Root caries risk indicators: a systematic review of risk models.
To identify risk indicators that are associated with root caries incidence in published predictive risk models. Abstracts (n = 472) identified from a MEDLINE, EMBASE, and Cochrane registry search were screened independently by two investigators to exclude articles not in English (n = 39), published prior to 1970 (none), or containing no information on either root caries incidence, risk indicators, or risk models (n = 209). A full-article duplicate review of the remaining articles (n = 224) selected those reporting predictive risk models based on original/primary longitudinal root caries incidence studies. The quality of the included articles was assessed based both on selected criteria of methodological standards for observational studies and on the statistical quality of the modeling strategy. Data from these included studies were extracted and compiled into evidence tables, with information about the cohort location, incidence period, sample size, age of the study participants, risk indicators included in the model, root caries incidence, modeling strategy, significant risk indicators/predictors, and parameter estimates and statistical findings. Thirteen articles were selected for data extraction. The overall quality of the included articles was poor to moderate. Root caries incidence ranged from 12% to 77% (mean ± SD = 45 ± 17%); follow-up time of the published studies was ≤ 10 years (range = 9; median = 3); sample size ranged from 23-723 (mean ± SD = 264 ± 203; median = 261); person-years ranged from 23 to 1540 (mean ± SD = 760 ± 556; median = 746). Variables most frequently tested and significantly associated with root caries incidence were (times tested; % significant; directionality): baseline root caries (12; 58%; positive); number of teeth (7; 71%; three times positive, twice negative), and plaque index (4; 100%; positive). Ninety-two other clinical and nonclinical variables were tested: 27 were tested three times or more and were significant between 9% and 100% of the times tested; and 65 were tested but never significant. The root caries incidence indicators/predictors most frequently reported were root caries prevalence at baseline, number of teeth, and plaque index. This finding can guide targeted root caries prevention. There was substantial variation among published models of root caries risk in terms of variable selection, sample size, cohort location, assessment methods, incidence periods, association directionality, and analytical techniques. Future studies should emphasize variables frequently tested and often significant, and validate existing models in independent databases.


Benign violations: making immoral behavior funny.
Humor is an important, ubiquitous phenomenon; however, seemingly disparate conditions seem to facilitate humor. We integrate these conditions by suggesting that laughter and amusement result from violations that are simultaneously seen as benign. We investigated three conditions that make a violation benign and thus humorous: (a) the presence of an alternative norm suggesting that the situation is acceptable, (b) weak commitment to the violated norm, and (c) psychological distance from the violation. We tested the benign-violation hypothesis in the domain of moral psychology, where there is a strong documented association between moral violations and negative emotions, particularly disgust. Five experimental studies show that benign moral violations tend to elicit laughter and amusement in addition to disgust. Furthermore, seeing a violation as both wrong and not wrong mediates behavioral displays of humor. Our account is consistent with evolutionary accounts of laughter, explains humor across many domains, and suggests that humor can accompany negative emotion.


The perinucleolar compartment and transcription.
The perinucleolar compartment (PNC) is a unique nuclear structure localized at the periphery of the nucleolus. Several small RNAs transcribed by RNA polymerase III and two hnRNP proteins have been localized in the PNC (Ghetti, A., S. Piñol-Roma, W.M. Michael, C. Morandi, and G. Dreyfuss. 1992. Nucleic Acids Res. 20:3671-3678; Matera, A.G., M.R. Frey, K. Margelot, and S.L. Wolin. 1995. J. Cell Biol. 129:1181- 1193; Timchenko, L.T., J.W. Miller, N.A. Timchenko, D.R. DeVore, K.V. Datar, L. Lin, R. Roberts, C.T. Caskey, and M.S. Swanson. 1996. Nucleic Acids Res. 24: 4407-4414; Huang, S., T. Deerinck, M.H. Ellisman, and D.L. Spector. 1997. J. Cell Biol. 137:965-974). In this report, we show that the PNC incorporates Br-UTP and FITC-conjugated CTP within 5 min of pulse labeling. Selective inhibition of RNA polymerase I does not appreciably affect the nucleotide incorporation in the PNC. Inhibition of all RNA polymerases by actinomycin D blocks the incorporation completely, suggesting that Br-UTP incorporation in the PNC is due to transcription by RNA polymerases II and/or III. Treatment of cells with an RNA polymerase II and III inhibitor induces a significant reorganization of the PNC. In addition, double labeling experiments showed that poly(A) RNA and some of the factors required for pre-mRNA processing were localized in the PNC in addition to being distributed in their previously characterized nucleoplasmic domains. Fluorescence recovery after photobleaching (FRAP) analysis revealed a rapid turnover of polypyrimidine tract binding protein within the PNC, demonstrating the dynamic nature of the structure. Together, these findings suggest that the PNC is a functional compartment involved in RNA metabolism in the cell nucleus.


Characterization of platinum-iron catalysts supported on MCM-41 synthesized with rice husk silica and their performance for phenol hydroxylation.
Mesoporous material RH-MCM-41 was synthesized with rice husk silica by a hydrothermal method. It was used as a support for bimetallic platinum-iron catalysts Pt-Fe/RH-MCM-41 for phenol hydroxylation. The catalysts were prepared by co-impregnation with Pt and Fe at amounts of 0.5 and 5.0 wt.%, respectively. The RH-MCM-41 structure in the catalysts was studied with x-ray diffraction, and their surface areas were determined by nitrogen adsorption. The oxidation number of Fe supported on RH-MCM-41 was + 3, as determined by x-ray absorption near edge structure (XANES) analysis. Transmission electron microscopy (TEM) images of all the catalysts displayed well-ordered structures, and metal nanoparticles were observed in some catalysts. All the catalysts were active for phenol hydroxylation using H2O2 as the oxidant at phenol : H2O2 mole ratios of 2 : 1, 2 : 2, 2 : 3 and 2 : 4. The first three ratios produced only catechol and hydroquinone, whereas the 2 : 4 ratio also produced benzoquinone. The 2 : 3 ratio gave the highest phenol conversion of 47% at 70 °C. The catalyst prepared by co-impregnation with Pt and Fe was more active than that prepared using a physical mixture of Pt/RH-MCM-41 and Fe/RH-MCM-41.


Expression of the pea (Pisum sativum L.) alpha-tubulin gene TubA1 is correlated with cell division activity.
Microtubules are thought to be major determinants of plant morphogenesis, through effects on planes of cell division and on directions of differential cell expansion. In differentiation and redifferentiation processes, tubulin expression may prove a useful early indicator of cell activity. We examined the expression and localization of the pea alpha-tubulin gene TubA1 in situ and in transgenic alfalfa (Medicago sativa) to explore its use as a probe for plant development, and as a test case for correct developmental expression between two legume species commonly compared for studies of symbiosis with Rhizobium. The TubA1 mRNA was more abundant in root tips and immature leaves than in other tissues of pea. The promoter of TubA1 was fused to beta-glucuronidase (GUS) to analyze alpha-tubulin expression in transgenic alfalfa. Transient assays indicated that the TubA1 gene is transcribed at moderate levels compared to the cauliflower mosaic virus (CaMV) 35S promoter. Histochemical staining for GUS activity confirmed a correlation between TubA1 expression and cell division in nodules, roots and leaves. TubA1 promoter activity was first detected in the inner cortex of the root between 18 h and 24 h after spot inoculation with Rhizobium meliloti. Expression of a c-myc epitope fused to the carboxy-terminus of TubA1 resulted in an incorporation into the microtubular cytoskeleton, demonstrating the effectiveness of at least one epitope tag in creating functional tubulin fusions.


A method to diagnose opioid dependence resulting from heroin versus prescription opioids using the Composite International Diagnostic Interview.
Treatment research with opioid-dependent populations has not traditionally distinguished between those dependent on prescription opioids versus dependent upon heroin. Evidence suggests there is a substantial subpopulation of individuals with opioid dependence resulting largely or exclusively from prescription opioid use. Because this subpopulation may respond to treatment differently from heroin users, a method for discriminating DSM-IV opioid dependence due to prescription opioid use would provide more precision when examining this population. This paper describes an innovative method using a currently available diagnostic instrument, to diagnose DSM-IV opioid dependence and distinguish between dependence resulting from prescription opioids versus dependence upon heroin.


Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales.
Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by regression of language and motor skills, cognitive impairment, and frequent seizures. Although the diagnostic criteria focus on communication, motor impairments, and hand stereotypies, behavioral abnormalities are a prevalent and disabling component of the RTT phenotype. Among these problematic behaviors, anxiety is a prominent symptom. While the introduction of the Rett Syndrome Behavioral Questionnaire (RSBQ) represented a major advancement in the field, no systematic characterization of anxious behavior using the RSBQ or other standardized measures has been reported. This study examined the profiles of anxious behavior in a sample of 74 girls with RTT, with a focus on identifying the instrument with the best psychometric properties in this population. The parent-rated RSBQ, Anxiety, Depression, and Mood Scale (ADAMS), and Aberrant Behavior Checklist-Community (ABC-C), two instruments previously employed in children with neurodevelopmental disorders, were analyzed in terms of score profiles, relationship with age and clinical severity, reliability, concurrent validity, and functional implications. The latter were determined by regression analyses with the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) and the Child Health Questionnaire (CHQ), a quality of life measure validated in RTT. We found that scores on anxiety subscales were intermediate in range with respect to other behavioral constructs measured by the RSBQ, ADAMS, and ABC-C. Age did not affect scores, and severity of general anxiety was inversely correlated with clinical severity. We demonstrated that the internal consistency of the anxiety-related subscales were among the highest. Test-retest and intra-rater reliability was superior for the ADAMS subscales. Convergent and discriminant validity were measured by inter-scale correlations, which showed the best profile for the social anxiety subscales. Of these, only the ADAMS Social Avoidance showed correlation with quality of life. We conclude that anxiety-like behavior is a prominent component of RTT's behavioral phenotype, which affects predominantly children with less severe neurologic impairment and has functional consequences. Based on available data on standardized instruments, the ADAMS and in particular its Social Avoidance subscale has the best psychometric properties and functional correlates that make it suitable for clinical and research applications.


