Matrix metalloproteinase-9 genotypes and haplotypes are associated with multiple sclerosis and with the degree of disability of the disease

Multiple sclerosis (MS) is an autoimmune disease causing severe neurological disability. This study was carried out in order to determine whether the MMP-9 C(-1562)T and (CA)(13-25) polymorphisms are associated with MS. A total of 165 patients (92 whites/73 mulattos) and 191 controls (96 whites/95 mulattos) were enrolled in the study. While no difference in C(-1562)T polymorphism was observed between MS and healthy subjects, (CA)(n) genotypes and alleles were associated with MS. Moreover, the haplotypes are not associated with MS but seem to be relevant to the clinical status of MS. Thus the (CA)(n) polymorphism may contribute to MS susceptibility, but C(-1562)T and (CA)(n) haplotypes may modulate disease severity. (c) 2009 Elsevier B.V. All rights reserved.

Polymorphisms at GLUT1 Gene Are Not Associated With the Development of TSP/HAM in Brazilian HTLV-1 Infected Individuals and the Discovery of a New Polymorphism at GLUT1 Gene

The development of HTLV-1 associated clinical manifestations, such as TSP/HAM and ATLL, occur in 2-4% of the infected population and it is still unclear why this infection remains asymptomatic in most infected carriers. Recently, it has been demonstrated that HTLV uses the Glucose transporter type 1 (GLUT1) to infect T-CD4(+) lymphocytes and that single nucleotide polymorphisms (SNP) in the GLUT1 gene are associated with diabetic nephropathy in patients with diabetes mellitus in different populations. These polymorphisms could contribute to a higher GLUT1 protein expression on cellular membrane, facilitating the entry of HTLV and its transmission cell by cell. This could result in a higher provirus load and consequently in the development of TSP/HAM. To evaluate the role of GLUT1 gene polymorphisms in the development of TSP/HAM in HTLV-1 infected individuals, the g.22999G > T, g.15339T > C and c.-2841A > T sites were analyzed by PCR/RFLP or sequencing in 244 infected individuals and 102 normal controls. The proviral load of the HTLV-1 infected patients was also analyzed using Real Time Quantitative PCR. Genotypic and allelic frequencies of the three sites did not differ significantly between controls and HTLV-1 infected individuals. There was no difference in genotypic and allelic distributions among patients as to the presence or absence of HTLV-1 associated clinic manifestations. As regards the quantification of the provirus load, we observed a significant reduction in the asymptomatic individuals compared with the oligosymptomatic and TSP/HAM individuals. These results suggest that g.22999G > T, g.15339T > C, and c.-2841A > T SNP do not contribute to HTLV-1 infection nor to the genetic susceptibility of TSP/HAM in Brazilian HTLV-1 infected individuals. J. Med. Virol. 81:552557, 2009. (C) 2009 Wiley-Liss, Inc.

Intravitreal Bevacizumab for Diabetic Macular Edema Associated With Severe Capillary Loss: One-Year Results of a Pilot Study

PURPOSE: To evaluate the effects of intravitreal bevacizumab in patients with diabetic macular edema (DME) associated with severe capillary loss. DESIGN: Multicenter, open-label, nonrandomized study. METHODS: SETTING: Two tertiary ophthalmic referral centers in Brazil. STUDY POPULATION: Ten consecutive patients with DME and ""severe"" capillary loss. OBSERVATION PROCEDURES: Intravitreal injection(s) of bevacizumab (1.5 mg). Standardized ophthalmic evaluation was performed at baseline and at weeks 8, 16, 24, and 54. MAIN OUTCOME MEASURES: Changes in best-corrected visual acuity (BCVA) and in optical coherence tomography variables (central macular thickness [CMT] and total macular volume [TMV]). RESULTS: Significant changes in BCVA and in CMT/TMV were noted throughout the study (P<.001, P=.009, and P<.001, respectively). The mean logarithm of the minimal angle of resolution Early Treatment Diabetic Retinopathy Study BCVA was 0.786 (similar to 20/125(+1)) at baseline, 0.646 (similar to 20/80(-2)) at week 8, 0.580 (20/80(+1)) at week 16, 0.574 (similar to 20/80(+1)) at week 24, and 0.558 (similar to 20/80(+2)) at week 54. Compared with baseline, a significant change in BCVA was noted at all follow-up visits (P <=.008). The mean CMT/TMV values were, respectively, 472.6/10.9 at baseline, 371.4/9.9 at week 8, 359.5/9.8 at week 16, 323.9/9-4 at week 24, and 274.6/8.7 at week 54. Compared with baseline, a significant change in both CMT and TMV was noted only at 24 and 54 weeks (P <=.007). At 54 weeks, fluorescein angiography demonstrated no change in the extent of macular capillary loss and reduced dye leakage as compared with baseline in all patients. CONCLUSIONS: Favorable changes in BCVA and in CMT/TMV observed throughout 1 year suggest that intra-vitreal bevacizumab may be a viable alternative treatment for the management of patients with DME and severe capillary loss. (Am J Ophthalmol 2009;147:1022-1030. (C) 2009 by Elsevier Inc. All rights reserved.)

