Early Rheumatoid Arthritis in Latin America: Low Socioeconomic Status Related to High Disease Activity at Baseline

Objective. To determine the influence of socioeconomic factors on disease activity in a Latin American (LA) early rheumatoid arthritis (RA) multinational inception cohort at baseline. Methods. Clinical evaluation, ethnicity, socioeconomic status (SES), 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR), Health Assessment Questionnaire (HAQ) disability index (DI), and erosions were recorded in 1,093 patients with early RA (<1 year from onset). Multivariate analyses evaluated influences of sex, age, marital status, education, medical coverage, SES, and ethnicity on HAQ DI, DAS28-ESR, and presence of erosions. Results. Ethnicities included 43% Mestizo, 31% Caucasian, 19% African LA, 4% Amerindian, and 3% other. Fifty-eight percent were of low/low-middle SES, 42% had <8 years of education, 21% had no medical coverage, median disease duration was 6 months (25th, 75th percentiles 4, 9 months), median HAQ DI score was 1.25 (25th, 75th percentiles 0.63, 2.00), median DAS28-ESR score was 6.2 (25th, 75th percentiles 4.9, 7.2), and 25% had erosions. Women and Mestizos, African LA, and Amerindians had earlier onset than men or Caucasians (P < 0.01). When adjusted by country, the analysis of covariance model showed that low/low-middle SES, female sex, partial coverage, and older age were associated with worse HAQ DI scores; only low/low-middle SES was associated with higher DAS28 scores. Statistically significant differences were found in HAQ DI and DAS28 scores between countries. When excluding country, low/low-middle SES, female sex, and no coverage were associated with worse HAQ DI and DAS28 scores, whereas separated/divorced/widowed status was associated with worse HAQ DI scores and age was associated with worse DAS28 scores. Logistic regression showed that older age, no coverage, and the Amerindian and other ethnic groups were associated with erosions. Conclusion. We compared early RA patients from the main LA ethnic groups. Our findings suggest that low/low-middle SES is important in determining disease activity. A more genetic-related background for erosions is possible.

Is there a therapeutic window for pentoxifylline after the onset of acute pancreatitis?

PURPOSE: To investigate the effects of pentoxifylline (PTX) in experimental acute pancreatitis (AP) starting drug administration after the induction of the disease. METHODS: One hundred male Wistar rats were submitted to taurocholate-induced AP and divided into three groups: Group Sham: sham-operated rats, Group Saline: AP plus saline solution, and Group PTX: AP plus PTX. Saline solution and PTX were administered 1 hour after induction of AP. At 3 hours after AP induction, peritoneal levels of tumor necrosis factor (TNF)-alpha, and serum levels of interleukin (IL)-6 and IL-10 levels were assayed by Enzyme-Linked Immunosorbent Assay (ELISA). Determinations of lung myeloperoxidase activity (MPO), histological analysis of lung and pancreas, and mortality study were performed. RESULTS: PTX administration 1 hour after induction of AP caused a significant decrease in peritoneal levels of TNF-alpha and in serum levels of IL-6 and IL-10 when compared to the saline group. There were no differences in lung MPO activity between the two groups with AP. A decrease in mortality was observed in the PTX treatment compared to the saline group. CONCLUSIONS: Administration of PTX after the onset of AP decreased the systemic levels of proinflammatory cytokines, raising the possibility that there is an early therapeutic window for PTX after the initiation of AP.

Alveolar hemorrhage: distinct features of juvenile and adult onset systemic lupus erythematosus

