Novel pathogenic mutations and copy number variations in the VPS13A Gene in patients with chorea‐acanthocytosis

Chorea‐acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult‐onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real‐time quantitative PCR and long‐range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc. © 2011 Wiley‐Liss, Inc.     

Spastic Paraplegia, Optic Atrophy, and Neuropathy: New Observations, Locus Refinement, and Exclusion of Candidate Genes

SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive.     

Sexual function in women with type 1 diabetes matched with a control group: depressive and psychosocial aspects

IntroductionSexual dysfunction in women with diabetes, despite its important consequences to their quality of life, has been investigated only recently with conflicting results about its prevalence and association with complications and psychological factors.AimsTo assess the prevalence of the alteration of sexual function and the influence of metabolic control and psychological factors on female sexuality.MethodsSeventy-seven adult Italian women with type 1 diabetes, matched with a control group (n = 77), completed questionnaires evaluating sexual function (Female Sexual Function Index, FSFI), depressive symptoms (Self-Rating Depression Scale, SRDS), social and family support (Multidimensional Scale of Perceived Social Support), and diabetes-related quality of life (Diabetes Quality of Life). Clinical and metabolic data were collected.Main Outcome MeasuresPrevalence and magnitude of sexual dysfunction in terms of alteration of sexual functioning as measured by the FSFI scores.ResultsThe prevalence of sexual dysfunction was similar in diabetes and control groups (33.8% vs. 39.0%, not significant), except for higher SRDS scores in the diabetes group (47.39 ± 11.96 vs. 43.82 ± 10.66; P = 0.047). Diabetic patients with an alteration of sexual function showed a significantly higher SRDS score (53.58 ± 14.11 vs. 44.24± 9.38, P = 0.004). Depression symptoms and good glycemic control (A1C < 7.0%) were predictors of alteration of sexual function only in diabetic patients (odds ratio [OR] = 1.082; 95% confidence interval [CI]: 1.028–1.140; OR = 5.085; 95% CI: 1.087–23.789), since we have not found any significant predictor of sexual dysfunction in the control group.ConclusionsThe prevalence of sexual dysfunction in our type 1 diabetes patients' sample is similar to those reported in other studies. Diabetic patients are similar to healthy people except for higher depression scores. Further studies are necessary to understand whether the correlation between an alteration of sexual function and good glycemic control may be related to the role of control as a mental attitude. Tagliabue M, Gottero C, Zuffranieri M, Negro M, Carletto S, Picci RL, Tomelini M, Bertaina S, Pucci E, Trento M, and Ostacoli L. Sexual function in women with type 1 diabetes matched with a control group: Depressive and psychosocial aspects.     

Effectiveness of cervical cancer screening using visual inspection with acetic acid in Peru

Objective

To evaluate the effectiveness of screening using visual inspection with acetic acid (VIA).

Methods

In a low-resource area of Peru in 2005-2008, a randomly selected sample of women who had previously screened negative by VIA and Pap (intervention group), and a group of eligible women previously unscreened by VIA (comparison group) were screened by VIA. The outcome measures were histologically confirmed cervical intraepithelial neoplasia (CIN) 2-3 and invasive cervical cancer.

Results

There were 4252 women in the intervention group and 4392 in the comparison group. Histologically confirmed CIN 2 or worse was diagnosed in 31 (0.7%) and 115 (2.6%) women, and invasive cancer was diagnosed in 4 women (0.09%) and 43 women (1.00%), in the intervention and comparison groups, respectively. The adjusted odds ratio was 4.2 (95% confidence interval [CI], 2.7-6.4) for CIN 2 or worse, and 13.9 (95% CI, 4.9-39.6) for invasive cervical cancer in the comparison group.

Conclusion

A lower prevalence of CIN 2-3 and invasive cervical cancer was seen in women previously screened by VIA, as compared with women not previously screened by VIA, implying that a single VIA screening can lower the population risk for cervical cancer.     

