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1.
Artigo em Inglês | MEDLINE | ID: mdl-34348541

RESUMO

Background: Although noninvasive ventilation (NIV) improves survival and quality of life (QOL) in ALS, use of NIV is suboptimal. Objective: To determine compliance with "early" NIV initiation, requisite for the feasibility of a large study of early NIV initiation, and examine factors impacting compliance. Methods: Seventy-three ALS participants with forced vital capacities (FVC) >50% were enrolled. Participants with FVC over 80% (Group 1) were initiated on NIV early (FVC between 80 and 85%). Participants with FVC between 50 and 80% (Group 2) started NIV at FVC between 50 and 55%. Symptom surveys, QOL scores, and NIV compliance (machine download documenting use ≥4 hours/night >60% of time) were collected following NIV initiation. Results: 53.6% of Group 1 and 50% of Group 2 were compliant 28 days following NIV initiation, with increased compliance over time. Participants who were unmarried, had lower income, lower educational attainment, or limited caregiver availability were less likely to be compliant. Bothersome symptoms in non-compliant participants included facial air pressure, frequent arousals with difficulty returning to sleep, and claustrophobia. Both compliant and noncompliant participants felt improved QOL with NIV; improvement was significantly greater in compliant participants. Conclusions: These data suggest ALS patients can comply with NIV early in their disease, and potentially benefit as evidenced by improved QOL scores, supporting both feasibility and need for a study comparing early versus late NIV initiation. Moreover, modifiable symptoms were identified that could be optimized to improve compliance. Further studies are needed to determine the impact of "early" intervention on survival and QOL.


Assuntos
Esclerose Amiotrófica Lateral , Ventilação não Invasiva , Insuficiência Respiratória , Esclerose Amiotrófica Lateral/terapia , Humanos , Cooperação do Paciente , Qualidade de Vida , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Capacidade Vital
2.
Artigo em Inglês | MEDLINE | ID: mdl-32597982

RESUMO

AIMS: None of the existing studies on adherence have directly measured levels of medications (or their metabolites) in patients with heart failure. METHODS AND RESULTS: We used liquid chromatography-tandem mass spectrometry to measure the presence of prescribed drugs (diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists) in the urine of patients reviewed 4 to 6 weeks after hospitalisation with heart failure. Patients were unaware that adherence was being assessed. Of the 341 patients studied, 281 (82.4%) were adherent i.e. had all prescribed drugs of interest detectable in their urine. Conversely, 60 patients (17.6%) were partially or completely non-adherent. Notably, 24 of the 60 were non-adherent to only diuretic therapy and only 7 out of all 341 patients studied (2.1%) were completely non-adherent to all prescribed heart failure drugs. There were no major differences in baseline characteristics between adherent and non-adherent patients. CONCLUSION: Non-adherence, assessed using a single spot urine measurement of drug levels, was confirmed in 1 of 5 patients evaluated 4 to 6 weeks after hospitalisation with heart failure.

3.
Psychol Med ; 46(10): 2215-26, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27087657

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with elevated risk for metabolic syndrome (MetS). However, the direction of this association is not yet established, as most prior studies employed cross-sectional designs. The primary goal of this study was to evaluate bidirectional associations between PTSD and MetS using a longitudinal design. METHOD: A total of 1355 male and female veterans of the conflicts in Iraq and Afghanistan underwent PTSD diagnostic assessments and their biometric profiles pertaining to MetS were extracted from the electronic medical record at two time points (spanning ~2.5 years, n = 971 at time 2). RESULTS: The prevalence of MetS among veterans with PTSD was just under 40% at both time points and was significantly greater than that for veterans without PTSD; the prevalence of MetS among those with PTSD was also elevated relative to age-matched population estimates. Cross-lagged panel models revealed that PTSD severity predicted subsequent increases in MetS severity (ß = 0.08, p = 0.002), after controlling for initial MetS severity, but MetS did not predict later PTSD symptoms. Logistic regression results suggested that for every 10 PTSD symptoms endorsed at time 1, the odds of a subsequent MetS diagnosis increased by 56%. CONCLUSIONS: Results highlight the substantial cardiometabolic concerns of young veterans with PTSD and raise the possibility that PTSD may predispose individuals to accelerated aging, in part, manifested clinically as MetS. This demonstrates the need to identify those with PTSD at greatest risk for MetS and to develop interventions that improve both conditions.


