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PubMed2005

Role of radiography in predicting progression of osteoarthritis of the hip: prospective cohort study.

OBJECTIVES: To investigate which variables identify people at high risk of progression of osteoarthritis of the hip. DESIGN: Population based cohort study. SETTING: Ommoord district in Rotterdam, Netherlands. PARTICIPANTS: 1904 men and women aged 55 years and older from the Rotterdam study were selected on the basis of the presence of osteoarthritic signs on radiography at baseline, as defined by a Kellgren and Lawrence score > or = grade 1. MAIN OUTCOME MEASURES: Radiological progression of osteoarthritis of the hip, defined as a decrease of joint space width (> or = 1.0 mm) at follow-up or the presence of a total hip replacement. METHODS: Potential determinants of progression of hip osteoarthritis were collected at baseline. x Ray films of the hip at baseline and follow-up (mean follow-up time 6.6 years) were evaluated. Multivariate logistic regression models were used to assess the association between potential risk factors and progression of hip osteoarthritis. RESULTS: In 13.1% (1904 subjects) of the study population (mean age 66.2 years), progression of hip osteoarthritis was evident on the radiograph. Starting with a simple model of only directly obtainable variables, the Kellgren and Lawrence score at baseline, when added to the model, was a strong predictor (odds ratio 5.8, 95% confidence interval 4.0 to 8.4), increasing to 24.3 (11.3 to 52.1) in subjects with hip pain at baseline. CONCLUSIONS: The Kellgren and Lawrence score at baseline was by far the strongest predictor for progression of hip osteoarthritis, especially in patients with existing hip pain at baseline. In patients with hip pain, a radiograph has strong additional value in identifying those at high risk of progression of hip osteoarthritis.

Aged↗
PubMed2003

Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients.

OBJECTIVES: To compare the rate of hepatic fibrosis progression in hepatitis C virus (HCV) infected and human immunodeficiency virus (HIV)-HCV coinfected patients, and to identify factors that may influence fibrosis progression. PATIENTS AND METHODS: A total of 153 HCV infected and 55 HCV-HIV coinfected patients were identified from two London hospitals. Eligible patients had known dates of HCV acquisition, were HCV-RNA positive, and had undergone a liver biopsy, which was graded using the Ishak score. Univariate and multivariate logistic regression analyses were used to identify factors associated with fibrosis progression rate and the development of advanced fibrosis (stages 3 and 4). RESULTS: The estimated median fibrosis progression rate was 0.17 units/year (interquartile range (IQR) 0.10-0.25) in HIV-HCV coinfected and 0.13 (IQR 0.07-0.17) in HCV monoinfected patients (p=0.01), equating to an estimated time from HCV infection to cirrhosis of 23 and 32 years, respectively. Older age at infection (p<0.001), HIV positivity (p=0.019), higher alanine aminotransferase (ALT) level (p=0.039), and higher inflammatory activity (p<0.001) on first biopsy were all independently associated with more rapid fibrosis progression. ALT was correlated with histological index (r=0.35, p<0.001). A CD4 cell count < or =250 x 10(6)/l was independently associated with advanced liver fibrosis (odds ratio 5.36 (95% confidence interval 1.26-22.79)) and was also correlated with a higher histological index (r=-0.42, p=0.002). CONCLUSION: HIV infection modifies the natural history of HCV by accelerating the rate of fibrosis progression by 1.4 fold, and the development of advanced fibrosis threefold. A low CD4 cell count was independently associated with advanced disease and correlated with higher histological index, which suggests that early antiretroviral therapy may be of benefit in slowing HCV progression in coinfected patients.

Adult↗
PubMed2005

Cognitive performance after first ever stroke related to progression of vascular brain damage: a 2 year follow up CT scan study.

