increasingly been used in this setting. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs), comparing the role of FC-SEMS and MPS in the treatment of ABS post-LT. We conducted a bibliographic search using PubMed and EMBASE, aimed at identifying available RCTs that compared MPS to FC-SEMS in patients with ABS post LT from January 2000 to October 2017. Primary outcomes were ABS resolution and recurrence, while secondary outcomes were adverse events and number of procedures performed. Pooled estimates were calculated using random-effects models. Four RCTs (205 patients) were included. ABS resolution and recurrence did not differ significantly between the groups (odds ratio [OR] 1.05, 95% confidence interval [CI] 0.43-2.56, P=0.92; and OR 2.37, 95%CI 0.54-10.38, P=0.25). The same was true for adverse events (OR 0.91, 95%CI 0.84-3.48, P=0.86) and migration rate (OR 1.31, 95%CI 0.46-3.71, P=0.61). The mean number of endoscopic retrograde cholangiopancreatography procedures was lower for FC-SEMS (mean difference [MD] -2.08). FC-SEMS and MPS had equal ABS resolution and recurrence, although there was a trend towards a higher recurrence rate in FC-SEMS that disappeared when trials with a shorter stent indwelling time were excluding. No difference was found in overall adverse events or migration rate.


Code Generation in Computational Neuroscience: A Review of Tools and Techniques.
Advances in experimental techniques and computational power allowing researchers to gather anatomical and electrophysiological data at unprecedented levels of detail have fostered the development of increasingly complex models in computational neuroscience. Large-scale, biophysically detailed cell models pose a particular set of computational challenges, and this has led to the development of a number of domain-specific simulators. At the other level of detail, the ever growing variety of point neuron models increases the implementation barrier even for those based on the relatively simple integrate-and-fire neuron model. Independently of the model complexity, all modeling methods crucially depend on an efficient and accurate transformation of mathematical model descriptions into efficiently executable code. Neuroscientists usually publish model descriptions in terms of the mathematical equations underlying them. However, actually simulating them requires they be translated into code. This can cause problems because errors may be introduced if this process is carried out by hand, and code written by neuroscientists may not be very computationally efficient. Furthermore, the translated code might be generated for different hardware platforms, operating system variants or even written in different languages and thus cannot easily be combined or even compared. Two main approaches to addressing this issues have been followed. The first is to limit users to a fixed set of optimized models, which limits flexibility. The second is to allow model definitions in a high level interpreted language, although this may limit performance. Recently, a third approach has become increasingly popular: using code generation to automatically translate high level descriptions into efficient low level code to combine the best of previous approaches. This approach also greatly enriches efforts to standardize simulator-independent model description languages. In the past few years, a number of code generation pipelines have been developed in the computational neuroscience community, which differ considerably in aim, scope and functionality. This article provides an overview of existing pipelines currently used within the community and contrasts their capabilities and the technologies and concepts behind them.


Struggling for a feasible tool - the process of implementing a clinical pathway in intensive care: a grounded theory study.
Clinical pathways can enhance care quality, promote patient safety and optimize resource utilization. However, they are infrequently utilized in intensive care. This study aimed to explain the implementation process of a clinical pathway based on a bottom-up approach in an intensive care context. The setting was an 11-bed general intensive care unit in Sweden. An action research project was conducted to implement a clinical pathway for patients on mechanical ventilation. The project was managed by a local interprofessional core group and was externally facilitated by two researchers. Grounded theory was used by the researchers to explain the implementation process. The sampling in the study was purposeful and theoretical and included registered nurses (n31), assistant nurses (n26), anesthesiologists (n11), a physiotherapist (n1), first- and second-line managers (n2), and health records from patients on mechanical ventilation (n136). Data were collected from 2011 to 2016 through questionnaires, repeated focus groups, individual interviews, logbooks/field notes and health records. Constant comparative analysis was conducted, including both qualitative data and descriptive statistics from the quantitative data. A conceptual model of the clinical pathway implementation process emerged, and a central phenomenon, which was conceptualized as 'Struggling for a feasible tool,' was the core category that linked all categories. The phenomenon evolved from the 'Triggers' ('Perceiving suboptimal practice' and 'Receiving external inspiration and support'), pervaded the 'Implementation process' ('Contextual circumstances,' 'Processual circumstances' and 'Negotiating to achieve progress'), and led to the process 'Output' ('Varying utilization' and 'Improvements in understanding and practice'). The categories included both facilitating and impeding factors that made the implementation process tentative and prolonged but also educational. The findings provide a novel understanding of a bottom-up implementation of a clinical pathway in an intensive care context. Despite resonating well with existing implementation frameworks/theories, the conceptual model further illuminates the complex interaction between different circumstances and negotiations and how this interplay has consequences for the implementation process and output. The findings advocate a bottom-up approach but also emphasize the need for strategic priority, interprofessional participation, skilled facilitators and further collaboration.


Nonlinear switching in fibre Bragg gratings.
We report on our recent experiments on nonlinear switching in fibre Bragg gratings. Using an all-fibre source we show an increase in transmission of a FBG from 4% to 40% at high powers. This switching is associated with the formation of gap solitons inside the grating. We also demonstrate an all-optical AND gate using polarization coupled gap solitons and the optical pushbroom.


