Thalidomide treatment down-regulates SDF-1 alpha and CXCR4 expression in multiple myeloma patients

The chemokine stromal-derived factor-1 alpha (SDF-1 alpha) and its receptor CXCR4 are critically involved in directional migration and homing of plasma cells in multiple myeloma. Here, we show that the expression of SDF-1 alpha and CXCR4 was significantly down-regulated in patients treated with thalidomide (n = 10) as compared to newly diagnosed MM patients (n = 31) and MM patients treated with other drugs (n = 38). SDF-1 alpha and CXCR4 expression was also significantly decreased in a RPMI 8226 cell line treated with 10 and 20 mu mol/L of thalidomide. Our findings indicate that thalidomide therapy induces down-regulation of CXCR4 and its ligand SDF-1 alpha in multiple myeloma. (c) 2008 Elsevier Ltd. All rights reserved.

Quantifying subclinical central nervous lesions in primary antiphospholipid syndrome: The role of magnetization transfer imaging

Purpose: To define the role of magnetization transfer imaging (MTI) in detecting subclinical central nervous system (CNS) lesions in primary antiphospholipid syndrome (PAPS). Materials and Methods: Ten non-CNS PAPS patients were compared to 10 CNS PAPS patients and 10 age- and sex-matched controls. All PAPS patients met Sapporo criteria. All Subjects underwent conventional MRI and complementary MTI analysis to compose histograms. CNS viability was determined according to the magnetization transfer ratio (MTR) by mean pixel intensity (MPI) and the mean peak height (MPH). Volumetric cerebral measurements were assessed by brain parenchyma factor (BPF) and total/cerebral volume. Results: MTR histograms analysis revealed that MPI was significantly different among groups (P < 0.0001). Non-CNS PAPS had a higher MPI than CNS PAPS, (30.5 +/- 1.01 vs. 25.1 +/- 3.17 percent unit (pu); P < 0.05) although lower than controls (30.5 +/- 1.01 vs. 31.20 < 0.50 pu; P < 0.05). MPH in non-CNS PAPS (5.57 +/- 0.20% (1/pu)} was similar to controls (5.63 +/- 0.20% (1/pu), P > 0.05) and higher than CNS PAPS (4.71 +/- 0.30% (1/pu), P < 0.05). A higher peak location (PL) was also observed in the CNS PAPS group in comparison with the other groups (P < 0.0001). In addition, a lower BPF was found in non-CNS PAPS compared to controls (0.80 +/- 0.03 vs. 0.84 +/- 0.02 units; P < 0.05) but similar to CNS PAPS (0.80 +/- 0.03 vs. 0.79 +/- 0.05 units; P > 0.05). Conclusion: Our findings suggest that non-CNS PAPS patients have subclinical cerebral damage. The long-term-clinical relevance of MTI analysis in these patients needs to be defined by prospective studies.

The phylogeography of African Brazilians

Background/Aims: Approximately four million Africans were taken as slaves to Brazil, where they interbred extensively with Amerindians and Europeans. We have previously shown that while most White Brazilians carry Y chromosomes of European origin, they display high proportions of African and Amerindian mtDNA lineages, because of sex-biased genetic admixture. Methods: We studied the Y chromosome and mtDNA haplogroup structure of 120 Black males from Sao Paulo, Brazil. Results: Only 48% of the Y chromosomes, but 85% of the mtDNA haplogroups were characteristic of sub-Saharan Africa, confirming our previous observation of sexually biased mating. We mined literature data for mtDNA and Y chromosome haplogroup frequencies for African native populations from regions involved in Atlantic Slave Trade. Principal Components Analysis and Bayesian analysis of population structure revealed no genetic differentiation of Y chromosome marker frequencies between the African regions. However, mtDNA examination unraveled considerable genetic structure, with three clusters at Central-West Africa, West Africa and Southeast Africa. A hypothesis is proposed to explain this structure. Conclusion: Using these mtDNA data we could obtain for the first time an estimate of the relative ancestral contribution of Central-West (0.445), West (0.431) and Southeast Africa (0.123) to African Brazilians from Sao Paulo. These estimates are consistent with historical information. Copyright (c) 2008 S. Karger AG, Basel.

