We have recently identified a novel 190-kD calmodulin-binding protein (p190) associated with the actin-based cytoskeleton from mammalian brain (Larson, R. E., D. E. Pitta, and J. A. Ferro. 1988. Braz. J. Med. Biol. Res. 21:213-217; Larson, R. E., F. S. Espindola, and E. M. Espreafico. 1990. J. Neurochem. 54:1288-1294). These studies indicated that p190 is a phosphoprotein substrate for calmodulin-dependent kinase II and has calcium- and calmodulin-stimulated MgATPase activity. We now have biochemical and immunological evidence that this protein is a novel calmodulin-binding myosin whose properties include (a) Ca2+ dependent action activation of its Mg-ATPase activity, which seems to be mediated by Ca2+ binding directly to calmodulin(s) associated with p190 (maximal activation by actin requires the presence of Ca2+ and is further augmented by addition of exogenous calmodulin); (b) ATP-sensitive cross-linking of skeletal muscle F-actin, as demonstrated by the low-speed actin sedimentation assay; and (c) cross-reactivity with mAbs specific for epitopes in the head of brush border myosin I. We also show that p190 has properties distinct from conventional brain myosin II and brush border myosin I, including (a) separation of p190 from brain myosin II by gel filtration on a Sephacryl S-500 column; (b) lack by p190 of K(+)-stimulated EDTA ATPase activity characteristic of most myosins; (c) lack of immunological cross-reactivity of polyclonal antibodies which recognize p190 and brain myosin II, respectively; (d) lack of immunological recognition of p190 by mAbs against an epitope in the tail region of brush border myosin I; and (e) distinctive proteolytic susceptibility to calpain. A survey of rat tissues by immunoblotting indicated that p190 is expressed predominantly in the adult forebrain and cerebellum, and could be detected in embryos 11 d post coitus. Immunocytochemical studies showed p190 to be present in the perikarya and dendritic extensions of Purkinje cells of the cerebellum.

Antibody to the capsid (PORF2) protein of hepatitis E virus (HEV) is sufficient to confer immunity, but knowledge of B-cell epitopes in the intact capsid is limited. A panel of murine monoclonal antibodies (MAbs) was generated following immunization with recombinant ORF2.1 protein, representing the C-terminal 267 amino acids (aa) of the 660-aa capsid protein. Two MAbs reacted exclusively with the conformational ORF2.1 epitope (F. Li, J. Torresi, S. A. Locarnini, H. Zhuang, W. Zhu, X. Guo, and D. A. Anderson, J. Med. Virol. 52:289-300, 1997), while the remaining five demonstrated reactivity with epitopes in the regions aa 394 to 414, 414 to 434, and 434 to 457. The antigenic structures of both the ORF2.1 protein expressed in Escherichia coli and the virus-like particles (VLPs) expressed using the baculovirus system were examined by competitive enzyme-linked immunosorbent assays (ELISAs) using five of these MAbs and HEV patient sera. Despite the wide separation of epitopes within the primary sequence, all the MAbs demonstrated some degree of cross-inhibition with each other in ORF2. 1 and/or VLP ELISAs, suggesting a complex antigenic structure. MAbs specific for the conformational ORF2.1 epitope and a linear epitope within aa 434 to 457 blocked convalescent patient antibody reactivity against VLPs by approximately 60 and 35%, respectively, while MAbs against epitopes within aa 394 to 414 and 414 to 434 were unable to block patient serum reactivity. These results suggest that sequences spanning aa 394 to 457 of the capsid protein participate in the formation of strongly immunodominant epitopes on the surface of HEV particles which may be important in immunity to HEV infection.

BACKGROUND

The International Society for Sexual Medicine (ISSM) Ad Hoc Committee for the Definition of Premature Ejaculation developed the first evidence-based definition for lifelong premature ejaculation (PE) in 2007 and concluded that there were insufficient published objective data at that time to develop a definition for acquired PE.

OBJECTIVE

The aim of this article is to review and critique the current literature and develop a contemporary, evidence-based definition for acquired PE and/or a unified definition for both lifelong and acquired PE.