Biofabrication of Zinc Oxide Nanoparticles With Syzygium aromaticum Flower Buds Extract and Finding Its Novel Application in Controlling the Growth and Mycotoxins of Fusarium graminearum.
Fusarium graminearum is a leading plant pathogen that causes Fusarium head blight, stalk rot, and Gibberella ear rot diseases in cereals and posing the immense threat to the microbiological safety of the food. Herein, we report the green synthesis of zinc oxide nanoparticles from Syzygium aromaticum (SaZnO NPs) flower bud extract by combustion method and investigated their application for controlling of growth and mycotoxins of F. graminearum. Formation of SaZnO NPs was confirmed by spectroscopic methods. The electron microscopic (SEM and TEM) analysis revealed the formation of triangular and hexagonal shaped SaZnO NPs with size range 30-40 nm. The synthesized SaZnO NPs reduced the growth and production of deoxynivalenol and zearalenone of F. graminearum in broth culture. Further analysis revealed that treatment of mycelia with SaZnO NPs resulted in the accumulation of ROS in the dose-dependent manner. Also, SaZnO NPs treatment enhanced lipid peroxidation, depleted ergosterol content, and caused detrimental damage to the membrane integrity of fungi. Moreover, SEM observations revealed that the presence of diverged micro-morphology (wrinkled, rough and shrank surface) in the macroconidia treated with SaZnO NPs. Taken together, SaZnO NPs may find a potential application in agriculture and food industries due to their potent antifungal activity.


Conventional Vs Digital Impressions: Acceptability, Treatment Comfort and Stress Among Young Orthodontic Patients.
The objective of the present study was to compare patients' acceptability, comfort and stress with conventional and digital impressions. Thirty young orthodontic patients (15 males and 15 females) who had no previous experience of impressions were enrolled in this study. Conventional impressions for orthodontic study models of the dental arches were taken using an alginate impression material (Hydrogum®, Zhermack Spa, Badia Polesine, Rovigo, Italy). Fifteen days later, digital impressions of both arches were acquired using an intraoral scanner (CS3600®, Carestream Dental, Rochester, NY, USA). Immediately after impression taking, patients' acceptability, comfort and stress were measured using two questionnaires and the State anxiety scale. Data showed no difference in terms of anxiety and stress; however, patients preferred the use of digital impressions systems instead of conventional impression techniques. Alginate impressions resulted as fast as digital impressions. Digital impressions resulted the most accepted and comfortable impression technique in young orthodontic patients, when compared to conventional techniques.


pfk13-Independent Treatment Failure in Four Imported Cases of Plasmodium falciparum Malaria Treated with Artemether-Lumefantrine in the United Kingdom.
We present case histories of four patients treated with artemether-lumefantrine for falciparum malaria in UK hospitals in 2015 to 2016. Each subsequently presented with recurrent symptoms and Plasmodium falciparum parasitemia within 6 weeks of treatment with no intervening travel to countries where malaria is endemic. Parasite isolates, all of African origin, harbored variants at some candidate resistance loci. No evidence of pfk13-mediated artemisinin resistance was found. Vigilance for signs of unsatisfactory antimalarial efficacy among imported cases of malaria is recommended.


Adjustment in patients with rheumatoid arthritis and their children.
To assess everyday life stress and emotional adjustment in patients with rheumatoid arthritis (RA) and their children. We conducted a 6 month study of 14 patients with RA with children aged 4-16 years (25 children) and 24 control families (53 children). Life event stress and functional capacity were assessed at the beginning and end of the study, and minor stressors (hassles), positive events (uplifts), and salivary cortisol were recorded weekly. Emotional adjustment was measured monthly in adults by self-report, and bimonthly in children using the Child Behavior Checklist (completed by parents). Social support and psychological coping responses were also measured. Patients with RA experienced fewer positive events than did controls, and they tended to have smaller support networks. Daily hassle levels correlated with severity of disability, and differences in psychological coping were also observed. Children from RA families reported nearly 50% more hassles per week than did controls, and their social networks were significantly smaller. They were rated as having greater problems of social adjustment than controls. Cortisol concentration was greater among children who experienced more life event stress over the study period, but did not differ between groups. The patients with RA in this study showed good adaptation, but experienced less pleasure in their daily lives. The children of patients with RA may have heightened vulnerability to stress related problems, with fewer social resources and difficulties in behavioral adjustment.


