Retinoic Acids Potentiate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells

As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is one of the most osteogenic BMPs. Retinoic acid (RA) signaling is known to play an important role in development, differentiation and bone metabolism. In this study, we investigate the effect of RA signaling on BMP9-induced osteogenic differentiation of mesenchymal progenitor cells (MPCs).Both primary MPCs and MPC line are used for BMP9 and RA stimulation. Recombinant adenoviruses are used to deliver BMP9, RARalpha and RXRalpha into MPCs. The in vitro osteogenic differentiation is monitored by determining the early and late osteogenic markers and matrix mineralization. Mouse perinatal limb explants and in vivo MPC implantation experiments are carried out to assess bone formation. We find that both 9CRA and ATRA effectively induce early osteogenic marker, such as alkaline phosphatase (ALP), and late osteogenic markers, such as osteopontin (OPN) and osteocalcin (OC). BMP9-induced osteogenic differentiation and mineralization is synergistically enhanced by 9CRA and ATRA in vitro. 9CRA and ATRA are shown to induce BMP9 expression and activate BMPR Smad-mediated transcription activity. Using mouse perinatal limb explants, we find that BMP9 and RAs act together to promote the expansion of hypertrophic chondrocyte zone at growth plate. Progenitor cell implantation studies reveal that co-expression of BMP9 and RXRalpha or RARalpha significantly increases trabecular bone and osteoid matrix formation.Our results strongly suggest that retinoid signaling may synergize with BMP9 activity in promoting osteogenic differentiation of MPCs. This knowledge should expand our understanding about how BMP9 cross-talks with other signaling pathways. Furthermore, a combination of BMP9 and retinoic acid (or its agonists) may be explored as effective bone regeneration therapeutics to treat large segmental bony defects, non-union fracture, and/or osteoporotic fracture

The French national prospective cohort of patients co-infected with HIV and HCV (ANRS CO13 HEPAVIH): Early findings, 2006-2010

<p>Abstract</p> <p>Background</p> <p>In France, it is estimated that 24% of HIV-infected patients are also infected with HCV. Longitudinal studies addressing clinical and public health questions related to HIV-HCV co-infection (HIV-HCV clinical progression and its determinants including genetic dimension, patients' experience with these two diseases and their treatments) are limited. The ANRS CO 13 HEPAVIH cohort was set up to explore these critical questions.</p> <p>To describe the cohort aims and organization, monitoring and data collection procedures, baseline characteristics, as well as follow-up findings to date.</p> <p>Methods</p> <p>Inclusion criteria in the cohort were: age > 18 years, HIV-1 infection, chronic hepatitis C virus (HCV) infection or sustained response to HCV treatment. A standardized medical questionnaire collecting socio-demographic, clinical, biological, therapeutic, histological, ultrasound and endoscopic data is administered at enrolment, then every six months for cirrhotic patients or yearly for non-cirrhotic patients. Also, a self-administered questionnaire documenting socio-behavioral data and adherence to HIV and/or HCV treatments is administered at enrolment and yearly thereafter.</p> <p>Results</p> <p>A total of 1,175 patients were included from January 2006 to December 2008. Their median age at enrolment was 45 years and 70.2% were male. The median CD4 cell count was 442 (IQR: 304-633) cells/μl and HIV RNA plasma viral load was undetectable in 68.8%. Most participants (71.6%) were on HAART. Among the 1,048 HIV-HCV chronically co-infected patients, HCV genotype 1 was predominant (56%) and cirrhosis was present in 25%. As of January, 2010, after a median follow-up of 16.7 months (IQR: 11.3-25.3), 13 new cases of decompensated cirrhosis, nine hepatocellular carcinomas and 20 HCV-related deaths were reported, resulting in a cumulative HCV-related severe event rate of 1.9/100 person-years (95% CI: 1.3-2.5). The rate of HCV-related severe events was higher in cirrhotic patients and those with a low CD4 cells count, but did not differ according to sex, age, alcohol consumption, CDC clinical stage or HCV status.</p> <p>Conclusion</p> <p>The ANRS CO 13 HEPAVIH is a nation-wide cohort using a large network of HIV treatment, infectious diseases and internal medicine clinics in France, and thus is highly representative of the French population living with these two viruses and in care.</p

