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NEW FINDINGS: What is the central question of the study? Is there a sex-based difference in the incidence of apnoea of prematurity and the success or failure of caffeine therapy in preterm infants? What is the main finding and its importance? Our data show that females received fewer days of caffeine treatment than males. This was most noticeable in infants born between 260/7 and 276/7 weeks of gestational age. These results highlight the importance of considering sex in clinical and basic research investigating the pathophysiology of apnoea of prematurity. ABSTRACT: This retrospective cohort study assessed whether sex influences the occurrence of apnoea of prematurity (AOP) in preterm infants. The analysis included a cohort of 24,387 preterm infants born between the gestational ages (GA) of 240/7 and 336/7 weeks that were admitted to tertiary neonatal care units participating in the Canadian Neonatal Network from January 2011 to December 2015. Of those, 13,983 (57%) were diagnosed with AOP. More females were diagnosed with AOP than males, but the difference in the male/female ratio was marginal (P = 0.058). The majority (89%) of infants diagnosed with AOP received caffeine (89% of males; 89% of females). By using the discontinuation of caffeine therapy as a proxy for the resolution of significant AOP, data analysis showed that females born before 336/7 weeks of GA stopped caffeine treatment earlier than males whether the caffeine was discontinued before 34 or 37 weeks of GA. Consequently, females had fewer days of caffeine therapy than males, especially infants born between 260/7 and 276/7 weeks (P < 0.004), 280/7 and 296/7 weeks (P < 0.03), and 320/7 and 336/7 weeks of GA (P < 0.04). Similar trends were observed when the corrected GA at discontinuation of caffeine was used. Given that AOP is indicative of an immature respiratory system, our data suggest that the maturation of the respiratory system might occur more rapidly in females than males. We conclude that sex needs to be considered in future studies on AOP.
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Recien Nacido Prematuro/fisiología , Síndromes de la Apnea del Sueño/fisiopatología , Cafeína/uso terapéutico , Canadá , Femenino , Edad Gestacional , Humanos , Recién Nacido , Masculino , Estudios Retrospectivos , Caracteres Sexuales , Síndromes de la Apnea del Sueño/tratamiento farmacológicoRESUMEN
Lipoprotein apheresis (LA) with dextran sulfate adsorption (DSA) is a reliable method to decrease LDL-cholesterol (C) concentrations in patients with homozygous familial hypercholesterolemia (HoFH). The objective of the present study was to investigate the impact of LA with DSA on the mRNA expression of genes associated with cardiovascular health in the whole blood of HoFH patients. Blood samples were collected before and after LA treatment with DSA in 9 HoFH patients. Microarray analyses were performed to measure the whole blood expression of >30 000 annotated genes pre- and post-LA. Concomitant reductions in LDL-C (median -73.8%, range: -55.9 to -82.0, P = .0001) and lipoprotein (a) concentrations (median -74.1%, range -65.6 to -84.1, P = .003) were induced with LA treatment. LA with DSA did not impact the whole blood mRNA expression of most key genes involved in cardiovascular health, including those associated with cholesterol, fatty acid and lipoprotein metabolism. However, LA with DSA significantly upregulated the whole blood expression of early growth response protein (EGR)1 (1.94-fold, P = .02), EGR3 (1.56-fold, P = .0008) and B-cell lymphoma 3-encoded protein (BCL3; 1.25-fold, P = .03). In conclusion, this study demonstrated that a single LA treatment with DSA has very limited impact on the whole blood expression of a broad spectrum of genes associated with cardiovascular health. Our results suggest that contact between blood cells and the primary membrane or extracorporeal circulation could upregulate the expression of EGR1, EGR3, BCL3, and MMP9 in blood cells.
