[Health-related quality of life in patients consuming benzodiazepine]. / Calidad de vida relacionada con la salud en pacientes consumidores de benzodiacepinas.

OBJECTIVE: To describe the health-related quality of life (HRQoL) in benzodiazepine users and to verify whether there is an association with the characteristics of the treatment, its effectiveness, and the sociodemographic variables. DESIGN: Descriptive cross-sectional study. LOCATION: Family medicine consultations. PARTICIPANTS: Four hundred and fifty 2patients over 18 years of age consuming benzodiazepines or similar drugs. MAIN MEASUREMENTS: HRQoL was assessed using the EuroQol5-D questionnaire. Other variables: symptoms of anxiety or insomnia, sociodemographic variables and characteristics of the treatment. RESULTS: The mean score in health status was 62.80 (95% CI: 60.69-64.86), lower in people without studies (59.27±21.97 SD; P=.004) and lower social category (60.02±21.27 SD; P<.001). Regarding the social rate (EQ index), a mean score of 0.6025 (95% CI: 0.5659-0.6391) was obtained, higher in people with higher education (0.6577±0.3574 SD; P=.001), plus social category (0.7286±0.3381 SD; P<.001) and age less than 65 years (0.6603±0.3426 SD; P<.001). The variables that were associated with the value of the EQ index by means of multiple regression were absence of anxiety/insomnia, belonging to higher social classes, age less than 65 years and less consumption of anxiolytics/hypnotics. CONCLUSIONS: Patients who use benzodiazepines show, despite treatment, a moderate HRQL, lower than that obtained in the general population or in primary care patients. The situation is more favorable in the youngest, in those who do not present anxiety/insomnia, in those belonging to higher social classes and when the consumption of drugs is lower.

Prenatal diagnosis of a female fetus with ring chromosome 9, 46,XX,r(9)(p24q34), and a de novo interstitial 9p deletion.

Ring chromosomes are circular structures formed as a result of breaks in the chromosome arms and the fusion of the proximal broken ends with a loss of distal material, or by fusion of dysfunctional telomeres without any loss. The mechanism underlying this process has not yet been sufficiently explained. Commonly, rings occur as acquired genetic abnormalities; however, sometimes they are found as constitutional aberrations with a prevalence of around 1:50,000 live births. Here, we present a new case of r(9) in a female fetus with intrauterine growth retardation and slight craniofacial dysmorphisms. Both parents had a normal phenotype. Amniotic fluid karyotype showed r(9)(p24q34). An array CGH revealed 3 deletion segments: a ring chromosome with a 2.57-Mb deletion at 9pterp24.2 (chr9:163,131-2,729,722), a 2.60-Mb deletion at 9q34.3qter (chr9:138,523,302-141,122,055), and also a 0.15-Mb interstitial deletion at 9p24.1 (chr9:5,090,443-5,235,765). These deletions overlap with proposed regions for the 9p24.3 deletion and Kleefstra syndrome. Segregation analysis revealed a maternal origin of the rearranged chromosome. We conclude that both the ring chromosome and the interstitial deletion occurred de novo. This last deletion has not been reported before. Prenatal array CGH, combined with fine mapping of breakpoints contributes to the assessment of genotype-phenotype correlations.

A novel dominant mutation in CRYAB gene leading to a severe phenotype with childhood onset.

BACKGROUND: αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance. METHODS: The whole exome sequence was subjected to phenotype-driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C-terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico-chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques. RESULTS: CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico-chemical properties predicted for the C-terminal domain: hydrophobicity, stiffness, and isomerization. CONCLUSIONS: The described mutation leads to elongation of the protein at the carboxi-terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.

Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature.

Beals-Hecht syndrome or congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disorder characterized by crumpled ears, arachnodactyly, contractures, and scoliosis. Recent reports also mention aortic root dilatation, a finding previously thought to differentiate the condition from Marfan syndrome (MFS). In many cases, the condition is caused by mutations in the fibrillin 2 gene (FBN2) with 26 mutations reported so far, all located in the middle region of the gene (exons 23-34). We directly sequenced the entire FBN2 gene in 32 probands clinically diagnosed with CCA. In 14 probands, we found 13 new and one previously described FBN2 mutation including a mutation in exon 17, expanding the region in which FBN2 mutations occur in CCA. Review of the literature showed that the phenotype of the FBN2 positive patients was comparable to all previously published FBN2-positive patients. In our FBN2-positive patients, cardiovascular involvement included mitral valve prolapse in two adult patients and aortic root enlargement in three patients. Whereas the dilatation regressed in one proband, it remained marked in a child proband (z-score: 4.09) and his father (z-score: 2.94), warranting echocardiographic follow-up. We confirm paradoxical patellar laxity and report keratoconus, shoulder muscle hypoplasia, and pyeloureteral junction stenosis as new features. In addition, we illustrate large intrafamilial variability. Finally, the FBN2-negative patients in this cohort were clinically indistinguishable from all published FBN2-positive patients harboring a FBN2 mutation, suggesting locus heterogeneity.

