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BACKGROUND/PURPOSE: Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. METHODS: Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. RESULTS: Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960-8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804-12,401) in the control group (n = 48); corresponding to a Hodges-Lehmann median difference of 3560 ml [95% confidence interval 1614-5302]; p < 0.001). Outcome data on all-cause mortality, days alive and free of mechanical ventilation and acute kidney injury or ischemic events in the ICU within 90 days of inclusion were recorded in 98/98 (100%), 95/98 (98%) and 95/98 (98%) of participants respectively. Cognition and health-related quality of life at six months were recorded in 39/52 (75%) and 41/52 (79%) of surviving participants, respectively. Ninety out of 134 patients (67%) of eligible patients were randomized, and 15/98 (15%) of the participants experienced at least one protocol violation. CONCLUSION: Protocolized reduction of non-resuscitation fluids in patients with septic shock resulted in a large decrease in fluid administration compared with usual care. A trial using this design to test if reducing non-resuscitation fluids improves outcomes is feasible. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05249088, 18 February 2022. https://clinicaltrials.gov/ct2/show/NCT05249088.
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Estudos de Viabilidade , Hidratação , Unidades de Terapia Intensiva , Choque Séptico , Humanos , Masculino , Choque Séptico/terapia , Choque Séptico/mortalidade , Feminino , Pessoa de Meia-Idade , Hidratação/métodos , Hidratação/normas , Idoso , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , SuéciaRESUMO
AIM: The aim of this study was to evaluate district nurses' (DN) perceived nutritional care and actual level of knowledge about nutritional care before and after a continuing educational intervention. BACKGROUND: Nutritional treatment is an important part of nursing care, and health professionals responsible for nutritional care for older adults must therefore have sufficient understanding of nutritional problems to provide appropriate support. Previous research has shown that nutritional problems frequently go unrecognized and that health care personnel often lacks knowledge about nutritional care and relevant methods of assessing nutritional status. However, little is known about DNs' knowledge about nutritional care. METHODS: An evaluative study with a study-specific questionnaire administered before and after a 2.5-day continuing educational course for DNs in primary health care in Stockholm County, Sweden. The course was given over a period of two to three months. The questionnaire measured DNs' perceived nutritional care and actual level of knowledge about nutritional care. FINDINGS: A total of 456 DNs completed the questionnaire both before and after the intervention. Participants' mean age was 50 years. They had worked a mean of 26 years in health care and 10 years as DNs. Before the intervention, many DNs reported that they did not work with nutritional care in an optimal way. After the intervention, significant improvements were found in perceived nutritional care and actual level of knowledge about the topic. However, not all DNs achieved the learning objectives of the course, so work remains to be done to ensure that DNs have sufficient knowledge of nutritional care to provide appropriate support and correctly prescribe oral nutritional supplements. CONCLUSIONS: The study provides new information on DNs' perceived nutritional care and actual level of knowledge. The result of the intervention helps lay the foundation for good nutritional care for older patients in primary care.
Assuntos
Suplementos Nutricionais , Educação em Enfermagem , Desnutrição/enfermagem , Desnutrição/prevenção & controle , Atenção Primária à Saúde , Administração Oral , Adulto , Humanos , Pessoa de Meia-Idade , Pesquisa Qualitativa , Inquéritos e Questionários , SuéciaRESUMO
BACKGROUND AND PURPOSE: Studies on cognitive decline in myotonic dystrophy type 1 (DM1) are characterized by conflicting results. The purpose of the present study was to analyse possible decline in classical/adult onset DM1 at a 5-year follow-up and to explore the correlation with disease-related and demographic factors. METHODS: Patients with DM1 (n = 37) were examined with a comprehensive neuropsychological test battery yielding measures on memory, attention, verbal, visuospatial and executive functions. Assessment of muscle impairment and CTG repeat expansion size was performed. RESULTS: A majority of the participants (65%) performed worse at follow-up. Compared to normative data, patients scored significantly worse on tests measuring memory, attention, visuospatial construction and verbal ability. Neither CTG repeat size nor muscle impairment related to cognitive decline. However, age at onset and disease duration were correlated with the number of tests in which performance was below 1 SD at both baseline and follow-up examination. CONCLUSIONS: Measurements show that classical/adult onset DM1 is characterized by cognitive decline. Both earlier onset and longer duration of the disease are indicative of more cognitive deficits.