High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes.
To investigate the contribution of mutations in maturity-onset diabetes of the young (MODY) and mitochondrial genes to early-onset diabetes with a strong family history of diabetes in a cohort with a high prevalence of Type I (insulin-dependent) diabetes mellitus. Screening for sequence variants in the hepatocyte nuclear factor (HNF)-4alpha (MODY1), glucokinase (MODY2), HNF-1alpha (MODY3) genes and mitochondrial DNA was carried out in 115 Finnish and Swedish patients with early-onset ( </= 40 years) diabetes using the single strand conformation polymorphism (SSCP) technique and direct sequencing. Allele frequencies were compared with 118 patients with onset of diabetes Type II (non-insulin-dependent) diabetes mellitus after the age of 40 and 92 non-diabetic control subjects without a family history of diabetes. In total 52 sequence variants were found in the HNF-1alpha, HNF-4alpha and glucokinase genes, 12 of which were considered as MODY mutations. Three families had the A3243G mutation in the mitochondrial tRNA(Leu) gene, which resulted in an overall prevalence of these mutations of 13 %. Among 115 Scandinavian families, mutations in the HNF-1alpha gene represented the most common cause of familial early-onset ( </= 40 years) diabetes: MODY3 (5.2 %) more than MODY2 (3.5 %) more than MIDD (2.6 %) more than MODY1 (1.7 %).


Transcranial Doppler: correlation of blood velocity measurement with clinical status in subarachnoid hemorrhage.
Subarachnoid hemorrhage affects approximately 30,000 people each year in North America. Up to 50% of patients who survive the initial hemorrhage experience cerebral vasospasm, often resulting in permanent disability or death. Early detection allows interventions which may prevent catastrophic complications. Diagnosing vasospasm has always been dependent on invasive testing and correlation of the clinical picture. Alterations in neurological assessment, including Glasgow Coma Scale score changes, merely reflect poor cerebral perfusion secondary to the vasospasm, and may not be apparent for days. Transcranial Doppler (TCD) ultrasonography is an exciting diagnostic alternative. This noninvasive test may be done daily at the bedside, and may accurately predict impending vasospasm.


Articulating novel words: children's oromotor skills predict nonword repetition abilities.
Pronouncing a novel word for the first time requires the transformation of a newly encoded speech signal into a series of coordinated, exquisitely timed oromotor movements. Individual differences in children's ability to repeat novel nonwords are associated with vocabulary development and later literacy. Nonword repetition (NWR) is often used to test clinical populations. While phonological/auditory memory contributions to learning and pronouncing nonwords have been extensively studied, much less is known about the contribution of children's oromotor skills to this process. Two independent cohorts of children (7-13 years [N = 40] and 6.9-7.7 years [N = 37]) were tested on a battery of linguistic and nonlinguistic tests, including NWR and oromotor tasks. In both cohorts, individual differences in oromotor control were a significant contributor to NWR abilities; moreover, in an omnibus analysis including experimental and standardized tasks, oromotor control predicted the most unique variance in NWR. Results indicate that nonlinguistic oromotor skills contribute to children's NWR ability and suggest that important aspects of language learning and consequent language deficits may be rooted in the ability to perform complex sensorimotor transformations.


Activation of sphingosine-1-phosphate signalling as a potential underlying mechanism of the pleiotropic effects of statin therapy.
The mechanisms by which statins are beneficial are incompletely understood. While the lowering of low-density lipoprotein concentration is associated with regression of atherosclerosis, the observed benefit of statin therapy begins within months after its initiation, making regression an unlikely cause. Although LDL-C lowering is the main mechanism by which statin therapy reduces cardiovascular events, evidence suggests that at least some of the beneficial actions of statins may be mediated by their pleiotropic effects. Thus, statins may modulate the function of cardiovascular cells and key signalling proteins, including small G-proteins, to ultimately exert their pleiotropic effects. Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates diverse physiological functions in a variety of different organ systems. Within the cardiovascular system, S1P mediates cardioprotection following ischemia/reperfusion injury, anti-inflammatory response, improvement of endothelial function, increased mobilization and differentiation of endothelial progenitor cells, inhibition of oxidation, and anti-atherogenic and anti-thrombotic actions. Early evidence suggests that the pleiotropic effects of statins may be related to an increase in S1P signalling. This review focuses on S1P signalling as the potential mechanism underlying the pleiotropic effects of statins. An improved understanding of this mechanism may be vital for establishing the clinical relevance of statins and their importance in the treatment and prevention of coronary artery disease. Key points Several studies have demonstrated a benefit from lowering serum LDL-C with statins in patients with and without clinical evidence of CAD. These may be mediated by the pleiotropic effects of statins-the mechanisms of which are incompletely understood. Early evidence suggests that statins may increase S1P signalling pathways through upregulation of the expression of S1P receptors and an increase in plasma levels of S1P to ultimately exert their pleiotropic effects. Future clinical trials and basic science research aimed at the underlying mechanisms of the pleiotropic effects of statins should enlighten us to their relative clinical relevance and importance.


Cytochrome P4501A is induced in endothelial cell lines from the kidney and lung of the bottlenose dolphin, Tursiops truncatus.
Marine mammals respond to the presence of polycyclic and planar halogenated aromatic hydrocarbons (PAH or PHAH) with the induced expression in endothelium of cytochrome P4501A1, regulated through the aryl hydrocarbon receptor (AHR) transcription factor. Physiological responses in other animals, such as edema and inflammation indicate that the endothelium may be compromised by exposure to AHR agonists, which are ubiquitous in the marine environment. In other mammals and fish the cellular and molecular consequences of exposure to AHR agonists have been elucidated in cultured endothelial cells. We have cultured and characterized cetacean endothelial cells (EC) and used them in induction studies. Endothelial cells were cultured from the lung and kidney of the bottlenose dolphin, Tursiops truncates, and exposed to the AHR agonists beta-naphthoflavone (betaNF) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). betaNF (1-3 microM) induced significant increases in CYP1A1 (O-deethylation of 7-ethoxyresorufin to resorufin; EROD) activity to 3.6 and 0.92 pmol/mg/min in lung and kidney EC, respectively. TCDD was more potent than betaNF, and more efficacious, with maximum induction of CYP1A1 activity of 10.1 and 15.2 pmol/mg/min in lung and kidney EC at 3-10 nM TCDD. The differential response indicates that the lung and kidney endothelial cells in culture retain the ability to respond in a selective manner to specific stimuli. Both the molecular mechanisms of induction and the physiological consequences, especially in the vasculature, of toxicant exposure can be studied in this system.


Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women's Intervention Nutrition Study.
Preclinical and observational studies suggest a relationship between dietary fat intake and breast cancer, but the association remains controversial. We carried out a randomized, prospective, multicenter clinical trial to test the effect of a dietary intervention designed to reduce fat intake in women with resected, early-stage breast cancer receiving conventional cancer management. A total of 2437 women were randomly assigned between February 1994 and January 2001 in a ratio of 40:60 to dietary intervention (n = 975) or control (n = 1462) groups. An interim analysis was performed after a median follow-up of 60 months when funding for the intervention ceased. Mean differences between dietary intervention and control groups in nutrient intakes and anthropometric variables were compared with t tests. Relapse-free survival was examined using Kaplan-Meier analysis, stratified log-rank tests, and Cox proportional hazards models. Statistical tests were two-sided. Dietary fat intake was lower in the intervention than in the control group (fat grams/day at 12 months, 33.3 [95% confidence interval {CI} = 32.2 to 34.5] versus 51.3 [95% CI = 50.0 to 52.7], respectively; P<.001), corresponding to a statistically significant (P = .005), 6-pound lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in 96 of 975 (9.8%) women in the dietary group and 181 of 1462 (12.4%) women in the control group. The hazard ratio of relapse events in the intervention group compared with the control group was 0.76 (95% CI = 0.60 to 0.98, P = .077 for stratified log rank and P = .034 for adjusted Cox model analysis). Exploratory analyses suggested a differential effect of the dietary intervention based on hormonal receptor status. A lifestyle intervention reducing dietary fat intake, with modest influence on body weight, may improve relapse-free survival of breast cancer patients receiving conventional cancer management. Longer, ongoing nonintervention follow-up will address original protocol design plans, which called for 3 years of follow-up after completion of recruitment.


Exit interviews to reduce turnover amongst healthcare professionals.
Exit interviews are widely used in healthcare organisations to identify reasons for staff attrition, yet their usefulness in limiting turnover is unclear. To determine the effectiveness of various exit interview strategies in decreasing turnover rates amongst healthcare professionals. We searched the Cochrane EPOC Group Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL), Issue 11, 2012; MEDLINE, Ovid (1950- ); EMBASE, Ovid (1947- ); CINAHL, EbscoHost (1980- ), and PsycINFO, OVID (1806-) between October 31 and November 6, 2012. We also screened the reference lists of included studies and relevant reviews; and searched trial registries for planned and on-going trials. We did not restrict searches by language or publication date. Randomised controlled trials, controlled clinical trials, controlled before-after studies and interrupted time series studies comparing turnover rates between healthcare professionals who had undergone one form of exit interview with another form of exit interview or with no interview. Two review authors independently assessed trial quality and extracted data. The original search identified 1560 citations, of which we considered 19 potentially relevant. The two authors independently reviewed the abstracts of these studies and retrieved the full texts of eight studies. We excluded all eight following independent assessment; they were either interviews, commentaries on how to do an exit interview or descriptive studies about reasons for leaving. We found no trials that matched our inclusion criteria. For this first update, we screened 2220 citations and identified no new trials. Evidence about the effectiveness of exit interviews to reduce turnover is currently not available. However, exit interviews may provide useful information about the work environment which, in turn, may be useful in the development of interventions to reduce turnover.