Proteomic characterization of the multiple forms of the PLAs from the venom of the social wasp Polybia paulista

The phospholipases A(1) (PLA(1)s) from the venom of the social wasp Polybia paulista occur as a mixture of different molecular forms. To characterize the molecular origin of these structural differences, an experimental strategy was planned combining the isolation of the pool of PLAs from the wasp venom with proteomic approaches by using 2-D, MALDI-TOF-TOF MS and classical protocols of protein chemistry, which included N- and C-terminal sequencing. The existence of an intact form of PLA(1) and seven truncated forms was identified, apparently originating from controlled proteolysis of the intact protein; in addition to this, four of these truncated forms also presented carbohydrates attached to their molecules. Some of these forms are immunoreactive to specific-IgE, while others are not. These observations permit to raise the hypothesis that naturally occurring proteolysis of PLA(1), combined with protein glycosylation may create a series of different molecular forms of these proteins, with different levels of allergenicity. Two forms of PLA(2)s, apparently related to each other, were also identified; however, it was not possible to determine the molecular origin of the differences between both forms, except that one of them was glycosylated. None of these forms were immunoreactive to human specific IgE.

Congenic strains provide evidence that four mapped loci in chromosomes 2, 4, and 16 influence hypertension in the SHR

Aneas I, Rodrigues MV, Pauletti BA, Silva GJ, Carmona R, Cardoso L, Kwitek AE, Jacob HJ, Soler JM, Krieger JE. Congenic strains provide evidence that four mapped loci in chromosomes 2, 4, and 16 influence hypertension in the SHR. Physiol Genomics 37: 52-57, 2009. First published January 6, 2009; doi: 10.1152/physiolgenomics.90299.2008. - To dissect the genetic architecture controlling blood pressure (BP) regulation in the spontaneously hypertensive rat (SHR) we derived congenic rat strains for four previously mapped BP quantitative trait loci (QTLs) in chromosomes 2, 4, and 16. Target chromosomal regions from the Brown Norway rat (BN) averaging 13 - 29 cM were introgressed by marker-assisted breeding onto the SHR genome in 12 or 13 generations. Under normal salt intake, QTLs on chromosomes 2a, 2c, and 4 were associated with significant changes in systolic BP (13, 20, and 15 mmHg, respectively), whereas the QTL on chromosome 16 had no measurable effect. On high salt intake (1% NaCl in drinking water for 2 wk), the chromosome 16 QTL had a marked impact on SBP, as did the QTLs on chromosome 2a and 2c (18, 17, and 19 mmHg, respectively), but not the QTL on chromosome 4. Thus these four QTLs affected BP phenotypes differently: 1) in the presence of high salt intake (chromosome 16), 2) only associated with normal salt intake (chromosome 4), and 3) regardless of salt intake (chromosome 2c and 2a). Moreover, salt sensitivity was abrogated in congenics SHR. BN2a and SHR. BN16. Finally, we provide evidence for the influence of genetic background on the expression of the mapped QTLs individually or as a group. Collectively, these data reveal previously unsuspected nuances of the physiological roles of each of the four mapped BP QTLs in the SHR under basal and/or salt loading conditions unforeseen by the analysis of the F2 cross.

Use of multiple channel pH monitoring for evaluation of ultra-distal reflux in patients after fundoplication for treatment of Barrett`s esophagus

Dysplasia and esophageal adenocarcinoma may arise in patients with Barrett`s esophagus after fundoplication esophageal pH monitoring showing no acid in esophagus. This suggests the need to develop methodology to evaluate the occurrence of ultra-distal reflux (1 cm above the LES). The objective of the study was to compare acid exposition in three different levels: 5 cm above the upper border of the LES, 1 cm above the LES and in the intrasphincteric region. Eleven patients with Barrett`s esophagus after Nissen fundoplication with no clinical, endoscopic and radiologic evidence of reflux were selected. Four-channel pH monitoring took place: channel A, 5 cm above the upper border of the LES; channel B, 1 cm above the LES; channel C, intrasphincteric; channel D, intragastric. The results of channels A, B and C were compared. There was significant increase in number of reflux episodes and a higher fraction of time with pH <4.0 in channel B compared to channel A. There was significant decrease in fraction of time with pH <4.0 in channel B compared to channel C. Two cases of esophageal adenocarcinoma were diagnosed in the studied patients. The region 1 cm above the upper border of the LES is more exposed to acid than the region 5 cm above the upper border of the LES, although this exposure occurred in reduced levels. The region 1 cm above the upper border of the LES is less exposed to acid than the intrasphincteric region.