Expression of epithelial cell adhesion molecule and pituitary tumor transforming gene in adamantinomatous craniopharyngioma and its correlation with recurrence of the tumor.

Craniopharyngiomas are benign tumors of the sellar region generally associated with endocrine disorders and often locally aggressive. The reliable criteria for predicting the tumor behavior are still lacking. It has been suggested that proliferative potential of the tumor cells is necessary for recurrence. The aim of this study was to evaluate the activity and correlation of epithelial cell adhesion molecule (Ep-CAM) and pituitary tumor transforming gene (PTTG-1) immunoexpression that is possibly related to relapse in 40 patients with adamantinomatous craniopharyngioma. The study involved clinical and pathologic analysis. Of the subjects, 49% were females and 51% were males. The mean age of the patients was 37 years. Relapsing rate at 5 years was 46% and for death was 22.5%. Histologically, whorl-like arrays and dense or hypercellular stellate reticulum cells were correlated with recurrence. Epithelial CAM and PTTG-1 were also higher in stellate reticulum cells and in whorl-like arrays. Both were higher in recurrence/regrowth tumors than in primary one. The PTGG-1 expression in craniopharyngioma may suggest hypophyseal metaplasia. The Ep-CAM and PTTG-1 expression in craniopharyngioma could be used as prediction markers of relapsing tumor. It has been suggested that proliferative potential of the tumor cells is necessary for recurrence.

Characterization of trisomic natural killer cell abnormalities in a patient with constitutional trisomy 8 mosaicism.

Malignancies found in children and adults with constitutional trisomy 8 mosaicism (CT8M) could be in part the consequence of dysfunction of trisomic immune cells. An adult patient exhibiting trisomy in the entire natural killer (NK) cell population has made possible the characterization of trisomy 8-positive NK cells. The study showed normal cytotoxic activity but predominance of an immunosenescent phenotype (CD56(dim)CD94/NKG2(bright)) characterized by a weak response to IL-2, increased upregulation of CD95/Fas, and impaired TNF-alpha production. As these defects may contribute to the escape and expansion of neoplastic cells, the authors hypothesize that cancer predisposition in CT8M may be partly a result of altered immunosurveillance.

Clinical evaluation of endothelial cell decrease with VisThesia in phacoemulsification surgery.

PURPOSE: To assess the endothelial cell decrease after the use of sodium hyaluronate 0.3% and lidocaine hydrochloride 2% (VisThesia) to determine whether the addition of lidocaine 1% to sodium hyaluronate 1.5% makes the solution more toxic to the cornea. SETTING: Instituto de Oftalmologia Avanzada, Madrid, Spain, and Unita Operative Oculistica, Cesena, Italy. METHODS: VisThesia is an ophthalmic viscosurgical device (OVD) that incorporates lidocaine 1% to provide better comfort to patients under topical anesthesia. Fifty eyes 50 patients were operated on following the same patient selection and surgical technique. After the povidone-iodine (Betadine) ocular asepsis, 1 full ampoule of VisThesia Topical was applied over the corneal surface. The intracameral product was used as a routine OVD during the phacoemulsification procedure. The endothelium of the central cornea was examined preoperatively and 3 months after surgery using a noncontact endothelium microscope. RESULTS: At the last follow-up visit, the mean best corrected visual acuity was 0.88 +/- 0.18 and the mean manifest SE was -0.36 +/- 1.78 D. The mean endothelial cell density had decreased from 2363.57 +/- 435.4 cells/mm2 preoperatively to 2222.6 +/- 537.69 cells/mm2 at 3 months. These values are comparable with results obtained in other investigations published in the literature using other, similar OVD. CONCLUSIONS: The results observed in this investigation indicate that the addition of lidocaine to the sodium hyaluronate in VisThesia does not induce additional toxicity nor does it result in increased endothelial cell loss when compared with other, similar OVDs.

Classification of chronic obstructive pulmonary disease severity according to the new Global Initiative for Chronic Obstructive Lung Disease 2011 guidelines: COPD assessment test versus modified Medical Research Council scale.