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Cognição , Distrofia Miotônica/psicologia , Adulto , Atenção , Disfunção Cognitiva , Progressão da Doença , Função Executiva , Feminino , Seguimentos , Humanos , Masculino , Memória , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Doenças Musculares/epidemiologia , Doenças Musculares/etiologia , Distrofia Miotônica/epidemiologia , Distrofia Miotônica/genética , Fatores Socioeconômicos , Percepção Espacial , Expansão das Repetições de Trinucleotídeos , Adulto JovemRESUMO
Neutron stars may harbor the true ground state of matter in the form of strange quark matter. If present, this type of matter is expected to be a color superconductor, a consequence of quark pairing with respect to the color and flavor degrees of freedom. The stellar magnetic field threading the quark core becomes a color-magnetic admixture and, in the event that superconductivity is of type II, leads to the formation of color-magnetic vortices. In this Letter, we show that the volume-averaged color-magnetic vortex tension force should naturally lead to a significant degree of nonaxisymmetry in systems such as radio pulsars. We show that gravitational radiation from such color-magnetic "mountains" in young pulsars, such as the Crab and Vela, could be observable by the future Einstein Telescope, thus, becoming a probe of paired quark matter in neutron stars. The detectability threshold can be pushed up toward the sensitivity level of Advanced LIGO if we invoke an interior magnetic field about a factor ten stronger than the surface polar field.
RESUMO
BACKGROUND: Myotonic dystrophy type 1 (DM1) is associated with brain morphology changes including neurofibrillary degeneration. METHODS: We have examined cerebrospinal fluid (CSF) markers indicative of neuronal degeneration and amyloidogenesis; total tau (T-tau), phosphorylated tau (P-tau) and beta amyloid 1-42 (Abeta42), in 32 patients with DM1. RESULTS AND CONCLUSIONS: Associations between CSF markers and CTG repeat expansion size, brain MRI findings, and neuropsychological test results were analysed. As compared with matched controls Abeta42 was significantly decreased (P = 0.001), whilst levels of T-tau were increased (P < 0.001). No difference was found between measures considering P-tau levels. At present the clinical implications of these findings is unclear, because of an overlap between CSF values of DM1 patients and healthy controls, but also regarding modest associations between CSF markers and other measures. However notably, the Tau pathology, as seen in DM1, differs from Alzheimers disease, considering the lack of increased levels of P-tau.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Distrofia Miotônica/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adulto , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Ventrículos Cerebrais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/patologia , Testes Neuropsicológicos , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas tau/químicaRESUMO
We estimate the maximal deformation that can be sustained by a rotating neutron star with a crystalline color-superconducting quark core. Our results suggest that current gravitational-wave data from the Laser Interferometer Gravitational-Wave Observatory have already reached the level where a detection would have been possible over a wide range of the poorly constrained QCD parameters. This leads to the nontrivial conclusion that compact objects do not contain maximally strained color crystalline cores drawn from this range of parameter space. We discuss the uncertainties associated with our simple model and how it can be improved in the future.
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We report on three patients with MeCP2 mutation and male Rett phenotypes. Two brothers with T158M mutations and normal karyotype had a severe early onset encephalopathy, progressive microcephaly, severe feeding problems, breathing and sleep disturbances. They died at the ages of 1 year and 8 months, and 3 years and 1 month. This mutation has previously been reported in three males. The phenotypes show a strong resemblance, and might in fact represent a clinical-genetic entity of the T158M mutation within the complex of congenital encephalopathies in males with MeCP2 mutations. We also report a 3-year-old boy with a R294X mutation, normal karyotype, and a more protracted course. He was inactive and sucked poorly from start. The head growth decelerated from the age of 6 months and the feeding problems increased requiring gastrostomy. He had a rapid deterioration period at 2 years and lost sitting and hand grasping functions. He had prolonged periods with tremor and epileptic myoclonus, shifting tonus, and dystonic extension of the trunk and legs, bruxism, and irregular breathing. He was clinically stable with preserved visual and emotional contact function by the age of four years. None of the boys had dysmorphic features.
