HFE gene mutations in patients with primary iron overload: Is there a significant improvement in molecular diagnosis yield with HFE sequencing?

Rare HFE variants have been shown to be associated with hereditary hemochromatosis (HH), an iron overload disease. The low frequency of the HFE p.C282Y mutation in HH-affected Brazilian patients may suggest that other HFE-related mutations may also be implicated in the pathogenesis of HH in this population. The main aim was to screen for new HFE mutations in Brazilian individuals with primary iron overload and to investigate their relationship with HH. Fifty Brazilian patients with primary iron overload (transferrin saturation >50% in females and 60% in males) were selected. Subsequent bidirectional sequencing for each HFE exon was performed. The effect of HFE mutations on protein structure were analyzed by molecular dynamics simulation and free binding energy calculations. p.C282Y in homozygosis or in heterozygosis with p.H63D were the most frequent genotypic combinations associated with HH in our sample population (present in 17 individuals, 34%). Thirty-six (72.0%) out of the 50 individuals presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n = 11, 22.0%). One novel mutation (p.V256I) was indentified in heterozygosis with the p.H63D mutation. In silico modeling analysis of protein behavior indicated that the p.V256I mutation does not reduce the binding affinity between HFE and beta 2-microglobulin ((beta 2M) in the same way the p.C282Y mutation does compared with the native HFE protein. In conclusion, screening of HFE through direct sequencing, as compared to p.C282Y/p.H63D genotyping, was not able to increase the molecular diagnosis yield of HH. The novel p.V256I mutation could not be implicated in the molecular basis of the HH phenotype, although its role cannot be completely excluded in HH-phenotype development. Our molecular modeling analysis can help in the analysis of novel, previously undescribed, HFE mutations. (C) 2010 Elsevier Inc. All rights reserved.

Hemojuvelin and Hepcidin Genes Sequencing in Brazilian Patients with Primary Iron Overload

Background: Most hereditary hemochromatosis (HH) patients are homozygous for the p. C282Y mutation in the HFE gene. Some studies reported that HH phenotypic expression could be modulated by genetic factors such as HJV and HAMP gene mutations. Aims: The aims of this study were to identify HJV and HAMP mutations and to analyze their impact on HH phenotype in non-p. C282Y homozygous individuals. Methods: Twenty-four Brazilian patients with primary iron overload and non-p. C282Y homozygous genotype (transferrin saturation >50% in women and >60% in men and absence of secondary causes) were selected. Subsequent bidirectional sequencing of the HJV and HAMP exons was performed. Results: Sequencing revealed a substitution in heterozygosis, c. 929C>G, which corresponds to p.A310G polymorphism in HJV exon 4 (rs7540883). In the same gene, in another individual, an IVS1-36C>G intronic variant was detected in heterozygosis. In the HAMP gene, an IVS3 + 42G>A intronic variant was identified. There were six (25.0%) patients carrying a heterozygous genotype for the HFE p. C282Y and nine (37.5%) patients carrying a heterozygous genotype for the HFE p. H63D. Conclusion: HJV p.A310G polymorphism and two intronic variants were found, but none of these alterations were associated with digenic inheritance with the HFE gene. Our data indicate that HJV and HAMP functional mutations are not frequent in these patients.

Quercetin inhibits UV irradiation-induced inflammatory cytokine production in primary human keratinocytes by suppressing NF-kappa B pathway