METHODS

In April 2013, the ISSM convened a second Ad Hoc Committee for the Definition of Premature Ejaculation in Bangalore, India. The same evidence-based systematic approach to literature search, retrieval, and evaluation used by the original committee was adopted.

RESULTS

The committee unanimously agreed that men with lifelong and acquired PE appear to share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. Men with acquired PE are older, have higher incidences of erectile dysfunction, comorbid disease, and cardiovascular risk factors, and have a longer intravaginal ejaculation latency time (IELT) as compared with men with lifelong PE. A self-estimated or stopwatch IELT of 3 minutes was identified as a valid IELT cut-off for diagnosing acquired PE. On this basis, the committee agreed on a unified definition of both acquired and lifelong PE as a male sexual dysfunction characterized by (i) ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy.

CONCLUSIONS

The ISSM unified definition of lifelong and acquired PE represents the first evidence-based definition for these conditions. This definition will enable researchers to design methodologically rigorous studies to improve our understanding of acquired PE. Serefoglu EC, McMahon CG, Waldinger MD, Althof SE, Shindel A, Adaikan G, Becher EF, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An evidence-based unified definition of lifelong and acquired premature ejaculation: Report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. Sex Med 2014;2:41-59.

Carotenoids are suitable photoprotectants, and beta-carotene supplements are used for protection against ultraviolet (UV) light-induced erythema. Protective effects are also observed when carotenoids are provided with the diet. Here, we investigated the photoprotective effects of synthetic lycopene in comparison with a tomato extract (Lyc-o-Mato) and a drink containing solubilized Lyc-o-Mato (Lyc-o-Guard-Drink). With these different sources, the volunteers ingested similar amounts of lycopene (about 10 mg/day). After 12 weeks of supplementation, significant increases in lycopene serum levels and total skin carotenoids were observed in all groups. Significant increases in the serum levels of phytofluene and phytoene occurred in the Lyc-o-Mato and the Lyc-o-Guard-Drink group. At weeks 0, 4, and 12 an erythema was induced with a solar light simulator. Dorsal skin of each subject was irradiated with 1.25 minimal erythemal dose (MED). Reddening of the skin was evaluated before and 24 hours after irradiation by chromametry and expressed as positive a-values (red/green-axis). delta a-values (difference of a-value before irradiation and after 24 hours) were used as an index of erythema intensity. A decrease in the delta a-value from week 0 to week 12, indicating prevention of erythema formation, was observed in all groups. Compared to week 0, the delta a-value at week 12 was 25% lower in the synthetic lycopene group. The protective effect was more pronounced in the Lyc-o-Mato (38%) and Lyc-o-Guard-Drink (48%) groups. In the two latter groups, phytofluene and phytoene may have contributed to protection. Both of these carotenoids exhibit absorption maxima at wavelengths of UV light. Absorption of UV light protects skin from photodamage and might explain the differences observed between groups.

Previous work [Burgess et al., Med. Phys. 28, 419-437 (2001)] has shown that anatomical noise in projection mammography results in a power spectrum well modeled over a range of frequencies by a power law, and the exponent (beta) of this power law plays a critical role in determining the size at which a growing lesion reaches the threshold for detection. In this study, the authors evaluated the power-law model for breast computed tomography (bCT) images, which can be thought of as thin sections through a three-dimensional (3D) volume. Under the assumption of a 3D power law describing the distribution of attenuation coefficients in the breast parenchyma, the authors derived the relationship between the power-law exponents of bCT and projection images and found it to be betasection=betaproj-1. They evaluated this relationship on clinical images by comparing bCT images from a set of 43 patients to Burgess' findings in mammography. They were able to make a direct comparison for 6 of these patients who had both a bCT exam and a digitized film-screen mammogram. They also evaluated segmented bCT images to investigate the extent to which the bCT power-law exponent can be explained by a binary model of attenuation coefficients based on the different attenuation of glandular and adipose tissue. The power-law model was found to be a good fit for bCT data over frequencies from 0.07 to 0.45 cyc/mm, where anatomical variability dominates the spectrum. The average exponent for bCT images was 1.86. This value is close to the theoretical prediction using Burgess' published data for projection mammography and for the limited set of mammography data available from the authors' patient sample. Exponents from the segmented bCT images (average value: 2.06) were systematically slightly higher than bCT images, with substantial correlation between the two (r=0.84).