Knowledge about the research and ethics committee at Makerere University, Kampala.
All research involving human participants should be reviewed by a competent and independent institutional research and ethics committee. Research conducted at Makerere University College of Health Sciences should be subjected to a rigorous review process by the ethics committee in order to protect human participants' interests, rights and welfare. To evaluate researchers' knowledge about the functions and ethical review process of the College of Health Sciences research and ethics committee. A cross sectional study. 135 researchers consented to participate in the study, but 70 questionnaires were answered giving a 52% response. Age ranged between 30 to 61 years, majority of participants 30-39 years. Most of the respondents do agree that the REC functions include Protocol review 86%, protection of research participants 84.3%, and monitoring of ongoing research. During ethical review, the RECpays special attention to scientific design [79.7%] and ethical issues [75.3%], but less to the budget and literature review. More than 97% of the respondents believe that the REC is either average or very good, while 2.8% rank it below average. Respondents knew the major functions of the committee including protection of the rights and welfare of research participants, protocol review and monitoring of on going research, and the elements of protocol review that are given more attention include ;scientific design and ethical issues. Overall performance of the REC was ranked as average by respondents. The committee should limit delays in approval and effectively handle all functions of the committee.


Treatment of dural sinus thrombosis using selective catheterization and urokinase.
Thrombosis of the cerebral dural venous sinuses, cortical draining veins, and deep cerebral veins is a rare clinical finding. Because of its low incidence and multiple etiologies, the optimum therapy for this condition will only be elucidated by a multicenter, randomized prospective study. At our institution, we favor early and aggressive management of cerebral venous sinus thrombosis with transfemoral, venous intradural infusions of the fibrinolytic agent urokinase. To date, treatment of only 13 patients using this technique has been reported in the English literature. This report adds 12 more such treated patients. Despite the presence of preinfusion infarcts in 5 patients, four of which were hemorrhagic, we incurred no major therapeutic morbidity. Functional sinus patency was achieved in 11 of 12 patients, with our only true failure occurring in an individual with symptoms of at least 2 months' duration. Good to excellent clinical outcome was achieved in 10 of 11 patients (one newborn had inadequate follow-up).


Global gene expression analysis by combinatorial optimization.
Generally, there is a trade-off between methods of gene expression analysis that are precise but labor-intensive, e.g. RT-PCR, and methods that scale up to global coverage but are not quite as quantitative, e.g. microarrays. In the present paper, we show how how a known method of gene expression profiling (K. Kato, Nucleic Acids Res. 23, 3685-3690 (1995)), which relies on a fairly small number of steps, can be turned into a global gene expression measurement by advanced data post-processing, with potentially little loss of accuracy. Post-processing here entails solving an ancillary combinatorial optimization problem. Validation is performed on in silico experiments generated from the FANTOM data base of full-length mouse cDNA. We present two variants of the method. One uses state-of-the-art commercial software for solving problems of this kind, the other a code developed by us specifically for this purpose, released in the public domain under GPL license.


Correlation between atherosclerosis and periodontal putative pathogenic bacterial infections in coronary and internal mammary arteries.
Chronic infections, such as periodontitis, have been associated with an increased risk for atherosclerosis and coronary artery disease. The aim of this study was to investigate biopsy samples of coronary and internal mammary arteries for the presence of putative pathogenic bacteria (Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Prevotella intermedia, and Tannerella forsythensis), Chlamydia pneumoniae, and human cytomegalovirus (CMV). Patients with a diagnosis of coronary artery disease were included in the study. Fifteen coronary arteries with atherosclerosis and 15 internal mammary arteries without clinically assessable atherosclerotic degeneration were investigated. Both groups of specimens were obtained during coronary artery bypass grafting surgery. In all cases, the coronary and mammary artery specimens were taken from the same patient. The detection of periodontal pathogens, C. pneumoniae, and CMV was done by polymerase chain reaction analysis. Bacterial DNA was found in nine of 15 (60%) coronary artery biopsy samples: P. gingivalis in eight (53.33%), A. actinomycetemcomitans in four (26.67%), P. intermedia in five (33.33%), and T. forsythensis in two (13.33%) samples; CMV was detected in 10 (66.67%) samples, and C. pneumoniae was detected in five (33.33%) samples. Some of the samples contained more than one type of bacteria. Periodontal pathogens were not detected in internal mammary artery biopsies, whereas CMV was present in seven (46.67%) samples and C. pneumoniae was present in six (40%) samples. The absence of putative pathogenic bacteria in internal mammary arteries, which are known to be affected rarely by atherosclerotic changes, and their presence in a high percentage of atherosclerotic coronary arteries support the concept that periodontal organisms are associated with the development and progression of atherosclerosis.


Atypical presentation of intravascular leiomyomatosis mimicking advanced uterine sarcoma: modified laterally extended endopelvic resection with preservation of pelvic neural structures.
Intravascular leiomyomatosis is a rare, benign tumour of myometrial smooth muscle. Despite being non-invasive, these tumours can proliferate aggressively within vascular structures including pelvic vessels, the vena cava and the heart. We discuss a 77-year-old woman presenting with a 9 cm uterine mass extending into the right adnexa and ovarian vein. Following hysteroscopic biopsy, palliative radical surgical resection was performed for suspected stage IV leiomyosarcoma. Tumour extension into the pelvic sidewall and obturator fossa indicated a modified laterally extended endopelvic resection combined with skeletonisation and preservation of the pelvic neurovasculature, ultimately providing a curative procedure with minimal functional neurological morbidity. We present this unusual case to assist in the development of a consensus for optimal case management where formal guidelines are not yet available. We summarise current understanding of intravascular leiomyomatosis and highlight the value of advanced surgical techniques using knowledge of complex ontogenetic and pelvic neuroanatomy in its management.


Marital histories, marital support, and bone density: findings from the Midlife in the United States Study.
We examined the association between marital life history and bone mineral density (BMD) in a national sample from the US. In men, being stably married was independently associated with better lumbar spine BMD, and in women, more spousal support was associated with better lumbar spine BMD. Adult bone mass may be influenced by stressors over the life course. We examined the association between marital life history and bone mineral density (BMD) net socioeconomic and behavioral factors known to influence bone mass. We sought evidence for a gender difference in the association between marital history and adult BMD. We used data from 632 adult participants in the Midlife in the United States Study to examine associations between marital history and BMD, stratified by gender, and adjusted for age, weight, menopausal stage, medication use, childhood socioeconomic advantage, adult financial status, education, physical activity, smoking, and alcohol consumption. Compared to stably married men, men who were currently divorced, widowed, or separated, men who were currently married but previously divorced, widowed, or separated, and never married men had 0.33 (95% CI: 0.01, 0.65), 0.36 (95% CI: 0.10, 0.83), and 0.53 (95% CI: 0.23, 0.83) standard deviations lower lumbar spine BMD, respectively. Among men married at least once, every year decrement in age at first marriage (under age 25) was associated with 0.07 SD decrement in lumbar spine BMD (95% CI: 0.002, 0.13). In women, greater support from the spouse was associated with higher lumbar spine BMD. Our findings suggest that marriage before age 25 and marital disruptions are deleterious to bone health in men, and that marital quality is associated with better bone health in women.


Superiority of radioisotope over blue dye for sentinel lymph node detection in breast cancer.
Sentinel lymph node biopsy (SLNB) is commonly performed using radioisotopes and/or blue dye. However, it is still undefined which reagent is more suitable for identifying sentinel lymph nodes (SLN). A consecutive series of 640 breast cancer patients who had undergone SLNB at the Keio University Hospital from 2001 to 2006 was analyzed. The SLN was identified by a combination of technetium-99m tin colloid and isosulfan blue dye. The correlation between clinicopathological factors and the distribution of radioisotopes and blue dye was analyzed. The single metastatic lymph node revealed by axillary lymph node dissection (ALND) is the 'true SLN', and the distribution of radioisotopes and blue dye to the 'true SLN' was also analyzed. Blue-dye- and radioisotope-positive SLN were identified in 79.6 and 94.7% of the patients, respectively. Taken together, SLN were identified in 625 patients (97.7%) by radioisotope and/or blue dye. No significant correlation was observed between clinicopathological features and the distribution of the reagents. ALND found 73 patients with single lymph node metastasis, and 73 'true SLN' were identified by blue dye in 65.7% (48/73), and by radioisotope in 95.9% (70/73) of the cases. These data suggest that radioisotopes are superior to blue dye in detecting SLN in breast cancer.


Are policy decisions on surgical procedures informed by robust economic evidence? A systematic review.
The aim of this study was to examine the empirical and methodological cost-effectiveness evidence of surgical interventions for breast, colorectal, or prostate cancer. A systematic search of seven databases including MEDLINE, EMBASE, and NHSEED, research registers, the NICE Web site and conference proceedings was conducted in April 2012. Study quality was assessed in terms of meeting essential, preferred and UK NICE specific requirements for economic evaluations. The seventeen (breast = 3, colorectal = 7, prostate = 7) included studies covered a broad range of settings (nine European; eight non-European) and six were published over 10 years ago. The populations, interventions and comparators were generally well defined. Very few studies were informed by literature reviews and few used synthesized clinical evidence. Although the interventions had potential differential effects on recurrence and mortality rates, some studies used relatively short time horizons. Univariate sensitivity analyses were reported in all studies but less than a third characterized all uncertainty with a probabilistic sensitivity analysis. Although a third of studies incorporated patients' health-related quality of life data, only four studies used social tariff values. There is a dearth of recent robust evidence describing the cost-effectiveness of surgical interventions in the management of breast, colorectal and prostate cancers. Many of the recent publications did not satisfy essential methodological requirements such as using clinical evidence informed by a systematic review and synthesis. Given the ratio of potential benefit and harms associated with cancer surgery and the volume of resources consumed by these, there is an urgent need to increase economic evaluations of these technologies.