Background: Topical flavonoids, such as quercetin, have been shown to reduce ultraviolet (UV) irradiation-mediated skin damage. However, the mechanisms and signaling pathways involved in this protective effect are not clear. UV irradiation leads to activation of two major signaling pathways, namely nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) pathways. Activation of NF-kappa B pathway by UV irradiation stimulates inflammatory cytokine expression, whereas activation of AP-1 pathway by UV irradiation promotes matrix metalloproteinase (MMP) production. Both pathways contribute to UV irradiation-induced skin damage, such as photoaging and skin tumor formation. Objective: To elucidate the underlying mechanism, we examined the effect of quercetin on UV irradiation induced activation of NF-kappa B and AP-1 pathways. Methods: Primary human keratinocytes, the major skin cell type subjected to physiological solar UV irradiation, were used to study the effects of quercetin on UV irradiation-induced signal transduction pathways. Results: Quercetin decreased UV irradiation-induced NF-kappa B DNA-binding by 80%. Consequently, quercetin suppressed UV irradiation-induced expression of inflammatory cytokines IL-1 beta (similar to 60%), IL-6 (similar to 80%), IL-8 (similar to 76%) and TNF-alpha (similar to 69%). In contrast, quercetin had no effect on UV irradiation activation of three MAP kinases, ERK, JNK, or p38. Accordingly, induction of AP-1 target genes such as MMP-1 and MMP-3 by UV irradiation was not suppressed by quercetin. Conclusion: Our data indicate that the ability of quercetin to block UV irradiation-induced skin inflammation is mediated, at least in part, by its inhibitory effect on NF-kappa B activation and inflammatory cytokine production. (C) 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

The impact of Six Sigma in the performance of a Pollution Prevention program

The diffusion of Pollution Prevention faces organizational barriers as for instance resistance to change, insufficient support from decision-makers, unclear project leadership, insufficient employee accountability and inflexible organizational structures. To understand how to overcome such barriers, the performance of a Pollution Prevention program of a multinational corporation is analyzed. The quantitative analyses of 2096 Pollution Prevention projects conducted between 1995 and 2007 support the conclusion that the performance of the Pollution Prevention program increased after the implementation of the Six Sigma program. Moreover, the analyses of 1906 Pollution Prevention projects and 31,133 Six Sigma projects for cost reduction in 27 countries indicate that in countries where the implementation of Six Sigma is more expressive, pollution is prevented more than in countries with less expressive Six Sigma implementation. In fact, the Six Sigma implementation improved the organizational capability for data based project management. Therefore, comparing six years before and six years after the Six Sigma implementation, the total number of Pollution Prevention projects recognized increased 6.9 times and the total amount of pollution prevented increased by 62%. The qualitative analysis describes how the Six Sigma program interacts with the Pollution Prevention program in the studied company. (C) 2009 Elsevier Ltd. All rights reserved.

Francoist Primary education: the schoolbook as an instrument of child indoctrination

The Francoist rule, mainly in its first decades, exerted a strong control upon education, which was left in the hands of the Catholic nationalist. Innumerous children`s schoolbooks were published driven by strong patriotic and religious bias. The authors aimed to shape the children`s minds based on the premises that supported the regimen: authority, hierarchy, order, abeyance, fear and devotion to God and the leader Francisco Franco. This paper analyzes the content of the elementary education books and shows how they were important instruments of child indoctrination marked by intolerance. The content and the images of the books contributed to construct an excluding national identity based on a heightened Catholic patriotism, stimulated heroism, martyrdom, child sacrifice, and hatred for the enemies of the religion and of ""mother Spain"".

Primary Antiphospholipid Syndrome and Thyroid Involvement

Background: Data on thyroid involvement in primary antiphospholipid syndrome are scarce and inconclusive. Objectives: The aim of this study was to evaluate the frequency of thyroid dysfunction and antibodies in patients with primary antiphospholipid syndrome ( PAPS) and the association of these alterations with clinical and immunologic features. Methods: The study group included 50 PAPS patients (44 females) with a mean age of 39.7 +/- 11.5 years and mean disease duration of 77.3 +/- 63.5 months. Clinical data related to thyroid dysfunction and PAPS were obtained by chart review, patient interview, and clinical examination. Serum levels of TSH, free T4, antithyroglobulin antibody (TgAb), antithyroperoxidase antibody (TPOAb), thyroid receptor antibody (TRAb), and antiphospholipid autoantibodies were analyzed by standard techniques. Results: We found no hyperthyroidism among patients and found 22% (11 patients) with hypothyroidism in this sample. There were no differences between the latter patients and the euthyroid group about demographic findings, disease duration, thrombotic or obstetric events, and frequency of antiphospholipid antibodies as well as prevalence of thyroid auto antibodies. The prevalence of thyroid autoantibodies found was 6 patients (12%) with TgAb, 5 with TPOAb (10%), and 2 patients (4%) with both TgAb and TPOAb, comprising 18% of positivity of at least one of the auto antibodies. Conclusion: Hypothyroidism is present among 22% of PAPS patients and thyroid autoantibodies in 18% of them. These findings suggest a common pathophysiologic mechanism between antiphospholipid syndrome and autoimmune thyroid diseases.