We compared outcomes of alveolar hemorrhage (AH) in juvenile (JSLE) and adult onset SLE (ASLE). From 263 JSLE and 1522 ASLE, the AH occurred in 13 (4.9%) and 15 (1.0%) patients, respectively (p < .001). Both groups had comparable disease duration (2.6 +/- 3.0 vs. 5.6 +/- 7.0 years, p = .151) and median SLEDAI scores [17.5 (2 to 32) vs. 17.5 (3 to 28), p = 1.000]. At AH onset, a higher frequency of JSLE were already on a high prednisone dose ( > 0.5 mg/kg/day) compared to ASLE (54% vs. 15%, p = .042). The mean drop of hemoglobin was significantly lower in JSLE (2.9 +/- 0.9 vs. 5.5 +/- 2.9 g/dL, p = .006). Although treatments with methylprednisolone, plasmapheresis, intravenous immunoglobulin and cyclophosphamide were similar in both groups (p > .050), regarding outcomes, there was a trend in high frequency of mechanical ventilation use (85% vs. 47%, p = .055) and also significant mortality (69% vs. 13%, p = .006) in JSLE compared to ASLE. The sepsis frequency was comparable in both groups (50% vs. 27%, p = .433). We have identified that AH in JSLE has a worse outcome most likely related to respiratory failure. The AH onset in JSLE already treated with high-dose steroids raises the concern of inadequate response to this treatment and reinforces the recommendation of early aggressive alternative therapies in this group of patients. Lupus (2012) 21, 872-877.

U-Pb zircon ages of orthogneisses and supracrustal rocks of the Cariris Velhos belt: Onset of Neoproterozoic rifting in the Borborema Province, NE Brazil

New geochronological and geochemical constraints on Precambrian sedimentary and volcanic successions exposed in the western part of the Central Domain of the Borborema Province, NE Brazil, indicate the presence of two distinct tectono-stratigraphic complexes: Riacho Gravata and Sao Caetano. Both complexes and associated orthogneisses are referred in the literature as the Cariris Velhos belt, having depositional, extrusive, or intrusive ages within the interval 985-913 Ma. The Riacho Gravata complex consists of bimodal (but mostly felsic) volcanic and volcanoclastic rocks, muscovite+/-graphite schists, quartzites, and marble with local occurrences of banded-iron-formation. The Sao Caetano complex mainly consists of metagreywackes, marbles, calc-silicate rocks, and rare meta-mafic rocks. Meta-mafic rocks from both complexes have geochemical signatures similar to those of continental flood basalts, with epsilon Nd (1.0 Ga) values ranging from -1.0 to -2.8. Felsic volcanic rocks from the Riacho Gravata complex show epsilon Nd (1.0 Ga) values ranging from -1.0 to -7.4 and geochemical signatures similar to A(2)-type granitoids. New SHRIMP U-Pb zircon data from felsic volcanic rocks within the Riacho Gravata complex yielded ages of 1091 +/- 13 Ma and 996 +/- 13 Ma. In contrast, meta-graywackes from the Sao Caetano complex show a maximum deposition age of ca. 806 Ma in the northern part and ca. 862 Ma in the southern part of the outcrop area. The orthogneisses show epsilon Nd (1.0 Ga) values ranging from 1.0 to -4.2 with U/Pb TIMS and SHRIMP ages ranging from 960 to 926 Ma and geochemical signatures of A(2)-type granitoids. The data reported in this paper suggest at least two periods of extension within the Central Domain of the Borborema Province, the first starts ca. 1091 Ma with magmatism and deposition, creating the Riacho Gravata basin and continued intrusion of A-type granites to 920 Ma. A second rift event, which reactivated old faults, generated a basin with a maximum deposition age of ca. 806 Ma. Furthermore, the oldest granitoids cutting these metasedimentary rocks have crystallization ages of ca. 600 Ma. This suggests that the second rift event could be early Brasiliano in age. The resulting Sao Caetano basin received detritus from a variety of sources, although detritus from the Riacho Gravata complex dominated. Deposition ages of the Riacho Gravata and the Sao Caetano complexes are coeval with deposits in other basins of the Borborema Province (Riacho do Tigre in the Central Domain; Macurure and Maranco in the Sergipano Belt of the Southern domain). The Macaubas Group from SE Brazil and its counterparts in Africa, the Zadanian and Mayumbian Groups, in the western edge of the Congo Craton are also coeval. Closure of the Riacho Gravata and Sao Caetano basins occurred during the Brasiliano convergence (705-600 Ma). During the last stage of convergence, ca. 612 Ma, pull-apart basins were created and filled; final basin closure took place 605-592 Ma, after deposition ceased. (C) 2011 Elsevier B.V. All rights reserved.