Phytophthora ramorum does not cause physiologically significant systemic injury to California bay laurel, its primary reservoir host.
California bay laurel trees (Umbellularia californica) play a crucial role in the reproduction and survival of Phytophthora ramorum in coastal California forests by supporting sporulation during the rainy season and by providing a means for the pathogen to survive the dry, Mediterranean summer. While bay laurel is thus critical to the epidemiology of sudden oak death and other P. ramorum diseases in California, the relatively minor symptoms observed on this reservoir host suggest that it may not sustain ecologically significant injury itself. The long-term role that P. ramorum will play in California forests will depend in part on the extent to which this pathogen decreases the ecological fitness of bay laurel. Despite the importance of this question, no study has yet investigated in detail the physiological impact that ramorum blight imposes on bay laurel. This experimental study quantifies the impact that P. ramorum has on artificially inoculated bay laurel seedlings with measurements that integrate the full injury that infection with an oomycete may cause: photosynthetic efficiency, total photosynthetic area, and growth. Leaf area and leaf mass were not impacted significantly by infection of P. ramorum. Photosynthetic efficiency was mildly depressed in symptomatic, but not asymptomatic leaves, despite unnaturally high levels of necrosis that were imposed on the seedlings. These results demonstrate that bay laurel trees suffer only minor injury from ramorum blight beyond visible necrotic symptoms. Consequently, it is highly likely that bay laurel will continue to be widely available as a host for P. ramorum in California forests, which has long-term implications for the composition of these forests.


Delayed matching to sample: reinforcement has opposite effects on resistance to change in two related procedures.
The effects of reinforcement on delayed matching to sample (DMTS) have been studied in two within-subjects procedures. In one, reinforcer magnitudes or probabilities vary from trial to trial and are signaled within trials (designated signaled DMTS trials). In the other, reinforcer probabilities are consistent for a series of trials produced by responding on variable-interval (VI) schedules within multiple-schedule components (designated multiple VI DMTS). In both procedures, forgetting functions in rich trials or components are higher than and roughly parallel to those in lean trials or components. However, during disruption, accuracy has been found to decrease more in rich than in lean signaled DMTS trials and, conversely, to decrease more in lean than in rich multiple VI DMTS components. In the present study, we compared these procedures in two groups of pigeons. In baseline, forgetting functions in rich trials or components were higher than and roughly parallel to those in lean trials or components, and were similar between the procedures. During disruption by prefeeding or extinction, accuracy decreased more in rich signaled DMTS trials, whereas accuracy decreased more in lean multiple VI DMTS components. These results replicate earlier studies and are predicted by a model of DMTS from Nevin, Davison, Odum, and Shahan (2007).


Fine structure of the retina and pigment epithelium in the creek chub, Semotilus atromaculatus (Cyprinidae, Teleostei).
The structure of the light- and dark-adapted retina, the pigment epithelium and the choroid of the creek chub, Semotilus atromaculatus (Cyprinidae, Teleostei) is examined by light and electron microscopy. An extensive network of vitreal blood vessels emanating from the hyaloid artery enters the eye with the optic nerve and overlies the inner limiting membrane. This membrane closely apposes the fine protrusions of the Müller cell processes which traverse the entire retina, dividing the inner retina into alternating fascicles of ganglion cells and optic axons. The inner nuclear layer consists of bipolar, amacrine, Müller cell soma and two layers of horizontal cells. The outer plexiform layer possesses both rod spherules and cone pedicles. Each rod spherule consists of a single synaptic ribbon in either a triad or quadrad junctional arrangement within the invaginating terminal endings of the bipolar and horizontal cell processes. In contrast, cone pedicles possess multiple synaptic ribbons within their junctional complexes and, in the light-adapted state, the horizontal cell processes show spinule formation. Four photoreceptor types are identified on morphological criteria; unequal double cones, large single cones, small single cones and rods. All but the small single cones are capable of retinomotor responses. The rod to cone ratio is approximately 5:1 and the rods form two ill-defined rows in the light-adapted condition. The retinal pigment epithelium possesses two types of osmiophilic granules. These are bound within slender microvilli and migrate vitread to surround the photoreceptors in response to light. Bruch's membrane is trilaminar and the vascularised choroid consists of up to three layers of melanocytes. The endothelial borders of the choroidal blood vessels abutting the outer lamina of Bruch's membrane are fenestrated.


Central versus local adjudication of myocardial infarction in a cardiac biomarker trial.
The impact of regulatory requirements, which require central adjudication for the diagnosis of acute myocardial infarction (AMI) in cardiac biomarker studies, is unclear. We determined the impact of local (at the site of subject enrollment) versus central adjudication of AMI on final diagnosis. This is a retrospective analysis of data from the Myeloperoxidase in the Diagnosis of Acute Coronary Syndromes Study, an 18-center prospective study of patients with suspected acute coronary syndromes, with enrollment from December 19, 2006, to September 20, 2007. Local adjudication of AMI was performed by a single site investigator at each center following the protocol-specified definition and according to the year 2000 definition of AMI, which based cardiac troponin (cTn) elevation on local cut points for each of the 13 different assays. After completion of the Myeloperoxidase in the Diagnosis of Acute Coronary Syndromes Study primary analysis and to evaluate a new troponin assay, a Food and Drug Administration-mandated central adjudication was performed by 3 investigators at different institutions. This adjudication used the 2007 Universal Definition of AMI, which differs by use of the manufacturer's 99th percentile cTn cut point. We describe the outcome of this process and compare it with the local adjudication. Central adjudicators were not blinded to local adjudications. For central adjudication, discrepant diagnoses were resolved by consensus. Local versus central cTn cut points differed for 6 assays. Both definitions required a rise and/or fall of cTn. Discrepant cases were reviewed by the lead author. Difficult cases were defined as having a difference between local and central adjudication, an elevated cTn with a temporal rise and fall, and a negative or absent risk stratification test. Statistics were by χ(2), κ, and logistic regression. Of 1,107 patients enrolled, 11 had indeterminate central adjudication, leaving 1,096 for analysis. In spite of high agreement across central versus local adjudicators, κ = 0.79 (95% CI [0.73, 0.85]), AMI was diagnosed more often by central adjudication, 134 (12.2%) versus 104 (9.5%), with 44 local diagnoses (4%) changed from non-AMI to AMI (n = 37) or AMI to non-AMI (n = 7) (P < .001). These 44 represented 34% (95% CI 26%-42%) of 141 cases in which either central or local adjudication was AMI. Of diagnoses changed to AMI, 3 reasons contributed approximately one-third each: the local use of a non-99th percentile cTn cutoff (32%), the possibility of human error (34%), and difficult cases (34%). Despite an acceptable κ, over a third of patients with a diagnosis of AMI were not assigned that diagnosis by both sets of adjudicators. This supports the importance of 1 standard method for diagnosis of AMI.