Prostatic Artery Embolization as a Primary Treatment for Benign Prostatic Hyperplasia: Preliminary Results in Two Patients

Symptomatic benign prostatic hyperplasia (BPH) typically occurs in the sixth and seventh decades, and the most frequent obstructive urinary symptoms are hesitancy, decreased urinary stream, sensation of incomplete emptying, nocturia, frequency, and urgency. Various medications, specifically 5-alpha-reductase inhibitors and selective alpha-blockers, can decrease the severity of the symptoms secondary to BPH, but prostatectomy is still considered to be the traditional method of management. We report the preliminary results for two patients with acute urinary retention due to BPH, successfully treated by prostate artery embolization (PAE). The patients were investigated using the International Prostate Symptom Score, by digital rectal examination, urodynamic testing, prostate biopsy, transrectal ultrasound (US), and magnetic resonance imaging (MRI). Uroflowmetry and postvoid residual urine volume complemented the investigation at 30, 90, and 180 days after PAE. The procedure was performed under local anesthesia; embolization of the prostate arteries was performed with a microcatheter and 300- to 500-mu m microspheres using complete stasis as the end point. One patient was subjected to bilateral PAE and the other to unilateral PAE; they urinated spontaneously after removal of the urethral catheter, 15 and 10 days after the procedure, respectively. At 6-month follow-up, US and MRI revealed a prostate reduction of 39.7% and 47.8%, respectively, for the bilateral PAE and 25.5 and 27.8%, respectively, for the patient submitted to unilateral PAE. The early results, at 6-month follow-up, for the two patients with BPH show a promising potential alternative for treatment with PAE.

Primary antiphospholipid syndrome with thrombotic thrombocytopenic purpura: a very unusual association

This report considers the rare situation in which primary antiphospholipid syndrome (PAPS) is linked with thrombotic thrombocytopenic purpura (TTP). It describes the case of a young lady with PAPS, characterized by recurring cerebro-vascular abnormalities and marked livedo reticularis, combined with circulating anticardiolipin and lupus anticoagulant antibodies. On follow-up, while on oral anticoagulation, she developed severe thrombocytopenia associated with hematuria, microangiophatic anaemia and neurological manifestations consistent with a diagnosis of TTP. The patient was treated with pulses of methylprednisolone and plasmapheresis with plasma exchange. The result was a favourable outcome. To our knowledge, this is the seventh report on this rare association in the English-language literature of this field. Lupus (2009) 18, 841-844.

Lipid Treatment Assessment Project 2 A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals

Background-Information about physicians` adherence to cholesterol management guidelines remains scant. The present survey updates our knowledge of lipid management worldwide. Methods and Results-Lipid levels were determined at enrollment in dyslipidemic adult patients on stable lipid-lowering therapy in 9 countries. The primary end point was the success rate, defined as the proportion of patients achieving appropriate low-density lipoprotein cholesterol (LDL-C) goals for their given risk. The mean age of the 9955 evaluable patients was 62 +/- 12 years; 54% were male. Coronary disease and diabetes mellitus had been diagnosed in 30% and 31%, respectively, and 14% were current smokers. Current treatment consisted of a statin in 75%. The proportion of patients achieving LDL-C goals according to relevant national guidelines ranged from 47% to 84% across countries. In low-, moderate-, and high-risk groups, mean LDL-C was 119, 109, and 91 mg/dL and mean high-density lipoprotein cholesterol was 62, 49, and 50 mg/dL, respectively. The success rate for LDL-C goal achievement was 86% in low-, 74% in moderate-, and 67% in high-risk patients (73% overall). However, among coronary heart disease patients with >= 2 risk factors, only 30% attained the optional LDL-C goal of < 70 mg/dL. In the entire cohort, high-density lipoprotein cholesterol was < 40 mg/dL in 19%, 40 to 60 mg/dL in 55%, and > 60 mg/dL in 26% of patients. Conclusions-Although there is room for improvement, particularly in very-high-risk patients, these results indicate that lipid-lowering therapy is being applied much more successfully than it was a decade ago. (Circulation. 2009; 120: 28-34.)