Antiretroviral Drug Resistance in a Respondent-Driven Sample of HIV-Infected Men Who Have Sex With Men in Brazil

Background: There are few studies on HIV subtypes and primary and secondary antiretroviral drug resistance (ADR) in community-recruited samples in Brazil. We analyzed HIV clade diversity and prevalence of mutations associated with ADR in men who have sex with men in all five regions of Brazil. Methods: Using respondent-driven sampling, we recruited 3515 men who have sex with men in nine cities: 299 (9.5%) were HIV-positive; 143 subjects had adequate genotyping and epidemiologic data. Forty-four (30.8%) subjects were antiretroviral therapy-experienced (AE) and 99 (69.2%) antiretroviral therapy-naive (AN). We sequenced the reverse transcriptase and protease regions of the virus and analyzed them for drug resistant mutations using World Health Organization guidelines. Results: The most common subtypes were B (81.8%), C (7.7%), and recombinant forms (6.9%). The overall prevalence of primary ADR resistance was 21.4% (i.e. among the AN) and secondary ADR was 35.8% (i.e. among the AE). The prevalence of resistance to protease inhibitors was 3.9% (AN) and 4.4% (AE); to nucleoside reverse transcriptase inhibitors 15.0% (AN) and 31.0% (AE) and to nonnucleoside reverse transcriptase inhibitors 5.5% (AN) and 13.2% (AE). The most common resistance mutation for nucleoside reverse transcriptase inhibitors was 184V (17 cases) and for nonnucleoside reverse transcriptase inhibitors 103N (16 cases). Conclusions: Our data suggest a high level of both primary and secondary ADR in men who have sex with men in Brazil. Additional studies are needed to identify the correlates and causes of antiretroviral therapy resistance to limit the development of resistance among those in care and the transmission of resistant strains in the wider epidemic.

Sexual behavior and knowledge of sexually transmitted infections among university students in Sao Paulo, Brazil

Objective: To investigate the sexual behavior and knowledge about sexually transmitted infections (STIs) among undergraduate students in Sao Paulo, Brazil. Methods: Self-reported questionnaires were used. Results: Most of the 447 students in the study were single (97.3%), in their first year of university (87.7%), and the mean ages were 20.4 years (males) and 19.8 years (females). Vaginal intercourse was practiced by 69.7% of males and 48.4% of females, oral sex by 64.5% of males and 43.7% of females, and anal sex by 18.4% of males and 14.1% of females. Use of a condom during vaginal sex was practiced by 80.4% of males and 74.8% of females and during anal sex by 47.8% of males and 30.0% of females. Knowledge of transmission of STIs was greater than 90% for HIV, syphilis, genital herpes, and gonorrhea; 63%-76% for HPV and genital warts; 30%-34% for Trichomonas and only 16% for Chlamydia. Only 25%-34% knew that HIV was transmitted by breastfeeding; 56%-60% knew that HIV was transmitted by anal sex. Conclusion: Many students engage in high-risk sexual behavior with multiple partners and use condoms inconsistently. Knowledge of the acquisition and modes of sexual and vertical transmission of HIV are strikingly deficient. (C) 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Background: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35). Methods: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies. Results: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08-1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95-1.09, P = 0.66; P-heterogeneity (P(het)) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12-1.34, P = 7 x 10(-6)) but not males (OR = 1.02, 95% CI = 0.97-1.08, P = 0.35; P(het) = 6 x 10(-4)). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P(het) = 0.86). Conclusions: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers. Impact: Further research is warranted to elucidate the mechanisms underlying these observations. Cancer Epidemiol Biomarkers Prev; 20(4); 658-64. (C) 2011 AACR.

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines

Because of the advent of a new influenza A H1N1. strain, many countries have begun mass immunisation programmes. Awareness of the background rates of possible adverse events will be a crucial part of assessment of possible vaccine safety concerns and will help to separate legitimate safety concerns from events that are temporally associated with but not caused by vaccination. We identified background rates of selected medical events for several countries. Rates of disease events varied by age, sex, method of ascertainment, and geography. Highly visible health conditions, such as Guillain-Barre syndrome, spontaneous abortion, or even death, will occur in coincident temporal association with novel influenza vaccination. On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21.5 cases of Guillain-Barre syndrome and 5.75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86.3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination.

Cognitive functioning in subjects with recent-onset psychosis from a low-middle-income environment: Multiple-domain deficits and longitudinal evaluation

Cognitive deficits are a key feature of recent-onset psychosis, but there is no consensus on whether such deficits are generalized or confined to specific domains. Besides, it is unclear whether cognitive deficits: a) are found in psychotic patients in samples from outside high-income countries; and b) whether they progress uniformly over time in schizophrenia and affective psychoses. We applied 12 tests organized into eight cognitive domains, comparing psychosis patients (n = 56, time from initial contact = 677.95+/-183.27 days) versus healthy controls (n = 70) recruited from the same area of Sao Paulo, Brazil. Longitudinal comparisons (digit span and verbal fluency) were conducted between a previous assessment of the subjects carried out at their psychosis onset, and the current follow-up evaluation. Psychosis patients differed significantly from controls on five domains, most prominently on verbal memory. Cognitive deficits remained detectable in separate comparisons of the schizophrenia subgroup and, to a lesser extent, the affective psychosis subjects against controls. Longitudinal comparisons indicated significant improvement in schizophrenia, affective psychoses, and control subjects, with no significant group-by-time interactions. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non-affective nature, which persist over time. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Sex differences in the phenotypic expression of obsessive-compulsive disorder: an exploratory study from Brazil