An approach to the quantitative spectral analysis of substrate binding and inactivation of cytochrome P-450 in microsomes is described. The method is based on the application of the principal component analysis technique on the Soret-region spectra measured at different temperatures at various concentrations of substrate. This approach allowed us to study the thermodynamic parameters of substrate binding and spin transitions in human cytochrome P-450 3A4 expressed in yeast (Saccharomyces cerevisiae) microsomes. These parameters are discussed in comparison with the values reported earlier by Ristau et al. [(1979) Acta Biol. Med. Ger. 38, 177-185] for rabbit liver cytochrome P-450 2B4 in solution with benzphetamine as a substrate. Our analysis shows the substrate-free states of 2B4 and 3A4 to be very similar. However, substrate binding seems to perturb haem-protein interactions in 3A4 in contrast with 2B4, where the effect of substrate binding on the thermodynamic parameters of spin transitions was insignificant. The implication of the results for the mechanism of substrate-induced spin shift is discussed.

OBJECTIVE

To examine the long-term effects of a brief family intervention on aggressive and hostile behaviors of adolescents in the general population.

METHODS

Randomized trial including 22 public schools assigned to the Iowa Strengthening Families Program or a control condition. Analyses supported sample representativeness and failed to show differential attrition effects 4 years after baseline.

METHODS

Seven-session intervention for parents and their sixth-grade children.

METHODS

The multi-informant, multimethod measures included independent observer ratings of adolescent aggressive and hostile behaviors in adolescent-parent interactions, family-member report of aggressive and hostile behaviors in those interactions, and adolescent self-report of aggressive and destructive conduct across settings. Data were collected during the 6th (preintervention and postintervention), 7th, 8th, and 10th grades.

RESULTS

All measures showed a generally positive trend in intervention-control group differences over time. During 10th grade, significant intervention-control differences were found for adolescent self-report of aggressive and destructive conduct (P =. 01), with relative reduction rates ranging from 31.7% to 77.0%. Significant differences were shown for observer-rated aggressive and hostile behaviors in adolescent-parent interactions (P =.01); differences in family member reports of those behaviors were not significant. Supplemental analyses of both interactional behavior measures, specific to parent sex, indicated significant experimental group differences in interactions with mothers (P =.04 for both measures) but not with fathers.

CONCLUSIONS

Brief family competency-training interventions designed for general populations can reduce aggressive and hostile behaviors in adolescents' interactions with parents and adolescent aggressive behaviors outside of the home setting. Thus, this type of intervention has important public health implications. Arch Pediatr Adolesc Med. 2000;154:1248-1257.

BACKGROUND

Mitochondria are the major source of oxidative stress. Acute oxidative stress causes serious damage to tissues, and persistent oxidative stress is one of the causes of many common diseases, cancer and the aging process; however, there has been little success in developing an effective antioxidant with no side effect. We have reported that molecular hydrogen has potential as an effective antioxidant for medical applications [Ohsawa et al., Nat. Med. 13 (2007) 688-694].

METHODS

We review the recent progress toward therapeutic and preventive applications of hydrogen. Since we published the first paper in Nature Medicine, effects of hydrogen have been reported in more than 38 diseases, physiological states and clinical tests in leading biological/medical journals. Based on this cumulative knowledge, the beneficial biological effects of hydrogen have been confirmed. There are several ways to intake or consume hydrogen, including inhaling hydrogen gas, drinking hydrogen-dissolved water, taking a hydrogen bath, injecting hydrogen-dissolved saline, dropping hydrogen-dissolved saline into the eyes, and increasing the production of intestinal hydrogen by bacteria. Hydrogen has many advantages for therapeutic and preventive applications, and shows not only anti-oxidative stress effects, but also has various anti-inflammatory and anti-allergic effects. Preliminary clinical trials show that drinking hydrogen-dissolved water seems to improve the pathology of mitochondrial disorders.

CONCLUSIONS

Hydrogen has biological benefits toward preventive and therapeutic applications; however, the molecular mechanisms underlying the marked effects of small amounts of hydrogen remain elusive.