Public health nursing care for adolescent mothers: impact on infant health and selected maternal outcomes at 1 year postbirth.
To compare effects of an early intervention program (EIP) of intense home visitation by public health nurses (PHNs) with effects of traditional public health nursing care (TPHN) on infant health and selected maternal outcomes of adolescent mothers. EIP adolescents (N = 102) received preparation-for-motherhood classes and individual home visits (from pregnancy through 1 year postpartum) from PHNs employed in a county health department. Participants were predominantly Latina (64%) and African-American (11%) and from impoverished backgrounds. Infant health outcomes were determined based on medical record data; interviews and standardized questionnaires evaluated other program effects (e.g., maternal educational achievement and psychological status). Data were analyzed using Chi-square and repeated measures ANOVA. Infants of EIP mothers experienced significantly fewer total days (n = 74) and actual episodes (n = 14) of hospitalization during the first year of life than those receiving TPHN (n = 154, n = 24, respectively). Similarly, positive program effects were found for immunization rates. There were no group differences in emergency room visits or repeat pregnancy rates. Alcohol, tobacco, and marijuana use significantly increased from pregnancy through 1 year postpartum in both groups but remained markedly lower than rates prior to pregnancy (lifetime rates). These findings demonstrate the positive effects of a PHN home visitation program on health outcomes for children of adolescent mothers. Days of infant hospitalization were substantially reduced and immunization rates increased during the first year of life for children of EIP mothers. Greater efforts need to be directed toward preventing repeat pregnancy and return to substance use following childbirth in at-risk adolescent mothers.


N6-Methyladenosine-Related lncRNA Signature Predicts the Overall Survival of Colorectal Cancer Patients.
The N6-methyladenosine (m6A) RNA modification can modify long non-coding RNAs (lncRNAs), thereby affecting the tumorigenesis and progression of tumors. However, the underlying role of m6A-modified lncRNAs in colorectal cancer (CRC) remains largely unknown. Therefore, our aim was to assess the prognostic value of m6A-modified lncRNAs in CRC patients. The gene expression and clinicopathological data of CRC were extracted from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was used to investigate the m6A-modified lncRNAs. Consensus clustering was conducted to identify molecular subtypes of CRC, and the clinical significance of molecular subtypes was identified. The least absolute shrinkage and selection operator analysis (LASSO) was applied to establish a risk signature. Finally, a prognostic nomogram with risk score and clinicopathological variables was established. In total, 29 m6A-modified lncRNAs were identified as prognostic lncRNAs. Two molecular clusters were identified and significant differences were found with respect to clinicopathological features and prognosis. Cluster1 is associated with poor overall survival (OS), down-regulation of Programmed cell death ligand-1 (PD-L1) expression, lower immune score, and less immune cell infiltration. Then, an m6A-modified lncRNA signature for predicting OS was constructed in the TCGA training cohort. The signature demonstrated favorable prediction performance in both training and validation sets. Compared with low-risk patients, patients with high risk showed worse clinical outcomes, lower immune scores, and downregulated PD-L1 expression. Further analysis indicated that the signature was an independent prognostic indicator, and then a prognostic nomogram based on risk score, tumor location, and tumor stage was established. Our study identified a seven m6A-modified lncRNA signature and established a prognostic nomogram that reliably predicts OS in CRC. These findings may improve the understanding of m6A modifications in CRC and provide insights into the prognosis and treatment strategy of CRC.


Drosophila matrix metalloproteinases are required for tissue remodeling, but not embryonic development.
The matrix metalloproteinase (MMP) family is heavily implicated in many diseases, including cancer. The developmental functions of these genes are not clear, however, because the >20 mammalian MMPs can be functionally redundant. Drosophila melanogaster has only two MMPs, which are expressed in embryos in distinct patterns. We created mutations in both genes: Mmp1 mutants have defects in larval tracheal growth and pupal head eversion, and Mmp2 mutants have defects in larval tissue histolysis and epithelial fusion during metamorphosis; neither is required for embryonic development. Double mutants also complete embryogenesis, and these represent the first time, to our knowledge, that all MMPs have been disrupted in any organism. Thus, MMPs are not required for Drosophila embryonic development, but, rather, for tissue remodeling.


Polyamine-Targeting Gefitinib Prodrug and its Near-Infrared Fluorescent Theranostic Derivative for Monitoring Drug Delivery and Lung Cancer Therapy.
The therapy of non-small-cell lung cancer (NSCLC) is challenging because of poor prognosis. There are urgent demands for targeting anti-tumor drugs with reliable efficacy and clear pharmacokinetics. Methods: We designed and synthesized an active tumor-targeting prodrug for the precision therapy of NSCLC. The prodrug polyamine analog Gefitinib (PPG) was derived from the conjugation between a tumor-targeting ligand polyamine analog (PA) and an epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib via a cleavable disulfide linker. Furthermore, the integration of the near-infrared azo-BODIPY fluorophore into the structure of the prodrug PPG yielded an activatable fluorescent theranostics (TPG), which could be used to monitor the in real-time delivery of prodrug PPG and initiate precise medicine in vivo. Results: PPG efficiently delivered the anti-tumor drug to cancer cells and reduced the serious side effects of the drug to normal cells, thereby increasing the potent of the anti-tumor drug. PPG was not only efficacious for killing Gefitinib-sensitive PC9 cells, but also for inhibiting the growth of Gefitinib-resistant H1650 cells. We provided a new evidence that the tumor-targeting PA ligand could inhibit the Akt pathway in H1650 cells, and had a synergistic effect with Gefitinib for anticancer efficacy. The in vivo results on nude mice bearing tumors of NSCLC cell lines demonstrated that PPG could target tumor lesions and had the expected therapeutic effects. Finally, we used TPG for fluorescent labeling of transbronchial lung biopsy (TBLB) specimens. The results indicated that TPG could provide rapid diagnosis for lung cancer within 4 h. Conclusion: Our work had identified that PPG could be effectively used for the treatment of Gefitinib-resistance NSCLC in cells and in mice models. The theranostic TPG emerged as a promising fluorescent imaging tool for the application in the therapy and diagnosis of NSCLC.


The effect of cognitive reappraisal on long-term emotional experience and emotional memory.
One's ability to properly regulate emotion is critical to psychological and physical well-being. Among various strategies to regulate emotion, cognitive reappraisal has been shown to modulate both emotional experience and emotional memory. However, most studies of reappraisal have focused on reappraisal of negative situations, with reappraisal of positive emotion receiving considerably less attention. In addition, the effects of reappraisal on emotional reactions to stimuli are typically only assessed either immediately or after a short delay, and it remains unclear whether reappraisal effects persist over longer time periods. We investigated the effect of cognitive reappraisal on emotional reactions and long-term episodic memory for positive and negative stimuli. Men and women viewed emotionally negative, positive, and neutral pictures while they were instructed to either increase, decrease, or maintain the initial emotional reactions elicited by the pictures. Subjective ratings of emotional valence and arousal were assessed during the regulation task and again after 1 week. Memory for the pictures was assessed with free recall. Results indicated that pictures accompanied by instructions to increase emotion were better recalled than pictures reappraised to decrease emotion. Modulation of emotional arousal elicited by stimuli persisted over a week, but this effect was observed only for men. These findings suggest that cognitive reappraisal can have long-lasting effects on emotional reactions to stimuli. However, the sex differences observed for the effects of reappraisal on emotional reactions highlight the importance of considering individual differences in the effects of regulation.


The effect of equipment usage and residual task difficulty on use of personal assistance, days in bed, and nursing home placement.
To determine whether residual difficulty in functioning in spite of equipment use is linked with increased use of personal assistance. Longitudinal. Two waves of the Asset and Health Dynamics Among the Oldest Old (AHEAD) database were used to test the effect of residual difficulty on hours of personal assistance and bed days at Wave 1 on hours of personal assistance, bed days, and nursing home placement at Waves 1 and 2. A nationally representative setting of community-dwelling persons aged 70 and older and their spouses, regardless of age at Wave 1 AHEAD. There was movement of some respondents into nursing homes by the Wave 2 interview. Respondents to the AHEAD survey, N=8,222 at Wave 1. The dependent variables were hours of personal assistance in the month before the AHEAD survey (Waves 1 and 2), number of days in month before the survey in which the person did not get out of bed (Waves 1 and 2), and residence in a nursing home at Wave 2. The key explanatory variable was a mutually exclusive (four category) variable that specified whether there was residual difficulty (yes/no) in indoor mobility in spite of using equipment to aid specifically with indoor mobility. The four-category variable was defined by the four categories created by a cross-tabulation of equipment use (yes/no) and difficulty with indoor mobility (yes/no). A similar four-category variable was also defined for transferring in the home. In cross section, equipment users with residual difficulty reported more hours of personal assistance in the case of indoor mobility impairment and were more likely to have some hours of personal assistance than those without residual difficulty with indoor mobility and transferring. Longitudinally, those with residual difficulty at Wave 1 were more likely to need some personal assistance hours at Wave 2 (odds ratio=1.67, 95% confidence interval= 1.23-2.26 for indoor mobility). For transferring, those with residual difficulty had 43 more hours of personal assistance per month (P=.001) than those for whom equipment resolved their disability. Residual disability was linked to more bed days for users of indoor mobility and transferring equipment, but it was not predictive of nursing home placement by Wave 2. Equipment for indoor mobility or transfers apparently resolves difficulty for some users of the equipment but not for others. Residual task difficulty in spite of equipment for indoor mobility and transferring is linked with worse outcomes, including increased dependency on personal assistance and more days in bed. This shows that more attention is needed to determine whether equipment prescribed is appropriate for a patient's difficulty and that follow-up assessment is crucial after equipment is prescribed.


Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial.
Very short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option. To test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events. Multicenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019. Patients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522). The primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding. Among 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, -1.34% [95% CI, -2.57% to -0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, -0.55% [95% CI, -1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, -1.13% [95% CI, -1.84% to -0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority). Among patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations. ClinicalTrials.gov Identifier: NCT02619760.


