Evidence of new risk genetic factor to systemic lupus erythematosus: the UBASH3A gene

The ubiquitin associated and Src-homology 3 (SH3) domain containing A (UBASH3a) is a suppressor of T-cell receptor signaling, underscoring antigen presentation to T-cells as a critical shared mechanism of diseases pathogenesis. The aim of the present study was to determine whether the UBASH3a gene influence the susceptibility to systemic lupus erythematosus (SLE) in Caucasian populations. We evaluated five UBASH3a polymorphisms (rs2277798, rs2277800, rs9976767, rs13048049 and rs17114930), using TaqMan® allelic discrimination assays, in a discovery cohort that included 906 SLE patients and 1165 healthy controls from Spain. The SNPs that exhibit statistical significance difference were evaluated in a German replication cohort of 360 SLE patients and 379 healthy controls. The case-control analysis in the Spanish population showed a significant association between the rs9976767 and SLE (Pc = 9.9E-03 OR = 1.21 95%CI = 1.07-1.37) and a trend of association for the rs2277798 analysis (P = 0.09 OR = 0.9 95%CI = 0.79-1.02). The replication in a German cohort and the meta-analysis confirmed that the rs9976767 (Pc = 0.02; Pc = 2.4E-04, for German cohort and meta-analysis, respectively) and rs2277798 (Pc = 0.013; Pc = 4.7E-03, for German cohort and meta-analysis, respectively) UBASH3a variants are susceptibility factors for SLE. Finally, a conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs9976767 polymorphism. Our results suggest that UBASH3a gene plays a role in the susceptibility to SLE. Moreover, our study indicates that UBASH3a can be considered as a common genetic factor in autoimmune diseases.

Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index.

INTRODUCTION Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes. METHODS Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14), luminal B (ER + and/or PR+, HER2-, Ki-67 ≥14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER-, PR-, HER2-, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2-, Ki-67 ≥14, any CK 5/6, any EGFR), HER2-enriched (ER-, PR-, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER-, PR-, HER2-, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER-, PR-, HER2-, any Ki-67, CK 5/6-, EGFR-). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki-67 ≥14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value. RESULTS Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 ≥14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 ≥14% show sharp peak at nearly 18 months. CONCLUSIONS Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients.

Free flaps in surgical dermatology. Comparison between fasciocutaneous and myocutaneous free flaps in facial reconstructions.

BACKGROUND Dermatologic surgeons routinely harvest pedicled flaps at distance with an axial or random pattern to repair facial defects. These types of skin flaps are time-consuming and have high economic, social and personal costs. These drawbacks could be avoided with the introduction of a single-step transfer of free flaps to the recipient site, with microvascular anastomosis. OBJECTIVE To demonstrate that better results are obtained with myocutaneous or fasciocutaneous free flaps and which one is more suitable in surgical dermatology. MATERIAL AND METHODS We selected two patients of opposite sexes and similar ages who had undergone Mohs surgery to remove recurrent malignant tumors that were located in the upper cheek bordering the zygomatic zone. The woman was treated with a fasciocutaneous radial free flap and the man with a rectus abdominis free flap. RESULTS Both patients had excellent immediate postoperative outcomes. Complications observed in the male patient were related to a previous pulmonary alteration. The fasciocutaneous radial free flap reconstruction was easier to perform than the rectus abdominis free flap; nevertheless, the radial free flap is very thin and, although the palmaris longus tendon is used, it does not yield enough volume, requiring later use of implants. In contrast, the rectus abdominis free flap transfers a wide flap with enough fat tissue to expand in the future. As for the cosmetic results regarding the donor site, the rectus abdominis free flap produces better-looking scars, since secondary defects of the palmar surface cannot be directly closed and usually require grafting - a situation that some patients do not accept. CONCLUSIONS In surgical dermatology, each case, once the tumor has been extirpated, requires its own reconstructive technique. The radial free flap is suitable for thin patients who are willing to cover their arm with a shirt. The rectus abdominis free flap is best suited for obese patients with deep and voluminous defects, although it is necessary to dislocate the navel from its original position.

Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsorption in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.

Association between magnesium-deficient status and anthropometric and clinical-nutritional parameters in posmenopausal women.

Background: During menopause occurs weight gain and bone loss occurs due to the hormone decline during this period and other factors such as nutrition. Magnesium deficiency suggests a risk factor for obesity and osteoporosis. OBJECTIVE: To evaluate the clinical and nutritional magnesium status in a population of postmenopausal women, assessing intake and serum levels of magnesium in the study population and correlation with anthropometric parameters such as body mass index(BMI) and body fat, and biochemical parameters associated. SUBJECTS AND METHOD: The study involved 78 healthy women aged 44-76, with postmenopausal status, from the province of Grenade, Spain. The sample was divided into two age groups: group1, aged < 58, and group 2 aged >/= 58. Anthropometric parameters were recorded and nutritional intake was assessed by 72-hour recall, getting the RDAs through Nutriber(R) program. To assess the biochemical parameters was performed a blood sample was taken. Magnesium was analyzed by flame atomic absorption spectrophotometry (FAAS) in erythrocyte and plasma wet-mineralized samples. RESULTS: Our results show that 37.85% of the total subjects have an overweight status. Magnesium intake found in our population is insufficient in 36% of women,while plasma magnesium deficiency corresponds to 23% of the population and 72% of women have deficient levels of magnesium in erythrocyte. Positive correlations were found between magnesium intake and dietary intake of calcium, of phosphorus,and with prealbumin plasma levels, as well as with a lower waist / hip ratio Magnesium levels in erythrocyte were correlated with lower triglycerides and urea values. CONCLUSION: It is important to control and monitor the nutritional status of magnesium in postmenopausal women to prevent nutritional alterations and possible clinical and chronic degenerative diseases associated with magnesium deficiency and with menopause.

Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat.

β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα) in white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (e)WAT was monitored. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs), and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.

Human endogenous retrovirus HERV-Fc1 association with multiple sclerosis susceptibility: a meta-analysis.

BACKGROUND Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts. METHODS A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data. RESULTS Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11-1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14-1.53)]. CONCLUSION Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.

Suicidal ideation and the risk of suicide in patients with fibromyalgia: a comparison with non-pain controls and patients suffering from low-back pain.

Fibromyalgia is associated with an increased rate of mortality from suicide. In fact, this disease is associated with several characteristics that are linked to an increased risk of suicidal behaviors, such as being female and experiencing chronic pain, psychological distress, and sleep disturbances. However, the literature concerning suicidal behaviors and their risk factors in fibromyalgia is sparse. The objectives of the present study were to evaluate the prevalence of suicidal ideation and the risk of suicide in a sample of patients with fibromyalgia compared with a sample of healthy subjects and a sample of patients with chronic low-back pain. We also aimed to evaluate the relevance of pain intensity, depression, and sleep quality as variables related to suicidal ideation and risks. Logistic regression was applied to estimate the likelihood of suicidal ideation and the risk of suicide adjusted by age and sex. We also used two logistic regression models using age, sex, pain severity score, depression severity, sleep quality, and disease state as independent variables and using the control group as a reference. Forty-four patients with fibromyalgia, 32 patients with low-back pain, and 50 controls were included. Suicidal ideation, measured with item 9 of the Beck Depression Inventory, was almost absent among the controls and was low among patients with low-back pain; however, suicidal ideation was prominent among patients with fibromyalgia (P<0.0001). The risk of suicide, measured with the Plutchik Suicide Risk Scale, was also higher among patients with fibromyalgia than in patients with low-back pain or in controls (P<0.0001). The likelihood for suicidal ideation and the risk of suicide were higher among patients with fibromyalgia (odds ratios of 26.9 and 48.0, respectively) than in patients with low-back pain (odds ratios 4.6 and 4.7, respectively). Depression was the only factor associated with suicidal ideation or the risk of suicide.

