Determination of hepatitis B phenotype using biochemical and serological markers.

The aim of this study was to assess the validity of categorization of chronic hepatitis B viral infection into stages or phases based upon measures of disease activity and viral load, assuming these phenotypes will be useful for prognostication and determining the need for antiviral therapy. We assessed the phenotype of hepatitis B of 1,390 adult participants enrolled in the Hepatitis B Research Network Cohort Study, using a computer algorithm. Only 4% were immune tolerant, while 35% had chronic hepatitis B (18% e antigen positive and 17% e antigen negative) while 23% were inactive carriers. Strikingly, 38% of participants did not fit clearly into any one of these groups and were considered indeterminant. The largest subset of indeterminants had elevated serum aminotransferases with low levels of HBV DNA (less than 10,000 iu/mL). Subsequent determination of hepatitis B phenotype on the next available laboratory tests showed that 64% remained indeterminant. These findings call into question the validity of conventional staging of hepatitis B, in large part because of the substantial proportion of patients who do not fit readily into one of the usual stages or phases. Further studies are needed of the indeterminant category of chronic hepatitis B viral infection, including assessments of whether patients in this group are perhaps in transition to another phase or if they are a distinct phenotype with a need to assess liver disease severity and need for antiviral therapy. (ClinicalTrials.gov identifier NCT01263587).

Serum lipids and their associations with viral levels and liver disease severity in a treatment-naïve chronic hepatitis C type 1-infected cohort.

In patients with chronic hepatitis C virus (HCV) infection, steatosis and fibrosis have been shown to be inversely associated with total cholesterol (TC) and low-density lipoprotein cholesterol. Steatosis and fibrosis have also been found to be associated with triglyceride (TG) levels; though, the direction of the relationship is inconsistent across studies. The objective of this study was to assess whether viral level and histological factors are associated with the serum lipid profile in a treatment-naïve cohort with chronic HCV genotype 1 infection. Participants were from the prospective Study of Viral Resistance to Antiviral Therapy (Virahep-C). Fasting lipid profiles were analysed for 160 African Americans and 170 Caucasian Americans. Linear regression was used to evaluate associations of each lipid with viral load and liver disease. TG levels were significantly and directly associated with HCV levels (P = 0.0034) and steatosis (P < 0.0001). Other lipid parameters were significantly lower in those with fibrosis [HDLc (P = 0.001) and TC levels (P = 0.004)] than in those without fibrosis. In patients with HCV genotype 1 infection, more severe liver disease was associated with lower lipid levels, with the exception of TG levels that were directly related to steatosis. The direct relationship between viral load and TG levels is consistent with proposed the mechanisms of very low density lipoprotein/HCV particle secretion. In contrast, the direct relationship between TG level and steatosis is inconsistent with posited mechanisms of HCV-induced steatosis, a possible reflection of HCV genotype 1 infection and a metabolic aetiology of steatosis.

Risk of breast cancer to relatives of young breast cancer patients.

Breast cancer risk among sisters and mothers of a population-based series of 1,137 breast cancer patients diagnosed in Metropolitan Detroit before the age of 55 years was compared with risk to the same relatives of 1,001 age-matched, population-based controls. After adjusting for age of the relative, for age of the case or control, and for race, the odds ratio for breast cancer for women with affected sisters was 2.2; for women with affected daughters, 3.2; and for women with affected mothers and sisters, 9.9. Breast cancer in aunts had no independent influence on risk. Among white women, cumulative risk of breast cancer before the age of 50 years was approximately 1% for relatives of controls, 3% for sisters of older cases, but about 17% for women either with sisters diagnosed before the age of 40 years or with affected sisters and mothers. Sisters of the older patients had a 13% risk of breast cancer by 70 years of age, compared to 5% for sisters of controls. White women with affected mothers and sisters were at 50% risk by 65 years of age. This study identifies the criteria for women who could receive particular benefit from screening for breast cancer.

Marital status and cancer incidence: differences in the black and white populations.