BACKGROUND: Stroke is one of the most common causes of cognitive impairment in the elderly. Ischaemic brain damage (white matter lesions and silent infarcts) progresses in a substantial number of stroke patients. The aim of this study was to investigate whether the progression of ischaemic brain damage is associated with cognitive functioning after first ever stroke. METHODS: A total of 101 stroke patients were followed up for 2 years. Neuropsychological functioning was assessed at 1, 6, 12, and 24 months after stroke. Computed tomography was performed on all patients at baseline and 2 years after stroke. Progression in white matter lesions and (silent) infarcts was recorded. RESULTS: Patients with progressive vascular brain damage performed worse on cognitive tasks, both 1 and 24 months after stroke, yet change in cognitive functioning was not different from that of patients without progressive vascular damage. During the follow up, improvement was noticed on most cognitive domains. CONCLUSIONS: Although patients with progressive vascular brain damage after a first stroke performed somewhat worse on cognitive tests than those without such damage, both groups showed an improved or stable performance 2 years later. Thus, there is not a simple relation between progression of ischaemic brain damage and decline in cognitive functioning after first ever stroke.

Aged↗
PubMed1997

Cerebrospinal fluid analysis differentiates between relapsing-remitting and secondary progressive multiple sclerosis.

OBJECTIVES: To find whether CSF analysis may differentiate between relapsing-remitting and secondary progressive multiple sclerosis. METHODS: In 17 patients with relapsing-remitting and 16 patients with secondary progressive multiple sclerosis, all without current or recent relapses, albumin CSF: peripheral blood ratio, mononuclear cell number, CD4+, CD8+, and B1+ subsets, CD4+:CD8+ ratio, IgG, IgG index, IgM, IgM index, complement components C3 and C4, and C3 and C4 indices, myelin basic protein, neuron specific enolase, S100, and lactate were determined. For each measure the statistical distance measure D2 was calculated. For computation of a discriminant score variables with a P value< or =0.15 were included (two sided univariate t test). These were albumin CSF: peripheral blood ratio, mononuclear cell number, IgM, IgM index, C3, C4, neuron specific enolase, S100, and lactate. Simultaneous distributions of the variables were compared between both groups (multivariate t test) and a discriminant score was computed (linear discriminant analysis). RESULTS: The discriminant score allocated all 14 relapsing-remitting patients to the relapsing-remitting group (positive score) and 12 of 13 secondary progressive patients to the secondary progressive group (negative score). One secondary progressive patient was allocated to the relapsing-remitting group. CONCLUSIONS: Patients with relapsing-remitting or secondary progressive multiple sclerosis differ in CSF profile and CSF analysis may help to differentiate between relapsing-remitting and secondary progressive multiple sclerosis.

Adult↗
PubMed1998

Truncal muscle tonus in progressive supranuclear palsy.

OBJECTIVE: To elucidate the character and distribution of the abnormal muscle tonus in the body axis in progressive supranuclear palsy. Although neck hypertonus has been well described in progressive supranuclear palsy, little is known about the involvement of the truncal muscles. METHODS: Muscle tonus of the neck and trunk was separately investigated in 13 patients with progressive supranuclear palsy by clinical examination and surface EMG during passive rotation. Muscle hypertonus was graded according to a four point scale, and subjected to statistical analysis. The results were compared with those from 13 age matched patients with Parkinson's disease and six healthy volunteers. RESULTS: In all but one patient with progressive supranuclear palsy, there was a distinct difference in muscle tonus between the neck and trunk. A tonic shortening reaction characteristic of dystonia and an increased tonic stretch reflex (rigidity) were present in the neck muscles of patients with progressive supranuclear palsy, whereas only normal to moderately increased tonus was noted in the truncal muscles (neck v trunk, shortening reaction p=0.0001; stretch reflex p=0.0241). Follow up studies disclosed an increase in axial muscle tonus with predilection for the neck in three of four patients. In the 13 patients with Parkinson's disease, however, no significant difference was found in muscle rigidity between the neck and trunk. CONCLUSION: Mild changes in truncal muscle tonus with prominent neck dystonia and rigidity are characteristic of progressive supranuclear palsy. It is suggested that separate clinical evaluation of muscle tonus in the neck and trunk may be helpful for distinguishing progressive supranuclear palsy from Parkinson's disease.