El proyecto EMECAS: protocolo del estudio multicéntrico en España de los efectos a corto plazo de la contaminación atmosférica sobre la salud.

The EMECAM Project demonstrated the short-term effect of air pollution on the death rate in 14 cities in Spain throughout the 1990-1995 period. The Spanish Multicentre Study on Health Effects of Air Pollution (EMECAS) is broadening these objectives by incorporating more recent data, information on hospital disease admissions and totaling 16 Spanish cities. This is an ecological time series study in which the response variables are the daily deaths and the emergency hospitalizations due to circulatory system diseases and respiratory diseases among the residents in each city. Pollutants analyses: suspended particles, SO2, NO2, CO and O3. Control variables: meteorological, calendar, seasonality and influenza trend and incidence. Statistical analysis: estimate of the association in each city by means of the construction of generalized additive Poisson regression models and metanalysis for obtaining combined estimators. The EMECAS Project began with the creation of three working groups (Exposure, Epidemiology and Analysis Methodology) which defined the protocol. The average levels of pollutants were below those established under the current regulations for sulfur dioxide, carbon monoxide and ozone. The NO2 and PM10 values were around those established under the regulations (40 mg/m3). This is the first study of the relationship between air pollution and disease rate among one group of Spanish cities. The pollution levels studied are moderate for some pollutants, although for others, especially NO2 and particles, these levels could entail a problem with regard to complying with the regulations in force.

Atención al paciente quirúrgico : proceso asistencial integrado

Publicado en la página web de la Consejería de Igualdad, Salud y Políticas Sociales: www.juntadeandalucia.es/salud (Consejería de Salud / Profesionales / Nuestro Compromiso por la Calidad / Procesos Asistenciales Integrados)

Foto de familia, un estudio descriptivo de los recursos de información científica en las bibliotecas del Sistema Sanitario Público Español

G17+1 está integrado por: Elena Primo (Biblioteca Nacional de Ciencias de la Salud), Verónica Juan (BV Andalucía), Montserrat Salas (BV Aragón), Mercedes Corrales y Raquel Lavandera (BV Asturias), Virgili Paéz (BV Baleares), Beatriz Duque (BV Canarias), Fanny Ribes (BV Cantabria), Marisa Alonso (BV Castilla-La Mancha), Pilar Díaz Ruiz (BV Castilla y León), Pilar Roqué (BV Cataluña), Francisco Javier Moreno (BV Extremadura), Teresa Mejuto (BV Galicia), Mayra García Berges y José Manuel Estrada (BV Madrid), Enrique Aguinaga y Juan Antonio Sánchez Sánchez (BV Murcia), Idoia Gaminde (BV Navarra) y Ricardo Aróstegui y Mª Asunción García Martín (BV País Vasco).

HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV.

BACKGROUND Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested. RESULTS MSRV transcription levels were higher in MS patients than in controls (U-Mann-Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann-Whitney; p = 0.039) or TT patients (U-Mann-Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann-Whitney; p = 0.003). CONCLUSIONS Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS.

Suicidal ideation and the risk of suicide in patients with fibromyalgia: a comparison with non-pain controls and patients suffering from low-back pain.