Mammal decline, linked to invasive Burmese python, shifts host use of vector mosquito towards reservoir hosts of a zoonotic disease.
Invasive apex predators have profound impacts on natural communities, yet the consequences of these impacts on the transmission of zoonotic pathogens are unexplored. Collapse of large- and medium-sized mammal populations in the Florida Everglades has been linked to the invasive Burmese python, Python bivittatus Kuhl. We used historic and current data to investigate potential impacts of these community effects on contact between the reservoir hosts (certain rodents) and vectors of Everglades virus, a zoonotic mosquito-borne pathogen that circulates in southern Florida. The percentage of blood meals taken from the primary reservoir host, the hispid cotton rat, Sigmodon hispidus Say and Ord, increased dramatically (422.2%) from 1979 (14.7%) to 2016 (76.8%), while blood meals from deer, raccoons and opossums decreased by 98.2%, reflecting precipitous declines in relative abundance of these larger mammals, attributed to python predation. Overall species diversity of hosts detected in Culex cedecei blood meals from the Everglades declined by 40.2% over the same period (H(1979) = 1.68, H(2016) = 1.01). Predictions based upon the dilution effect theory suggest that increased relative feedings upon reservoir hosts translate into increased abundance of infectious vectors, and a corresponding upsurge of Everglades virus occurrence and risk of human exposure, although this was not tested in the current study. This work constitutes the first indication that an invasive predator can increase contact between vectors and reservoirs of a human pathogen and highlights unrecognized indirect impacts of invasive predators.


Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10.
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by variable obesity, pigmentary retinopathy, polydactyly, mental retardation, hypogonadism and renal failure. In order to identify novel BBS loci we undertook autozygosity mapping studies using high-density SNP microarrays in consanguineous kindreds. We mapped a BBS locus to a 10.1 Mb region at 12q15-q21.2 in a large Omani BBS family (peak lod score 8.3 at theta = 0.0 for marker D12S1722) that contained the recently described BBS10 locus. Mutation analysis of candidate genes within the target interval, including the BBS10 gene, revealed a homozygous frameshift mutation in FLJ23560 and mutations were also detected in four smaller consanguineous families with regions of autozygosity at 12q21.2. These findings (a) confirm a previous report that FLJ23560 (BBS10) mutations are a significant cause of BBS, and (b) further demonstrate the utility of high-density SNP array mapping in consanguineous families for the mapping and identification of recessive disease genes.


Probabilistic analysis of cost-effectiveness models: choosing between treatment strategies for gastroesophageal reflux disease.
When choosing between mutually exclusive treatment options, it is common to construct a cost-effectiveness frontier on the cost-effectiveness plane that represents efficient points from among the treatment choices. Treatment options internal to the frontier are considered inefficient and are excluded either by strict dominance or by appealing to the principle of extended dominance. However, when uncertainty is considered, options excluded under the baseline analysis may form part of the cost-effectiveness frontier. By adopting a Bayesian approach, where distributions for model parameters are specified, uncertainty in the decision concerning which treatment option should be implemented is addressed directly. The approach is illustrated using an example from a recently published cost-effectiveness analysis of different possible treatment strategies for gastroesophageal reflux disease. It is argued that probabilistic analyses should be encouraged because they have potential to quantify the strength of evidence in favor of particular treatment choices.


Post-traumatic stress disorder and severe head injury.
Post-traumatic stress disorder (PTSD) is described following a road traffic accident in which the patient suffered a severe head injury. The stress reaction was associated with intrusive thoughts and avoidance of cognitive and physical events associated with consequences of the accident. The condition was successfully treated by behavioural intervention. It seems clear that PTSD can occur even where there is loss of consciousness and organic amnesia for the event and its immediate sequelae.