Aged↗
PubMed1998

Brain muscarinic receptors in progressive supranuclear palsy and Parkinson's disease: a positron emission tomographic study.

OBJECTIVES: To assess muscarinic acetylcholine receptors (mAChRs) in the brains of patients with progressive supranuclear palsy and Parkinson's disease, and to correlate the cholinergic system with cognitive function in progressive supranuclear palsy and Parkinson's disease. METHODS: Positron emission tomography (PET) and [11C]N-methyl-4-piperidyl benzilate ([11C]NMPB) was used to measure mAChRs in the brain of seven patients with progressive supranuclear palsy, 12 patients with Parkinson's disease, and eight healthy controls. All of the patients with progressive supranuclear palsy were demented. The Parkinson's disease group consisted of 11 non-demented patients and one demented patient. The mini mental state examination (MMSE) was used to assess the severity of cognitive dysfunction in all of the subjects. The modified Wisconsin card sorting test (WCST) was used to evaluate frontal cognitive function in the non-demented patients with Parkinson's disease and controls. RESULTS: The mean K3 value, an index of mAChR binding, was significantly higher for the frontal cortex in the patients with Parkinson's disease than in the controls (p<0.01). By contrast, the patients with progressive supranuclear palsy had no significant changes in the K3 values of any cerebral cortical regions. The mean score of the MMSE in the progressive supranuclear palsy group was significantly lower than that in the control group. Although there was no difference between the Parkinson's disease and control groups in the MMSE, the non-demented patients with Parkinson's disease showed significant frontal lobe dysfunction in the WCST. CONCLUSIONS: The increased mAChR binding in the frontal cortex of the patients with Parkinson's disease may reflect denervation hypersensitivity caused by loss of the ascending cholinergic input to that region from the basal forebrain and may be related to frontal lobe dysfunction in Parkinson's disease. The cerebral cortical cholinergic system may not have a major role in cognitive dysfunction in progressive supranuclear palsy.

Aged↗
PubMed2002

Rapidly progressive dementia syndrome associated with a novel four extra repeat mutation in the prion protein gene.

OBJECTIVE: To gain a better understanding of how mutations of the prion protein (PrP) gene are responsible for progressive dementia syndrome and to clarify the correlation between genotype and phenotype, which should help to explain how the prion promotes neurological symptoms. BACKGROUND: Genetic prion diseases are associated with point or insertional mutations in the PrP gene. The insertional mutations described so far consist of one to nine extra octapeptide repeats, except three repeats. Insertions of one to four extra octapeptide repeats cause Creutzfeldt-Jakob disease (CJD) in patients without a family history of neurological disorders. CJD generally presents as progressive dementia. METHODS: Routine clinical assessment and sequence analysis of the PrP gene of DNA from a 56 year old Japanese man with progressive dementia syndrome. RESULTS: Sequence analysis disclosed a novel four octapeptide repeat insertion within the PrP gene. The patient was initially affected by progressive cerebellar and brainstem signs; a few months later myoclonus and rapidly progressive dementia appeared. These symptoms were similar to those of sporadic CJD. CONCLUSION: Taken together with previous investigations of CJD patients with insertional mutations, the current observation strengthens the notion that small octapeptide insertions from one to four extra repeats within the PrP gene cause CJD, which is characterised by late onset after the sixth decade, rapid progression, death within a few months, and lack of a family history of neurological disorders, the latter suggesting incomplete penetrance. Different patients with four extra octapeptide repeats have different patterns of extra insertions, suggesting that progression of the disease depends on the number of extra repeats.

Creutzfeldt-Jakob Syndrome↗
PubMed2006

Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist.