Lifetime Prevalence, Age and Gender Distribution and Age-of-Onset of Psychiatric Disorders in the Sao Paulo Metropolitan Area, Brazil: Results from the Sao Paulo Megacity Mental Health Survey

Objectives: To estimate prevalence, age-of-onset, gender distribution and identify correlates of lifetime psychiatric disorders in the Sao Paulo Metropolitan Area (SPMA). Methods: The Sao Paulo Megacity Mental Health Survey assessed psychiatric disorders on a probabilistic sample of 5,037 adult residents in the SPMA, using the World Mental Health Survey Version of the Composite International Diagnostic Interview. Response rate was 81.3%. Results: Lifetime prevalence for any disorder was 44.8%; estimated risk at age 75 was 57.7%; comorbidity was frequent. Major depression, specific phobias and alcohol abuse were the most prevalent across disorders; anxiety disorders were the most frequent class. Early age-of-onset for phobic and impulse-control disorders and later age-of-onset for mood disorders were observed. Women were more likely to have anxiety and mood disorders, whereas men, substance use disorders. Apart from conduct disorders, more frequent in men, there were no gender differences in impulse-control disorders. There was a consistent trend of higher prevalence in the youngest cohorts. Low education level was associated to substance use disorders. Conclusions: Psychiatric disorders are highly prevalent among the general adult population in the SPMA, with frequent comorbidity, early age-of-onset for most disorders, and younger cohorts presenting higher rates of morbidity. Such scenario calls for vigorous public health action.

Health education intervention in early and late postmenopausal Brazilian women

Aim To identify aspects of health in postmenopausal Brazilian women using a health-related educational program provided by a multidisciplinary team as part of the primary care approach for early and late postmenopausal symptoms. Design A prospective cohort was formed with 69 postmenopausal women; they were divided into groups corresponding to early (n = 32) and late postmenopause (n = 37) through gynecological and clinical evaluations. We administered the Kuppermann-Blatt Menopausal Index and the Women's Health Questionnaire before and after health education instructions. Results The average age for the onset of menopause was 47.9 years (n = 69). Fifty women (72.5%) in this study had completed their primary education, 78.3% (n = 54) performed manual labor, and 60.9% (n = 42) showed concomitant chronic illnesses. After attending a series of health-related presentations, the mean weight of the women was reduced by 3.54% in early postmenopausal women (p < 0.001) and by 2.06% in the late postmenopausal group (p < 0.001). The mean abdominal circumference was reduced by 1.75% (p < 0.001) in the early postmenopausal group. In addition, the total score in the Kuppermann-Blatt Menopausal Index decreased by 34.38% in the early and by 33.33% in the late postmenopausal groups. According to the Women's Health Questionnaire, there was a decrease in the domain Depressive mood by 0.839 to 0.700 (p < 0.001) in the early and by 0.814 to 0.648 (p < 0.001) in the late postmenopausal groups. Conclusion Regardless of improving menopausal symptoms and anthropometric parameters, the effects of the multidisciplinary team activities in early postmenopausal women may be similar to those in late postmenopausal women.

Unveiling novel genes upregulated by both rhBMP2 and rhBMP7 during early osteoblastic transdifferentiation of C2C12 cells

Abstract Findings We set out to analyse the gene expression profile of pre-osteoblastic C2C12 cells during osteodifferentiation induced by both rhBMP2 and rhBMP7 using DNA microarrays. Induced and repressed genes were intercepted, resulting in 1,318 induced genes and 704 repressed genes by both rhBMP2 and rhBMP7. We selected and validated, by RT-qPCR, 24 genes which were upregulated by rhBMP2 and rhBMP7; of these, 13 are related to transcription (Runx2, Dlx1, Dlx2, Dlx5, Id1, Id2, Id3, Fkhr1, Osx, Hoxc8, Glis1, Glis3 and Cfdp1), four are associated with cell signalling pathways (Lrp6, Dvl1, Ecsit and PKCδ) and seven are associated with the extracellular matrix (Ltbp2, Grn, Postn, Plod1, BMP1, Htra1 and IGFBP-rP10). The novel identified genes include: Hoxc8, Glis1, Glis3, Ecsit, PKCδ, LrP6, Dvl1, Grn, BMP1, Ltbp2, Plod1, Htra1 and IGFBP-rP10. Background BMPs (bone morphogenetic proteins) are members of the TGFβ (transforming growth factor-β) super-family of proteins, which regulate growth and differentiation of different cell types in various tissues, and play a critical role in the differentiation of mesenchymal cells into osteoblasts. In particular, rhBMP2 and rhBMP7 promote osteoinduction in vitro and in vivo, and both proteins are therapeutically applied in orthopaedics and dentistry. Conclusion Using DNA microarrays and RT-qPCR, we identified both previously known and novel genes which are upregulated by rhBMP2 and rhBMP7 during the onset of osteoblastic transdifferentiation of pre-myoblastic C2C12 cells. Subsequent studies of these genes in C2C12 and mesenchymal or pre-osteoblastic cells should reveal more details about their role during this type of cellular differentiation induced by BMP2 or BMP7. These studies are relevant to better understanding the molecular mechanisms underlying osteoblastic differentiation and bone repair.