Allergens of the house dust mite, Dermatophagoides pteronyssinus, in patients with mite allergic rhinitis: a clinical investigation by intracutaneous skin tests and nasal provocation tests.
To determine the allergens of mite allergic rhinitis, we studied 31 patients with mite allergic rhinitis by skin tests and nasal provocation tests (15 for skin and 16 for nasal tests) using 6 fractions of Dermatophagoides pteronyssinus (Dp) extract differing in molecular weights (15, 25, 32, 53, 95 and 190 kDMW). In skin testing, patients showed intense positive reactions to the fractions of 15, 25, 32, 95 and 190 kDMW, among which the most patients showed positive reactions to the fractions of 15 and 25 kDMW. Significant differences were found in patients' positive reactivity among each fraction and between low (15 and 25 kD) and high (95 and 190 kD) molecular weight fractions as well. In nasal provocation tests, patients showed intense positive reactions to the fractions of 15, 32, 53 and 95 kDMW, especially to the fractions of 15 and 95 kDMW. Furthermore, the insidence of positive reactions to the 15 kDMW fraction was significantly higher than that to any other fraction in the skin tests (P < 0.05). From these results, the low molecular weight fraction, 15 kDMW, is considered to be the main allergen of this mite and the high molecular weight fractions, 95 and 190 kDMW, may also be considered to be allergens of this mite.


Anxiolytic effects of theaflavins via dopaminergic activation in the frontal cortex.
Epidemiological investigations have reported that the habit of drinking tea reduces the risk of developing a mental disorder, including anxiety disorder and depression. Theaflavins, black tea polyphenols, show antibacterial and anti-oxidative effects, but their effects on brain function, especially mental condition, have not been elucidated. The present study demonstrated that theaflavins increased dopamine (DA) turnover in the frontal cortex and showed an anxiolytic effect in mice. Theaflavin consumption increased the time spent by mice in the open arms of an elevated plus maze test. Theaflavin administration increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and the ratios of DOPAC/DA and (DOPAC+homovanillic acids)/DA indicating DA turnover, in the frontal cortex. These results suggest that the consumption of theaflavins induced anxiolytic effects via activation of the dopaminergic system in the frontal cortex, which support the findings of previous epidemiological studies. Theaflavins in black tea may be helpful to reduce anxiety in daily life. (150/150 words).


Molecular characterisation of a cypovirus isolated from the western spruce budworm Choristoneura occidentalis.
A novel cypovirus, assigned CoCPV, was isolated from natural populations of the western spruce budworm, Choristoneura occidentalis. The complete nucleotide sequences of genomic segments S2-S5 and S7-S10 were determined. Each segment contained a single open reading frame. Conserved motifs 5' (AGUUU......UUUGUGC) 3' were found at the ends of each segment. Analysis of S2, which encoded a putative RNA-dependent RNA polymerase protein, confirmed CoCPV belonged to the genus Cypovirus within the family Reoviridae. Further phylogenetic analysis using S10 (the polyhedrin gene) aligned this virus with species type-16, closely related to a cypovirus isolated from C. fumiferana.


Enrolling children in public insurance: SCHIP, Medicaid, and state implementation.
The Balanced Budget Act of 1997 established federal grants to the states to create the State Children's Health Insurance Program (SCHIP). This presented the states with a number of implementation choices concerning administrative models for the new programs, as well as choices about eligibility standards, enrollment simplification, crowd-out, and cost sharing requirements. At the same time, the states were also implementing welfare reform. We describe the most important of these implementation choices, and using data from the Current Population Survey, we estimate the impacts of state policy on enrollment in this multiprogram environment. The results indicate that SCHIP programs that are administered as Medicaid expansions are more successful than either separate SCHIP plans or combination programs in enrolling children. States that remove asset tests and implement presumptive eligibility and self-declaration of income have higher enrollment levels. Continuous eligibility and adoption of mail-in applications have no effect on overall enrollment. Waiting periods and premiums reduce enrollment. Stringent welfare reform reduces children's enrollment, despite federal policy that was intended to protect children from the consequences of welfare reform. The negative impacts of a number of these policy reforms substantially reduce enrollment, potentially offsetting the more favorable impacts of other policy choices. We estimate that if all states adopted the policy options that facilitate program use, enrollment for children with family incomes less than 200 percent of the poverty line could be raised from the current rate of 42 percent to 58 percent.


Despeckling of medical ultrasound images.
Speckle noise is an inherent property of medical ultrasound imaging, and it generally tends to reduce the image resolution and contrast, thereby reducing the diagnostic value of this imaging modality. As a result, speckle noise reduction is an important prerequisite, whenever ultrasound imaging is used for tissue characterization. Among the many methods that have been proposed to perform this task, there exists a class of approaches that use a multiplicative model of speckled image formation and take advantage of the logarithmical transformation in order to convert multiplicative speckle noise into additive noise. The common assumption made in a dominant number of such studies is that the samples of the additive noise are mutually uncorrelated and obey a Gaussian distribution. The present study shows conceptually and experimentally that this assumption is oversimplified and unnatural. Moreover, it may lead to inadequate performance of the speckle reduction methods. The study introduces a simple preprocessing procedure, which modifies the acquired radio-frequency images (without affecting the anatomical information they contain), so that the noise in the log-transformation domain becomes very close in its behavior to a white Gaussian noise. As a result, the preprocessing allows filtering methods based on assuming the noise to be white and Gaussian, to perform in nearly optimal conditions. The study evaluates performances of three different, nonlinear filters--wavelet denoising, total variation filtering, and anisotropic diffusion--and demonstrates that, in all these cases, the proposed preprocessing significantly improves the quality of resultant images. Our numerical tests include a series of computer-simulated and in vivo experiments.


Adolescents' heightened risk-seeking in a probabilistic gambling task.
This study investigated adolescent males' decision-making under risk, and the emotional response to decision outcomes, using a probabilistic gambling task designed to evoke counterfactually mediated emotions (relief and regret). Participants were 20 adolescents (aged 9-11), 26 young adolescents (aged 12-15), 20 mid-adolescents (aged 15-18) and 17 adults (aged 25-35). All were male. The ability to maximize expected value improved with age. However, there was an inverted U-shaped developmental pattern for risk-seeking. The age at which risk-taking was highest was 14.38 years. Although emotion ratings overall did not differ across age, there was an increase between childhood and young adolescence in the strength of counterfactually mediated emotions (relief and regret) reported after receiving feedback about the gamble outcome. We suggest that continuing development of the emotional response to outcomes may be a factor contributing to adolescents' risky behaviour.


An interactive web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations.
Factor H (FH) is a central complement regulator comprised of 20 short complement repeat (SCR) domains. Nucleotide changes within this gene (CFH) have been observed in patients with hemolytic uremic syndrome (HUS), and also membranoproliferative glomerulonephritis and age-related macular degeneration. All parts of FH are affected, but many mutations are clustered in the C-terminal part of FH. Up to now, structural analyses of HUS have been based on SCR-20, a domain that is involved in FH interactions with C3b, heparin, and endothelial cells. In order to identify the structural and functional consequence of HUS mutations, further disease-associated mutations were analyzed in terms of homology and nuclear magnetic resonance (NMR) models for factor H SCR domains. An interactive web database of 54 human HUS-associated mutations and others was created from the literature (www.FH-HUS.org). This has comprehensive search and analysis tools, integrating phenotypic and genetic data with structural analysis. Each mutation can be highlighted on the SCR structure together with the patient FH and C3 levels where available. Two new insights were obtained from our collection of data. First, phenotypic data on FH clarify our previously-proposed classification of Type I and Type II disorders that both lead to HUS, where Type I affects FH secretion and folding, and Type II leads to expressed protein in plasma that is functionally defective. Second, the new mutations show more clearly that SCR domains from SCR-16 to SCR-19 are important for the ligand binding activities of FH as well as SCR-20. This FH web database will facilitate the interpretation of new mutations and polymorphisms when these are identified in patients, and it will clarify the functional role of FH.


CHO feeding before prolonged exercise: effect of glycemic index on muscle glycogenolysis and exercise performance.
This study examined the effect of preexercise carbohydrate (CHO) ingestion on muscle CHO metabolism and performance during prolonged exercise. Six endurance-trained men performed three exercise trials on a cycle ergometer after ingesting either a high glycemic index (HGI), low glycemic index (LGI), or placebo (Con) meal 45 min before exercise. During each trial, subjects cycled at a workload corresponding to 70% peak oxygen uptake for 120 min, followed by a 15-min performance cycle where total work (kJ) was measured. Ingestion of HGI resulted in an elevated (P < 0.01) blood glucose concentration 15 min after ingestion, compared with LGI and Con, but there were no differences in the glycemic responses to the meals thereafter, despite plasma insulin concentration being higher (P < 0.01) throughout the rest period after ingestion of HGI compared with LGI and Con. Plasma free fatty acid concentrations were lower (P < 0.05) throughout exercise in HGI compared with LGI and Con. In addition, concentrations of this metabolite were lower (P < 0.05) during the first hour of exercise in LGI compared with Con. Despite these results, no differences were observed in either the rate of muscle glycogen utilization during submaximal exercise or work output during the performance cycle when the three trials were compared. These results demonstrate that preexercise CHO ingestion has no effect on muscle glycogen utilization or exercise performance, irrespective of the glycemic or insulinemic responses to the ingested meals.