CONCLUSIONS

Hydrogen is a novel antioxidant with great potential for actual medical applications. This article is part of a Special Issue entitled Biochemistry of Mitochondria.

Microglia provide surveillance in the central nervous system and become activated following tissue insult. Detailed mechanisms by which microglia detect and respond to their environment are not fully understood, but it is known that microglia express a number of surface receptors and ion channels, including voltage-gated sodium channels, that participate in transduction of external stimuli to intra-cellular responses. To determine whether activated microglia are affected by the activity of sodium channels, we examined the expression of sodium channel isoforms in cultured microglia and the action of sodium channel blockade on multiple functions of activated microglia. Rat microglia in vitro express tetrodotoxin (TTX)-sensitive sodium channels Nav1.1 and Nav1.6 and the TTX-resistant channel Nav1.5, but not detectable levels of Nav1.2, Nav1.3, Nav1.7, Nav1.8, and Nav1.9. Sodium channel blockade with phenytoin (40 microM) and TTX (0.3 microM) significantly reduced by 50-60% the phagocytic activity of microglia activated with lipopolysaccharide (LPS); blockade with 10 microM TTX did not further reduce phagocytic activity. Phenytoin attenuated by approximately 50% the release of IL-1 alpha, IL-1 beta, and TNF-alpha from LPS-stimulated microglia, but had minimal effects on the release of IL-2, IL-4, IL-6, IL-10, MCP-1, and TGF-alpha. TTX (0.3 microM) reduced, but to a smaller extent, the release of IL-1 alpha, IL-1 beta, and TNF-alpha from activated microglia. Phenytoin and TTX also significantly decreased by approximately 50% adenosine triphosphate-induced migration by microglia; studies with microglia cultured from med mice (which lack Nav1.6) indicate that Nav1.6 plays a role in microglial migration. The results demonstrate that the activity of sodium channels contributes to effector roles of activated microglia.

Previously, we demonstrated that the potent antiproliferative activity of the di-2-pyridylketone thiosemicarbazone (DpT) series of Fe chelators was due to their ability to induce Fe depletion and form redox-active Fe complexes (Richardson, D. R.; et al. J. Med. Chem. 2006, 49, 6510-6521). We now examine the role of aromatic substituents on the antiproliferative and redox activity of novel DpT analogues, namely, the 2-benzoylpyridine thiosemicarbazone (BpT) and 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (NBpT) series. Both series exhibited selective antiproliferative effects, with the majority having greater antineoplastic activity than their DpT homologues. This makes the BpT chelators the most active anticancer agents developed within our laboratory. The BpT series Fe complexes exhibit lower redox potentials than their corresponding DpT and NBpT complexes, highlighting their enhanced redox activity. The increased ability of BpT-Fe complexes to catalyze ascorbate oxidation and benzoate hydroxylation, relative to their DpT and NBpT analogues, suggested that redox cycling plays an important role in their antiproliferative activity.

BACKGROUND

Recently published studies analyzing sensitivity and specificity scores have demonstrated that the brief version of the Patient Health Questionnaire (PHQ [J. Am. Med. Assoc. 282 (1999) 1734]) is a useful tool for the detection of panic disorder and depression.

METHODS

We aimed to get normative data for the brief PHQ in a representative population-based sample. Sociodemographic data and PHQ data from 2066 subjects were included.

RESULTS

Base rates for PHQ criteria of major depression were 3.8% with the typical 1:2 ratio between males and females (frequency of minor depressive forms: 9.2%). Normative data for the depression total scores were reported. Marital status, education and family income were significantly associated with depression, even after controlling for age and sex. For panic disorder, base rates were 1.8%; age, gender, and marital status were significant predictors. Frequency for panic attacks as a less restrictively defined version were 4.5%.

CONCLUSIONS

The normative data provide a framework for the interpretation of depression and panic scores of the PHQ.