Lifetime Prevalence, age and gender distribution and age-of-onset of psychiatric disorders in the São Paulo Metropolitan Area, Brazil: results from the São Paulo Megacity Mental Health Survey

OBJECTIVES: To estimate prevalence, age-of-onset, gender distribution and identify correlates of lifetime psychiatric disorders in the São Paulo Metropolitan Area (SPMA). METHODS: The São Paulo Megacity Mental Health Survey assessed psychiatric disorders on a probabilistic sample of 5,037 adult residents in the SPMA, using the World Mental Health Survey Version of the Composite International Diagnostic Interview. Response rate was 81.3%. RESULTS: Lifetime prevalence for any disorder was 44.8%; estimated risk at age 75 was 57.7%; comorbidity was frequent. Major depression, specific phobias and alcohol abuse were the most prevalent across disorders; anxiety disorders were the most frequent class. Early age-of-onset for phobic and impulse-control disorders and later age-of-onset for mood disorders were observed. Women were more likely to have anxiety and mood disorders, whereas men, substance use disorders. Apart from conduct disorders, more frequent in men, there were no gender differences in impulse-control disorders. There was a consistent trend of higher prevalence in the youngest cohorts. Low education level was associated to substance use disorders. CONCLUSIONS: Psychiatric disorders are highly prevalent among the general adult population in the SPMA, with frequent comorbidity, early age-of-onset for most disorders, and younger cohorts presenting higher rates of morbidity. Such scenario calls for vigorous public health action.

The influence of asthma onset and severity on malocclusion prevalence in children and adolescents

OBJECTIVE: The influence of asthma, its severity levels and onset time on malocclusion occurrence were investigated. METHODS: The sample was composed by 176 children/adolescents, of both genders, aged 3 to 15 years, that were divided in two groups. The asthma group (AG) enrolled 88 children/adolescents that were seen at the Breathe Londrina Program. The asthma-free group (AFG) enrolled 88 preschool and school children recruited in 2 public schools. Malocclusion diagnosis was made according to WHO criteria (OMS, 1999). RESULTS: A higher prevalence in malocclusions in asthmatic patients in mixed dentition was observed when compared to controls (p<0.05). On the other hand, these results were not observed for deciduous (p>0.05) and permanent dentition (p>0.05). A significant association was seen between asthma onset time and marked maxillary overjet (p<0.05), and open bite (p<0.05) in the mixed dentition, being both conditions more common among those that have presented the symptoms of asthma prior to 12 months of age. CONCLUSION: The results of this study indicate that the early manifestation of asthma at first year of life can cause dentofacial changes. Therefore, the prompt diagnostic of the illness, as well as the establishment of a proper therapy could improve the symptoms and chronic complications of asthma and also reduce its impact on craniofacial development.

New molecular approaches to control rhabdomyosarcoma onset and metastasis in preclinical systems