The crystal structure of beta-lactamase from Staphylococcus aureus at 0.5 nm resolution.
The preparation, crystallization and low-resolution structure determination of beta-lactamase (EC 22.214.171.124, 'penicillinase') from Staphylococcus aureus is described. The enzyme crystallizes in space group I222 with 1 molecule per asymmetric unit and cell dimensions a = 5.45(1), b = 9.39(1) and c = 13.87(2) nm. The structure was determined at 0.5 nm resolution by using phases calculated from (NH4)2Pt(CN)4 and KAu(CN)2 derivatives. The mean figure of merit mean value of m, for the 1106 reflexions used was 0.70. Difference Fourier syntheses for data collected from crystals soaked in platinum D-methionine and in 6-(4-hydroxy-3,5-di-iodobenzamido)penicilloic acid revealed the likely position of the active site of the enzyme.


3D Bioprinting of Carboxymethylated-Periodate Oxidized Nanocellulose Constructs for Wound Dressing Applications.
Nanocellulose has a variety of advantages, which make the material most suitable for use in biomedical devices such as wound dressings. The material is strong, allows for production of transparent films, provides a moist wound healing environment, and can form elastic gels with bioresponsive characteristics. In this study, we explore the application of nanocellulose as a bioink for modifying film surfaces by a bioprinting process. Two different nanocelluloses were used, prepared with TEMPO mediated oxidation and a combination of carboxymethylation and periodate oxidation. The combination of carboxymethylation and periodate oxidation produced a homogeneous material with short nanofibrils, having widths <20 nm and lengths <200 nm. The small dimensions of the nanofibrils reduced the viscosity of the nanocellulose, thus yielding a material with good rheological properties for use as a bioink. The nanocellulose bioink was thus used for printing 3D porous structures, which is exemplified in this study. We also demonstrated that both nanocelluloses did not support bacterial growth, which is an interesting property of these novel materials.


Impaired cardiopulmonary baroreflex control of renal nerves in renal hypertension.
We recently reported that arterial baroreflex control of renal nerve traffic is impaired in renal hypertensive rabbits. The purpose of this study was to determine if vagal cardiopulmonary baroreflex control of renal nerve traffic is also impaired. Experiments were performed in 10 hypertensive (mean arterial pressure +/- SE in conscious state, 110 +/- 3 mm Hg) and 10 normotensive (79 +/- 1 mm Hg) chloralose-anesthetized rabbits. Responses to graded blood volume expansion (+5, +10, +15 ml/kg) with dextran in saline were recorded with all baroreflexes intact, after sinoaortic baroreceptor denervation, and after vagotomy. With arterial and cardiopulmonary baroreflexes intact, volume expansion resulted in decreases in renal nerve traffic of -12 +/- 2%/mm Hg increase in left atrial pressure in normotensive rabbits, but of only -5 +/- 2%/mm Hg in the hypertensive rabbits (P less than 0.05). This difference is particularly striking in view of the larger maximum increases in arterial (25 +/- 7 vs. 12 +/- 3 mm Hg) and left atrial pressure (9 +/- 1 vs. 6 +/- 1 mm Hg) during volume expansion in hypertensive vs. normotensive rabbits. After sinoaortic baroreceptor denervation, the responses of normotensive rabbits were preserved (-11 +/- 3%/mm Hg), while those of hypertensive rabbits were impaired further (-2 +/- 1%/mm Hg). Vagotomy abolished responses of renal nerves to volume expansion in both groups. These data demonstrate striking impairment of vagal cardiopulmonary baroreflex control of renal nerve traffic in renal hypertension. Even though arterial baroreflexes have been shown to be abnormal in renal hypertension, they still may partially compensate for markedly impaired cardiopulmonary baroreflex control of the renal nerves.


Perspectives on the impact on vocal function of heavy vocal load among working professional music theater performers.
Music theater singers (MTS) typically have a heavy vocal load, but the impact on their voices has not been previously evaluated. A group of 49 MTS from two professional productions were administered the Singing Voice Handicap Index (SVHI). Responses for the SVHI demonstrated that, although the SVHI supported the performers' self-report of healthy vocal status, it lacked the sensitivity to detect potential subtle fluctuations or changes in physical functioning of the voice for working singers. Secondarily, descriptive data regarding professional working singers' perspectives were collected regarding how their singing voices typically responded to performing in a music theater production after a show, across a working week, and across a production season. Seventy-nine currently performing MTS were involved in a series of focus group interviews (n=43) or a written survey (n=36) to detail their perception of the impact of performing in an eight-show per week professional production on their vocal function and vocal health. Thematic analysis revealed the MTS commonly perceived transient and variable changes in their singing voice status in both positive and negative directions after heavy vocal load. Based on these data, a list of 97 descriptors of these perceptual changes was generated using the singers' own terminology and experiences. These included symptoms of vocal impairment and vocal fatigue but also some novel descriptors of positive vocal changes to the physical functioning of the singing voice as a perceived consequence of heavy vocal load. This study offers new and valuable insights into performers' perceptions of the impact of performing in a musical theater production on physical aspects of vocal function.