Connected health care has several applications including telecare medicine information system, personally controlled health records system, and patient monitoring. In such applications, user authentication can ensure the legality of patients. In user authentication for such applications, only the legal user/patient himself/herself is allowed to access the remote server, and no one can trace him/her according to transmitted data. Chang et al. proposed a uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care (Chang et al., J Med Syst 37:9902, 2013). Their scheme uses the user's personal biometrics along with his/her password with the help of the smart card. The user's biometrics is verified using BioHashing. Their scheme is efficient due to usage of one-way hash function and exclusive-or (XOR) operations. In this paper, we show that though their scheme is very efficient, their scheme has several security weaknesses such as (1) it has design flaws in login and authentication phases, (2) it has design flaws in password change phase, (3) it fails to protect privileged insider attack, (4) it fails to protect the man-in-the middle attack, and (5) it fails to provide proper authentication. In order to remedy these security weaknesses in Chang et al.'s scheme, we propose an improvement of their scheme while retaining the original merit of their scheme. We show that our scheme is efficient as compared to Chang et al.'s scheme. Through the security analysis, we show that our scheme is secure against possible attacks. Further, we simulate our scheme for the formal security verification using the widely-accepted AVISPA (Automated Validation of Internet Security Protocols and Applications) tool to ensure that our scheme is secure against passive and active attacks. In addition, after successful authentication between the user and the server, they establish a secret session key shared between them for future secure communication.

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

OBJECTIVE

Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).

METHODS

After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes.

RESULTS

We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects.

CONCLUSIONS

We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371.

The body's vascular system is thought to have developed in order to supply oxygen and nutrients to cells beyond the reach of simple diffusion. Hence, relative hypoxia in the growing central nervous system (CNS) is a major driving force for the ingression and refinement of the complex vascular bed that serves it. However, even before the establishment of this CNS vascular system, CNS-specific macrophages (microglia) migrate into the brain. Recent studies in mice point to the fundamental importance of microglia in shaping CNS vasculature during development, and re-shaping these vessels during pathological insults. In this review, we discuss the origin of CNS microglia and their localization within the brain based on data obtained in mice. We then review evidence supporting a functional role of these microglia in developmental angiogenesis. Although pathologic processes such as CNS ischemia may subvert the developmental functions of microglia/macrophages with significant effects on brain neo-angiogenesis, we have left this topic to other recent reviews (Nat Rev Immunol 9:259-270, 2009 and Trends Mol Med 17:743-752, 2011).

The purpose of the present study was to examine whether combined ingestion of a large amount of fructose and glucose during cycling exercise would lead to exogenous carbohydrate oxidation rates >1 g/min. Eight trained cyclists (maximal O(2) consumption: 62 +/- 3 ml x kg(-1) x min(-1)) performed four exercise trials in random order. Each trial consisted of 120 min of cycling at 50% maximum power output (63 +/- 2% maximal O(2) consumption), while subjects received a solution providing either 1.2 g/min of glucose (Med-Glu), 1.8 g/min of glucose (High-Glu), 0.6 g/min of fructose + 1.2 g/min of glucose (Fruc+Glu), or water. The ingested fructose was labeled with [U-(13)C]fructose, and the ingested glucose was labeled with [U-(14)C]glucose. Peak exogenous carbohydrate oxidation rates were approximately 55% higher (P < 0.001) in Fruc+Glu (1.26 +/- 0.07 g/min) compared with Med-Glu and High-Glu (0.80 +/- 0.04 and 0.83 +/- 0.05 g/min, respectively). Furthermore, the average exogenous carbohydrate oxidation rates over the 60- to 120-min exercise period were higher (P < 0.001) in Fruc+Glu compared with Med-Glu and High-Glu (1.16 +/- 0.06, 0.75 +/- 0.04, and 0.75 +/- 0.04 g/min, respectively). There was a trend toward a lower endogenous carbohydrate oxidation in Fruc+Glu compared with the other two carbohydrate trials, but this failed to reach statistical significance (P = 0.075). The present results demonstrate that, when fructose and glucose are ingested simultaneously at high rates during cycling exercise, exogenous carbohydrate oxidation rates can reach peak values of approximately 1.3 g/min.

OBJECTIVE

This systematic review and meta-analysis aimed to critically appraised data from comparable studies leading to quantitative assessment of any independent association between use of oral smokeless tobacco in any form, of betel quid without tobacco and of areca nut with incidence of oral cancer in South Asia and the Pacific.