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Eliminación de Componentes Sanguíneos/métodos , Sulfato de Dextran/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hiperlipoproteinemia Tipo II/sangre , Lipoproteína(a)/sangre , Adsorción , Adulto , Proteínas del Linfoma 3 de Células B , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Receptores ErbB/genética , Femenino , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Lipoproteína(a)/aislamiento & purificación , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/sangre , Factores de Transcripción/genéticaRESUMEN
Although techniques using calcaneus screws have shown high union rates, posterior heel pain due to prominent hardware at the posterior and plantar aspect of the calcaneal tuberosity seems to be a significant complaint that often leads to hardware removal. The purpose of the present study was to identify the clinical and radiologic risk factors associated with calcaneus screw removal. A retrospective study of adult patients who required calcaneus screw fixation from January 2008 to December 2016 was conducted. We reviewed the medical records and radiographs to evaluate the risk factors for screw removal. Of the 123 patients included in the present study, 63 were male and 60 were female. The mean age was 55.0 ± 6.0 years, and the mean body mass index was 31.0 ± 6.0 kg/m2. The removal rate was 8.8% (10 of 114 evaluated) at the 1-year follow-up point and 13.6% (12 of 88 evaluated) at the 2-year follow-up point. The mean interval to removal was 1.23 ± 1.22 years. A total of 16 screws (72.7%) were removed for heel pain. At the 1-year follow-up examination, the removal rate due to inflammatory arthritis was 25.0% (p = .07). Moreover, the proportion of screw removal was greater at 2 years in illicit drug users (p = .008). Screw sizes ≤6.5 mm showed a tendency (p = .12) toward a lower rate of removal at the 2-year follow-up point. Calcaneus screws should be used with caution in specific patient populations such as illicit drug users and those with inflammatory arthritis. The use of smaller diameter calcaneus screws might be an option to lower the rate of screw removal due to heel pain.
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Tornillos Óseos , Calcáneo/lesiones , Calcáneo/cirugía , Remoción de Dispositivos , Fijación Interna de Fracturas/instrumentación , Fracturas Óseas/cirugía , Adulto , Femenino , Fijación Interna de Fracturas/efectos adversos , Fracturas Óseas/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Low-density lipoprotein (LDL) apheresis (LA) is a reliable method to decrease LDL-C concentrations and remains the gold standard therapy in homozygous familial hypercholesterolemia (HoFH). The objective of this study was to compare the efficacy of two LA systems [heparin-induced extracorporeal LDL precipitation (HELP) vs. dextran sulfate adsorption (DS) on the reduction of lipids, inflammatory markers, and adhesion molecules in a sample of genetically defined HoFH subjects (n = 9)]. Fasting blood samples were collected before and after LA. All subjects served as their own control and were first treated with the HELP system then with DS in this single sequence study. Compared with HELP, DS led to significantly greater reductions in total cholesterol (-63.3% vs. -59.9%; P = 0.05), LDL-C (-70.5% vs. -63.0%; P = 0.02), CRP (-75.3% vs. -48.8%; P < 0.0001), and TNF-α (-23.7% vs. +14.7%; P = 0.003). Reductions in the plasma levels of PCSK9 (-45.3% vs. -63.4%; P = 0.31), lipoprotein (a) (-70.6% vs. -65.0%; P = 0.30), E-selectin (-16.6% vs. -18.3%; P = 0.65), ICAM-1 (-4.0 vs. 5.6%; P = 0.56), and VCAM-1 (8.3% vs. -1.8%; P = 0.08) were not different between the two systems. For the same volume of filtered plasma (3,000 mL), however, HELP led to greater reductions in plasma apoB (-63.1% vs. -58.3%; P = 0.04), HDL-C (-20.6% vs. -6.5%; P = 0.003), and PCSK9 (-63.4% vs. -28.5%; P = 0.02) levels. These results suggest that both LA systems are effective in reducing plasma lipids and inflammatory markers in HoFH. Compared with HELP, greater reductions in lipid levels and inflammatory markers were achieved with DS, most likely because this method allows for a larger plasma volume to be filtered. J. Clin. Apheresis 31:359-367, 2016. © 2015 Wiley Periodicals, Inc.