A study of 59,070 cancers newly diagnosed during the years 1978 through 1982 among black and white males and females was conducted to assess variations in age-adjusted incidence rates across four marital categories, single, married, divorced, and widowed. Population data were obtained from the 1980 Census. Distinct patterns of cancer incidence by marital status were observed for black and white males and females. Single black males had the highest age-adjusted incidence rates for all 15 of the 15 sites analyzed among men. Similarly single black females' rates were highest for 14 of the 18 sites analyzed among women. Among white females, age-adjusted incidence rates were highest or second highest in widows for 16 of 18 sites analyzed. The variation in cancer incidence by marital status was not statistically significant for white men. In addition, there is a statistically significant concordance of cancer incidence by marital status across the four race-gender groups for three digestive tract sites. Clues to cancer etiology are suggested by this study, as well as potential directions for preventive health programs.

Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study.

BACKGROUND: Specific patterns of decline over time were evaluated across a spectrum of cognitive measures in presymptomatic Alzheimer disease (AD) within a community sample. METHODS: A total of 551 individuals completed a battery of standard cognitive tests 3.5 and 1.5 years before outcome (clinical onset of AD vs continued nondemented status) within a prospective community-based study of AD. Test score changes in 68 cases (who subsequently developed symptomatic AD) and 483 controls (who remained nondemented) on each of 15 cognitive measures were transformed into z scores adjusted for age, sex, and education. A case-control rate ratio of the proportions of individuals who showed "cognitive decline" on each test was calculated, representing the relative magnitude of cognitive decline on each test in presymptomatic AD compared with normal aging. RESULTS: Declines in Trail-Making Tests A and B and Word List delayed recognition of originals and third immediate learning trial had the highest rate ratios, larger than 3.0 (P<.01). These were followed by Word List delayed recognition of foils and delayed recall, Consortium to Establish a Registry for Alzheimer's Disease Praxis, Clock Drawing, the Boston Naming Test, and Orientation, with rate ratios between 1.7 and 3.0 (P<.05). CONCLUSIONS: Memory and executive dysfunction showed the greatest decline over time in individuals who would clinically manifest AD 1.5 years later. These findings might help us understand the underlying evolution of the early neurodegenerative process. They highlight the importance of executive dysfunction early in the disease process and might facilitate early detection of AD.

Brain imaging abnormalities in mental disorders of late life.

Psychiatric inpatients with dementia (N = 61) or depression (N = 67) in late life were 2.6 times more likely to manifest magnetic resonance imaging abnormalities of the brain than were elderly controls (N = 44). Controlling for the effects of age and gender, demented patients were distinguishable from controls by an increased prevalence of cortical atrophy and infarction, while depressed patients exhibited an increased prevalence of cortical infarctions and leukoencephalopathy. Patients with dementia were distinguishable from those with major depression by an increased prevalence of cortical atrophy. These results indicate that major depression in late life, like dementia, is associated with a remarkable increase in overt pathologic changes in the brain.

Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study.

BACKGROUND: The APOE*E4 allele of the gene for apolipoprotein E (APOE) has been reported as a risk factor for Alzheimer disease (AD) to varying degrees in different ethnic groups. OBJECTIVE: To compare APOE*E4-AD epidemiological associations in India and the United States in a cross-national epidemiological study. DESIGN: Case-control design within 2 cohort studies, using standardized cognitive screening and clinical evaluation to identify AD and other dementias and polymerase chain reaction to identify APOE genotyping. PARTICIPANTS: Rural community samples, aged 55 years or older (n=4450) in Ballabgarh, India, and 70 years or older (n=886) in the Monongahela Valley region of southwestern Pennsylvania. MAIN OUTCOME MEASURES: Criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association for probable and possible AD and Clinical Dementia Rating (CDR) scale for dementia staging. RESULTS: Frequency of APOE*E4 was significantly lower (P<.001) in Ballabgarh vs the Monongahela Valley (0.07 vs 0.11). Frequency of probable or possible AD, with CDR of at least 1.0, in the Indian vs US samples, was as follows: aged 55 to 69 years, 0.1% (Indian sample only); aged 70 to 79 years, 0.7% vs 3.1%; aged 80 years or older, 4.0% vs 15.7%. Among those aged 70 years or older, adjusted odds ratios (95% confidence interval) for AD among carriers of APOE*E4 vs noncarriers were 3.4 (1.2-9.3) and 2.3 (1.3-4.0) in the Indian and US samples, respectively, and not significantly different between cohorts (P=. 20). CONCLUSION: This first report of APOE*E4 and AD from the Indian subcontinent shows very low prevalence of AD in Ballabgarh, India, but association of APOE*E4 with AD at similar strength in Indian and US samples. Arch Neurol. 2000.

Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented.

OBJECTIVE: To identify the most accurate cognitive measures in discriminating between individuals with presymptomatic AD and individuals who remained nondemented. METHODS: During a 10-year prospective community study, 120 nondemented subjects completed a battery of standard cognitive tests and clinically manifested AD 1.5 years later. Performance on each of 16 cognitive tests was compared between these 120 presymptomatic cases and 483 controls who remained nondemented over the 10-year follow-up period. The area under the receiver operating characteristic (AUC) curve for each test was used to measure its accuracy of discrimination between cases and controls. RESULTS: Among the 16 neuropsychological tests, Word List Delayed Recall discriminated best between cases and controls (AUC = 0.806), followed by the Word List 3rd Learning Trial (0.787), Word List 1st Learning Trial (0.774), and Trail-making Test B (0.773), compared to the Mini-Mental State Examination (MMSE) (0.726). Both Word List Delayed Recall and Word List 3rd Learning Trial were significantly more accurate than the MMSE. The combination of Word List Delayed Recall and Trail-making Test B comprised the optimal set of cognitive measures, with the highest AUC (0.852). CONCLUSION: Measures of delayed recall and executive functions were the best discriminators between those who would manifest AD 1.5 years later and those who would remain nondemented. These findings are relevant for the early detection of AD and, therefore, for prevention and early intervention trials. Executive dysfunction may be a subtle manifestation of incipient AD, along with memory dysfunction.

Cognitive deficits and clinical diagnosis of Alzheimer's disease.

We used cognitive deficits detected by neuropsychological testing to evaluate clinical diagnosis of Alzheimer's disease. Deficits were defined with respect to performance of control subjects according to procedural guidelines set by a NINCDS-ADRDA Work Group. The most frequent deficits were in recent memory and lexical-semantic language abilities. Clinical diagnosis of Alzheimer's disease was compared with diagnosis based on a criterion of two or more cognitive deficits both on initial neuropsychological testing and on testing repeated a year later in some subjects. Initial clinical diagnosis identified 96% of cases who met the criterion when first tested and 100% of those with multiple deficits at follow-up. Specificity with respect to the criterion was 86% on initial testing and 89% at follow-up. These findings support the validity of clinical diagnosis of Alzheimer's disease using the NINCDS-ADRDA criteria.

Incidence of Alzheimer's disease in a rural community in India: the Indo-US study.

OBJECTIVE: To determine overall and age-specific incidence rates of AD in a rural, population-based cohort in Ballabgarh, India, and to compare them with those of a reference US population in the Monongahela Valley of Pennsylvania. METHODS: A 2-year, prospective, epidemiologic study of subjects aged > or =55 years utilizing repeated cognitive and functional ability screening, followed by standardized clinical evaluation using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for the diagnosis, and the Clinical Dementia Rating scale for the staging, of dementia and AD. RESULTS: Incidence rates per 1000 person-years for AD with CDR > or =0.5 were 3.24 (95% CI: 1.48-6.14) for those aged > or =65 years and 1.74 (95% CI: 0.84-3.20) for those aged > or =55 years. Standardized against the age distribution of the 1990 US Census, the overall incidence rate in those aged > or =65 years was 4.7 per 1000 person-years, substantially lower than the corresponding rate of 17.5 per 1000 person-years in the Monongahela Valley. CONCLUSION: These are the first AD incidence rates to be reported from the Indian subcontinent, and they appear to be among the lowest ever reported. However, the relatively short duration of follow-up, cultural factors, and other potential confounders suggest caution in interpreting this finding.