Previous studies have shown differences in clinical features of obsessive-compulsive disorder (OCD) between men and women, including mean age at onset of obsessive-compulsive symptoms (OCS), types of OCS, comorbid disorders, course, and prognosis. The aim of this study was to compare male and female Brazilian patients with OCD on several demographic and clinical characteristics. Three hundred thirty Outpatients with OCD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV], criteria) who sought treatment at 3 Brazilian public universities and at 2 private practice clinics in the city of Sao Paulo were evaluated. The assessment instruments used were the Yale-Brown Obsessive-Compulsive Scale to evaluate OCD severity and symptoms, the Beck Depression and Anxiety Inventories, the Yale Global Tic Severity Scale, and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders to assess psychiatric comorbidity. Fifty-five percent of the patients (n = 182) were men who were significantly more likely than women to be single and to present sexual, religious, and symmetry obsessions and mental rituals. They also presented earlier onset of OCS and earlier symptom interference in functioning, and significantly more comorbid tic disorders and posttraumatic stress disorder. Women, besides showing significantly higher mean scores in the Beck Depression and Anxiety Inventories, were more likely to present comorbid simple phobias, eating disorders in general and anorexia in particular, impulse control disorders in general, and compulsive buying and skin picking in particular. No significant differences were observed between sexes concerning family history of OCS or OCD, and global symptoms severity, either in obsession or compulsive subscale. The present study confirms the presence of sex-related differences described in other countries and cultures. The fact that the OCS start earlier and probably have a worse impact in men can eventually lead to more specific and efficacious treatment approaches for these patients. (C) 2009 Elsevier Inc. All rights reserved.

Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

Objective: Only few large families with multiple endocrine neoplasia type 1 (MEN1) have been documented. Here, we aimed to investigate the clinical features of a seven-generation Brazilian pedigree. which included 715 at-risk family members. Design: Genealogical and geographic analysis was used to identify the MEN1 pedigree. Clinical and genetic approach was applied to characterize the phenotypic and genotypic features of the family members. Results: Our genetic data indicated that a founding mutation in the MEN1 gene has occurred in this extended Brazilian family. Fifty family members were diagnosed with MEN1. Very high frequencies of functioning and non-functioning MEN1-related tumors were documented and the prevalence of prolactinoma (29.6%) was similar to that previously described in prolactinoma-variant Burin (32%). In addition, bone mineral density analysis revealed severe osteoporosis (T,-2.87 +/- 0.32) of compact bone (distal radius) in hyperparathyroidism (HPT)/MEN1 patients. while marked bone mineral loss in the lumbar spine (T,-1.95 +/- 0.39). with most cancellous bone, and femoral neck (mixed composition: T,-1.48 +/- 0.27) were also present. Conclusions: In this study, we described clinically and genetically the fifth largest MEN1 family in the literature. Our data confirm previous findings suggesting that prevalence of MEN1-related tumors in large families may differ from reports combining cumulative data of small families. Furthermore. we were able to evaluate the bone status in HPT/MEN1 cases, a subject that has been incompletely approached in the literature. We discussed the bone loss pattern found in our MEN1 patients comparing with that of patients with sporadic primary HPT.

A new morphological variant of uterine PEComas with sex-cord-like pattern and WT1 expression: more doubts about the existence of uterine PEComas

PEComas are rare neoplasms that are sometimes associated with the tuberous sclerosis complex. They typically contain perivascular epithelioid cells that coexpress muscle and melanocytic markers. However, apart from these classical features, considerable clinical, pathologic, and immunohistochemical variation has been reported. WT1, the Wilms tumor gene product, can be expressed in various tumors from different anatomical sites, including sex-cord and other ovarian tumors with a sertoliform pattern. Neither a sex-cord like pattern nor WT1 expression has been described in PEComas. Here, we describe a case of uterine PEComa with a pattern of infiltration into the myometrium that is similar to stromal sarcomas, characterized by tongues and endovascular growing. The architecture and cellular morphology were similar to sex-cord tumors, and the PEComa was diffusely and strongly positive for WT1. We reviewed, from our files, an additional 9 cases of PEComa from different sites, and found WT1 expression in one more soft tissue tumor. We discuss the relationship between PEComas and other uterine sarcomas. (C) 2010 Elsevier Inc. All rights reserved.