Progressive bilateral enophthalmos associated with cerebrospinal shunting

A 22-year-old woman was examined for a complaint of bilateral progressive enophthalmos that had begun after the cerebrospinal fluid shunting procedure 9 years ago. Photographs and CT scans taken before surgery proved that the position of her eyes was normal before surgery. The enophthalmos was so severe that it induced a poor eyelid-globe apposition with trichiasis and superficial keratopathy. CT of the orbits showed that both orbital roofs were arched and displaced toward the anterior cranial fossa. The placement of porous polyethylene sheets on the orbital roofs through a coronal approach corrected the eye position. A literature review indicated that cerebrospinal shuntings are plagued by a variety of complications including bone changes and craniosynostosis. We believe that enophthalmos associated with cerebrospinal fluid shunting results from a rare acquired bony orbital anomaly.

Cesarean delivery is associated with an increased risk of obesity in adulthood in a Brazilian birth cohort study

Background: Obesity is epidemic worldwide, and increases in cesarean delivery rates have occurred in parallel. Objective: This study aimed to determine whether cesarean delivery is a risk factor for obesity in adulthood in a birth cohort of Brazilian subjects. Design: We initiated a birth cohort study in Ribeirao Preto, southeastern Brazil, in 1978. A randomly selected sample of 2057 subjects from the original cohort was reassessed in 2002-2004. Type of delivery, birth weight, maternal smoking, and schooling were obtained after birth. The following data from subjects were collected at 23-25 y of age: body mass index (BMI; in kg/m(2)), physical activity, smoking, and income. Obesity was defined as a BMI >= 30. A Poisson multivariable model was performed to determine the association between cesarean delivery and BMI. Results: The obesity rate in adults born by cesarean delivery was 15.2% and in those born by vaginal delivery was 10.4% (P = 0.002). Adults born by cesarean delivery had an increased risk (prevalence ratio: 1.58; 95% CI: 1.23, 2.02) of obesity at adulthood after adjustments. Conclusion: We hypothesize that increasing rates of cesarean delivery may play a role in the obesity epidemic worldwide. Am J Clin Nutr 2011;93:1344-7.

Obesity due to Melanocortin 4 Receptor (MC4R) Deficiency Is Associated with Increased Linear Growth and Final Height, Fasting Hyperinsulinemia, and Incompletely Suppressed Growth Hormone Secretion

Context: Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity. Objective: The objective of the investigation was to study the somatotroph axis in obese MC4R-deficient patients and equally obese controls. Patients and Methods: We obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjects and 1392 controls matched for age and severity of obesity. We measured fasting IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficient patients and 36 control subjects. We examined pulsatile GH secretion in six adult MC4R-deficient subjects and six obese controls. Results: Height so score was significantly greater in MC4R-deficient children under 5 yr of age compared with controls (mean +/- SEM: 2.3 +/- 0.06 vs. 1.8 +/- 0.04, P < 0.001), an effect that persisted throughout childhood. Final height (cm) was greater in MC4R-deficient men (mean +/- SEM 173 +/- 2.5 vs. 168 +/- 2.1, P < 0.001) and women (mean 165 +/- 2.1 vs. 158 +/- 1.9, P < 0.001). Fasting IGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups. GH levels were markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency. The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increased in MC4R deficiency, consistent with increased pulsatile and total GH secretion. Fasting insulin levels were markedly elevated in MC4R-deficient children. Conclusions: In MC4R deficiency, increased linear growth in childhood leads to increased adult final height, greater than predicted by obesity alone. GH pulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role for MC4R in controlling hypothalamic somatostatinergic tone. Fasting insulin levels are significantly higher in children carrying MC4R mutations. Both of these factors may contribute to the accelerated growth phenotype characteristic of MC4R deficiency. (J Clin Endocrinol Metab 96: E181-E188, 2011)

Vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (NOS3) polymorphisms are associated with high relapse risk in childhood acute lymphoblastic leukemia (ALL)

Background: Angiogenesis has been shown as an important process in hematological malignancies. It consists in endothelial proliferation, migration, and tube formation following pro-angiogenic factors releasing, specially the vascular endothelial growth factor (VEGF), which angiogenic effect seems to be dependent on nitric oxide (NO). We examined the association among functional polymorphism in these two angiogenesis related genes: VEGF (-2578C>A, -1154G>A, and -634G>C) and NOS3 (-786T>C, intron 4 b>a, and Glu298Asp) with prognosis of childhood acute lymphoblastic leukemia (ALL). Methods: The genotypes were determined and haplotypes estimated in 105 ALL patients that were divided in 2 groups: high risk (HR) and low risk of relapse (LR) patients. In addition, event-free survival curves according to genotypes were assessed. Results: The group HR compared to the LR showed a higher frequency of the alleles -2578C and -634C and the haplotype CGC for VEGF (0.72 vs. 0.51, p<0.008; 0.47 vs. 0.26, p<0.008; and 42.1 vs. 14.5, p<0.006; respectively) and a lower frequency of the haplotype CbGlu (0.4 vs. 8.8, p<0.006), for NOS3. Conclusion: Polymorphisms of VEGF and NOS3 genes are associated with high risk of relapse, therefore may have a prognostic impact in childhood ALL. (C) 2010 Elsevier B.V. All rights reserved.

mRNA Expression Profile of Multidrug Resistance Genes in Childhood Acute Lymphoblastic Leukemia. Low Expression Levels Associated With a Higher Risk of Toxic Death

Background. Increased activity of multidrug resistance (MDR) genes has been associated with treatment failure in acute leukemias, although with controversial reports. The objective of the present study was to assess the expression profile of the genes related to MDR: ABCB1, ABCC1, ABCC3, ABCC2, and LRP/MVP in terms of the clinical and biological variable and the survival of children with acute lymphoblastic leukemia (ALL). Procedure. The levels of mRNA expression of the drug resistance genes ABCB1, ABCC1, ABCC3, ABCG2, and LRP/MVP were analyzed by quantitative real-time PCR using the median Values as cut-off points, in consecutive samples from 140 children with ALL at diagnosis. Results. Expression levels of the ABCG2 gene in the patient group as a whole (P=0.05) and of the ABCG2 and ABCC1 genes in patients classified as being at high risk were associated with higher rates of 5-year event-free survival (EFS) (P=0.04 and P=0.01). Expression levels of the ABCG2 gene below the median were associated with a greater chance of death related to treatment toxicity for the patient group as a whole (P=0.009) and expression levels below the median of the ABCG2 and ABCC1 genes were associated with a greater chance of death due to treatment toxicity for the high-risk group (P=0.02 and P=0.03, respectively). Conclusion. The present data suggest a low participation of the drug efflux genes in treatment failure in patients with childhood ALL. However, the low expression of some of these genes may be associated with a higher death risk related to treatment toxicity. Pediatr Blood Cancer 2009;53:996-1004. (C) 2009 Wiley-Liss, Inc.

ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency

Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA-severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children`s growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 and #NCT00599781. (Blood. 2009; 114: 3216-3226)

The-202 A Allele of Insulin-Like Growth Factor Binding Protein-3 (IGFBP3) Promoter Polymorphism Is Associated with Higher IGFBP-3 Serum Levels and Better Growth Response to Growth Hormone Treatment in Patients with Severe Growth Hormone Deficiency