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The aim of this study was to identify molecular events involved in rhabdomyosarcoma onset for the development of new therapeutic approaches against specific molecular targets. BALB-p53neu mice develop pelvic rhabdomyosarcoma and combines the activation of HER-2/neu oncogene with the inactivation of an allele of p53 oncosuppressor gene. Gene expression profiling led to the identification of genes potentially involved in rhabdomyosarcoma genesis and therefore of candidate targets. The pattern of expression of p53, HER-2/neu, CDKN2A/p19ARF and IGF-2 suggested that these alterations might be involved in gender-, site- and strain-specific development of rhabdomyosarcoma. Other genes such as CDKN1A/p21 might be involved. The role of IGF-2, CDKN2A/p19ARF and CDKN1A/p21 in tumor growth was investigated with siRNA in murine rhabdomyosarcoma cells. Silencing of p19ARF and p21 induced inhibition of growth and of migration ability, indicating a possible pro-tumor and pro-metastatic role in rhabdomyosarcoma in absence of p53. In addition the autocrine IGF-2/IGF-1R loop found in early phases of cancer progression strengthens its key role in sustaining rhabdomyosarcoma growth. As rhabdomyosarcoma displays defective myogenic differentiation, a therapeutic approach aimed at enhancing myogenic differentiation of rhabdomyosarcoma cells. Forced expression of myogenin was able to restore myogenic differentiation, significantly reduced cell motility and impaired tumor growth and metastatic spread. IL-4 treatment increased rhabdomyosarcoma cell growth, decreased myogenin expression and promoted migration of cells lacking myogenin. Another approach was based on small kinase inhibitors. Agents specifically targeting members of the HER family (Lapatinib), of the IGF system (NVP-AEW541) or downstream signal transducers (NVP-BEZ235) were investigated in vitro in human rhabdomyosarcoma cell lines as therapeutic anti-tumor and anti-metastatic tools. The major effects were obtained with NVP-BEZ235 treatment that was able to strongly inhibit cell growth in vitro and showed anti-metastatic effects in vivo.

Early effects of carbachol on the morphology of motor endplates of mammalian skeletal muscle fibers

Long-term disturbance of the calcium homeostasis of motor endplates (MEPs) causes necrosis of muscle fibers. The onset of morphological changes in response to this disturbance, particularly in relation to the fiber type, is presently unknown. Omohyoid muscles of mice were incubated for 1-30 minutes in 0.1 mM carbachol, an acetylcholine agonist that causes an inward calcium current. In these muscles, the structural changes of the sarcomeres and the MEP sarcoplasm were evaluated at the light- and electron-microscopic level. Predominantly in type I fibers, carbachol incubation resulted in strong contractures of the sarcomeres underlying the MEPs. Owing to these contractures, the usual beret-like form of the MEP-associated sarcoplasm was deformed into a mushroom-like body. Consequently, the squeezed MEPs partially overlapped the adjacent muscle fiber segments. There are no signs of contractures below the MEPs if muscles were incubated in carbachol in calcium-free Tyrode's solution. Carbachol induced inward calcium current and produced fiber-type-specific contractures. This finding points to differences in the handling of calcium in MEPs. Possible mechanisms for these fiber-type-specific differences caused by carbachol-induced calcium entry are assessed.

Cannabis use disorder and age at onset of psychosis--a study in first-episode patients

INTRODUCTION Age at onset of psychosis (AAO) may be younger in patients with cannabis use disorders (CUD) compared to those without CUD (NCUD). Previous studies included CUD co-morbid with other substance use disorders (SUD), and many did not control for confounders. METHODS Controlling for relevant confounders, differences in AAO between patients with and without CUD excluding those with any other SUD were analyzed in a large representative file audit of 625 first-episode psychosis (FEP) patients (age 14 to 29years) admitted to the Early Psychosis Prevention and Intervention Centre in Melbourne, Australia. RESULTS Three quarters of the 625 FEP patients had a CUD. Cannabis use started before psychosis onset in 87.6% of patients. AAO was not significantly different between CUD (without other SUD, n=201) and NCUD (n=157). However, AAO was younger in those with early CUD (starting age 14 or younger) compared to NCUD (F(1)=5.2; p=0.024; partial η(2)=0.026). Earlier age at onset of cannabis use predicted earlier age at onset of psychosis (β=-0.49, R(2)-change=0.25, p<0.001). CONCLUSION Only CUD starting age 14 or younger was associated with an earlier AAO at a small effect size. These findings suggest that CUD may exert an indirect effect on brain maturation resulting in earlier AAO potentially only in cannabis sensitive subjects.