INTRODUCTION: The GOLD2011 revision proposes to stratify patients with chronic obstructive pulmonary disease (COPD) by measuring the impact of the disease using the modified Medical Research Council (mMRC) scale or COPD assessment test (CAT). Our aim was to determine whether both methods are equivalent. PATIENTS AND METHODS: Observational study on a cohort of 283 patients diagnosed with COPD. We analyzed the demographic and lung function results. Patients were assessed by CAT and mMRC on the same day by the same interviewer, and divided into GOLD2011 categories according to the result of the evaluation. The degree of concordance and Spearman correlation were determined. We used ANOVA on the clinical and functional variables of the four GOLD2011 categories. RESULTS: Assessing the classification of patients according to the method used, an overall correlation ρ=0.613 and a degree of concordance κ=0.63 (moderate) were obtained. κ=0.44 was obtained for the 152 patients in categoriesA and B (moderate-low), and 0.38 for the 131 patients in categoriesC and D (low). Differences were observed between categories in terms of functional parameters. CONCLUSIONS: The classification of patients with COPD using the assessment proposed by GOLD2011 varies according to the method used (CAT or mMRC); more than 25% of patients were reclassified into different categories, implying differences in the recommended therapeutic strategy. Longitudinal studies are needed to appraise which method better classifies patients, according to its prognostic ability.

Characterization of a balanced complex chromosomal rearrangement carrier ascertained through a fetus with dup15q26.3 and del5p15.33: case report.

Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than two chromosomes which rarely appear in individuals with normal phenotypes. These individuals report fertility problems, recurrent miscarriages, or congenital anomalies in newborn offspring as a consequence of either meiotic failure or imbalanced chromosome segregation. A CCR involving chromosomes 5, 15, and 18 was discovered in a phenotypically normal man through a fetus with congenital malformations and partial trisomy of chromosome 15 and monosomy of chromosome 5. Ultrasound examination at 20 weeks of gestation showed severe oligoamnios and hydrothorax. Prenatal cytogenetic analysis and array comparative genomic hybridization (array-CGH) revealed a female fetus with dup15q26.3 and del5p15.33. We diagnosed the CCR using three-color fluorescence in situ hybridization (three-color FISH), and a balanced CCR using array-CGH and FISH was diagnosed in the paternal karyotype. The father is a carrier of a balanced translocation 46,XY,t(5;15;18)(p15.31;q26.3;p11.2). Due to the complexity of these rearrangements the diagnosis is difficult and the reproductive outcome uncertain. Reporting such rare cases is important to enable such information to be used for genetic counseling in similar situations and help estimate the risk of miscarriage or of newborns with congenital abnormalities.

Live-attenuated Tetravalent Dengue Vaccine in Dengue-naïve Children, Adolescents, and Adults in Mexico City: Randomized Controlled Phase 1 Trial of Safety and Immunogenicity.

BACKGROUND: Preliminary results in healthy, young US adults showed that a tetravalent, live-attenuated dengue vaccine (TDV) was safe and immunogenic, but no data are available in children. METHODS: In a multicenter, randomized, controlled, observer-blinded study in the city of Mexico, children aged 2 to 5, 6 to 11, and 12 to 17 years (36 children per age group), and adults (n = 18) aged <45 years received the following: 3 injections of TDV at months 0, 3.5, and 12 (TDV-TDV-TDV), or 1 injection of yellow fever vaccine (YF) at month 0, and 2 injections of TDV at months 3.5 and 12 (YF-TDV-TDV). Adverse events and biologic safety (biochemistry and hematology) were documented. Plaque reduction neutralization test (PRNT50) antibody titers against the TDV parental viruses were measured 28 days after vaccination. Seropositivity was defined as antibody titers ≥10 1/dil. RESULTS: No vaccine-related serious adverse events, other significant clinical adverse events, or clinically significant trends in biologic safety were observed. Reactogenicity did not increase with successive TDV injections, and mild-to-moderate injection site pain, headache, myalgia, and malaise were most commonly reported (14%-40% after each vaccination). After 3 TDV vaccinations, the seropositivity rate against each dengue serotype was in the range 77% to 92%, compared with 85% to 94% after completion of the YF-TDV-TDV regimen. Of the 2- to 11-year-old participants, 95% were seropositive against ≥3 serotypes after 3 vaccinations. CONCLUSIONS: A 3-dose TDV regimen had a favorable safety profile in children and adults and elicited neutralizing antibody responses against all 4 serotypes. These findings support the continued development of this vaccine.

Hereditary renal adysplasia, pulmonary hypoplasia and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a case report.