Androgen-dependent human LNCaP 104-S tumor xenografts progressed to androgen-independent relapsed tumors (104-Rrel) in athymic mice after castration. The growth of 104-Rrel tumors was suppressed by testosterone. However, 104-Rrel tumors adapted to androgen and regrew as androgen-stimulated 104-Radp tumors. Androgen receptor expression in tumors and serum prostate-specific antigen increased during progression from 104-S to 104-Rrel but decreased during transition from 104-Rrel to 104-Radp. Expression of genes related to liver X receptor (LXR) signaling changed during progression. LXRalpha, LXRbeta, ATP-binding cassette transporter A1 (ABCA1), and sterol 27-hydroxylase decreased during progression from 104-S to 104-Rrel. These coordinated changes in LXR signaling in mice during progression are consistent with our previous findings that reduction of ABCA1 gene expression stimulates proliferation of LNCaP cells. To test if attenuation of LXR signaling may enhance prostate cancer progression from an androgen-dependent state to an androgen-independent state, castrated mice carrying 104-S tumors were given the synthetic LXR agonist T0901317 by gavage. T0901317 delayed progression from 104-S to 104-Rrel tumors. Based on our in vivo model, androgen is beneficial for the treatment of androgen-independent androgen receptor-rich prostate cancer and modulation of LXR signaling may be a potentially useful therapy for prostate cancer.

Androgens↗
PubMed2004

Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence.

Androgen ablation, the most common therapeutic treatment used for advanced prostate cancer, triggers the apoptotic regression of prostate tumors. However, remissions are temporary because surviving prostate cancer cells adapt to the androgen-deprived environment and form androgen-independent (AI) tumors. We hypothesize that adaptive responses of surviving tumor cells result from dysregulated gene expression of key cell survival pathways. Therefore, we examined temporal alterations to gene expression profiles in prostate cancer during progression to androgen independence at several time points using the LNCaP xenograft tumor model. Two key genes, sterol response element-binding protein (SREBP)-1 and -2 (SREBP-1a,-1c, and -2), were consistently dysregulated. These genes are known to coordinately control the expression of the groups of enzymes responsible for lipid and cholesterol synthesis. Northern blots revealed modest increased expression of SREBP-1a, -1c, and -2 after castration, and at androgen independence (day 21-28), the expression levels of both SREBP-1a and -1c were significantly greater than precastrate levels. Changes in SREBP-1 and -2 protein expression were observed by Western analysis. SREBP-1 68-kDa protein levels were maintained throughout progression, however, SREBP-2 68-kDa protein expression increased after castration and during progression (3-fold). SREBPs are transcriptional regulators of over 20 functionally related enzymes that coordinately control the metabolic pathways of lipogenesis and cholesterol synthesis, some of which were likewise dysregulated during progression to androgen independence. RNA levels of acyl-CoA-binding protein/diazepam-binding inhibitor and fatty acid synthase decreased significantly after castration, and then, during progression, increased to levels greater than or equal to precastrate levels. Expression of farnesyl diphosphate synthase did not decrease after castration but did increase significantly during progression to androgen independence. Levels of SREBP cleavage-activating protein, a regulator of SREBP transcriptional activity, decreased after castration and increased significantly at androgen independence. In clinical prostate cancer specimens from patients with varying grades of disease, the stained tissue sections showed high levels of SREBP-1 protein compared with noncancerous prostate tissue. After hormone withdrawal therapy, tumor levels of SREBP-1 decreased significantly after 6 weeks. AI tumors expressed significantly higher levels of SREBP-1. In summary, the LNCaP xenograft model of human prostate cancer as well as clinical specimens of prostate cancer demonstrated an up-regulation of SREBPs and their downstream effector genes during progression to androgen independence. As the AI phenotype emerges, enzymes critical for lipogenesis and cholesterol synthesis are activated and likely contribute significantly to cell survival of AI prostate cancer.

Androgens↗
PubMed2004

Predictive significance of the alterations of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen expression in the progression of cervical cancer.