Assessment of endothelium and inflammatory response at the onset of reperfusion injury in hand surgery

Background Activation of the endothelium, complement activation and generation of cytokines are known events during ischemia-reperfusion (I/R) that mediate tissue injury. Our aim was to elucidate their respective participation at the onset of the reperfusion phase. Tourniquet application in hand surgery causes short-term ischemia, followed by reperfusion and was therefore used as the model in this study. Methods Ten patients were included in the study after obtaining informed consent. A tourniquet was placed on the upper arm and inflated to 250 mmHg for 116 ± 16 min, during which the surgery was performed. Venous blood and tissue samples from the surgical area were taken at baseline as well as 0, 2, and 10 min after reperfusion and analyzed for the following parameters: Endothelial integrity and/or activation were analyzed by measuring heparan sulfate and syndecan-1 in serum, and vWF, heparan sulfate proteoglycan as well as CD31on tissue. Complement activation was determined by C3a and C4d levels in plasma, levels of C1-inhibitor in serum, and IgG, IgM, C3b/c, and C4b/c deposition on tissue. Cytokines and growth factors IL-5, IL-6, IL-7, IL-8, IL-10, IL-17, G-CSF, GM-CSF, MCP-1, TNFα, VEGF, and PDGF bb were measured in the serum. Finally, CK-MM levels were determined in plasma as a measure for muscle necrosis. Results Markers for endothelial activation and/or integrity as well as complement activation showed no significant changes until 10 min reperfusion. Among the measured cytokines, IL-6, IL-7, IL-17, TNFα, GM-CSF, VEGF, and PDGF bb were significantly increased at 10 min reperfusion with respect to baseline. CK-MM showed a rise from baseline at the onset of reperfusion (p < 0.001) and dropped again at 2 min (p < 0.01) reperfusion, suggesting ischemic muscle damage. Conclusions In this clinical model of I/R injury no damage to the endothelium, antibody deposition or complement activation were observed during early reperfusion. However, an increase of pro-inflammatory cytokines and growth factors was shown, suggesting a contribution of these molecules in the early stages of I/R injury.

Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis

Numerous studies have found a robust association between cannabis use and the onset of psychosis. Nevertheless, the relationship between cannabis use and the onset of early (or, in retrospect, prodromal) symptoms of psychosis remains unclear. The study focused on investigating the relationship between cannabis use and early and high-risk symptoms in subjects at clinical high risk for psychosis.

Differential expression of IGF-I mRNA and peptide in the male and female gonad during early development of a bony fish, the tilapia Oreochromis niloticus

Insulin-like growth factor I (IGF-I) plays a key role in the complex system that regulates bony fish growth, differentiation, and reproduction. The major source of circulating IGF-I is liver, but IGF-I-producing cells also occur in other organs, including the gonads. Because no data are available on the potential production sites of IGF-I in gonad development, developmental stages of monosex breedings of male and female tilapia from 0 day postfertilization (DPF) to 90 DPF were investigated for the production sites of IGF-I at the peptide (immunohistochemistry) and mRNA (in situ hybridization) level. IGF-I mRNA first appeared in somatic cells of the male and female gonad anlage at 7 DPF followed by IGF-I peptide around 9-10 DPF. Gonad anlagen were detected from 7 DPF. Starting at 7 DPF, IGF-I peptide but no IGF-I mRNA was observed in male and female primordial germ cells (PGCs) provided that IGF-I mRNA was not under the detection level, this observation may suggest that IGF-I originates from the somatic cells and is transferred to the PGCs or is of maternal origin. While in female germ cells IGF-I mRNA and peptide appeared at 29 DPF, in male germ cells both were detected as late as at 51-53 DPF. It is assumed that the production of IGF-I in the germ cells is linked to the onset of meiosis that in tilapia ovary starts at around 28 DPF and in testes at around 52-53 DPF. In adult testis, IGF-I mRNA and peptide occurred in the majority of spermatogonia and spermatocytes as well as in Leydig cells, the latter indicating a role of IGF-I in the synthesis of male sex steroids. In adult ovary, IGF-I mRNA and IGF-I peptide were always present in small and previtellogenic oocytes but only IGF-I peptide infrequently occurred in oocytes at the later stages. IGF-I expression appeared in numerous granulosa and some theca cells of follicles at the lipid stage and persisted in follicles with mature oocytes. The results suggest a crucial role of local IGF-I in the formation, differentiation and function of tilapia gonads.