Characterization of a novel telomerase-immortalized human endometrial stromal cell line, St-T1b.
Coordinated differentiation of the endometrial compartments in the second half of the menstrual cycle is a prerequisite for the establishment of pregnancy. Endometrial stromal cells (ESC) decidualize under the influence of ovarian progesterone to accommodate implantation of the blastocyst and support establishment of the placenta. Studies into the mechanisms of decidualization are often hampered by the lack of primary ESC. Here we describe a novel immortalized human ESC line. Primary ESC were immortalized by the transduction of telomerase. The resultant cell line, termed St-T1b, was characterized for its morphological and biochemical properties by immunocytochemistry, RT-PCR and immunoblotting. Its progestational response was tested using progesterone and medroxyprogesterone acetate with and without 8-Br-cAMP, an established inducer of decidualization in vitro. St-T1b were positive for the fibroblast markers vimentin and CD90 and negative for the epithelial marker cytokeratin-7. They acquired a decidual phenotype indistinguishable from primary ESC in response to cAMP stimulation. The decidual response was characterized by transcriptional activation of marker genes, such as PRL, IGFBP1, and FOXO1, and enhanced protein levels of the tumor suppressor p53 and the metastasis suppressor KAI1 (CD82). Progestins alone had no effect on St-T1b cells, but medroxyprogesterone acetate greatly enhanced the cAMP-stimulated expression of IGFBP-1 after 3 and 7 days. Progesterone, albeit more weakly, also augmented the cAMP-induced IGFBP-1 production but only after 7 days of treatment. The cell line remained stable in continuous culture for more than 150 passages. St-T1b express the appropriate phenotypic ESC markers and their decidual response closely mimics that of primary cultures. Decidualization is efficiently induced by cAMP analog and enhanced by medroxyprogesterone acetate, and, to a lesser extent, by natural progesterone. St-T1b cells therefore serve as a useful model for primary ESC.


Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons.
Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are homologs of the well-known neurotrophic factor nerve growth factor. The three members of this family display distinct patterns of target specificity. To examine the distribution in brain of messenger RNA for these molecules, in situ hybridization was performed. Cells hybridizing intensely to antisense BDNF probe were located throughout the major targets of the rat basal forebrain cholinergic system, that is, the hippocampus, amygdala, and neocortex. Strongly hybridizing cells were also observed in structures associated with the olfactory system. The distribution of NT3 mRNA in forebrain was much more limited. Within the hippocampus, labeled cells were restricted to CA2, the most medial portion of CA1, and the dentate gyrus. In human hippocampus, cells expressing BDNF mRNA are distributed in a fashion similar to that observed in the rat. These findings point to both basal forebrain cholinergic cells and olfactory pathways as potential central targets for BDNF.


Retinal implants: a systematic review.
Retinal implants present an innovative way of restoring sight in degenerative retinal diseases. Previous reviews of research progress were written by groups developing their own devices. This systematic review objectively compares selected models by examining publications describing five representative retinal prostheses: Argus II, Boston Retinal Implant Project, Epi-Ret 3, Intelligent Medical Implants (IMI) and Alpha-IMS (Retina Implant AG). Publications were analysed using three criteria for interim success: clinical availability, vision restoration potential and long-term biocompatibility. Clinical availability: Argus II is the only device with FDA approval. Argus II and Alpha-IMS have both received the European CE Marking. All others are in clinical trials, except the Boston Retinal Implant, which is in animal studies. Vision restoration: resolution theoretically correlates with electrode number. Among devices with external cameras, the Boston Retinal Implant leads with 100 electrodes, followed by Argus II with 60 electrodes and visual acuity of 20/1262. Instead of an external camera, Alpha-IMS uses a photodiode system dependent on natural eye movements and can deliver visual acuity up to 20/546. Long-term compatibility: IMI offers iterative learning; Epi-Ret 3 is a fully intraocular device; Alpha-IMS uses intraocular photosensitive elements. Merging the results of these three criteria, Alpha-IMS is the most likely to achieve long-term success decades later, beyond current clinical availability.


Neurobehavioral protection by the neuronal calcium channel blocker ziconotide in a model of traumatic diffuse brain injury in rats.
Abnormal accumulation of intracellular calcium following traumatic brain injury (TBI) is thought to contribute to a cascade of cellular events that lead to neuropathological conditions. Therefore, the possibility that specific calcium channel antagonists might exert neuroprotective effects in TBI has been of interest. The focus of this study was to examine whether Ziconotide produces such neuroprotective effects. The authors report that the acceleration-deceleration model of TBI developed by Marmarou, et al., induces a long-lasting deficit of neuromotor and behavioral function. The voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) exerts neuroprotective effects in this model of diffuse brain injury (DBI) in rats. The dose and time of injection of Ziconotide chosen for the present study was based on the authors' previous biochemical studies of mitochondria. Rats were trained in a series of motor and memory tasks, following which they were subjected to DBI using the Marmarou, et al., model. At 3, 5, and 24 hours, all rats were injected with 2 mg/kg Ziconotide for a total cumulative dose of 6 mg/kg Ziconotide. Control brain-injured animals were injected with an equal volume of saline vehicle at each of these time points. The rats were tested for motor and cognitive performance at 1, 3, 7,14, 21, 28, 35, and 42 days postinjury. Saline-treated rats displayed severe motor and cognitive deficits after DBI. Compared with saline-treated control animals, rats treated with Ziconotide displayed better motor performance during inclined plane, beam balance, and beam walk tests; improved memory while in the radial arm maze; and improved learning while in the Morris water maze. These results demonstrated that the acceleration-deceleration model, which had been developed by Marmarou, et al., induces severe motor and cognitive deficits. We also demonstrated that Ziconotide exhibits substantial neuroprotective activity in this model of TBI. Improvement was observed in both motor and cognitive tasks, even though treatment was not initiated until 3 hours after injury. These findings support the development of neuronal N-type calcium channel antagonists as useful therapeutic agents in the treatment of TBI.


Association of Arterial Stiffness With Kidney Function Among Adults Without Chronic Kidney Disease.
Our aims were to assess whether arterial stiffness is associated with a higher risk for kidney dysfunction among persons without chronic kidney disease (CKD). We analyzed data from the national health checkup system in Japan; for our analyses, we selected records of individuals who completed assessments of cardio-ankle vascular index (CAVI) and kidney function from 2005 to 2016. We excluded participants who had CKD at baseline, defined as the presence of proteinuria or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. We compared 2 groups of CAVI measurements-the highest quartile (≧8.1) and the combined lower 3 quartiles (<8.1). We used Cox proportional hazards models to assess associations between these 2 groups and subsequent CKD events, proteinuria, eGFR <60 ml/min/1.73 m2, and rapid eGFR decline (greater than or equal to -3 ml/min/1.73 m2 per year). The mean age of the 24,297 included participants was 46.2 years, and 60% were female. Over a mean follow-up of 3.1 years, 1,435 CKD events occurred. In a multivariable analysis, the hazard ratios with 95% confidence intervals (CIs) for the highest vs. combined lower quartiles of CAVI measurements were 1.3 (1.1, 1.5) for CKD events, 1.3 (0.96, 1.62) for proteinuria, 1.4 (1.1, 1.7) for eGFR <60 ml/min/1.73 m2, and the odds ratio with 95% CI was 1.3 (1.1, 1.4) for rapid eGFR decline. Persons with CAVI measurements ≧8.1 had a higher risk for CKD events compared with their counterparts with CAVI measurements <8.1. Greater arterial stiffness among adults without CKD may be associated with kidney dysfunction.


A genetic tool kit for cellular and behavioral analyses of insect sugar receptors.
Arthropods employ a large family of up to 100 putative taste or gustatory receptors (Grs) for the recognition of a wide range of non-volatile chemicals. In Drosophila melanogaster, a small subfamily of 8 Gr genes is thought to mediate the detection of sugars, the fly's major nutritional source. However, the specific roles for most sugar Gr genes are not known. Here, we report the generation of a series of mutant sugar Gr knock-in alleles and several composite sugar Gr mutant strains, including a sugar blind strain, which will facilitate the characterization of this gene family. Using Ca(2+) imaging experiments, we show that most gustatory receptor neurons (GRNs) of sugar blind flies (lacking all 8 sugar Gr genes) fail to respond to any sugar tested. Moreover, expression of single sugar Gr genes in most sweet GRNs of sugar-blind flies does not restore sugar responses. However, when pair-wise combinations of sugar Gr genes are introduced to sweet GRNs, responses to select sugars are restored. We also examined the cellular phenotype of flies homozygous mutant for Gr64a, a Gr gene previously reported to be a major contributor for the detection of many sugars. In contrast to these claims, we find that sweet GRNs of Gr64a homozygous mutant flies show normal responses to most sugars, and only modestly reduced responses to maltose and maltotriose. Thus, the precisely engineered genetic mutations of single Gr genes and construction of a sugar-blind strain provide powerful analytical tools for examining the roles of Drosophila and other insect sugar Gr genes in sweet taste.


Contributions of two types of calcium channels to synaptic transmission and plasticity.
In Aplysia sensory and motor neurons in culture, the contributions of the major classes of calcium current can be selectively examined while transmitter release and its modulation are examined. A slowly inactivating, dihydropyridine-sensitive calcium current does not contribute either to normal synaptic transmission or to any of three different forms of plasticity: presynaptic inhibition, homosynaptic depression, and presynaptic facilitation. This current does contribute, however, to a fourth form of plasticity--modulation of transmitter release by tonic depolarization of the sensory neuron. By contrast, a second calcium current, which is rapidly inactivating and dihydropyridine-insensitive, contributes to release elicited by the transient depolarization of an action potential and to the other three forms of plasticity.