PURPOSE: The purpose of this research was to evaluate the clinical significance of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen (PCNA) expression in tumor progression of cervical cancer. DESIGN: Seventeen patients (40 samples) with consecutive cervical lesions from normal squamous epithelium, inflammation of the cervix to cervical intraepithelial neoplasm (CIN) and invasive cervical squamous cell cancer (SCC), or from CIN to SCC were collected for this study. Expression of p16INK4A, p14ARF, p53, and PCNA were detected by immunohistochemistry on paraffin-embedded sections. Human papillomavirus DNA was detected simultaneously with PCR and typed according to its DNA sequence. RESULTS: p16INK4A overexpression was significantly higher in CIN (75%) and in SCC (75%) than in normal or inflammation of the cervix (12.5%; P < 0.01, P < 0.05, respectively). The positive rate of p14ARF expression was higher in SCC (83%) than in normal/inflammation of the cervix (25%; P < 0.05). PCNA expression was negative in normal or inflammation of the cervix, but an increased in expression was seen in 63.2% in CIN and 100% in SCC (P < 0.01, P < 0.05). When the time interval for disease progression from initial biopsy to CIN 3 or invasive cancer was compared with states of p16INK4A expression, cases stained positive for p16INK4A progressed within 64.2 months as compared with 122.3 months among those stained negatively (P < 0.01). Cases with increased p14ARF expression also had a short time interval for disease progression of 78.8 months as compared with 108.3 months in cases that were p14ARF negative. Cases with stable or decreased p53 expression had the shortest time interval for progression of 32.3 months in contrast to cases with no p53 expression (113.9 months). However, cases with increasing p53 expression progressed within 60.8 months. CONCLUSIONS: Our results suggested that altered states of p16INK4A, p14ARF, p53, and PCNA may be valuable markers to predict the progression of cervical neoplasia.

Adult↗
PubMed2006

The chemokine CCL5 as a potential prognostic factor predicting disease progression in stage II breast cancer patients.

PURPOSE: The aim of this study was to determine the prognostic value of the chemokine CCL5, considered as a promalignancy factor in breast cancer, in predicting breast cancer progression and to evaluate its ability to strengthen the prognostic significance of other biomarkers. EXPERIMENTAL DESIGN: The expression of CCL5, alone and in conjunction with estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), and HER-2/neu (ErbB2), was determined in breast tumor cells by immunohistochemistry. The study included 142 breast cancer patients, including individuals in whom disease has progressed. RESULTS: Using Cox proportional hazard models, univariate analysis suggested that, in stage I breast cancer patients, CCL5 was not a significant predictor of disease progression. In contrast, in stage II patients, the expression of CCL5 (CCL5(+)), the absence of ER-alpha (ER-alpha(-)), and the lack of PR expression (PR(-)) increased significantly the risk for disease progression (P = 0.0045, 0.0041, and 0.0107, respectively). The prognostic strength of CCL5, as well as of ER-alpha(-), improved by combining them together (CCL5(+)/ER-alpha(-): P = 0.0001), being highly evident in the stage IIA subgroup [CCL5(+)/ER-alpha(-) (P = 0.0003); ER-alpha(-) (P = 0.0315)]. In the stage II group as a whole, the combinations of CCL5(-)/ER-alpha(+) and CCL5(-)/PR(+) were highly correlated with an improved prognosis. Multivariate analysis indicated that, in stage II patients, ER-alpha and CCL5 were independent predictors of disease progression. CONCLUSIONS: CCL5 could be considered as a biomarker for disease progression in stage II breast cancer patients, with the CCL5(+)/ER-alpha(-) combination providing improved prediction of disease progression, primarily in the stage IIA subgroup.

Adult↗
PubMed1998

Significance of bladder neck involvement on progression in superficial bladder cancer.

OBJECTIVES: To determine the significance of bladder neck involvement in predicting disease progression in superficial (stage Ta and T1) transitional cell carcinoma (TCC) of the urinary bladder. PATIENTS AND METHODS: A series of 277 patients with newly diagnosed superficial TCCs of the bladder was reviewed, and disease progression (to T2 or worse) was considered. The significance of several risk factors including bladder neck involvement was assessed in univariate and multivariate analysis. RESULTS: Progression occurred in 28 (10.1%) of 277 patients during a median follow-up period of 7.7 years. Nineteen died of bladder cancer. The following variables were found to be statistically significant at the univariate analysis (p < 0.05): irritative symptoms, urine cytology, tumor stage, involvement of the bladder neck, and tumor grade. Indeed, only involvement of the bladder neck, tumor stage, and grade retained their value as independent factors for progression at multivariate analysis. Patients were divided into three groups according to the number of independent risk factors they had. Groups having none, one, and two or three risk factors included 129, 99, and 49 patients with 5-year progression rates of 0.8, 4.6 and 27.5%, and 15-year rates of 4.0, 20.1 and 42.7%, respectively. CONCLUSION: Involvement of the bladder neck is a significant and independent risk factor for progression of superficial TCCs in addition to the histologic grade and stage. The combination of these three risk factors offers better prediction of progression in an individual patient.