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Eliminación de Componentes Sanguíneos/métodos , Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas LDL/aislamiento & purificación , Adsorción/efectos de los fármacos , Adulto , Biomarcadores/sangre , Eliminación de Componentes Sanguíneos/normas , Precipitación Química/efectos de los fármacos , LDL-Colesterol/sangre , Sulfato de Dextran/uso terapéutico , Heparina/uso terapéutico , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/sangre , Inflamación/sangre , Lipoproteínas LDL/sangre , Persona de Mediana EdadRESUMEN
BACKGROUND: Statins are the leading lipid-lowering drugs, reducing blood cholesterol by controlling its synthesis. Side effects are linked to the use of statins, in particular statin-associated muscle symptoms (SAMS). Some data suggest that vitamin D supplementation could reduce SAMS. OBJECTIVE: The purpose of this study was to evaluate the potential benefits of vitamin D supplementation in a randomized controlled trial. METHODS: Men (n = 23) and women (n = 15) (50.5 ± 7.7 years [mean ± SD]) in primary cardiovascular prevention, self-reporting or not SAMS, were recruited. Following 2 months of statin withdrawal, patients were randomized to supplementation (vitamin D or placebo). After 1 month of supplementation, statins were reintroduced. Before and 2 months after drug reintroduction, muscle damage (creatine kinase and myoglobin) was measured. Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (FHG) were also measured with isokinetic and handheld dynamometers, respectively. The Short Form 36 Health Survey (SF-36) questionnaire and a visual analog scale (VAS) were administrated to assess participants' self-reported health-related quality of life and SAMS intensity, respectively. Repeated-measures analysis was used to investigate the effects of time, supplementation, and their interaction, according to the presence of SAMS. RESULTS: Despite no change for objective measures, subjective measures worsened after reintroduction of statins, independent of supplementation (VAS, SF-36 mental component score, all p < 0.05). However, no interaction between time and supplementation according to the presence of SAMS was observed for any variables. CONCLUSIONS: Vitamin D supplementation does not appear to mitigate SAMS.
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Enfermedades Cardiovasculares , Suplementos Dietéticos , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Calidad de Vida , Vitamina D , Humanos , Masculino , Femenino , Vitamina D/uso terapéutico , Vitamina D/administración & dosificación , Persona de Mediana Edad , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológico , Adulto , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/prevención & control , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Fuerza Muscular/efectos de los fármacos , Prevención Primaria/métodosRESUMEN
BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. METHODS: Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. RESULTS: Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). CONCLUSIONS: Whether suffering from "true" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted. TRIAL REGISTRATION: This study is registered in clinicaltrials.gov (NCT01493648).
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Femenino , Humanos , Masculino , Trastorno de Personalidad Antisocial , Terapia por Ejercicio , Fuerza de la Mano , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Músculos , Persona de Mediana EdadRESUMEN
OBJECTIVE: To determine the opinion of medical students attending Laval University (Québec, Québec) regarding the controversial subject of corporal punishment in children. METHOD: For five consecutive years, from the 2006/2007 through to the 2010/2011 school year, an opinion poll was completed by the fourth year medical students at Laval University during a seminar concerning the maltreatment of children. RESULTS: Of the 712 students questioned, 91% were younger than 30 years of age and 74% were female. With respect to the use of corporal punishment on children, 22% of the respondents declared they were in favour of it. More men than women were in favour of this disciplinary practice, with 31% of the men in favour compared with 18% of the woman (adjusted RC 2.2 [95% CI 1.4 to 3.4]; P=0.0003). Approximately 36% of the students who had experienced corporal punishment were in favour of it, compared with only 4% of those who had not experienced this form of discipline (adjusted RC 16.5 [95%CI 8.6 to 31.4]; P<0.0001). Among those who stated that they had been victims of physical abuse, 25% declared themselves in favour of this practice, which was a similar proportion to those who had not been victims of physical abuse (21%) (P=0.52). CONCLUSION: While several medical organizations have declared opposition to the use of corporal punishment, greater than one in five future Quebec doctors are in favour of this disciplinary method and could influence the behaviour of parents in this regard.
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BACKGROUND: Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH. METHODS: A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n = 226; receptor-negative [RN] genotype: n = 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models. RESULTS: There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P = 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P = 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN: -31.1% (95% CI -34.7% to -27.4) vs RD -36.5% (95% CI -40.4% to -32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R2 = 2.3%; P = 0.0001). CONCLUSION: The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.
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LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hiperlipoproteinemia Tipo II , Metabolismo de los Lípidos , Receptores de LDL/genética , Canadá/epidemiología , Femenino , Perfil Genético , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Pruebas de FarmacogenómicaRESUMEN
Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene (NEB) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the NEB. The variant was predicted by in silico tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy.
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Pyridoxine-dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in PLPBP gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay-Lac-St-Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced PLPBP mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal-5-phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.