Assuntos
Síndrome Metabólica/epidemiologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Veteranos/estatística & dados numéricos , Adulto , Campanha Afegã de 2001- , Idoso , Comorbidade , Feminino , Humanos , Guerra do Iraque 2003-2011 , Estudos Longitudinais , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
5.
Neurology ; 73(15): 1218-26, 2009 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-19822872

RESUMO

OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS. RESULTS: The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. RECOMMENDATIONS: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B) and to slow the decline of forced vital capacity (Level B). NIV may be considered to improve quality of life (Level C) [corrected].Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).


Assuntos
Esclerose Amiotrófica Lateral/terapia , Terapia Respiratória/métodos , Esclerose Amiotrófica Lateral/dietoterapia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Nutrição Enteral/métodos , Medicina Baseada em Evidências , Humanos , Carbonato de Lítio/uso terapêutico , Qualidade de Vida , Riluzol/uso terapêutico
6.
Neurology ; 73(15): 1227-33, 2009 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-19822873

RESUMO

OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS. RESULTS: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS. RECOMMENDATIONS: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.


Assuntos
Esclerose Amiotrófica Lateral/terapia , Transtornos Cognitivos/diagnóstico , Equipe de Assistência ao Paciente , Esclerose Amiotrófica Lateral/diagnóstico , Demência/diagnóstico , Medicina Baseada em Evidências , Fadiga/tratamento farmacológico , Humanos , Cãibra Muscular/tratamento farmacológico , Cuidados Paliativos/métodos , Paralisia Pseudobulbar/tratamento farmacológico , Sialorreia/tratamento farmacológico , Sialorreia/radioterapia , Assistência Terminal/métodos , Revelação da Verdade
9.
Muscle Nerve ; 37(4): 473-6, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18236463

RESUMO

We developed a disease-specific, 10-point functional rating scale for patients with inclusion body myositis (IBMFRS). The IBMFRS was utilized as a secondary outcome measure in a multicenter pilot trial of the clinical safety and tolerability of high-dose beta interferon-1a. In this trial, 28 IBM patients completed the IBMFRS at baseline and monthly for 6 months. The IBMFRS showed statistically significant correlations (P < 0.001) with maximal voluntary isometric contraction, manual muscle testing, handgrip dynamometry, and the amyotrophic lateral sclerosis (ALS) functional rating scale (ALSPRS). Compared to these other outcome measures, the IBMFRS was also the most sensitive measure of change over the course of the study.


Assuntos
Avaliação da Deficiência , Miosite de Corpos de Inclusão/fisiopatologia , Índice de Gravidade de Doença , Atividades Cotidianas , Humanos , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
Hum Genet ; 118(1): 115-22, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16078048

RESUMO

Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%) while observed in only 10.6% in outbred American and European populations. Furthermore, haplogroups J and K are less frequent (1.0%) than in the outbred data set (9.4-11.2%). Affected case matrilines and unaffected control lines were chosen from pedigrees to test whether specific haplogroups and their defining SNPs confer risk of AD. We did not observe frequency differences between AD cases compared to controls overall or when stratified by sex. Therefore, we suggest that the genetic effect responsible for AD dementia in the affected Amish pedigrees is unlikely to be of mitochondrial origin and may be caused by nuclear genetic factors.