METHODS

Studies (case control and/or cohort) were identified by searching Pub Med, CINAHL and Cochrane databases through June 2013 using the keywords oral cancer: chewing tobacco; smokeless tobacco; betel quid; betel quid without tobacco; areca nut; Asia, the Pacific and the reference lists of retrieved articles. A random effects model was used to compute adjusted summary OR(RE) for the main effect of these habits along with their corresponding 95% confidence intervals. To quantify the impact of between-study heterogeneity on adjusted main-effect summary OR(RE), Higgins' H and I2 statistics along with their 95% uncertainty intervals were used. Funnel plots and Egger's test were used to evaluate publication bias.

RESULTS

Meta-analysis of fifteen case-control studies (4,553 cases; 8,632 controls) and four cohort studies (15,342) which met our inclusion criteria showed that chewing tobacco is significantly and independently associated with an increased risk of squamous-cell carcinoma of the oral cavity (adjusted main-effect summary for case- control studies OR(RE) = 7.46; 95% CI = 5.86-9.50, P<0.001), (adjusted main-effect summary for cohort studies RR = 5.48; 95% CI = 2.56-11.71, P<0.001). Furthermore, meta-analysis of fifteen case control studies (4,648 cases; 7,847 controls) has shown betel quid without tobacco to have an independent positive association with oral cancer, with OR = 2.82 (95% CI = 2.35-3.40, P<0.001). This is presumably due to the carcinogenicity of areca nut. There was no significant publication bias.

CONCLUSIONS

There is convincing evidence that smokeless (aka chewing) tobacco, often used as a component of betel quid, and betel quid without tobacco, are both strong and independent risk factors for oral cancer in these populations. However, studies with better separation of the types of tobacco and the ways in which it is used, and studies with sufficient power to quantify dose-response relationships are still needed.

We selected descriptive measures of the centre of pressure (CoP) displacement in quiet standing, by means of a procedure based on principal component analysis, in two groups particularly different in terms of postural behaviours, such as subjects with Parkinson's disease (PD) in the levodopa off and on states. We computed 14 measures of the CoP: 5 measures of CoP trajectory over the support surface, 3 measures that estimated the area covered by the CoP, 1 measure that estimated the principal CoP sway direction, 1 measure that quantified the CoP total power, 1 measure that estimated the variability of CoP frequency content and 3 measures of characteristic CoP frequencies [L. Rocchi, L. Chiari, A. Cappello, Feature selection of stabilometric parameters based on principal component analysis, Med. Biol. Eng. Comput. 42 (2004) 71-79; L. Rocchi, L. Chiari, F.B. Horak, Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry, 73 (2002) 267-274]. The feature selection, independently applied to the measures obtained in the two groups, resulted in different principal component (PC) subspaces of the 14-dimension original data set (4 PCs in the off and 3 PCs in the on state to account for over 90% of the original variance), but in the same 5 CoP measures (selected features) needed to describe the different postural behaviours: root mean square distance; mean velocity; principal sway direction; centroidal frequency of the power spectrum; frequency dispersion. The five selected features were found to provide insight into the postural control mechanisms and to describe changes in postural strategies in the two groups of PD subjects, off and on levodopa. Thus, the five selected features may be recommended for use in clinical practice and in research, in the direction toward the definition of a standard protocol in quantitative posturography.

The fastest growing segment of the United States HIV population is people aged 50 and older. This heterogeneous group includes people with diverse pathways into HIV positive status in later life, including aging with the disease as well as later life-acquired infections. As people with HIV live into older ages, solving problems of successful secondary prevention and ongoing treatment requires more specific knowledge of the particular aging-related contextual sociocultural, psychosocial, and personal factors salient to the situations of persons living with HIV. Greater knowledge of these factors will help solve challenges to reducing psychological burden and promoting health maintenance for people with HIV. Yet, the current literature on aging and HIV remains nascent. To assess the state of knowledge of the sociocultural and behavioral factors associated with aging with HIV, we conducted a systematic critical content review of peer-reviewed social and behavioral research on aging and HIV to answer the question, "How have older age, and social, cultural, and behavioral aspects of the intersection of HIV and age been addressed in the literature?" We searched First Search, Proquest, Psych Info, Pub Med, Wilson Select Plus, and World Cat and identified 1549 articles. We then reviewed these to select peer-reviewed articles reporting results of research on the social and behavioral aspects of living with HIV at age 50 and older. Fifty-eight publications were identified that met study inclusion criteria. While few publications reported clear age-related differences, there were significant ethnic differences in living with HIV in later life and also differences among older people when groups were defined by mode of transmission. Findings are discussed in light of constructs from gerontology which may contribute to clarifying how later life, life course stage, and psychological development intersect with, influence, and are influenced by HIV disease and long-term anti-retroviral therapy use.