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Bone marrow transplantation is the standard of care for a host of diseases such as leukemia and multiple myeloma, as well as genetically inherited metabolic diseases affecting the central nervous system. In mouse models, bone marrow transplantation has proven a valuable tool for understanding the hematopoietic system and the homing of hematopoietic cells to their target organs. Many techniques have been developed to create chimeric mice, animals with a hematopoietic system derived from a genetic background that differs from the rest of the body. Current genetic tools allow for virtually limitless possibilities in the choice of donor mice. This protocol describes methods of bone marrow transplantation in mouse models for studies of the brain under basal and pathological conditions. Specific points to be addressed include the preparation of recipient mice by irradiation or chemotherapy; the choice, isolation, and injection of donor cells; and analytical methods such as fluorescence-activated cell sorting and immunostaining. © 2018 by John Wiley & Sons, Inc.
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Trasplante de Médula Ósea , Encefalopatías/metabolismo , Encéfalo/metabolismo , Quimera por Trasplante/metabolismo , Animales , Encéfalo/patología , Encefalopatías/patología , Encefalopatías/terapia , Modelos Animales de Enfermedad , Supervivencia de Injerto , Inflamación/metabolismo , Inflamación/patologíaRESUMEN
BACKGROUND AND AIMS: FIT's value has been ascertained across Canada and worldwide, but still needs to be assessed within the province of Quebec. There also remains a gap between formal indications for FIT, and its actual use in clinical practice. This research aims to evaluate some aspects of FIT's effectiveness in our setting, and its application by prescribers. METHODS: We retrospectively identified and reviewed all the colonoscopies conducted for a positive FIT in 2014 at 2 hospitals located in Quebec City. RESULTS: Five hundred and fifty-nine (559) colonoscopies were reviewed. We obtained PPVs of 6.8% and 46.9% for the detection of CRC and AA, respectively. The PPV for the detection of SCL was higher in men compared to women (OR 1.56, 95%CI 1.11-2.20) and among justified FITs compared to unwarranted ones (OR 1.88, 95%CI 1.34-2.63). The PPV for CRC detection was 25.0% in the presence of unexplained iron deficiency anemia and 6.5% when anemia was absent (pâ¯=â¯0.0058). In 49.9% of cases, the prescription of a FIT was inappropriate. CONCLUSION: The FIT holds a better PPV for detecting SCL among men and when it is indicated. Anemia is associated with a higher CRC detection rate. Half of the FITs were not initially indicated.
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A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.
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INTRODUCTION: Bone mineral density has a strong genetic component but it is also influenced by environmental factors making it a complex trait to study. LRP5 gene was previously shown to be involved in rare diseases affecting bone mass. Mutations associated with gain-of-function were described as well as loss-of-function mutations. Following this discovery, many frequent LRP5 polymorphisms were tested against the variation of BMD in the normal population. MATERIALS AND METHODS: Heel bone parameters (SOS, BUA) were measured by right calcaneal QUS in 5021 healthy French-Canadian women and for 2104 women, BMD evaluated by DXA at two sites was available (femoral neck (FN) and lumbar spine (LS)). Among women with QUS measures and those with DXA measures, 26.5% and 32.8% respectively were premenopausal, 9.2% and 10.7% were perimenopausal and 64.2% and 56.5% were postmenopausal. About a third of the peri- and postmenopausal women never received hormone therapy. Two single nucleotide coding polymorphisms (Val667Met and Ala1330Val) in LRP5 gene were genotyped by allele-specific PCR. All bone measures were tested individually for associations with each polymorphism by analysis of covariance with adjustment for non genetic risk factors. Furthermore, haplotype analysis was performed to take into account the strong linkage disequilibrium between the two polymorphisms. RESULTS AND CONCLUSION: The two LRP5 polymorphisms were found to be associated with all five bone measures (L2L4 and femoral neck DXA as well as heel SOS, BUA and stiffness index) in the whole sample. Premenopausal women drove the association as expected from the proposed role of LRP5 in peak bone mass. Our results suggest that the Val667Met polymorphism is the causative variant but this remains to be functionally proven.