Adolescent↗
PubMedDate not supplied

Approximal caries prevalence in Danish recruits and progression of caries in the late teens: a retrospective radiographic study.

This study aimed to assess radiographically the prevalence and distribution of approximal caries in Danish recruits and to estimate the rate of caries progression during the recruits' late teens. To assess caries progression radiographs taken previously (when leaving the Public Dental Health Care Service, usually at the age of 16-18) were requested. Of 676 recruits previous radiographs (taken 1-7 years earlier) were procured for 640. Approximal surfaces from 7d to 4m in the maxilla and the mandible were assessed for the absence or presence/depth of caries and restorations. Caries progression was expressed by the incidence rate indicating the number of new lesions/number of lesions with progression per 100 years. In the maxilla the average prevalence of enamel and dentine caries was 8.3 and 6.2%, respectively. Overall, 6m had the highest caries experience. In the mandible the average prevalence of enamel and dentine caries was 10.7 and 5.8%, respectively. The highest caries experience was found in 6d. Twenty percent of the recruits had no caries experience in the surfaces under study, 9% had caries experience in 1 surface, 13% in 4-5 surfaces and 25% in more than 10 surfaces. For all surfaces combined, the median incidence rate for the transition from sound to enamel caries was 2.4 surfaces per 100 years, ranging from 0.4 in mandibular 7d to 5.5 in mandibular 6d. The median rate for progression from the enamel to the outer half of the dentine was 9.2 surfaces per 100 years, ranging from 4.4 in mandibular 5m to 18.9 in mandibular 6d. The median incidence rate for progression from the outer to the inner half of the dentine was 2.3 surfaces per 100 years. However, this figure was based on a small number of events and should therefore be interpreted with caution. In conclusion, enamel and dentine caries was found in 9 and 6% of the approximal surfaces in newly called up recruits, and one quarter of the recruits had caries experience in more than 10 approximal surfaces. Generally, the development of new approximal lesions and the progression of enamel caries was a slow process during the late teens.

Adolescent↗
PubMed2005

Influence of apolipoprotein E genotype on progression of diabetic nephropathy.

AIMS: Diabetic nephropathy progresses at a variable rate part of which may be explained by genetic polymorphisms. ApoE polymorphisms are associated with progression of atherosclerosis and because of the similarities between atherosclerosis and glomerulosclerosis, we chose to examine apoE and its role in progression of diabetic nephropathy. METHODS: The apoE genotypes of 90 patients with type 2 diabetes and nephropathy who were recruited into a 2-year prospective randomised controlled study comparing intensive medical management with routine clinical care were analysed. The primary endpoint was the rate of progression of renal disease in the second year. RESULTS: The apoE genotype frequencies were 49 with E3/3, 20 with E2/3, 17 with E3/4 and 4 with of E2/4. There were no significant differences in age, degree of renal failure, BP, albuminuria or glycaemic control between any genotype. The rate of progression of renal failure of patients with the E3/4 genotype was 0.80 ml/min/month compared to 0.30 ml/min/month for E2/3 and 0.18 ml/min/month for those with E3/3. Patients with E3/4 genotype had significantly faster rates of progression in the second year when compared with the other 3 genotypes (0.80 vs. 0.25 ml/min/month, p = 0.012). There was no difference in mortality according to apoE genotype. CONCLUSION: Patients who possess the apoE3/4 genotype had significantly faster rates of progression of renal failure.