The importance of pulsatile components of hypertension in predicting carotid stenosis in older adults.

OBJECTIVE: To evaluate pulsatile components of the blood pressure as risk markers for carotid stenosis in isolated systolic hypertension. DESIGN: Duplex scans with Doppler measures of the blood flow velocity were used to diagnose carotid stenosis in 187 participants in the Systolic Hypertension in the Elderly Program and in 187 normotensive and mildly hypertensive control subjects. METHODS: The systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure, and mean arterial pressure (MAP) were selected as independent variables. A logistic regression model for carotid stenosis was used to adjust for potentially confounding risk factors. Serial models, each containing single or double blood pressure variables, were run to compare risk markers for carotid stenosis. Receiver operating characteristic curves were compared to assess the predictive value of each model. RESULTS: In the multivariate analysis, both the SBP (P = 0.005) and the pulse pressure (P < 0.001) were predictive of carotid stenosis, but the DBP and MAP were not. However, when either the SBP or the pulse pressure was included in the model, the DBP was associated negatively with carotid stenosis (P < 0.001 and P = 0.023, respectively). An increased pulse pressure and a decreased DBP were independent risk markers for carotid stenosis. Comparison of receiver operating characteristic curves indicated that the pulse pressure had superior predictive value to the SBP (P = 0.034). CONCLUSIONS: The pulse pressure is the single best predictor of carotid stenosis. There is a negative correlation between the DBP and carotid stenosis for subjects with isolated systolic hypertension, but this can be demonstrated only after one has stratified for the SBP or for the pulse pressure. Thus, the pulsatile components of the blood pressure, increased pulse pressure and decreased DBP, are the most sensitive risk markers for the diagnoses of carotid stenosis.

Early allograft dysfunction after liver transplantation: a definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.

BACKGROUND: Poor graft function early after liver transplantation is an important cause of morbidity and mortality. We defined early allograft dysfunction (EAD) using readily available indices of function and identified donor, graft, and pretransplant recipient factors associated with this outcome. METHODS: This study examined 710 adult recipients of a first, single-organ liver transplantation for non-fulminant liver disease at three United States centers. EAD was defined by the presence of at least one of the following between 2 and 7 days after liver transplantation: serum bilirubin >10 mg/dl, prothrombin time (PT) > or =17 sec, and hepatic encephalopathy. RESULTS: EAD incidence was 23%. Median intensive care unit (ICU) and hospital stays were longer for recipients with EAD than those without (4 days vs. 3 days, P = 0.0001; 24 vs. 15 days, P = 0.0001, respectively). Three-year recipient and graft survival were worse in those with EAD than in those without (68% vs. 83%, P = .0001; 61% vs. 79%, P = 0.0001). A logistic regression model combining donor, graft, and recipient factors predicted EAD better than models examining these factors in isolation. Pretransplant recipient elevations in PT and bilirubin, awaiting a graft in hospital or ICU, donor age > or =50 years, donor hospital stay >3 days, preprocurement acidosis, and cold ischemia time > or =15 hr were independently associated with EAD. CONCLUSION: Recipients who develop EAD have longer ICU and hospital stays and greater mortality than those without. Donor, graft, and recipient risk factors all contribute to the development of EAD. Results of these analyses identify factors that, if modified, may alter the risk of EAD.

Age and liver transplantation: a report of the Liver Transplantation Database.