Assuntos
Arginina/genética , Metionina/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett/genética , Tirosina/genética , Pré-Escolar , Análise Mutacional de DNA/métodos , Humanos , Lactente , Masculino , IrmãosRESUMO
Trimethylamine-N-oxide (TMAO) and glycine betaine are counteracting osmolytes found in cellular systems under osmotic stress, often in association with high urea concentrations. TMAO is a characteristic component of cartilaginous fish and marine molluscs, while glycine betaine is more widely distributed, occurring in plants, bacteria and the mammalian kidney. As part of a project to explain and understand the action of these methylamines, the RNase A-catalysed degradation of polyuridylic acid in the presence of urea and various osmolytes (0-1.0 M) was studied using (31)P Nuclear Magnetic Resonance spectroscopy. The decrease in reaction rate induced by urea could be fully recovered with 1 molar equivalent of trimethylamine-N-oxide or 1.4 molar equivalents of glycine betaine. These results indicate that the modification of RNase A activity induced by urea is not associated with gross irreversible structural changes and that both glycine betaine and trimethylamine-N-oxide have kinetically detectable counteracting effects.
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Betaína/farmacologia , Metilaminas/farmacologia , Ribonuclease Pancreático/metabolismo , Ureia/farmacologia , Animais , Catálise , Bovinos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , RNA/química , RNA/metabolismo , SoluçõesRESUMO
AIM: Obesity is associated with increased levels of inflammatory mediators. The objective of this study was to evaluate changes in the leucocyte derived inflammatory mediators tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and the isoprostane 8-epi-prostaglandin (PG) F2alpha during BMI lowering with orlistat (Xenical(R), Roche) or placebo. METHODS: TNF-alpha, IL-6, and 8-epi PGF2alpha evaluated in 376 subjects aged 18-75 years with BMI 28-38 kg/m2 before and after 1 year of double-blind, randomized treatment with orlistat 120 mg or placebo three times daily. RESULTS: Weight reduction was associated with decreasing (p < 0.001) levels of TNF-alpha and IL-6 in both orlistat and placebo groups. After 12 months, TNF-alpha was lower (p < 0.05) in the orlistat compared with the placebo group. In the orlistat group, the change in TNF-alpha correlated with change in s-glucose (r = 0.22; p = 0.01), and the change in 8-epi-PGF2alpha correlated with changes in s-cholesterol (r = 0.27; p < 0.001) and s-LDL-cholesterol (r = 0.28; p < 0.001). CONCLUSION: Weight reduction was associated with decreasing levels of both TNF-alpha and IL-6. After 12 months of treatment, TNF-alpha levels were lower in orlistat than in placebo-treated subjects. Whether these results translate into reduced incidence of cardiovascular disease remains to be elucidated.
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Fármacos Antiobesidade/uso terapêutico , Índice de Massa Corporal , Doenças Cardiovasculares/etiologia , Dinoprosta/análogos & derivados , Interleucina-6/sangue , Lactonas/uso terapêutico , Obesidade/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Dinoprosta/sangue , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Orlistate , Fatores de Risco , Redução de PesoRESUMO
The most frequent clinical presentation of sciatica suggests injury of sensor root fibers alone. To evaluate whether thermal quantitative sensory testing (QST) is applicable in the study of sensory dysfunction in lumbosacral disc herniations, 36 men and 30 women with L4/5 or L5/S1 disc herniations underwent thermal QST of the L4, L5, and Si dermatomes. For both levels of disc herniation, there was a significant difference for all temperature modalities, i.e., cold, warmth and heat pain, between all dermatomes as well as between the side of the herniated disc and the corresponding asymptomatic side. However, the proportion of herniated discs classified correctly was only 48% in patients with disc herniations at the L4/5 level, while it was 71% at the L5/S1 level. We conclude that thermal QST measurements reflect and document sensory dysfunction in patients with lumbosacral disc herniation. The method offers a new means both to study the time course of a spontaneous recovery of sensory dysfunction and to evaluate the result of different treatment options. However, thermal QST seems to have the same poor predictive value for identifying the anatomic location of a herniated lumbar disc as conventional electrophysiologic methods.