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Densidad Ósea/genética , Densidad Ósea/fisiología , Proteínas Relacionadas con Receptor de LDL/genética , Polimorfismo Genético/genética , Adulto , Anciano , Anciano de 80 o más Años , Densidad Ósea/efectos de los fármacos , Canadá/etnología , Femenino , Francia/etnología , Haplotipos , Hormonas/uso terapéutico , Humanos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad , Menopausia , Persona de Mediana EdadRESUMEN
OBJECTIVES: We evaluated whether cumulative exposure to job strain increases blood pressure. METHODS: A prospective study of 8395 white-collar workers was initiated during 1991 to 1993. At follow-up, 7.5 years later, 84% of the participants were reassessed to estimate cumulative exposure to job strain. RESULTS: Compared with men who had never been exposed, men with cumulative exposure and those who became exposed during follow-up showed significant systolic blood pressure increments of 1.8 mm Hg (95% confidence interval [CI]=0.1, 3.5) and 1.5 mm Hg (95% CI=0.2, 2.8), respectively, and relative risks of blood pressure increases in the highest quintile group of 1.33 (95% CI = 1.01, 1.76) and 1.40 (95% CI = 1.14, 1.73). Effect magnitudes were smaller among women. Effects tended to be more pronounced among men and women with low levels of social support at work. CONCLUSIONS: Among these white-collar workers, exposure to cumulative job strain had a modest but significant effect on systolic blood pressure among men. The risk was of comparable magnitude to that observed for age and sedentary behavior. Men and women with low levels of social support at work appeared to be at higher risk for increases in blood pressure.
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Empleo/psicología , Encuestas Epidemiológicas , Hipertensión/psicología , Salud Laboral/estadística & datos numéricos , Apoyo Social , Estrés Psicológico/complicaciones , Adolescente , Adulto , Determinación de la Presión Sanguínea , Ejercicio Físico , Femenino , Agencias Gubernamentales , Humanos , Hipertensión/epidemiología , Hipertensión/etiología , Masculino , Persona de Mediana Edad , Ocupaciones/clasificación , Estudios Prospectivos , Quebec/epidemiología , Medición de Riesgo , Factores de Riesgo , Estrés Psicológico/epidemiologíaRESUMEN
OBJECTIVE: Microparticles (MP) are small extracellular vesicles present in body fluids. MP originate from different cellular lineages, principally from platelets in blood, and may expose phosphatidylserine (PS). In systemic lupus erythematosus (SLE), MP harbor immunoglobulin G (IgG), thereby forming MP-containing immune complexes (mpIC). We aimed to verify an association between SLE disease activity, damage, and surrogate markers of atherosclerosis and MP harboring IgG, taking into account the platelet origin and PS exposure of MP. METHODS: MP expressing surface IgG, platelet antigen (CD41+), and PS were quantified using flow cytometry in plasma of 191 women with SLE. Carotid ultrasounds (US) were available in 113 patients. Spearman correlation analysis was used to analyze whether levels of MP were associated with the following outcomes: SLE Disease Activity Index 2000 (SLEDAI-2K), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and carotid US plaques and intima-media thickness (CIMT) as surrogates for vascular damage. RESULTS: We found CD41+ MP harboring IgG present in SLE. A positive correlation was found between SLEDAI-2K and levels of CD41+ MP harboring IgG and exposing (p = 0.027) and non-exposing PS (p = 0.001). Conversely, SDI (p = 0.024) and CIMT (p = 0.016) correlated with concentrations of CD41- MP harboring IgG and exposing PS. Associations were independent of low-density lipoprotein cholesterol level, body mass index, and antimalarial drug use. CONCLUSION: Different subtypes of mpIC are produced in SLE and are associated with distinct clinical characteristics such as disease activity and vascular damage. The assessment of MP subtypes might serve for the design of predictive markers of disease activity and vascular damage in patients.