ICAM-1 is crucial for protection from TMEV-induced neuronal damage but not demyelination.
Previous work has suggested that the factors protecting mice from Theiler's murine encephalomyelitis virus (TMEV)-induced spinal cord demyelination are distinct from those involved in protection of the brain during the acute encephalitic phase. In this study, we examined the requirement for intercellular adhesion molecule-1 (ICAM-1) in both of these processes. During the acute phase of infection (days 7 to 10 after intracerebral infection with TMEV), no differences in brain or spinal cord pathology or virus burdens were observed between ICAM-1-knockout mice and the infected immunocompetent control mice of a similar background. Examination of brain pathology later in infection (that is, day 45 post infection [p.i.]) revealed that ICAM-1-deficient mice experienced increased levels of pathology in gray matter regions of the brain. We observed an increase in striatal damage and meningeal inflammation in the brains of TMEV-infected ICAM-1-knockout mice compared to C57BL/6J mice. Despite the increase in brain pathology, no immunoreactivity to viral antigens was detected, suggesting that the virus had been cleared by this time. Resistance to demyelination was similar in both groups, indicating that the resulting immune response was sufficient for protection of the spinal cord white matter.


[Citizenship and modernity: the emergence of the social issue on the public agenda]
The guiding thread of this article is the inclusion of the so-called "social issue" on the public agenda from modernity through its more current developments. The study seeks to demonstrate that one of the meanings of modernity is precisely the radical inversion of the meaning of public and private, providing for the broadening of public space. Far from being associated with a given bourgeois capitalist model, modernity thus projects itself as a reinvention of rights, citizenship, and contemporary democratic experience. Over this long course, the individualization process has been seen as a crucial factor for understanding both the ideology of modern societies and - paradoxically - the very emergence of social sciences. The individualist concept, emphasizing the specificity of modern representation of the social sphere, i.e., its characteristic as a self-instituting society, allows for a broadened understanding of the public domain. In this sense, the ideological polarization between liberal conceptions (favoring individualism) and Marxist ones (linked to holistic representations of the social sphere) should be reviewed, since this polarization has repercussions on the very analytical tools used by social sciences.


Two cases of male genital self-mutilation.
Male genital self-mutilation (GSM) is a rare but serious phenomenon. Some of the risk factors for this act are the presence of religious delusions, command hallucinations, low self-esteem, and feelings of guilt associated with sexual offences. Other risk factors include failures in the male role, problems in the early developmental period, such as experiencing difficulties in male identification and persistence of incestuous desires, depression, and having a history of GSM. The eponym Klingsor Syndrome, which involves the presence of religious delusions, is proposed for GSM. Psychiatric case reports of male GSM in the literature are rare and mostly anecdotal.


Impact of Occupational Therapy Education on Students' Disability Attitudes: A Longitudinal Study.
Discrimination based on disability-ableism-is pervasive and affects the opportunities of people with disabilities to fully engage in society. The aim of this study was to explore the impact of occupational therapy graduate education on students' explicit and implicit disability attitudes throughout their graduate education. Longitudinal observational study, measuring occupational therapy students' attitudes on an annual basis. Three Midwestern graduate occupational therapy programs. Occupational therapy students (N = 67). Outcomes and Measures: Participants completed the Symbolic Ableism Scale (to measure their explicit disability attitudes) and the Disability Attitude Implicit Association Test (to measure their implicit disability attitudes) on an annual basis, from when they entered their occupational therapy program to when they graduated. The students' explicit attitudes decreased (i.e., became more favorable) throughout their education; however, their implicit attitudes did not change. In fact, most students (68%) were implicitly ableist at graduation. Occupational therapy education programs have an important role to play in terms of intervening with students' beliefs and preconceived assumptions about disability. Our finding suggests that occupational therapy programs may fail to intervene with students' ableist attitudes. What This Article Adds: Little longitudinal research has examined how students' implicit disability bias may be affected by their academic experience. Our findings about ableism among occupational therapy students should open the door for further dialogue on the existence of ableism in program content, its potential impact on future client interactions, and the development of approaches to address it.


The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation.
Folate metabolism is central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism is thought to be important for proliferating cancer cells. The enzyme MTHFD2 in this pathway is highly expressed in human tumors and broadly required for survival of cancer cells. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in cancer cell biology. We here report that MTHFD2 is co-expressed with two distinct gene sets, representing amino acid metabolism and cell proliferation, respectively. Consistent with a role for MTHFD2 in cell proliferation, MTHFD2 expression was repressed in cells rendered quiescent by deprivation of growth signals (serum) and rapidly re-induced by serum stimulation. Overexpression of MTHFD2 alone was sufficient to promote cell proliferation independent of its dehydrogenase activity, even during growth restriction. In addition to its known mitochondrial localization, we found MTHFD2 to have a nuclear localization and co-localize with DNA replication sites. These findings suggest a previously unknown role for MTHFD2 in cancer cell proliferation, adding to its known function in mitochondrial folate metabolism.