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Deslocamento do Disco Intervertebral/diagnóstico , Limiar Sensorial , Termorreceptores/fisiologia , Adulto , Feminino , Humanos , Deslocamento do Disco Intervertebral/complicações , Masculino , Pessoa de Meia-Idade , Neurônios Aferentes/fisiologia , Ciática/diagnóstico , Ciática/etiologia , Distúrbios Somatossensoriais/diagnóstico , Distúrbios Somatossensoriais/etiologia , Raízes Nervosas Espinhais/fisiologiaRESUMO
Coeliac disease (CD) is a chronic inflammatory disorder where dietary gluten is not tolerated. In the lesion there are gluten reactive T cells predominantly secreting gamma-interferon. Both HLA and non-HLA genes contribute to CD susceptibility. Interleukin-12 (IL-12) regulates gamma-interferon production. The IL12B gene is located in a region (5q31.1-33.1) where there is evidence for linkage with CD. Allele 1 of an IL12B 3'UTR single-nucleotide polymorphism leads to increased expression of IL-12, and was recently implicated in susceptibility for type 1 diabetes (T1D). We found no evidence for association of allele 1 to CD by the transmission/disequilibrium test or case-control approach. No increased frequency was observed in patients belonging to families where the disease was linked to markers on chromosome 5q. Unlike T1D, allele 1 does not appear to confer susceptibility to CD.
Assuntos
Doença Celíaca/genética , Predisposição Genética para Doença , Interleucina-12/genética , Alelos , Doença Celíaca/patologia , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Humanos , Subunidade p40 da Interleucina-12 , Intestinos/patologia , Itália , Polimorfismo Genético , Países Escandinavos e NórdicosRESUMO
UNLABELLED: It is well-established that high levels of cAMP or glucose can produce insulin resistance. The aim of this study was to characterize the interaction between these agents and insulin with respect to adipose tissue/muscle glucose transporter isoform (glucose transporter 4, GLUT4) gene regulation in cultured 3T3-F442A adipocytes and to further elucidate the GLUT4-related mechanisms in insulin resistance. Insulin (10(4) microU/ml) treatment for 16 h clearly increased GLUT4 mRNA level in cells cultured in medium containing 5.6 mM glucose but not in cells cultured in medium with high glucose (25 mM). 8-Bromo-cAMP (1 or 4 mM) or N(6)-monobutyryl cAMP, a hydrolyzable and a non-hydrolyzable cAMP analog, respectively, markedly decreased the GLUT4 mRNA level irrespective of glucose concentrations. In addition, these cAMP analogs also inhibited the upregulating effect of insulin on GLUT4 mRNA level. Interestingly, the tyrosine phosphatase inhibitor vanadate (1-50 microM) clearly increased GLUT4 mRNA level in a time- and concentration-dependent manner. Furthermore, cAMP-induced inhibition of the insulin effect was also prevented by vanadate. In parallel to the effects on GLUT4 gene expression, both insulin, vanadate and cAMP produced similar changes in cellular GLUT4 protein content and cAMP impaired the effect of insulin to stimulate (14)C-deoxyglucose uptake. In contrast, insulin, vanadate or cAMP did not alter insulin receptor (IR) mRNA or the cellular content of IR protein. IN CONCLUSION: (1) Both insulin and vanadate elicit a stimulating effect on GLUT4 gene expression in 3T3-F442A cells, but a prerequisite is that the surrounding glucose concentration is low. (2) Cyclic AMP impairs the insulin effect on GLUT4 gene expression, but this is prevented by vanadate, probably by enhancing the tyrosine phosphorylation of signalling peptides and/or transcription factors. (3) IR gene and protein expression is not altered by insulin, vanadate or cAMP in this cell type. (4) The changes in GLUT4 gene expression produced by cAMP or vanadate are accompanied by similar alterations in GLUT4 protein expression and glucose uptake, suggesting a role of GLUT4 gene expression for the long-term regulation of cellular insulin action on glucose transport.