Assuntos
Doença de Alzheimer/genética , Cristianismo , Grupos Étnicos/genética , Impressão Genômica , DNA Mitocondrial/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único
12.
Neurosci Lett ; 379(3): 199-204, 2005 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-15843063

RESUMO

Apolipoprotein E (APOE) is the only universally confirmed susceptibility gene for late-onset Alzheimer disease (LOAD), although many loci are believed to modulate LOAD risk. The genetic homogeneity of isolated populations, such as the Amish, potentially provide increased power to identify LOAD susceptibility genes. Population homogeneity in these special populations may reduce the total number of susceptibility genes contributing to the complex disorder, thereby increasing the ability to identify any one susceptibility gene. Dementia in the Amish is clinically indistinguishable from LOAD in the general population. Previous studies in the Amish demonstrated a significantly decreased frequency of the APOE-4 susceptibility allele, but significant familial clustering of dementia [M.A. Pericak-Vance, C.C. Johnson, J.B. Rimmler, A.M. Saunders, L.C. Robinson, E.G. D'Hondt, C.E. Jackson, J.L. Haines, Alzheimer's disease and apolipoprotein E-4 allele in an Amish population, Ann. Neurol. 39 (1996) 700-704]. These data suggested that a genetic etiology independent of APOE may underlie the dementia observed in this population. In the present analysis, we focused on a large, multiplex, inbred Amish family (24 sampled individuals; 10 of whom are affected). We completed a genomic screen to identify novel LOAD loci (n=316 genetic markers), using both model-dependent "affecteds-only" analysis (dominant and recessive) and model-independent affected relative pair analysis. Interesting results (lod>1.5 or p<0.01) were obtained for markers on eight chromosomes (2q, 5q, 6q, 7p, 8p, 8q, 11p, 18p, 18q, and 19q). The highest overall score was a multipoint lod score of 3.1 on chromosome 11p. Most regions we identified were not previously detected by genomic screens of outbred populations and may represent population-specific susceptibilities to LOAD. These loci are currently under further investigation in a study of LOAD including additional Amish families.


Assuntos
Apolipoproteínas E/genética , Demência/genética , Grupos Étnicos , Saúde da Família , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E4 , Mapeamento Cromossômico , Cromossomos Humanos/genética , Demência/epidemiologia , Feminino , Ligação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Escore Lod , Modelos Moleculares , Linhagem
13.
J Intern Med ; 257(1): 18-26, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15606373

RESUMO

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumours, which are frequently carcinomas, and ossifying jaw fibromas. In addition, some patients may develop renal tumours and cysts. The gene causing HPT-JT, which is referred to as HRPT2 and is located on chromosome 1q31.2, encodes a 531 amino acid protein called PARAFIBROMIN. To date 42 mutations, of which 22 are germline, have been reported and 97% of these are inactivating and consistent with a tumour suppressor role for HRPT2. We have investigated another four HPT-JT families for germline mutations, searched for additional clinical phenotypes, and examined for a genotype-phenotype correlation. Mutations were found in two families. One family had a novel deletional-insertion at codon 669, and the other had a 2 bp insertion at codon 679, which has been reported in four other unrelated patients. These five unrelated patients and their families with the same mutation were not found to develop the same tumours, thereby indicating an absence of a genotype-phenotype correlation. An analysis of 33 HPT-JT kindreds revealed that affected women in 13 HPT-JT families suffered from menorrhagia in their second to fourth decades. This often required hysterectomy, which revealed the presence of uterine tumours. This resulted in a significantly reduced maternal transmission of the disease. Thus, the results of our analysis expand the spectrum of HPT-JT-associated tumours to include uterine tumours, and these may account for the decreased reproductive fitness in females from HPT-JT families.


Assuntos
Hiperparatireoidismo/genética , Neoplasias Maxilomandibulares/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias Uterinas/genética , Adulto , Saúde da Família , Feminino , Genótipo , Humanos , Hiperparatireoidismo/patologia , Neoplasias Maxilomandibulares/patologia , Masculino , Menorragia/complicações , Menorragia/patologia , Pessoa de Meia-Idade , Mutação , Neoplasias Primárias Múltiplas/patologia , Fenótipo , Proteínas/genética , Síndrome , Proteínas Supressoras de Tumor , Neoplasias Uterinas/patologia
15.
J Med Genet ; 41(7): 508-17, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15235021

RESUMO

BACKGROUND: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. METHODS: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. RESULTS: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. CONCLUSION: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.