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons

Sexual Timetables for Oral-Genital, Vaginal, and Anal Intercourse: Sociodemographic Comparisons in a Nationally Representative Sample of Adolescents

Objectives. We documented the prevalence and relative timing of oral-genital, vaginal, and anal intercourse during adolescence and examined whether these timetables varied by sociodemographic factors. Methods. We used data from almost 14 000 Wave IV respondents to the National Longitudinal Study of Adolescent Health to generate prevalence estimates for adolescents who reached age 18 years by 2001 and logistic and ordinary least squares regression to examine sociodemographic correlates of sexual patterns. Results. One in 5 adolescents did not engage in any of these sexual behaviors by age 18 years. More than two thirds reported vaginal or oral-genital sexual activity, but only about half experienced both. One in 10 reported anal intercourse experience. A third initiated 2 or more behaviors within a 1-year period. In longer timetables, vaginal intercourse was more often initiated first. Most sociodemographic characteristics examined were uniquely associated with prevalence and sexual timing. Conclusions. Diversity in patterns of sexual initiation occurring in the 1990s underscores the ongoing need for comprehensive and nuanced examinations of adolescent sexual trajectories and their implications for sexual health in more recent cohorts

Prevalence and Predictors of Sexual Inexperience in Adulthood

The emergence of partnered sexual behavior represents an important developmental transition. However, little is known about individuals who remain sexually inexperienced well into adulthood. We used data from 2,857 individuals who participated in Waves I, III, and IV of the National Longitudinal Study of Adolescent Health (Add Health) and reported no sexual activity (i.e., oral-genital, vaginal, or anal sex) by age 18 to identify, using discrete-time survival models, adolescent sociodemographic, biosocial, and behavioral characteristics that predicted adult sexual inexperience. The mean age of participants at Wave IV was 28.5 years (SD = 1.92). Over 1 out of 8 participants who did not initiate sexual activity during adolescence remained abstinent as young adults. Sexual non-attraction significantly predicted sexual inexperience among both males (aOR = 0.5) and females (aOR = 0.6). Males also had lower odds of initiating sexual activity after age 18 if they were non-Hispanic Asian, reported later than average pubertal development, or were rated as physically unattractive (aORs = 0.6–0.7). Females who were overweight, had lower cognitive performance, or reported frequent religious attendance had lower odds of sexual experience (aORs = 0.7–0.8) while those who were rated by the interviewers as very attractive or whose parents had lower educational attainment had higher odds of sexual experience (aORs = 1.4–1.8). Our findings underscore the heterogeneity of this unique population and suggest that there are a number of different pathways that may lead to either voluntary or involuntary adult sexual inexperience. Understanding the meaning of sexual inexperience in young adulthood may have important implications for the study of sexuality development across the life course

Hepatite crônica por vírus C: Parte 1. Considerações gerais Hepatitis C virus: Part 1. General considerations