Fibromyalgia in primary antiphospholipid (Hughes) syndrome

Fibromyalgia (FM) is a syndrome that can be associated with several rheumatic diseases. However, no study has evaluated its frequency in patients with primary antiphospholipid syndrome (PAPS). The objective of this study was to analyze the frequency of FM in PAPS patients compared with healthy controls, to determine the possible associations between FM and PAPS features, and also to evaluate quality of life and depression in these patients. This case-control study included 30 PAPS patients (by the Sapporo criteria) and 40 healthy subjects. Demographic and clinical data, drug use, and antiphospholipid antibodies were analyzed. FM was diagnosed based on international criteria (ACR). Questionnaires on quality of life, including the Short Form 36 Health Survey (SF-36), Beck Depression Inventory (BDI), Fibromyalgia Impact Questionnaire (FIQ), and Visual Analog Scale (VAS), were also applied. PAPS patients and controls were similar in mean age as well as in distributions of gender and Caucasian race. Mean disease duration was 5.4 +/- 4.2 years. A diagnosis of fibromyalgia was made in five (16.7%) PAPS patients and no controls (p = 0.012). PAPS patients had more diffuse pain (53% vs. 0%, respectively, p<0.0001), >= 11 tender points (23% vs. 5%, respectively, p = 0.032), and a greater total number (175 vs. 57, respectively, p<0.0001) as well as median number of tender points per patient than controls (5 [0-18] vs. 0 [0-11], respectively, p<0.0001). PAPS patients had lower values in all dimensions of the SF-36, as well as higher FIQ scores, higher BDI scores, more depression diagnoses according to BDI results, and increased VAS in comparison with controls. Analysis of PAPS patients with FM compared with those subjects without FM revealed no significant differences regarding demographic features or thrombotic or clinical events; however, PAPS patients who also had FM had lower values in SF-36 dimensions as well as higher FIQ (82.6 +/- 9.6 vs. 33.6 +/- 29.8, respectively, p<0.0001) and VAS scores (6.6 +/- 2.97 vs. 3.25 +/- 3.11, respectively, p = 0.03). BDI scores, in contrast, were similar in both groups. In conclusion, one-fifth of PAPS patients had fibromyalgia and a low quality of life when compared with healthy subjects. Lupus (2011) 20, 1182-1186.

Influence of gender on the clinical and laboratory spectra of patients with primary antiphospholipid syndrome

The objectives of this cross-sectional study were to evaluate the differences between males and females in the clinical and biochemical manifestations of primary antiphospholipid antibody syndrome (PAPS). The method involved 49 patients (38 premenopausal females and 11 males) diagnosed with PAPS (according to the Sapporo criteria) and their demographic data, clinical data, medications used and antiphospholipid antibodies were analyzed. The results of this study are as follows. Both the groups of patients were statistically similar regarding age, race, weight and body mass index. However, males were significantly taller than females (172 +/- A 8.9 vs. 159.2 +/- A 6.2 cm, p < 0.0001). The duration of disease was similar for females and males. The prevalence of pulmonary thromboembolism was higher in females than in males (34.2 vs. 0.0%, p = 0.024). Regarding other PAPS manifestations (arterial events, venous events, deep venous thrombosis, thrombocytopenia, acute myocardial infarction, angina, cerebrovascular accidents and Sneddon syndrome), comorbidities (arterial hypertension and dyslipidemia), lifestyle (physical activity, previous smoking and current smoking) and the use of medications (current and previous use of corticosteroids, as well as the use of statins or chloroquine), both groups were statistically similar (p > 0.05). More females than males tested positive for IgM anticardiolipin antibodies (76.3 vs. 36.4%, p = 0.025) or for at least one of the antiphospholipid antibodies tested (either IgM anticardiolipin or IgG anticardiolipin 84.2 vs. 45.5%, p = 0.016). However, both groups were similar regarding the frequency of positivity for lupus anticoagulant and isolated IgG anticardiolipin, as well as regarding mean levels of IgG and IgM anticardiolipin (p > 0.05). We concluded that, among PAPS patients, the frequency of pulmonary thromboembolism and of positivity for IgM anticardiolipin is higher in females than in males. Our findings show that there are gender differences in PAPS, differences that might be related to alterations in sex hormones.