Assuntos
Caderinas/genética , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , Caderinas/fisiologia , Criança , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Mutação em Linhagem Germinativa/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Mutação de Sentido Incorreto/fisiologia , Linhagem , Neoplasias Gástricas/diagnóstico
16.
Nat Genet ; 32(4): 676-80, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12434154

RESUMO

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.


Assuntos
Adenoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hiperparatireoidismo/genética , Neoplasias das Paratireoides/genética , Proteínas/genética , Adenoma/patologia , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 1 , Éxons , Etiquetas de Sequências Expressas , Genes Supressores de Tumor , Ligação Genética , Testes Genéticos , Genótipo , Heterozigoto , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , Fases de Leitura Aberta , Neoplasias das Paratireoides/química , Neoplasias das Paratireoides/patologia , Linhagem , Proteínas/química , Síndrome , Proteínas Supressoras de Tumor
17.
Mod Pathol ; 14(10): 942-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11598162

RESUMO

Loss of the cell adhesion molecule E-cadherin has been observed in a variety of human carcinomas, and germline E-cadherin mutations have been found in several familial cases of diffuse gastric cancer. We sought to determine the prevalence and nature of E-cadherin alterations in "sporadic" gastric carcinomas. We performed comprehensive sequencing of the coding region, loss of heterozygosity (LOH) analysis, and immunohistochemical protein expression determination on 40 sporadic gastric adenocarcinomas. In total, 7 of 25 diffuse-type cancers harbored genetic alterations in the E-cadherin gene. Novel mutations predicted to significantly compromise protein function were found within 4 of these cancers, 2 of which harbored alterations resulting in biallelic inactivation of the gene product. Three diffuse cancers failed to amplify Exon 8 of E-cadherin, suggesting the presence of a homozygous abnormality. Notably, one germline E-cadherin mutation was also identified within these "sporadic" diffuse cancers. Significant gene mutations were not found in the 14 intestinal-type or histologically mixed cancer. Immunohistochemistry revealed aberrant or negative protein expression in seven diffuse-type tumors, four of which correlated with the genetic alterations. Both diffuse and intestinal-type tumors exhibited low rates of LOH, suggesting that allelic loss at the locus is not a common mechanism for E-cadherin inactivation during gastric tumorigenesis. Our observations suggest that inactivation of the E-cadherin gene occurs only in a subset of diffuse-type gastric cancers, as the majority of cases did not contain genetic alterations or identifiable protein abnormalities. Germline E-cadherin alterations, although rare, may underlie some diffuse gastric cancer cases that have important biologic and practical implications


Assuntos
Adenocarcinoma/patologia , Caderinas/genética , Inativação Gênica , Neoplasias Gástricas/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Sequência de Bases , Caderinas/análise , Análise Mutacional de DNA , DNA de Neoplasias/química , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Mutação , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
18.
Surgery ; 130(4): 612-7; discussion 617-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11602891

RESUMO

BACKGROUND: An autosomal dominant syndrome of diffuse gastric cancer has been reported with germline mutations in the E-cadherin (CDH1) gene and has been identified in approximately 14 families and 50 individuals worldwide. Penetrance of the gene is 70% to 80%, and the average age of onset of gastric cancer is 37 years. These characteristics have led to the consideration of prophylactic total gastrectomy in family members with CDH1 mutations. METHODS: We report here the first use of prophylactic gastrectomy in 6 asymptomatic members of 2 families (2 males, 4 females; ages 22, 27, 28, 35, 39, and 40) based on family pedigree and genetic analysis. Total gastrectomy was performed via an upper midline incision, and reconstruction of the gastrointestinal tract was done via a Roux-en-Y esophagojejunostomy. Complete removal of all gastric mucosa was documented intraoperatively, and confirmation was made that only esophageal mucosa remained at the proximal specimen margin. RESULTS: The gastric specimens appeared normal, and the results of routine pathologic examination were negative for cancer. All specimens from patients who tested positive for E-cadherin mutations were subjected to a research protocol of microscopic sectioning in which 150 to 250 tissue blocks were examined. All of these patients had microscopic foci of cancer, often at multiple sites, with overlying normal gastric mucosa. CONCLUSIONS: E-cadherin gene mutations in association with familial gastric cancer is a new disease for which prophylactic surgery must be considered. The morbidity of this operation is much higher than that for other genetic diseases, but the alternative is a mortality risk of more than 80% at a young age.