O vírus da hepatite C foi identificado em 1989 como sendo o principal agente causador das hepatites não-A não-B e o seu reconhecimento como agente de alta prevalência nas infecções pós-tranfusionais e/ou uso de derivados do sangue ou em associação com o abuso de drogas endovenosas. A descoberta e a maior disponibilidade de novas técnicas para a seleção adequada de doadores de sangue, reduziu sensivelmente a incidência das hepatites pós-transfusionais. Cerca de 95% dos indivíduos infectados pelo vírus da hepatite C podem ser identificados pelos testes anti-vírus da hepatite C de terceira geração. Os estudos retrospectivos de infecções pelo vírus da hepatite C iatrogênicas, são as principais fontes de reconhecimento da história natural da doença. A distribuição dos diferentes genótipos do vírus da hepatite C varia de acordo com as regiões geográficas. Na América do Sul, Europa, Estados Unidos e Japão 1, 2, e 3 representam a maioria das infecções, sendo o subtipo 1-b o mais prevalente. Os parâmetros epidemiológicos (idade, fatores de risco e duração da infecção) podem estar associados com os genótipos do vírus da hepatite C, sendo os tipos 1-a e 3-a mais freqüentes nos drogaditos endovenosos e o 1-b nas hepatites pós-transfusionais. O subtipo 1-b ocasiona lesões hepáticas mais graves e prolongadas, com alterações ultraestruturais mitocondriais freqüentes e grande comprometimento dos processos de fosforilização oxidativa. A produção aumentada de radicais livres pode influenciar negativamente a evolução da doença hepática pelo reforço da ação citopática do vírus da hepatite C que provoca. O significado clínico dos níveis de vírus C no interior do fígado, nesses pacientes, não é determinado pelos fatores hospedeiro (idade, tipo e duração da infecção) ou pelos fatores virais (genótipos) e os repetidamente vírus da hepatite C RNA RT-PCR negativos no soro, não indicam necessariamente ausência de vírus da hepatite C no fígado. A associação de autoimunidade à hepatite C é questionável. Os marcadores imunes são freqüentemente detectados em baixos níveis. A modulação da resposta imune ao envelope protéico E2, após injeção de plasmídios DNA, tem sido usada para induzir respostas imunes específicas ao vírus da hepatite C. O espectro de tais respostas poderia ser ampliada mediante combinação de plasmídios, vias de administração e outras formas de imunógenos codificados (vacinas a base de peptídios). Tais estratégias podem vir a ser importantes, em breve, no combate aos altamente mutantes vírus da hepatite C. O papel patogênico dos novos vírus G e TT das hepatites está em estudos, porém é de consenso que suas associações com doença hepática ativa é fortuita.<br>Hepatitis C virus was identified in 1989 as the main causative agent of non-A, non-B and was followed by the recognition of a high prevalence of hepatitis C virus infection after transfusion of infected blood or blood products and in association with intravenous drug abuse. The availability of sensitive and reliable techniques to screen blood for hepatitis C virus has reduced the incidence of post-transfusion hepatitis. True healthy carriers of hepatitis C virus did not exist. Aproximately 95% of hepatitis C virus infected individuals can be identified by third generation anti- hepatitis C virus testing. Retrospective studies of iatrogenic hepatitis C virus infection are the main source of the natural history of the disease. The distribution of different hepatitis C virus genotypes varies according to the grographic region. In South America, Europe, The United States and Japan hepatitis C virus genotypes 1, 2 and 3 account for the majority of the infections, being (sub)type 1b the most prevalent. Epidemiological parameters (age, risk factors and duration of infection) may be associated with hepatitis C virus genotypes (intravenous drug abuse with types 1-a and 3-a and 1-b with post-transfusion hepatitic C). Subtype 1-b, lead to a more severe course of viral infection, with ultrastructural alterations of the mitochondria, and greater impairment of the process of oxidative phosphorylation. No increased production of free radicals may influence the evolution of the liver disease by an enhancement of the cytopathic effect of hepatitis C virus. The clinical significance of intrahepatic hepatitis C virus level in patients with chronic hepatitis C virus infection is not determined by host factors (age of patient, mode or duration of infection) or by virus factors (hepatitis C virus genotypes) and, repeatedly negative RT-PCR for hepatitis C virus RNA in serum does not indicate absence of hepatitis C virus from the liver. The association between autoimmunity and hepatitis C virus is questioned. Markers of its does occur with high frequency in these patients. Modulation of immune responses to hepatitis C virus envelope E2 protein following injection of plasmid DNA, has been used for induction of specific response to hepatitis C virus. The spectrum of such responses could likely be broadened by combining plasmids, delivery routes, and other forms of encoded immunogens (peptide vaccines). These may be important to the development of a vaccine against the high mutable hepatitis C virus. The pathogenic role of novel DNA virus (TTV) is under spotlight. As with hepatitis G, however, the association of TTV with disease is far from clear