401(k) plan asset allocation, account balances, and loan activity.
The Employee Benefit Research Institute (EBRI) and the Investment Company Institute (ICI) have been collaborating for the past two years to collect data on participants in 401(k) plans. This effort, known as the EBRI/ICI Participant-Directed Retirement Plan Data Collection Project, has obtained data for 401(k) plan participants from certain of EBRI and ICI sponsors and members serving as plan recordkeepers and administrators. The report includes 1996 information on 6.6 million active participants in 27,762 plans holding nearly $246 billion in assets. The data include demographic information, annual contributions, plan balances, asset allocation, and loans, and are currently the most comprehensive source of information on individual plan participants. In 1996, the first year for which data are ready for analysis, the EBRI/ICI database appears to be broadly representative of the universe of 401(k) plans. Key findings include: for all participants, 44.0 percent of the total plan balance is invested in equity funds, 19.1 percent in employer stock, 15.1 percent in guaranteed investment contracts (GICs), 7.8 percent in balanced funds, 6.8 percent in bond funds, 5.4 percent in money funds, 0.8 percent in other stable value funds, and 1.0 percent in other or unidentified investments. This allocation implies that over two-thirds of plan balances are invested directly or indirectly in equity securities. Asset allocation varies with age. For instance, on average, individuals in their twenties invested 76.8 percent of assets in equities and only 22.1 percent in fixed-income investments. By comparison, individuals in their sixties invested 53.2 percent of their assets in equities and 45.9 percent of assets in fixed-income investments. Investment options offered by 401(k) plans appear to influence asset allocation. For example, the addition of company stock substantially reduces the allocation to equity funds and the addition of GICs lowers allocations to bond and money funds. Employer contributions in the form of company stock affect participant allocation behavior. Participants in plans in which employer contributions are made in company stock appear to decrease allocations to equity funds and to increase the allocation of company stock in self-directed balances. The average account balance (net of plan loans) for all participants is $37,323. The balances, however, represent only amounts with current employers and do not include amounts remaining in the plans of prior employers. Nor do the balances indicate what savings would be in a "mature" 401(k) plan program. The average balances of older workers with long tenure at one employer indicate that a mature 401(k) plan program will produce substantial account balances. For example, individuals in their sixties with at least 30 years of tenure have average account balances in excess of $156,000; those in their fifties have balances in excess of $117,000.


No apparent costs for facultative antibiotic production by the soil bacterium Pseudomonas fluorescens Pf0-1.
Many soil-inhabiting bacteria are known to produce secondary metabolites that can suppress microorganisms competing for the same resources. The production of antimicrobial compounds is expected to incur fitness costs for the producing bacteria. Such costs form the basis for models on the co-existence of antibiotic-producing and non-antibiotic producing strains. However, so far studies quantifying the costs of antibiotic production by bacteria are scarce. The current study reports on possible costs, for antibiotic production by Pseudomonas fluorescens Pf0-1, a soil bacterium that is induced to produce a broad-spectrum antibiotic when it is confronted with non-related bacterial competitors or supernatants of their cultures. We measured the possible cost of antibiotic production for Pseudomonas fluorescens Pf0-1 by monitoring changes in growth rate with and without induction of antibiotic production by supernatant of a bacterial competitor, namely Pedobacter sp.. Experiments were performed in liquid as well as on semi-solid media under nutrient-limited conditions that are expected to most clearly reveal fitness costs. Our results did not reveal any significant costs for production of antibiotics by Pseudomonas fluorescens Pf0-1. Comparison of growth rates of the antibiotic-producing wild-type cells with those of non-antibiotic producing mutants did not reveal costs of antibiotic production either. Based on our findings we propose that the facultative production of antibiotics might not be selected to mitigate metabolic costs, but instead might be advantageous because it limits the risk of competitors evolving resistance, or even the risk of competitors feeding on the compounds produced.


B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids.
Short-chain fatty acids (SCFAs) butyrate and propionate are metabolites from dietary fiber's fermentation by gut microbiota that can affect differentiation or functions of T cells, macrophages and dendritic cells. We show here that at low doses these SCFAs directly impact B cell intrinsic functions to moderately enhance class-switch DNA recombination (CSR), while decreasing at higher doses over a broad physiological range, AID and Blimp1 expression, CSR, somatic hypermutation and plasma cell differentiation. In human and mouse B cells, butyrate and propionate decrease B cell Aicda and Prdm1 by upregulating select miRNAs that target Aicda and Prdm1 mRNA-3'UTRs through inhibition of histone deacetylation (HDAC) of those miRNA host genes. By acting as HDAC inhibitors, not as energy substrates or through GPR-engagement signaling in these B cell-intrinsic processes, these SCFAs impair intestinal and systemic T-dependent and T-independent antibody responses. Their epigenetic impact on B cells extends to inhibition of autoantibody production and autoimmunity in mouse lupus models.


Uncovering the immune tumor microenvironment in non-small cell lung cancer to understand response rates to checkpoint blockade and radiation.
The study of immunology has led to breakthroughs in treating non-small cell lung cancer (NSCLC). The recent approval of an anti-PD1 checkpoint drug for NSCLC has generated much interest in novel combination therapies that might provide further benefit for patients. However, a better understanding of which combinations may (or may not) work in NSCLC requires understanding the lung immune microenvironment under homeostatic conditions and the changes in that microenvironment in the setting of cancer progression and with radiotherapy. This review provides background information on immune cells found in the lung and the prognostic significance of these cell types in lung cancer. It also addresses current clinical directions for the combination of checkpoint inhibitors with radiation for NSCLC.


Using human pluripotent stem cells to study Friedreich ataxia cardiomyopathy.
Friedreich ataxia (FRDA) is the most common of the inherited ataxias. It is an autosomal recessive disease characterised by degeneration of peripheral sensory neurons, regions of the central nervous system and cardiomyopathy. FRDA is usually due to homozygosity for trinucleotide GAA repeat expansions found within first intron of the FRATAXIN (FXN) gene, which results in reduced levels of the mitochondrial protein FXN. Reduced FXN protein results in mitochondrial dysfunction and iron accumulation leading to increased oxidative stress and cell death in the nervous system and heart. Yet the precise functions of FXN and the underlying mechanisms leading to disease pathology remain elusive. This is particularly true of the cardiac aspect of FRDA, which remains largely uncharacterized at the cellular level. Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease model.


Roles of religious involvement and social support in the risk of colon cancer among Blacks and Whites.
This population-based case-control study of Blacks and Whites in North Carolina (1996-2000) examined the relation between social ties, etiology of colon cancer, and stage of disease at diagnosis. Interviews were conducted with 637 cases and 1,043 controls. Information was collected on two dimensions of social ties, structural (network) dimensions and functional (emotional and tangible help) dimensions. Infrequent attendance at religious services (less than once per month) was associated with a regional/advanced stage of colon cancer at diagnosis in Whites (odds ratio (OR) = 1.67, 95% confidence interval (CI): 1.09, 2.57; p for trend = 0.02) but not in Blacks (OR = 1.21, 95% CI: 0.66, 2.21; p for trend = 0.80). Among Blacks, minimal emotional support was strongly associated with risk of colon cancer (OR = 4.62, 95% CI: 2.06, 10.35; p for trend < 0.001) and with both local (OR = 3.69, 95% CI: 1.08, 12.69; p for trend < 0.001) and advanced (OR = 5.10, 95% CI: 2.03, 12.82; p for trend < 0.01) disease. No associations between emotional support and risk of colon cancer or stage of disease were observed among Whites. These results suggest that certain characteristics of social ties are associated with both risk of and prognostic indicators for colon cancer.


Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3.
Genome wide association studies (GWAS) for Parkinson's disease (PD) have previously revealed a significant association with a locus on chromosome 7p15.3, initially designated as the glycoprotein non-metastatic melanoma protein B (GPNMB) locus. In this study, the functional consequences of this association on expression were explored in depth by integrating different expression quantitative trait locus (eQTL) datasets (Braineac, CAGEseq, GTEx, and Phenotype-Genotype Integrator (PheGenI)). Top risk SNP rs199347 eQTLs demonstrated increased expressions of GPNMB, KLHL7, and NUPL2 with the major allele (AA) in brain, with most significant eQTLs in cortical regions, followed by putamen. In addition, decreased expression of the antisense RNA KLHL7-AS1 was observed in GTEx. Furthermore, rs199347 is an eQTL with long non-coding RNA (AC005082.12) in human tissues other than brain. Interestingly, transcript-specific eQTLs in immune-related tissues (spleen and lymphoblastoid cells) for NUPL2 and KLHL7-AS1 were observed, which suggests a complex functional role of this eQTL in specific tissues, cell types at specific time points. Significantly increased expression of GPNMB linked to rs199347 was consistent across all datasets, and taken in combination with the risk SNP being located within the GPNMB gene, these results suggest that increased expression of GPNMB is the causative link explaining the association of this locus with PD. However, other transcript eQTLs and subsequent functional roles cannot be excluded. This highlights the importance of further investigations to understand the functional interactions between the coding genes, antisense, and non-coding RNA species considering the tissue and cell-type specificity to understand the underlying biological mechanisms in PD.


Semantic Segmentation of Sorghum Using Hyperspectral Data Identifies Genetic Associations.
This study describes the evaluation of a range of approaches to semantic segmentation of hyperspectral images of sorghum plants, classifying each pixel as either nonplant or belonging to one of the three organ types (leaf, stalk, panicle). While many current methods for segmentation focus on separating plant pixels from background, organ-specific segmentation makes it feasible to measure a wider range of plant properties. Manually scored training data for a set of hyperspectral images collected from a sorghum association population was used to train and evaluate a set of supervised classification models. Many algorithms show acceptable accuracy for this classification task. Algorithms trained on sorghum data are able to accurately classify maize leaves and stalks, but fail to accurately classify maize reproductive organs which are not directly equivalent to sorghum panicles. Trait measurements extracted from semantic segmentation of sorghum organs can be used to identify both genes known to be controlling variation in a previously measured phenotypes (e.g., panicle size and plant height) as well as identify signals for genes controlling traits not previously quantified in this population (e.g., stalk/leaf ratio). Organ level semantic segmentation provides opportunities to identify genes controlling variation in a wide range of morphological phenotypes in sorghum, maize, and other related grain crops.