Genetic tests often identify variants whose significance cannot be determined at the time they are reported. In many situations, it is critical that clinicians be informed when new information emerges on these variants. It is already extremely challenging for laboratories to provide these updates. These challenges will grow rapidly as an increasing number of clinical genetic tests are ordered and as the amount of patient DNA assayed per test expands; the challenges will need to be addressed before whole-genome sequencing is used on a widespread basis.Information technology infrastructure can be useful in this context. We have deployed an infrastructure enabling clinicians to receive knowledge updates when a laboratory changes the classification of a variant. We have gathered statistics from this deployment regarding the frequency of both variant classification changes and the effects of these classification changes on patients. We report on the system's functionality as well as the statistics derived from its use.Genet Med advance online publication 5 April 2012.

BACKGROUND

This article addresses whether dissemination of short-term quality improvement (QI) interventions for depression to primary care practices improves patients' clinical outcomes and health-related quality of life (HRQOL) over 2 years, relative to usual care (UC).

METHODS

The sample included 1299 patients with current depressive symptoms and 12-month, lifetime, or no depressive disorder from 46 primary care practices in 6 managed care organizations. Clinics were randomized to UC or 1 of 2 QI programs that included training local experts and nurse specialists to provide clinician and patient education, assessment, and treatment planning, plus either nurse care managers for medication follow-up (QI-meds) or access to trained psychotherapists (QI-therapy). Outcomes were assessed every 6 months for 2 years.

RESULTS

For most outcomes, differences between intervention and UC patients were not sustained for the full 2 years. However, QI-therapy reduced overall poor outcomes compared with UC by about 8 percentage points throughout 2 years, and by 10 percentage points compared with QI-meds at 24 months. Both interventions improved patients' clinical and role outcomes, relative to UC, over 12 months (eg, a 10-11 and 6-7 percentage point difference in probable depression at 6 and 12 months, respectively).

CONCLUSIONS

While most outcome improvements were not sustained over the full 2 study years, findings suggest that flexible dissemination of short-term, QI programs in managed primary care can improve patient outcomes well after program termination. Models that support integrated psychotherapy and medication-based treatment strategies in primary care have the potential for relatively long-term patient benefits.

OBJECTIVE

This study was undertaken to compare the analgesic activity of antagonists acting at P2X1, P2X7, and P2Y12 receptors and agonists acting at P2Y1, P2Y2, P2Y4, and P2Y6 receptors in neuropathic, acute, and inflammatory pain.

METHODS

The effect of the wide spectrum P2 receptor antagonist PPADS, the selective P2X7 receptor antagonist Brilliant Blue G (BBG), the P2X1 receptor antagonist (4,4',4'',4-[carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino))]tetrakis-1,3-benzenedisulfonic acid, octasodium salt (NF449) and (8,8'-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-1,3,5-naphthalene-trisulphonic acid, hexasodium salt (NF023), the P2Y12 receptor antagonist (2,2-dimethyl-propionic acid 3-(2-chloro-6-methylaminopurin-9-yl)-2-(2,2-dimethyl-propionyloxymethyl)-propylester (MRS2395), the selective P2Y1 receptor agonist ([[(1R,2R,3S,4R,5S)-4-[6-amino-2-(methylthio)-9H-purin-9-yl]-2,3-dihydroxybicyclo[3.1.0]hex-1-yl]methyl] diphosphoric acid mono ester trisodium salt (MRS2365), the P2Y2/P2Y4 agonist uridine-5'-triphosphate (UTP), and the P2Y4/P2Y6 agonist uridine-5'-diphosphate (UDP) were examined on mechanical allodynia in the Seltzer model of neuropathic pain, on acute thermal nociception, and on the inflammatory pain and oedema induced by complete Freund's adjuvant (CFA).