Assuntos
Adipócitos/efeitos dos fármacos , AMP Cíclico/farmacologia , Glucose/farmacologia , Insulina/farmacologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Células 3T3 , Adipócitos/metabolismo , Animais , Western Blotting , Meios de Cultura , Desoxiglucose/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/análise , Transportador de Glucose Tipo 4 , Resistência à Insulina/genética , Camundongos , Proteínas de Transporte de Monossacarídeos/análise , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Tirosina Fosfatases/antagonistas & inibidores , RNA Mensageiro/análise , Vanadatos/farmacologiaRESUMO
Celiac disease (CD) is a common chronic inflammatory disorder of the small intestine with a multifactorial aetiology. HLA is a well-known risk factor, but other genetic factors also influence disease susceptibility. To identify the genes involved in this disorder, we performed a genome-wide scan on 106 well-defined Swedish and Norwegian families with at least two affected siblings. We investigated familial segregation of 398 microsatellite markers, and utilised non-parametric linkage analysis. The strongest linkage with disease was found to the HLA locus (6p) (P<0.000006). There were eight regions besides HLA with a point wise P value below 0.05. Among these eight regions were 11q and 5q, both of which have been suggested in several linkage studies of independent celiac disease families. We also performed a stratification analysis of families according to their HLA genotypes. This resulted in significant differences on chromosome 2q. These results indicate that 11q, 5q and possibly also 2q are true susceptibility regions in CD.
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Doença Celíaca/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 5/genética , Núcleo Familiar , Adolescente , Adulto , Idoso , Pré-Escolar , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Países Escandinavos e NórdicosRESUMO
The effect of the gene region on chromosome 2q33 containing the CD28 and the cytotoxic T-lymphocyte associated (CTLA4) genes has been investigated in several diseases with chronic inflammatory nature. In addition to celiac disease (CD), type I diabetes, Grave's disease, rheumatoid arthritis and multiple sclerosis have all demonstrated associations to the A/G single nucleotide polymorphism (SNP) in exon 1, position +49 of the CTLA4 gene. The purpose of this study was to investigate this gene region in a genetically homogeneous population consisting of 107 Swedish and Norwegian families with CD using genetic association and linkage methods. We found a significant association with preferential transmission of the A-allele of the exon 1 +49 polymorphism by using the transmission disequilibrium test (TDT). Suggestive linkage of this region to CD was moreover demonstrated by non-parametric linkage (NPL) analysis giving a NPL-score of 2.1. These data strongly indicates that the CTLA4 region is a susceptibility region in CD. Interestingly, of the several chronic inflammatory diseases that exhibit associations to the CTLA4 +49 A/G dimorphism, CD appears to be the only disease associated to the A allele. This suggests that the +49 alleles of the CTLA4 gene are in linkage disequilibrium with two distinct disease predisposing alleles with separate effects. The peculiar association found in the gut disorder CD may possibly relate to the fact that the gastrointestinal immune system, in contrast to the rest of the immune system, aims to establish tolerance to foreign proteins.