Context: Genetic factors that influence the response to recombinant human GH (rhGH) therapy remain mostly unknown. To date, only the GH receptor gene has been investigated. Objective: The aim of the study was to assess the influence of a polymorphism in the IGF-binding protein-3 (IGFBP-3) promoter region (-202 A/C) on circulating IGFBP-3 levels and growth response to rhGH therapy in children with GH deficiency (GHD). Design and Patients: -202 A/C IGFBP3 genotyping (rs2854744) was correlated with data of 71 children with severe GHD who remained prepubertal during the first year of rhGH treatment. Main Outcome Measures: We measured IGFBP-3 levels and first year growth velocity (GV) during rhGH treatment. Results: Clinical and laboratory data at the start of treatment were indistinguishable among patients with different -202 A/C IGFBP3 genotypes. Despite similar rhGH doses, patients homozygous for the A allele presented higher IGFBP-3 SD score levels and higher mean GV in the first year of rhGH treatment than patients with AC or CC genotypes (first year GV, AA = 13.0 +/- 2.1 cm/yr, AC = 11.4 +/- 2.5 cm/yr, and CC = 10.8 +/- 1.9 cm/yr; P = 0.016). Multiple linear regression analyses demonstrated that the influence of -202 A/C IGFBP3 genotype on IGFBP-3 levels and GV during the first year of rhGH treatment was independent of other variables. Conclusion: The -202 A allele of IGFBP3 promoter region is associated with increased IGFBP-3 levels and GV during rhGH treatment in prepubertal GHD children. (J Clin Endocrinol Metab 94: 588-595, 2009)

New recurrent deletions in the PPAR gamma and TP53 genes are associated with childhood myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a rare hematological malignancy in children. It was performed FISH analysis in 19 pediatric MDS patients to investigate deletions involving the PPAR gamma and TP53 genes. Significant losses in the PPAR gamma gene and deletions in the tumor suppressor gene TP53 were observed in 17 and 18 cases, respectively. Using quantitative RT-PCR, it was detected PPAR gamma transcript downexpression in a subset of these cases. G-banding analysis revealed 17p deletions in a small number of these cases. One MDS therapy-related patient had neither a loss of PPAR gamma nor TP53. These data suggest that the PPAR gamma and TP53 genes may be candidates for molecular markers in pediatric MDS, and that these potentially recurrent deletions could contribute to the identification of therapeutic approaches in primary pediatric MDS. (C) 2008 Elsevier Ltd. All fights reserved.

Hepatoportal Sclerosis and Extrahepatic Portal Venous Obstruction Associated with Anti-phospholipid Antibody Syndrome in Child

We report a 2-year-old child with extrahepatic portal venous obstruction, hepatoportal sclerosis and pulmonary thromboembolism whose sole hypercoagulability factor was the presence of anti-phospholipid antibodies.

Tumor necrosis factor region polymorphisms are associated with AIDS and with cytomegalovirus retinitis

Background: The tumor necrosis factor (TNF) gene is located within the highly polymorphic major histocompatibility complex region, exhibiting the -308 CA promoter region polymorphism and six microsatellites (TNFa-f) spanning the region nearby the TNF locus. Objective: In the present Study, we evaluated the frequency of -308 CA and TNFa-e polymorphisms and respective haplotypes (in chromosomal sequence: TNFd-TNFe-308GA-TNFc-TNFa-TNFb), in 222 patients with AIDS, 52 of whom exhibited cytomegalovirus retinitis, and in 202 healthy HIV-negative individuals. Method: TNF microsatellite and single nucleotide polymorphism typings were performed by PCR followed by polyacrylamide gel electrophoresis. Results: The TNF-308A allele and the 4-3-C-2-7-1 haplotype were associated with susceptibility to AIDS, whereas the TNFb4 allele and the 3-3-C-1-11-4 haplotype were associated with protection against AIDS development. The TNFc2 allele and the 4-1-G-2-2-1 haplotype, which contains the TNFc2 allele, were associated with cytomegalovirus retinitis. Conclusion: This study highlights that polymorphic sites spanning the region nearby the TNF locus are associated with AIDS per se and with cytomegalovirus retinitis in AIDS patients. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Case Report: Esophageal Histoplasmosis Associated with Disseminated Tuberculosis in Acquired Immunodeficiency Syndrome

Bacterial and fungal infections are common in acquired immunodeficiency syndrome (AIDS). Histoplasmosis is a common fungal disease in severely immunocompromised patients infected with human immunodeficiency virus (HIV) in endemic areas. In this population the most frequent form of presentation of histoplasmosis is disseminated, with the clinical manifestations being similar to those of disseminated tuberculosis. Esophageal histoplasmosis and the association of histoplasmosis with tuberculosis are infrequent. We report here a rare Case of esophageal histoplasmosis associated with disseminated tuberculosis in AIDS.