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Grosor Intima-Media Carotídeo , Micropartículas Derivadas de Células/inmunología , Inmunoglobulina G/inmunología , Lupus Eritematoso Sistémico/inmunología , Placa Aterosclerótica/diagnóstico por imagen , Adulto , Arterias Carótidas/diagnóstico por imagen , Femenino , Humanos , Lupus Eritematoso Sistémico/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , UltrasonografíaRESUMEN
UNLABELLED: Genes are important BMD determinants. We studied the association of an ESRRA gene functional variant with BMD in 1335 premenopausal women. The ESRRA genotype was an independent predictor of L2-L4 BMD, with an effect similar to smoking and equivalent to a 10-kg difference in weight. INTRODUCTION: Several genetic polymorphisms have been associated with osteoporosis or osteoporosis fractures, but no functional effect has been shown for most of these gene variants. Because functional studies have implicated estrogen-related receptor alpha (ESRRA) in bone metabolism, we evaluated whether a recently described regulatory variant of the ESRRA gene is associated with lumbar and hip BMD as measured by DXA and with heel bone parameters as measured by quantitative ultrasound (QUS). MATERIALS AND METHODS: Heel bone parameters were measured by right calcaneal QUS in 1335 healthy French-Canadian premenopausal women, and one-half of these women also had their BMD evaluated at two sites: femoral neck and lumbar spine (L2-L4) by DXA. All bone measures were tested separately for association with the ESRRA genotype by analysis of covariance. The significance of the ESRRA contribution to the model was also assessed by two different permutation tests. RESULTS: A statistically significant association between ESRRA genotype and lumbar spine BMD was observed: women carrying the long ESRRA genotype had a 3.9% (0.045 g/cm2) higher lumbar spine BMD than those carrying the short ESRRA genotype (p = 0.004), independently of other risk factors measured. This effect of ESRRA genotype is similar to the effect of smoking and equivalent to a 10-kg difference in weight. This association was confirmed by permutation tests (p = 0.004). The same trend was observed for femoral neck BMD (2.6%, p = 0.07). However, no association was observed between ESRRA and QUS heel bone measures. CONCLUSION: These results support the genetic influence of this ESRRA regulatory variant on BMD.
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Densidad Ósea , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Estrógenos/genética , Absorciometría de Fotón , Adulto , Huesos/diagnóstico por imagen , Huesos/metabolismo , Canadá , ADN Complementario/metabolismo , Femenino , Cuello Femoral/patología , Biblioteca de Genes , Variación Genética , Genotipo , Humanos , Vértebras Lumbares/patología , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo Genético , Premenopausia , Ultrasonografía , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
Lipoprotein lipase (LPL) plays a major role in triglyceride (TG)-rich lipoprotein catabolism. A mutation at codon 207 (P207L) in the exon 5 of the LPL gene has been associated with 50% reduction in postheparin plasma LPL activity and significant increase in plasma TG levels in heterozygous individuals with low HDL. However, heterogeneity in fasting TG concentrations among these carriers suggests that other factors may be involved in the expression of this hypertriglyceridemic state. Indeed, previous studies have shown that the rare S2 allele of the APOC3 Sst I polymorphism was associated with higher concentrations of TG levels in noncarriers of LPL defect. Therefore, we investigated the association of the APOC3 Sst I variant on fasting lipoprotein-lipid levels in a sample of 35 heterozygous men bearing the LPL P207L mutation. Genetic association analyses were performed using the two-genotype groups S1/S1 and S1/S2. The genotype S1/S2 group was characterized by greater plasma cholesterol (plasma-C, P=0.02), plasma-TG (P=0.04), very low-density lipoproteins (VLDL)-C (P=0.004), VLDL-TG (P=0.01), VLDL-apolipoprotein B (apoB) (P=0.001) levels and cholesterol/HDL-C ratio (P=0.008), as well as lower VLDL-TG/VLDL-apoB ratio compared to the S1/S1 genotype group. These results support an exacerbating effect of the APOC3 Sst I single-nucleotide polymorphism on fasting TG levels since a large number of smaller VLDL particles are observed in LPL-deficient men bearing the APOC3 S2 allele.
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Apolipoproteínas C/genética , Lipoproteína Lipasa/deficiencia , Polimorfismo de Nucleótido Simple , Triglicéridos/sangre , Adulto , Anciano , Apolipoproteína C-III , Índice de Masa Corporal , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow-derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired.
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Axones/inmunología , Células de la Médula Ósea/inmunología , Enfermedades Desmielinizantes/inmunología , Microglía/inmunología , Vaina de Mielina/inmunología , Fagocitos/inmunología , Animales , Axones/patología , Células de la Médula Ósea/patología , Receptor 1 de Quimiocinas CX3C , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Ratones , Ratones Noqueados , Microglía/patología , Vaina de Mielina/patología , Fagocitos/patología , Receptores CCR2/genética , Receptores CCR2/inmunología , Receptores de Quimiocina/genética , Receptores de Quimiocina/inmunologíaRESUMEN
Human molecular genetics has successfully identified the genes involved in several monogenic disorders. It now aims at pinpointing the genetic determinants of polygenic or complex traits with a strong genetic component. This constitutes a new challenge. We discuss the methodological and practical aspects of identifying such genes as well as the challenges facing physicians that will have to use efficiently these new diagnostic tools.