The Olympic Regeneration in East London (ORiEL) study: protocol for a prospective controlled quasi-experiment to evaluate the impact of urban regeneration on young people and their families.
Recent systematic reviews suggest that there is a dearth of evidence on the effectiveness of large-scale urban regeneration programmes in improving health and well-being and alleviating health inequalities. The development of the Olympic Park in Stratford for the London 2012 Olympic and Paralympic Games provides the opportunity to take advantage of a natural experiment to examine the impact of large-scale urban regeneration on the health and well-being of young people and their families. A prospective school-based survey of adolescents (11-12 years) with parent data collected through face-to-face interviews at home. Adolescents will be recruited from six randomly selected schools in an area receiving large-scale urban regeneration (London Borough of Newham) and compared with adolescents in 18 schools in three comparison areas with no equivalent regeneration (London Boroughs of Tower Hamlets, Hackney and Barking & Dagenham). Baseline data will be completed prior to the start of the London Olympics (July 2012) with follow-up at 6 and 18 months postintervention. Primary outcomes are: pre-post change in adolescent and parent mental health and well-being, physical activity and parental employment status. Secondary outcomes include: pre-post change in social cohesion, smoking, alcohol use, diet and body mass index. The study will account for individual and environmental contextual effects in evaluating changes to identified outcomes. A nested longitudinal qualitative study will explore families' experiences of regeneration in order to unpack the process by which regeneration impacts on health and well-being. The study has approval from Queen Mary University of London Ethics Committee (QMREC2011/40), the Association of Directors of Children's Services (RGE110927) and the London Boroughs Research Governance Framework (CERGF113). Fieldworkers have had advanced Criminal Records Bureau clearance. Findings will be disseminated through peer-reviewed publications, national and international conferences, through participating schools and the study website (http://www.orielproject.co.uk).


Type 3 deiodinase is highly expressed in infiltrating neutrophilic granulocytes in response to acute bacterial infection.
Macrophages and polymorphonuclear cells (PMNs) play an important role in the first line of defense against bacteria by infiltrating the infected organ in order to clear the harmful pathogen. Our earlier studies showed that granulocytes express type 3 deiodinase (D3) when activated during a turpentine-induced abscess. We hypothesized that D3 expression by granulocytes may also occur during bacterial infection. In order to test this hypothesis, we used the following experimental infection models: peritonitis induced by Escherichia coli and acute pneumonia induced by Streptococcus pneumoniae. E. coli-induced peritonitis was characterized by infiltration in the liver by inflammatory cells with abundant immunocytochemical D3 expression while no staining was present in hepatocytes of infected or control mice. Acute pneumonia induced by S. pneumoniae resulted in inflamed lungs characterized by numerous infiltrating granulocytes expressing D3 while no D3 staining was present in lung sections without an infiltrate. Serum thyroid hormones were negatively correlated to bacterial outgrowth in both lung and spleen, and thus to the severity of illness. Infiltrating granulocytes during acute bacterial infection express D3. Our work supports the hypothesis that D3 plays an important role during chemical and bacterial inflammation. Whether the resulting decreased local bioavailability of thyroid hormones or rather the increased local availability of iodide is an important element of the innate immune response remains to be studied.


Health conditions of recyclable waste pickers.
The presence of chronic non-communicable diseases (NCDs) among vulnerable populations is a rarely discussed subject. Thus, the present cross-sectional descriptive study aimed to analyse the health conditions and access to public health services of 268 waste pickers in southern Brazil. Regarding NCDs, their prevalence of hypertension was 32.8 %, diabetes 11.4 %, dyslipidemia 16.4 %, overweight 51.1 %, obesity 25.7 % and abdominal obesity 57.8 %. Regarding access to health services, 36.9 % of the sample had not consulted with a doctor in more than 1 year, 15.7 % had no access to a healthcare unit, 7.5 % had never measured their blood pressure, 45.9 % had never had a glucose test, and 61.2 % had never had a triglyceride test. The statistical analysis showed that whereas men had gone longer since their last medical consultation and blood pressure measurement, women had increased frequencies of overweight, abdominal obesity, awareness of their hypertension and use of anti-hypertensive drugs (p < 0.05). Therefore, the health profile of waste pickers is critical, with a high prevalence of NCDs and poor healthcare usage. Strategies to improve monitoring and treatment are recommended.


Birth delivery mode modifies the associations between prenatal polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) and neonatal thyroid hormone levels.
Developing infants may be especially sensitive to hormone disruption from chemicals including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). We investigated relationships between cord serum levels of PCBs and PBDEs and thyroid hormones measured in cord blood serum and neonatal blood spots. We measured PCBs and PBDEs, thyrotropin (TSH), thyroxine (T4) and free T4 (FT4) in cord blood serum from 297 infants who were delivered at the Johns Hopkins Hospital in 2004-2005. We abstracted results of total T4 (TT4) measured in blood spots collected in the hospital and at neonatal visits. We used delivery mode (augmented vaginal deliveries and nonelective cesarean deliveries) as a surrogate for intrapartum stress, which is known to alter cord blood thyroid hormones. In the full study population, no compounds were associated with a change in average TSH, FT4, or TT4. BDE-100 was associated with increased odds of low cord TT4, BDE-153 with increased odds of low cord TT4 and FT4, and no compounds were associated with increased odds of high TSH. For infants born by spontaneous, vaginal, unassisted deliveries, PCBs were associated with lower cord TT4 and FT4 and lower TT4 measured in neonatal blood spots. PBDEs showed consistent but mainly nonsignificant negative associations with TT4 and FT4 measurements. Prenatal PCB and PBDE exposures were associated with reduced TT4 and FT4 levels among infants born by spontaneous, unassisted vaginal delivery. Intrapartum stress associated with delivery mode may mask hormonal effects of PCBs and PBDEs.