Primary antiphospholipid syndrome with and without Sneddon`s syndrome

The main objective of this study was to compare clinical and laboratory data obtained from patients with primary antiphospholipid syndrome (PAPS) with and without Sneddon`s syndrome (SS). A transverse study with 54 (85.2% female) PAPS patients (Sapporo criteria) was performed. Demographic, drug use, and antiphospholipid antibodies data were evaluated, as well as clinical and laboratory findings of SS. Patients were subdivided into one of two groups: PAPS with SS and PAPS without SS. Both groups were similar with respect to age (p = 0.05), gender (p = 0.34), race (p = 0.31), weight (p = 0.93), height (p = 0.27), and body mass index (p = 0.75); however, the SS group exhibited higher disease duration (96.0 +/- A 54.9 vs. 55.2 +/- A 52.0 months, p = 0.01). By definition, all PAPS with SS patients suffer from stroke, an arterial event; the frequency of stroke events (28.5 vs. 7.5%, p = 0.04), as well as of limb ischemia (100 vs. 30.0%, p < 0.0001) was higher in this group than in the PAPS without SS group. On the other hand, patients in the PAPS without SS group had more venous events, such as deep venous thrombosis, than those in the PAPS with SS group (80.0 vs. 50.0%, p = 0.03). In conclusion, an understanding of the relationship between APS and SS is important in order to identify a subgroup for which more rigorous accompaniment and therapy may be necessary.

Pathological gambling and primary antiphospholipid (Hughes) syndrome: a unique neuropsychiatric association

Neuropsychiatric conditions are common in patients with primary antiphospholipid syndrome (APS) with or without vascular thrombosis of the central nervous system. There are frequent descriptions of memory alterations, cognition and mood disorders, such as depression, anxiety, and even conditions of mania and psychosis preceding the diagnosis of primary APS. However, this study is the first to present primary or secondary APS associated with habit or impulse control disorders. The authors describe the case of a 53-year-old male patient who had been a pathological gambler since adulthood and who has had APS for more than 20 years. We describe the case and review its characteristics, criteria for diagnosis and treatment offered for patients with this specific subtype of impulse disorder. Lupus (2011) 20, 1086-1089.

Evaluation of Primary Cleft Nose Repair: Severity of the Cleft Versus Final Position of the Nose

Background: Since 1957, when the concept of rotation-advancement repair was introduced by Millard, this technique has become the procedure of choice for unilateral cleft lip worldwide. More recently, modifications described by Noordhoof, Mohler, Skoog, and McComb started being jointly performed so that better results could be obtained. In this study, the nasal position was evaluated and related to the size of the cleft. The primary unilateral cleft lip repair was performed through a modified technique. Methods: Forty-five patients with unilateral cleft lip underwent primary surgical repair through this technique. To analyze aesthetic results, a severity classification of deformities and a scoring system for evaluation of the results were established based on nasal alar lateralization, dome position, alignment of bone segments, and deviation of the columella. Results: By means of the established system, 26.6% of mild forms, 13.4% of moderate forms, and 60% of severe forms were observed. Among aesthetic results, 17.8% were found to be good, and 82.2% were considered excellent. Among aspects considered negative, late deformity of the lower lateral cartilage prevailed. Conclusions: Through the presented evaluation, the authors observed that there was no relation between severity of the cleft and final position of the nose. Among the 27 patients considered to have had severe forms of cleft deformity, 22 were classified as excellent results (81.5%). To obtain better results along time, technical refinements and the critical analysis of results must be performed on a routinely basis.