Assessment of Epstein-Barr virus association with pediatric non-hodgkin lymphoma in immunocompetent and in immunocompromised patients in Argentina

CONTEXT: Epstein-Barr virus (EBV) has been classically associated with 3 malignancies, Burkitt lymphoma, B-cell lymphoproliferative syndromes, and nasopharyngeal carcinoma, and more recently with Hodgkin disease, T-cell lymphomas, and gastric and breast carcinomas, as well as with leiomyosarcoma and leiomyoma associated with immunosuppression. OBJECTIVE: To compare EBV expression in Argentine tumor samples with those reported elsewhere, we analyzed EBV expression in an Argentine pediatric population with non-Hodgkin lymphoma and correlated these results with clinical course and outcome. METHODS: We studied EBV presence by latent membrane protein-1 protein labeling by immunohistochemistry, by in situ hybridization, and by polymerase chain reaction for Epstein-Barr-encoded RNAs (EBERs) in formalin-fixed and paraffin-embedded non-Hodgkin lymphoma tissue samples (collected retrospectively) from 32 pediatric patients at Ricardo Gutiérrez Children's Hospital from 1993 to 2000. RESULTS: Eight out of the 32 (25%) non-Hodgkin lymphoma cases showed latent membrane protein-1 and EBERs by in situ hybridization positive staining in tumor cells. Among EBERs and latent membrane protein-1-positive cases, there were 5 immunocompromised patients, with either human immunodeficiency virus infection or primary immunodeficiency. The EBERs in situ hybridization results were confirmed by EBERs polymerase chain reaction in good-quality DNA from 11 samples, with 3 proving positive and 8 negative. CONCLUSIONS: The association of EBV with non-Hodgkin lymphoma in the Argentine pediatric population was low (25%), and this figure rose to 100% when only the immunocompromised patients subgroup was considered, confirming that the virus is probably a cofactor in the lymphomagenesis of some but not all pediatric non-Hodgkin lymphoma. So far, no differences in clinical outcome are discernible between EBV-positive and EBV-negative non-Hodgkin lymphoma patients.     

Human apolipoprotein A-I Gly26Arg stimulation of inflammatory responses via NF-kB activation: Potential roles in amyloidosis?

The cascade of molecular events leading to Human apolipoprotein A–I (apoA–I) amyloidosis is not completely understood, not even the pathways that determine clinical manifestations associated to systemic protein deposition in organs such as liver, kidney and heart. About twenty natural variants of apoA–I were described as inducing amyloidosis, but the mechanisms driving their aggregation and deposition are still unclear. We previously identified that the mutant Gly26Arg but not Lys107-0 induced the release of cytokines and reactive oxygen species from cultured RAW 264.7 murine macrophages, suggesting that part of the pathogenic pathway could elicit of an inflammatory signal. In this work we gained deep insight into this mechanism and determined that Gly26Arg induced a specific pro-inflammatory cascade involving activation of NF-κB and its translocation into the nucleus. These findings suggest that some but not all apoA–I natural variants might promote a pro-oxidant microenvironment which could in turn result in oxidative processing of the variants into a misfolded conformation.     

Effects of two aerobic exercise training protocols on parameters of oxidative stress in the blood and liver of obese rats

We evaluated the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) protocols on the alterations in oxidative stress parameters caused by a high-fat diet (HFD), in the blood and liver of rats. The HFD enhanced thiobarbituric acid reactive substances (TBA-RS) and protein carbonyl content, while reducing total sulfhydryl content and catalase (CAT) and glutathione peroxidase (GSH-Px) activities in the blood. Both training protocols prevented an increase in TBA-RS and protein carbonyl content, and prevented a reduction in CAT. HIIT protocol enhanced SOD activity. In the liver, HFD didn’t alter TBA-RS, total sulfhydryl content or SOD, but increased protein carbonyl content and CAT and decreased GSH-Px. The exercise protocols prevented the increase in protein carbonyl content and the MICT protocol prevented an alteration in CAT. In conclusion, HFD elicits oxidative stress in the blood and liver and both protocols prevented most of the alterations in the oxidative stress parameters.