Breast cancer cell proliferation is inhibited by BAD: regulation of cyclin D1.
Recent investigations suggest that functions of the proapoptotic BCL2 family members, including BAD, are not limited to regulation of apoptosis. Here we demonstrate that BAD inhibits G(1) to S phase transition in MCF7 breast cancer cells independent of apoptosis. BAD overexpression inhibited G(1) transit and cell growth as well as cyclin D1 expression. Inhibition of cyclin D1 expression was mediated through inhibition of transcription activated by AP1. Chromatin immunoprecipitation assays indicated that BAD is localized at the 12-O-tetradecanoylphorbol-13-acetate-response element (TRE) and cAMP-response element (CRE) in the cyclin D1 promoter. This was shown to reflect direct binding interactions of BAD with c-Jun, and this interaction inhibited the activity of AP1 complexes at TRE. BAD did not interact with phosphorylated forms of c-Jun. Our data suggest that inhibitory TRE/CRE-c-Jun-BAD complexes are present at the cyclin D1 promoter in quiescent cells. Estrogen stimulation displaced BAD from TRE/CRE elements in MCF7 cells, whereas BAD overexpression inhibited estrogen-induced cyclin D1 synthesis and cell proliferation. Inhibition of endogenous BAD in MCF7 cells markedly increased the proliferative fraction and DNA synthesis, activated Cdks, and increased cyclin D1 protein levels. This action of BAD required serine residues Ser(75) and Ser(99). Both phosphorylated and unphosphorylated forms of BAD localized to the nuclei of human breast epithelial cells. Thus, we demonstrate a novel role for BAD in cell cycle regulation dependent upon its phosphorylation state and independent of the BAD/BCL2 interaction and apoptosis.


Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone-Sensitive Prostate Cancer Treated With Androgen Deprivation With or Without Docetaxel.
Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database ( ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA ≤ 0.2, > 0.2 to 4, and > 4 ng/mL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA ≤ 0.2 ng/mL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P ≤ .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached ≤ 0.2 ng/mL compared with > 4 ng/mL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA ≤ 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA ≤ 0.2 ng/mL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA ≤ 0.2 ng/mL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA ≤ 0.2 ng/mL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood of a lower PSA and improved survival.


Langerhans cell counts in oral epithelial dysplasia and their correlation to clinicopathological parameters.
Langerhans cells (LCs) are antigen presenting cells. This study assessed the LC counts in oral epithelial dysplasia (OED) and their correlation to clinicopathological parameters. This study examined the LC counts in the epithelia and subepithelial connective tissues of 58 patients with OED (21 mild, 18 moderate, and 19 severe OED lesions) and 10 specimens of normal oral mucosa (NOM) by anti-S-100 protein immunostaining. We found that the mean LC counts in the epithelia or subepithelial connective tissues increased significantly from NOM samples through mild and moderate OED to severe OED samples. In addition, a significant correlation was found between higher mean LC counts in the dysplastic epithelia of OED samples and OED lesions with thicker epithelial layers (p<0.001) or wider inflammatory zones (p<0.001), and between higher mean LC counts in the subepithelial connective tissues of OED samples and OED lesions with wider inflammatory zones (p<0.001). Moreover, the nine OED lesions with malignant transformation had a significantly lower mean LC count than the 49 OED lesions without malignant transformation. The significant and gradual elevation in LC count from NOM through mild and moderate OED to severe OED lesions suggests an upregulation of immunosurveillance ability in OED patients during the early oral carcinogenesis process. A low LC count in OED lesions may suggest the partial loss of immunosurveillance ability against dysplastic cells; this in turn favors the malignant transformation of an OED lesion into oral cancer.


Dental adhesive compounds alter glutathione levels but not glutathione redox balance in human THP-1 monocytic cells.
The use of hydrophilic dental monomers in dentin bonding agents has vastly improved resin-dentin bond strengths, but incomplete polymerization of these monomers and their leaching into adjacent (pulpal) oral tissues has raised concerns about their biocompatibility. The sublethal effects of these resins are virtually unknown, but their electrophilic nature led to the hypothesis that they may alter cellular oxidative stress pathways. Glutathione balance between reduced (GSH) and oxidized (GSSG) is a major mechanism by which cells maintain redox balance and was therefore the focus of the current investigation. THP-1 human monocytic cells were exposed to hydroxyethyl methacrylate (HEMA), benzoyl peroxide (BPO), camphorquinone (CQ), or triethyelene glycol dimethacrylate (TEGDMA) for 24 h at sublethal doses, then GSH and GSSG levels were measured by means of Ellman's method adapted for cell culture. The results indicate that these dental resin compounds act at least partly via oxidative stress by increasing GSH levels at sublethal concentrations. However, the GSH-GSSG ratio was relatively unaffected. Only BPO altered the GSH-GSSG ratio at 24 h, again at sublethal levels (7.5-15 micromol/L). The results support the hypothesis that resin monomers act, at least in part, via oxidative stress, and that oxidative-stress pathways should be one focus of future investigations of monomer biocompatibility.