RESULTS

MRS2365, MRS2395 and UTP, but not the other compounds, significantly alleviated mechanical allodynia in the neuropathic pain model, with the following rank order of minimal effective dose (mED) values: MRS2365>> MRS2395>> UTP. All compounds had a dose-dependent analgesic action in acute pain except BBG, which elicited hyperalgesia at a single dose. The rank order of mED values in acute pain was the following: MRS2365>> MRS2395>> NF449>> NF023>> UDP = UTP>> PPADS. MRS2365 and MRS2395 had a profound, while BBG had a mild effect on inflammatory pain, with a following rank order of mED values: MRS2395>> MRS2365>> BBG. None of the tested compounds had significant action on oedema evoked by intraplantar injection of CFA.

CONCLUSIONS

Our results show that antagonism at P2X1, P2Y12, and P2X7 receptors and agonism at P2Y1 receptors define promising therapeutic strategies in acute, neuropathic, and inflammatory pain respectively.

BACKGROUND

Urinary tract infections (UTIs) account for 30% to 40% of nosocomial infections resulting in morbidity, mortality, and increased length of hospital stay.

OBJECTIVE

To assess the efficacy of a silver-alloy, hydrogel-coated latex urinary catheter for the prevention of nosocomial catheter-associated UTIs.

METHODS

A 12-month randomized crossover trial compared rates of nosocomial catheter-associated UTI in patients with silver-coated and uncoated catheters. A cost analysis was conducted.

RESULTS

There were 343 infections among 27,878 patients (1.23 infections per 100 patients) during 114,368 patient-days (3.00 infections per 1000 patient-days). The relative risk of infection per 1000 patient-days was 0.79 (95% confidence interval, 0.63-0.99; P =.04) for study wards randomized to silver-coated catheters compared with those randomized to uncoated catheters. Infections occurred in 291 of 11,032 catheters used on study units (2.64 infections per 100 catheters). The relative risk of infection per 100 silver-coated catheters used on study wards compared with uncoated catheters was 0.68 (95% confidence interval, 0.54-0.86; P =.001). Fourteen catheter-associated UTIs (4.1%) were complicated by secondary bloodstream infection. One death appeared related to the secondary infection. Estimated hospital cost savings with the use of the silver-coated catheters ranged from $14,456 to $573,293.

CONCLUSIONS

The risk of infection declined by 21% among study wards randomized to silver-coated catheters and by 32% among patients in whom silver-coated catheters were used on the wards. Use of the more expensive silver-coated catheter appeared to offer cost savings by preventing excess hospital costs from nosocomial UTI associated with catheter use. Arch Intern Med. 2000;160:3294-3298.

OBJECTIVE

To examine recent research work in the development and evaluation of controlled biomedical terminologies - especially, the representation of structured, controlled definitional knowledge about the terms themselves; such terminologies are often referred to as 'ontologies'.

METHODS

A review of the published literature using PubMed, as well as full-text searches of recent Medinfo and American Medical Informatics Association (AMIA) Symposia proceedings, searching for the terms 'ontology' and 'ontologies' and for articles discussing specific, prominent ontological work.

RESULTS

We summaries the ontologic aspects of twelve current terminology projects: Galen, the Unified Medical Language System (UMLS), the Medical Entities Dictionary (MED), SNOMED-CT, LOINC, the Foundational Model of Anatomy (FMA), the Gene Ontology (GO), ISO Reference Terminology Model for Nursing Diagnosis, NDF-RT, RxNorm, the NCI Thesaurus, and DOLCE+. We discuss the origins, domain, and ontologic representation of each of these and attempt to summarize the impact that each has had on terminologic work and biomedical applications. We also note the contributions of the Protégé tool to many of these efforts.

CONCLUSIONS

Terminologic research and development have advanced significantly in the past 20 years, especially since the recent orientation toward controlled biomedical ontologies. This work has had significant impact on the development of terminologies themselves, their acceptance and dissemination as standards, and their use in supporting biomedical information systems.