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Antígenos de Diferenciação/genética , Antígenos CD28/genética , Doença Celíaca/genética , Cromossomos Humanos Par 2 , Predisposição Genética para Doença , Imunoconjugados , Abatacepte , Antígenos CD , Antígeno CTLA-4 , Doença Crônica , Diabetes Mellitus Tipo 1/genética , Feminino , Humanos , Inflamação/genética , MasculinoRESUMO
Psoriasis is a heterogeneous disease in which several reports suggest the presence of a susceptibility gene in or in the proximity of the human leukocyte antigen complex in chromosome 6p. There is an association between HLA-Cw6 and young onset of the disease. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes. We have studied this gene in a large Swedish psoriasis population and we report a strikingly high degree of polymorphism in the coding parts of the gene, 1 every 100 base pairs. We used a stratified approach to compare the polymorphic variants in patients and controls. A single nucleotide polymorphism in the coding region leading to an amino acid exchange (Ser-->Phe) that differed significantly between patients and controls was identified (position 619). Owing to a high allele frequency in a larger control group, however, and an insignificant influence of the variant on the age at onset distribution curve based on a large psoriasis population, we could not confirm that this coding single nucleotide polymorphism was involved in disease etiology. We also examined the single nucleotide polymorphism in position 1243, recently proposed to have an influence on the pathogenesis of the disease. This polymorphism showed less association to the disease as compared with the single nucleotide polymorphism at positions 619 and 722. Such a high degree of variation present also in an HLA gene which is not involved in immune response indicates the difficulty involved in assessing the role of a specific allele in the pathogenesis of a complex disease in this region. A strong association effect due to linkage disequilibrium in an extended region in the HLA complex is also a complicating factor.
Assuntos
Glicoproteínas/genética , Psoríase/genética , Alelos , Enzimas de Restrição do DNA/análise , Feminino , Antígenos HLA/química , Antígenos HLA/genética , Antígenos HLA-C/genética , Proteínas de Choque Térmico/análise , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Fragmentos de Peptídeos/análise , Análise de Sequência de DNA , SuéciaRESUMO
Psoriasis vulgaris is strongly associated with certain human leukocyte antigens, especially in early onset. The purpose of this study was to study the HLA-Cw6 allele and its contribution to disease susceptibility in a set of 104 families with at least two affected siblings. A sequencing method was utilized to examine the two exons that build up the antigen binding site of the C locus receptor. DNA from patients homozygous for Cw6 based on haplotype information were sequenced. The results confirmed the identity of the Cw6 allele in affected individuals with the consensus sequence for Cw*0602. We screened the set of families for psoriasis patients homozygous for Cw6 and found 11 individuals with a mean age at onset of 16.1 years. The corresponding figure for the Cw6 heterozygotes was 18.45 years and for the Cw6-negatives 22.36 years. This is indicative of a gene dose effect. We performed a transmission disequilibrium test (TDT) on the Cw6 allele per se, used as a biallelic marker. The analysis resulted in a P-value of 5.3 x 10(-17) (t167/nt45). This greatly exceeds our previous results of a TDT in the region, including microsatellite markers and single nucleotide polymorphisms (SNPs) in the coding part of the S gene (corneodesmosin), which is a suggested candidate gene in the region. The maximum nonparametric linkage (NPL) value was also reached using HLA-C as a marker. We conclude that Cw6 is the allele which shows the highest degree of association with psoriasis in our set of families and we propose that it directly influences the age at onset of the disease rather than increasing the genetic load in accordance with a polygenic theory.
Assuntos
Glicoproteínas/genética , Antígenos HLA-C/genética , Psoríase/genética , Alelos , DNA/química , DNA/genética , Saúde da Família , Feminino , Genótipo , Haplótipos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , Polimorfismo Genético , Psoríase/patologia , Análise de Sequência de DNA , SuéciaRESUMO
We have performed a pair-wise linkage study in the search for psoriasis susceptibility regions. A preliminary scan was performed on 20 families. In this set we obtained indications of linkage on chromosome 3q21. This region was further investigated using material from a total of 104 families (set 1B) resulting in a non-parametric linkage (NPL) of 1.77. The material was stratified in families whose parental origin is in southwest Sweden (set 1C). A maximum NPL value of 2.77 was obtained in this group. A transmission disequilibrium test (TDT) was performed on the stratified material (set 1C) and a significant P value of 0.005 was obtained, at marker D3S1269. The locus was confirmed with TDT in replicate material consisting of 148 families in which a single member was affected (P value 0.0007) at marker D3S1551. Thus, we have observed a significant P value using TDT in the vicinity of markers D3S1269/D3S1551, suggesting a novel psoriasis susceptibility region.