Development and internal validation of a prediction rule for post-stroke infection and post-stroke pneumonia in acute stroke patients.
Patients with acute stroke are at high risk for infection. These infections are associated with unfavourable outcome after stroke. A prediction rule can identify the patients at the highest risk for strategies to prevent infection. We aim to develop a prediction rule for post-stroke pneumonia and other infections in patients with acute stroke. We used data from the Preventive Antibiotics in Stroke Study, a multicentre randomised trial comparing preventive ceftriaxone vs. standard stroke care in patients with acute stroke. Possible predictors for post-stroke pneumonia or infection were selected from the literature. Backward elimination logistic regression analysis was used to construct prediction rules for pneumonia or infection. Internal validation was performed and a risk chart was constructed. We adjusted for preventive antibiotic use. Pneumonia was diagnosed in 159 of the 2538 included patients, and infection in 348. Pneumonia was predicted by higher age, male sex, pre-stroke disability, medical history of chronic obstructive pulmonary disease, more severe stroke, dysphagia and intracerebral haemorrhage (rather than ischaemic stroke). Infections were predicted by higher age, male sex, history of diabetes, chronic obstructive pulmonary disease, more severe stroke, dysphagia, use of bladder catheter, preventive antibiotic use and intracerebral haemorrhage. With the prediction rule developed, risks for pneumonia ranged from 0.4% to 56.2% and from 1.8% to 88.0% for infection. Discrimination of the score was good (C-statistic, 0.84; 95% CI: 0.81-0.87 and 0.82; 95% CI: 0.79-0.84 for pneumonia and infection). The Preventive Antibiotics in Stroke Study pneumonia and infection rule identify patients at the highest risk for post-stroke pneumonia or infection and may be used for future studies and novel therapies, after confirmation in an external population.


Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations.
Mitochondrial myopathy in progressive external ophthalmoplegia (PEO) has been associated with POLG1 mutations. POLG1 encodes the catalytic alpha subunit of polymerase gamma and is the only polymerase known to be involved in mtDNA replication. It has two functionally different domains, one polymerase domain and one exonuclease domain with proofreading activity. In this study we have investigated whether mtDNA point mutations are involved, directly or indirectly, in the pathogenesis of PEO. Muscle biopsy specimens from patients with POLG1 mutations, affecting either the exonuclease or the polymerase domain, were investigated. Single cytochrome c oxidase (COX)-deficient muscle fibers were dissected and screened for clonally expanded mtDNA point mutations using a sensitive denaturing gradient gel electrophoresis analysis, in which three different regions of mtDNA, including five different tRNA genes, were investigated. To screen for randomly distributed mtDNA point mutations in muscle, two regions of mtDNA including deletion breakpoints were investigated by high-fidelity PCR, followed by cloning and sequencing. Long-range PCR revealed multiple mtDNA deletions in all the patients but not the controls. No point mutations were identified in single COX-deficient muscle fibers. Cloning and sequencing of muscle homogenate identified randomly distributed point mutations at very low frequency in patients and controls (<1:50 000). We conclude that mtDNA point mutations do not appear to be directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations.


Absence of telomerase reverse transcriptase promoter mutations in neuroblastoma.
Maintenance of telomere length is a critical hallmark of malignant transformation. While silenced in somatic cells, telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, is frequently overexpressed in malignant cells thereby maintaining their telomere length. Specific point mutations in the TERT promoter region have recently been identified in melanoma and other tumor entities resulting in high TERT expression. Neuroblastoma is the most common extracranial tumor of childhood, arising from neural-crest progenitor cells. TERT overexpression has been observed in the majority of neuroblastoma. Taking into consideration that TERT promoter mutations are frequently described in neural-crest-derived tumors such as melanoma, as well as a variety of other neuronal tumors, the present study analyzed the frequency of TERT promoter mutations in primary neuroblastoma and neuroblastoma cell lines. In 131 neuroblastoma primary tumors representing the whole spectrum of neuroblastoma, no TERT promoter mutations were detected. However, in 3 out of 19 neuroblastoma cell lines the previously described C228T TERT promoter mutation was present. In conclusion, the TERT promoter mutations are not a frequent mechanism of TERT overexpression in neuroblastoma.


[Gaucher disease in Latin America. A report from the Gaucher Disease International Registry and the Latin American Group for Gaucher Disease].
Gaucher disease -due to its low frequency- is considered an orphan disease. In 1991 the International Gaucher Registry was created and in 1992 the first patients from Latin America were enrolled. In 2008 the Latin American Group for Gaucher Disease was initiated. Its main objectives are to promote regional consensus, to stimulate the enrollment of patients into the International Gaucher Registry and the enhancement of knowledge on this disease, and to achieve better care and quality of life of patients in our Region. Until April 2010, 5828 patients have been enrolled all around the world, 911 (15.6%) from Latin America. This is the first comprehensive report of the disease in the Region. In our population there is a predominance of females, the most common clinical form is the type I (95%) and the age at diagnosis is before 20 years in 68% of patients. The most frequent clinical manifestations at diagnosis are splenomegaly (96%) and anemia (49%). Eighty percent of patients had radiographic findings of bone involvement. In our Region, the vast majority of patients (89%) had received enzyme replacement therapy with imiglucerase; with a long follow-up (up to 10 years) they have achieved the therapeutic goals, showing the great effectiveness of therapy. While the percentage of patients with therapy is high, discontinuations are common. The main deficiencies in our Region are: the lack of visceral volumetric evaluations and densitometries as well as molecular analysis for some patients. The main problem is the under-diagnosis of patients.


Impact of Intensive Versus Standard Blood Pressure Management by Tertiles of Blood Pressure in SPRINT (Systolic Blood Pressure Intervention Trial).
Intensive systolic blood pressure (SBP) control improved outcomes in SPRINT (Systolic Blood Pressure Intervention Trial). Our objective was to expand on reported findings by analysis of baseline characteristics, primary outcomes, adverse events, follow-up blood pressure, and medication use differences by baseline SBP (tertile 1 [T1], <132; tertile 2 [T2], 132-145; and tertile 3 [T3], >145 mm Hg). Participants with higher baseline SBP tertile were more often women and older, had higher cardiovascular risk, and lower utilization of antihypertensive medications, statins, and aspirin. Achieved SBP in both treatment arms was slightly higher in T2 and T3 compared with T1 and fewer in the T3 groups achieved SBP targets compared with T1 and T2 groups. The primary composite outcome with intensive versus standard SBP treatment was reduced by 30% in T1, 23% in T2, and 17% in T3 with no evidence of an interaction (P=0.77). Event rates were lower in the intensive arm, and there was no evidence that this benefit differed by SBP tertile. There was no difference in the hazard for serious adverse events in any of the 3 tertiles. Medication utilization differed across the SBP tertiles at baseline with a lesser percentage of diuretics and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker drugs in the higher tertiles-a finding that reversed during the trial. The beneficial effects of intensive SBP lowering were not modified by the level of baseline SBP. Within the parameters of this population, these findings add support for clinicians to treat blood pressure to goal irrespective of baseline SBP.


Autographa californica M nucleopolyhedrovirus early GP64 synthesis mitigates developmental resistance in orally infected noctuid hosts.
The unusual early synthesis of the Autographa californica M nucleopolyhedrovirus (AcMNPV) budded virus (BV) structural protein GP64 is an important virulence factor during oral infection of Heliothis virescens larvae. Considering the breadth of the AcMNPV host range, the importance of early GP64 synthesis in orally infected permissive hosts (Trichoplusia ni and Spodoptera exigua) from subfamilies other than that of H. virescens was assessed. An AcMNPV recombinant, having wild-type early and late GP64 synthesis, was compared with one in which only late GP64 synthesis occurred. Early GP64 synthesis was found to have more of an effect on virulence in orally inoculated T. ni than S. exigua and that virulence was dependent on two factors: the ability of the host to slough occlusion-derived virus (ODV)-infected midgut cells and the rapidity with which BV was transmitted to the tracheal cells. In both host species, insects inoculated orally with the control virus transmitted BV to tracheal cells hours before those inoculated with the gp64 temporal mutant. Moreover, with early GP64 synthesis, the lag between the onset of viral gene expression in midgut and tracheal cells was only 3-4 h, supporting the conclusion that in these insects, the first systemic infections arose from ODV-derived nucleocapsids repackaged as BV. These results provide further empirical proof that early GP64 synthesis is a component of a unique and selectively advantageous baculovirus infection strategy for exploiting larval lepidopterans by counteracting developmental resistance.


Lack of effectiveness of syndromic management in targeting vaginal infections in pregnancy in Entebbe, Uganda.
To measure the prevalence of reproductive tract infections (RTIs) during pregnancy in Entebbe, Uganda, and to evaluate the current syndromic diagnosis and management approach in effectively targeting infections, such as bacterial vaginosis (BV) and trichomoniasis, that are associated with low birth weight and prematurity among newborns. We enrolled 250 antenatal clinic attenders. Vaginal swabs and diagnostic tests were performed for BV, Trichomonas vaginalis (TV), candida, Neisseria gonorrhoeae, Chlamydia trachomatis and for HIV-1 and active (TPHA+/RPR+) syphilis infection. Same day treatment was offered for symptoms according to syndromic management guidelines. The treatment actually provided by healthcare workers was documented. Sensitivity, specificity, positive and negative predictive values were used to assess the effectiveness of syndromic management guidelines and practice. The prevalence of infections were: BV 47.7%, TV 17.3%, candida 60.6%, gonorrhoea 4.3%, chlamydia 5.9%, syphilis 1.6%, and HIV 13.1%. In total, 39.7% of women with BV and 30.2% of those with TV were asymptomatic. The sensitivity of syndromic management as applied by health workers in targeting BV and TV was 50.0% and 66.7%, respectively. This would have increased to 60.3% (BV) and 69.8% (TV) had the algorithm been followed exactly. The prevalence of BV and TV seen in this and other African populations is high. High rates of asymptomatic infection and a tendency of healthcare workers to deviate from management guidelines by following their own personal clinical judgment imply that many vaginal infections remain untreated. Alternative strategies, such as presumptive treatment of BV and TV in pregnancy, should be considered.