BACKGROUND: Hereditary renal adysplasia is an autosomal dominant trait with incomplete penetrance and variable expression that is usually associated with malformative combinations (including Müllerian anomalies) affecting different mesodermal organs such as the heart, lung, and urogenital system. CASE REPORT: A case showing pulmonary hypoplasia, hip dysplasia, hereditary renal adysplasia, and Mayer-Rokitansky-Kuster-Hauser syndrome in adulthood is reported here. The i.v. pyelography showed right renal agenesis with a normal left kidney and ureter. Ultrasound and Magnetic Resonance Imaging also showed right renal agenesis with multicystic embryonary remnants in the right hemipelvis probably corresponding to a dysgenetic kidney. An uretrocystoscopy showed absence of ectopic ureter and of the right hemitrigone. She was scheduled for a diagnostic laparoscopy and creation of a neovagina according to the McIndoe technique with a prosthesis and skin graft. Laparoscopy confirmed the absence of the uterus. On both sides, an elongated, solid, rudimentary uterine horn could be observed. Both ovaries were also elongated, located high in both abdominal flanks and somewhat dysgenetics. A conventional cytogenetic study revealed a normal female karyotype 46, XX at a level of 550 GTG bands. A CGH analysis was performed using a 244K oligoarray CGH detecting 11 copy number variants described as normal variants in the databases. The 17q12 and 22q11.21 microdeletions described in other MRKH patients were not present in this case. Four years after operation her evolution is normal, without symptoms and the neovagina is adequately functional. The geneticists have studied her family history and the pedigree of the family is shown. CONCLUSIONS: We suggest that primary damage to the mesoderm (paraaxil, intermediate, and lateral) caused by mutations in a yet unidentified gene is responsible for: 1) skeletal dysplasia, 2) inappropriate interactions between the bronchial mesoderm and endodermal lung bud as well as between the blastema metanephric and ureteric bud, and eventually 3) Müllerian anomalies (peritoneal mesothelium) at the same level. These anomalies would be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity.

Preimplantation genetic diagnosis of X-linked adrenoleukodystrophy with gender determination using multiple displacement amplification.

OBJECTIVE: To evaluate the use of multiple displacement amplification (MDA) for whole genome amplification in the preimplantation genetic diagnosis (PGD) of X-linked adrenoleukodystrophy. DESIGN: MDA was used to amplify the whole genome directly from a single blastomere. MDA products were used for polymerase chain reaction (PCR) analysis of two polymorphic markers flanking the ABCD1 gene and a new X/Y marker, X22, to sex embryos in an X-linked adrenoleukodystrophy PGD program. SETTING: Fertility and gynecology private center in Alicante, Spain. PATIENT(S): A couple in which the wife is a carrier of the ABCD1 gene mutation (676A-->C) that was previously identified in her family. INTERVENTION(S): MDA of single blastomere and PCR tests for PGD. MAIN OUTCOME MEASURE(S): The ability to analyze single blastomeres for X-linked adrenoleukodystrophy using MDA. RESULT(S): The development of an MDA-PGD protocol for X-linked adrenoleukodystrophy allowed for the diagnosis of five embryos. These were biopsied on day 3 of culture and analyzed. One embryo was an affected male and one embryo was a female carrier. Three healthy female embryos were transferred 48 hours after biopsy. Unfortunately, no pregnancy was achieved. CONCLUSION(S): The MDA technique is useful for overcoming the problem of insufficient genomic DNA in PGD and allows the simultaneous amplification of different targets to perform a diagnosis of any known gene defect and a sexing test by standard methods and conditions.

Preimplantation genetic diagnosis of Marfan syndrome using multiple displacement amplification.

OBJECTIVE: To evaluate the use of multiple displacement amplification (MDA) for whole-genome amplification in the preimplantation genetic diagnosis (PGD) of Marfan syndrome. DESIGN: Multiple displacement amplification was used to amplify the whole-genome directly from a single cell. The MDA product was used for polymerase chain reaction (PCR) analysis of five different loci. At this point MDA was used to develop a PGD-Marfan syndrome program. SETTING: Fertility and gynecology private center in Alicante, Spain. PATIENT(S): A couple in which the husband is affected by Marfan syndrome and carries a novel mutation in the FBN-1 gene. INTERVENTION(S): The MDA of single cells and PCR tests for PGD. MAIN OUTCOME MEASURE(S): Allele drop-out (ADO), amplification efficiency rates, and the ability to detect Marfan syndrome using MDA. RESULT(S): We report that isothermal whole-genome amplification from single cells allowed analysis of five different loci using standard conditions. The development of a MDA-PGD protocol for Marfan syndrome allowed for the diagnosis of seven embryos. These were biopsied on day 3 of culture and analyzed. Two healthy embryos were transferred 48 hours after culture, resulting in a singleton ongoing pregnancy and the birth of a healthy child. CONCLUSION(S): The MDA technique is useful for overcoming the problem of insufficient genomic DNA in PGD. The use of MDA as a universal step marks a new cycle for PGD as it allows for the diagnosis of any known gene defect by standard methods and conditions.