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Cromossomos Humanos Par 3/genética , Predisposição Genética para Doença/genética , Desequilíbrio de Ligação/genética , Psoríase/genética , Mapeamento Cromossômico , Família , Feminino , Ligação Genética , Humanos , Masculino , SuéciaRESUMO
Psoriasis is an inflammatory skin disorder affecting approximately 3% of the population. Genetic studies published so far have shown a complex genetic inheritance with heterogeneity and a putative major susceptibility locus in the HLA region on chromosome 6. We have collected a large amount of material consisting mostly of small nuclear families in order to perform a genome-wide scan for psoriasis-associated genes. In order to focus the scan properly on possible candidate regions, we performed a cytogenetic analysis of 477 unrelated psoriatics. We divided our findings into sporadic, affecting a minor fraction of the cells, and constitutional, i.e. they were present in all cells examined. We found three cases of balanced translocation, all of which involved chromosome 11q. Two of these had a breakpoint in q12-13, whilst one involved the telomeric part of chromosome 11q. In order to characterise further the breakpoint on 11q12-13, we used bacterial artificial chromosomes (BACs) analysed by fluorescent in situ hybridisation (FISH). We were able to show that the persons had a close, but not identical breakpoints; they were separated by at least 5 cM. The major atopy locus is located in this region, as well as a locus for insulin-dependent diabetes mellitus, both being conditions with a pathogenetic mechanism involving antigen presentation.
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Cromossomos Humanos Par 11 , Psoríase/genética , Adolescente , Aberrações Cromossômicas , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 7 , Feminino , Humanos , Masculino , Translocação GenéticaRESUMO
Factors determining change in ambulatory status were studied over a 12-year observation time in 60 ambulating patients with myelomeningocele. There were 26 female and 34 male subjects with a median age of 22 years (range, 12-54). We used the method of Lindseth to define the neurologic level of the lesion and classified walking ability according to the criteria of Hoffer. The prevalence of spasticity and spine and lower-limb deformities was assessed. Orthopedic and neurosurgical interventions and other medical events were registered, as well as occurrence of pressure sores, musculoskeletal pain, and use of orthoses. There were 19 patients with downward transitions in ambulatory level during the follow-up time. Factors explaining deterioration in these 19 patients included deterioration of the neurologic level of lesion, spasticity, knee and hip flexion contractures, low-back pain, lack of motivation, as well as those of major medical events like stroke, recurrent septicemia, lower limb edema, and invasive surgical interventions.
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Meningomielocele/fisiopatologia , Caminhada , Adolescente , Adulto , Criança , Contratura/fisiopatologia , Feminino , Seguimentos , Articulação do Quadril , Humanos , Articulação do Joelho , Masculino , Pessoa de Meia-Idade , Aparelhos OrtopédicosRESUMO
We have performed a genome scan, using markers spaced by 10 cM, in the search for psoriasis-susceptibility loci. The family material of 134 affected sibling pairs was ascertained on the basis of a population genetic study in which 65% of the probands had two healthy parents. Genotyping results were analyzed for non-random excessive allele-sharing between sib pairs by using GENEHUNTER ver 1.1. A stratification approach was applied to increase the homogeneity of the material by means of an operational definition of joint complaints among affected individuals. Significant linkage to the human leukocyte antigen region on chromosome 6p in a cohort including 42 families without joint complaints (nonparametric linkage score of 2.83, P=0.002) strongly supported the validity of this operational definition as it replicated results from an earlier linkage report with similar stratification criteria. New candidate regions on chromosomes 3 and 15 were identified. The highest non-parametric linkage values in this study, 2.96 (P=0.0017) and 2.89 (P=0.0020), were reached on chromosome 15 in a subgroup with joint complaints and on chromosome 3 in a subgroup without joint complaints. In addition, confirmation of previously reported loci was established on chromosomes 4q, 6p, and 17q. This study indicates that distinct disease loci might be involved in psoriasis etiology for various phenotypes.