BACKGROUND: The average age of liver transplant recipients has increased steadily during the last decade. The effects of recipient age on outcome of liver transplantation were evaluated in a large prospective database. METHODS: A total of 735 adult recipients of single-organ liver transplants for nonfulminant liver disease enrolled in a large prospective database between 1990 and 1994 were analyzed for associations of patient age with outcomes. Patients were categorized into two groups: younger being <60 and older being > or = 60 years of age. RESULTS: Older liver transplant recipients were more likely to be female, white, and have the diagnoses of primary biliary cirrhosis or cryptogenic cirrhosis than younger recipients, who were more likely to have the diagnosis of alcoholic liver disease. Disease severity was similar between the two groups. After transplantation, the durations of stay in the intensive care unit and hospital were longer for older than for younger transplant recipients, but episodes of acute rejection were less frequent. The quality of life at 1 year was similar among older and younger recipients. Patient survival was lower for older than for younger recipients (81% vs. 90% at 1 year; P=0.004), whereas graft survival was not different (80% vs. 85% at 1 year; P=0.163). The excess mortality among older recipients was largely due to nonhepatic causes, including infectious, cardiac, and neurological diseases occurring within 6 months after transplantation. CONCLUSIONS: Although patient survival was significantly lower among liver transplant recipients above the age of 60 years, the excess mortality was due to nonhepatic, largely age-related problems. The overall success of liver transplantation and improvement in quality of life for older recipients is excellent.

Changes in life-style after liver transplantation.

Sixty-five pediatric patients who received liver transplants between May 1981 and May 1984 were observed for as many as 5 years and examined for changes in life-style. Children were less frequently hospitalized, spent less time hospitalized, required fewer medications, and generally had excellent liver and renal function after hepatic transplantation as compared with their pretransplantation status. Most children were in age-appropriate and standard school classes or were only 1 year behind. Cognitive abilities remained unchanged. Children improved in gross motor function and patients' behavior significantly improved according to parents' perceptions. Enuresis was more prevalent, however, than in the population of children who had not received liver transplants. Parental divorce rates were no greater than those reported for other families with chronically ill children. Overall, objective changes in life-style as well as parents' perceptions of behavior of children appear to be improved after liver transplantation.

Neurologic factors associated with cognitive impairment in a rural elderly population in India: the Indo-US Cross-National Dementia Epidemiology Study.

Few reports exist of cognitive impairment and associated factors in developing countries. An age-stratified random sample of 388 men and women, 55 years and older, was drawn from a community-based population in the rural area of Ballabgarh in northern India. We classified as "cognitively impaired" those subjects who had scores below the 10th percentile of the population on a general mental status test (the Hindi Mental State Exam, HMSE) and, separately, on a memory test (Delayed Recall of a 10-Item Word List, DRWL). Three hundred seventy-six subjects also underwent a standardized neurologic history and examination. Neurologic factors associated with cognitive impairment, after adjusting for age, gender, and literacy, were history of impaired consciousness and findings of gait disturbance, diminished deep tendon reflexes, and the presence of at least one primitive reflex. We speculate that there may be unique risk factors in developing countries such as nutritional deficiencies leading to focal deficits and cognitive impairment.

Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials.

OBJECTIVE: To investigate the association between cholesterol lowering interventions and risk of death from suicide, accident, or trauma (non-illness mortality). DESIGN: Meta-analysis of the non-illness mortality outcomes of large, randomised clinical trials of cholesterol lowering treatments. STUDIES REVIEWED: 19 out of 21 eligible trials that had data available on non-illness mortality. INTERVENTIONS REVIEWED: Dietary modification, drug treatment, or partial ileal bypass surgery for 1-10 years. MAIN OUTCOME MEASURE: Deaths from suicides, accidents, and violence in treatment groups compared with control groups. RESULTS: Across all trials, the odds ratio of non-illness mortality in the treated groups, relative to control groups, was 1.18 (95% confidence interval 0.91 to 1.52; P=0.20). The odds ratios were 1.28 (0.94 to 1.74; P=0.12) for primary prevention trials and 1.00 (0.65 to 1.55; P=0.98) for secondary prevention trials. Randomised clinical trials using statins did not show a treatment related rise in non-illness mortality (0.84, 0.50 to 1.41; P=0.50), whereas a trend toward increased deaths from suicide and violence was observed in trials of dietary interventions and non-statin drugs (1.32, 0.98 to 1.77; P=0.06). No relation was found between the magnitude of cholesterol reduction and non-illness mortality (P=0.23). CONCLUSION: Currently available evidence does not indicate that non-illness mortality is increased significantly by cholesterol lowering treatments. A modest increase may occur with dietary interventions and non-statin drugs.