Assuntos
Caderinas/genética , Gastrectomia , Mutação , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia , Adulto , Aconselhamento Genético , Humanos , Perda de Peso
19.
J Neurol Sci ; 191(1-2): 75-8, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11676995

RESUMO

There is still no consensus as to which physiologic marker should be used as a trigger for the initiation of non-invasive positive pressure ventilation (NPPV) in patients with amyotrophic lateral sclerosis (ALS). Current practice parameters recommend that the decision to begin treatment be based upon forced vital capacity (FVC) measurements. A prospective, randomized study was performed in 20 ALS patients who had an FVC of 70-100%. Patients received baseline assessments including: ALS functional rating scale-respiratory version (ALSFRS-R), pulmonary symptom scale, Short form 36 (SF-36), FVC%, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and nocturnal oximetry. Patients were randomized to receive NPPV based upon nocturnal oximetry studies suggesting oxygen desaturation <90% for one cumulative minute ("early intervention") or a FVC <50% ("standard of care"). At enrollment, there was no significant correlation between FVC% and the ALSFRS-R, symptom score, MEP, MIP, or duration of nocturnal desaturation <90%. An increase in the vitality subscale of the SF-36 was demonstrated in 5/6 patients randomized to "early intervention" with NPPV. Our data indicate that FVC% correlates poorly with respiratory symptoms and suggests that MIP and nocturnal oximetry may be more sensitive measures of early respiratory insufficiency. In addition, intervention with NPPV earlier than our current standard of care may result in improved quality of life.


Assuntos
Hipoventilação/diagnóstico , Hipoventilação/fisiopatologia , Doença dos Neurônios Motores/fisiopatologia , Testes de Função Respiratória , Progressão da Doença , Humanos , Hipoventilação/etiologia , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/terapia , Oximetria , Respiração com Pressão Positiva , Valor Preditivo dos Testes , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Método Simples-Cego , Inquéritos e Questionários , Capacidade Vital
20.
N Engl J Med ; 344(25): 1904-9, 2001 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-11419427

RESUMO

BACKGROUND: Germ-line truncating mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer. These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance, predominantly in young persons. We describe genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 from two unrelated families with hereditary diffuse gastric cancer. METHODS: Mutation-specific predictive genetic testing was performed by polymerase-chain-reaction amplification, followed by restriction-enzyme digestion and DNA sequencing in Family 1 and by heteroduplex analysis in Family 2. A total gastrectomy was performed prophylactically in five carriers of mutations who were between 22 and 40 years old. In each case, the entire mucosa of the stomach was extensively sampled for microscopical analysis. RESULTS: Superficial infiltrates of malignant signet-ring cells were identified in the surgical samples from all five persons who underwent gastrectomy. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet-ring cells were present in 65 of the 140 tissue blocks analyzed, representing in aggregate less than 2 percent of the gastric mucosa. CONCLUSIONS: We recommend genetic counseling and consideration of prophylactic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer.


Assuntos
Adenocarcinoma/genética , Caderinas/genética , Mutação em Linhagem Germinativa , Neoplasias Gástricas/genética , Adulto , Idade de Início , Carcinoma de Células em Anel de Sinete/genética , Feminino , Gastrectomia , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Linhagem , Prevenção Primária , Estômago/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/prevenção & controle , Neoplasias Gástricas/cirurgia
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