Fibromyalgia is associated with an increased rate of mortality from suicide. In fact, this disease is associated with several characteristics that are linked to an increased risk of suicidal behaviors, such as being female and experiencing chronic pain, psychological distress, and sleep disturbances. However, the literature concerning suicidal behaviors and their risk factors in fibromyalgia is sparse. The objectives of the present study were to evaluate the prevalence of suicidal ideation and the risk of suicide in a sample of patients with fibromyalgia compared with a sample of healthy subjects and a sample of patients with chronic low-back pain. We also aimed to evaluate the relevance of pain intensity, depression, and sleep quality as variables related to suicidal ideation and risks. Logistic regression was applied to estimate the likelihood of suicidal ideation and the risk of suicide adjusted by age and sex. We also used two logistic regression models using age, sex, pain severity score, depression severity, sleep quality, and disease state as independent variables and using the control group as a reference. Forty-four patients with fibromyalgia, 32 patients with low-back pain, and 50 controls were included. Suicidal ideation, measured with item 9 of the Beck Depression Inventory, was almost absent among the controls and was low among patients with low-back pain; however, suicidal ideation was prominent among patients with fibromyalgia (P<0.0001). The risk of suicide, measured with the Plutchik Suicide Risk Scale, was also higher among patients with fibromyalgia than in patients with low-back pain or in controls (P<0.0001). The likelihood for suicidal ideation and the risk of suicide were higher among patients with fibromyalgia (odds ratios of 26.9 and 48.0, respectively) than in patients with low-back pain (odds ratios 4.6 and 4.7, respectively). Depression was the only factor associated with suicidal ideation or the risk of suicide.

Intronic variants in the NFKB1 gene may influence hearing forecast in patients with unilateral sensorineural hearing loss in Meniere's disease.

Meniere's disease is an episodic vestibular syndrome associated with sensorineural hearing loss (SNHL) and tinnitus. Patients with MD have an elevated prevalence of several autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and psoriasis), which suggests a shared autoimmune background. Functional variants of several genes involved in the NF-κB pathway, such as REL, TNFAIP3, NFKB1 and TNIP1, have been associated with two or more immune-mediated diseases and allelic variations in the TLR10 gene may influence bilateral affectation and clinical course in MD. We have genotyped 716 cases of MD and 1628 controls by using the ImmunoChip, a high-density genotyping array containing 186 autoimmune loci, to explore the association of immune system related-loci with sporadic MD. Although no single nucleotide polymorphism (SNP) reached a genome-wide significant association (p<10(-8)), we selected allelic variants in the NF-kB pathway for further analyses to evaluate the impact of these SNPs in the clinical outcome of MD in our cohort. None of the selected SNPs increased susceptibility for MD in patients with uni or bilateral SNHL. However, two potential regulatory variants in the NFKB1 gene (rs3774937 and rs4648011) were associated with a faster hearing loss progression in patients with unilateral SNHL. So, individuals with unilateral MD carrying the C allele in rs3774937 or G allele in rs4648011 had a shorter mean time to reach hearing stage 3 (>40 dB HL) (log-rank test, corrected p values were p = 0.009 for rs3774937 and p = 0.003 for rs4648011, respectively). No variants influenced hearing in bilateral MD. Our data support that the allelic variants rs3774937 and rs4648011 can modify hearing outcome in patients with MD and unilateral SNHL.

Adipose tissue concentrations of persistent organic pollutants and total cancer risk in an adult cohort from Southern Spain: preliminary data from year 9 of the follow-up.

There is an increasing trend in the incidence of cancer worldwide, and it has been accepted that environmental factors account for an important proportion of the global burden. The present paper reports preliminary findings on the influence of the historical exposure to a group of persistent organic pollutants on total cancer risk, at year 9 in the follow-up of a cohort from Southern Spain. A cohort of 368 participants (median age 51 years) was recruited in 2003. Their historical exposure was estimated by analyzing residues of persistent organic pollutants in adipose tissue. Estimation of cancer incidence was based on data from a population-based cancer registry. Statistical analyses were performed using multivariable Cox-regression models. In males, PCB 153 concentrations were positively associated with total cancer risk, with an adjusted hazard ratio (95% confidence interval) of 1.20 (1.01-1.41) for an increment of 100 ng/g lipid. Our preliminary findings suggest a potential relationship between the historical exposure to persistent organic pollutants and the risk of cancer in men. However, these results should be interpreted with caution and require verification during the future follow-up of this cohort.