Aged↗
PubMed2006

Subtype of mild cognitive impairment and progression to dementia and death.

BACKGROUND: Mild cognitive impairment (MCI) represents a common cognitive state between normal cognitive aging and dementia. There is limited information about the heterogeneity of MCI and how this heterogeneity may influence the clinical course of MCI. We determined the longitudinal course of subtypes of MCI and assessed the rate of progression to dementia and to death. METHODS: As part of the Alzheimer's Disease Research Centers of California, we studied 327 patients with MCI (250 with amnestic MCI, 34 with single nonmemory MCI, and 43 with multiple domain MCI) who were followed longitudinally. We determined if subtype of MCI was independently associated with time to dementia diagnosis and time to death using Cox proportional hazard models, and type of dementia using Fisher's exact test. RESULTS: Mean age of the patients with MCI was 72.9 +/- 9.3 years and mean Mini-Mental State Examination score was 25.7 +/- 4.3. After a mean follow-up of 3.1 years, 199 (65%) progressed to dementia and 80 (24%) died. After multivariate adjustment, compared to those with amnestic MCI, patients with single nonmemory or multiple subtype MCI were less likely to receive a diagnosis of dementia (HR = 0.60; 95% CI 0.35-1.05 and HR = 0.71; 95% CI 0.44-1.14) but more likely to die (HR = 2.57; 95% CI 1.13-5.84 and HR = 1.73; 95% CI 0.72-4.18), but these results were of borderline statistical significance. There were significant differences in the type of dementia diagnosed across MCI subtypes (p = 0.006). Among the patients who progressed to Alzheimer's disease, 76% had prior amnestic MCI; of the patients who progressed to vascular dementia, 50% had prior amnestic MCI; all patients who progressed to a frontal dementia syndrome had single nonmemory MCI previously. CONCLUSIONS: The majority of patients with MCI progressed to dementia and a significant proportion died. Subtype of MCI may influence rates of progression to death and to dementia and has a major influence on subsequent type of dementia diagnosis.

Aged↗
PubMed1995

Progression of HIV infection is associated with HLA-DQ antigens in Caucasians and African Americans.

In our previous work with human leukocyte antigen (HLA) association in human immunodeficiency virus (HIV) infection, African Americans (Afr Ams) and Caucasians (Caucs) exhibited HLA markers that were associated with protection or disease. The present study was designed to establish if HLAs were associated with the severity of HIV infection and progression to AIDS in Afr Am and Cauc adults. The frequency of serologically determined antigens (Ags) in the regional control population was compared to the HIV-infected population and the HIV-infected slow progressors were compared to rapid progressors by race. chi 2 analysis with Bonferroni adjustment, Kaplan-Meier survival analysis, linear logistic regression, Cox model of proportional hazards and standardized deltas were applied as applicable. Immune parameters were monitored over a mean follow-up period of 23 +/- 2 months for Afr Ams (n = 35) and 25 +/- 5 months for Caucs (n = 24). A better prognosis in the HIV+Afr Am group was associated with HLA-DQ1 with a risk ratio of 0.295. In the HIV+Cauc group, a preferable prognosis was associated with HLA-DQ3 with a risk ratio of 0.11, and a poor prognosis was associated with HLA-DQ2 with a risk ratio of 7. Afr Am haplotypes that appeared to have the greatest association with rapid progression of HIV infection were A69(28)-B40 and related haplotypes as well as B12-DR14(6). Cauc haplotypes with the strongest association with rapid and slow progression of HIV infection were A28-B17-DR9 and A30(19)-B67, respectively. The DR Ags of at least one haplotype that led to rapid progression in both races were associated with DQ9(3). An 'immune response' gene (DQ region) may control the progression of HIV infection in adults. The rapidly progressive DQ-associated peptide might block the progression of HIV if given as a novel vaccine.

Adolescent↗
PubMed2003

Progression of atherosclerosis is associated with variation in the alpha1-antitrypsin gene.

OBJECTIVE: Alpha1-Antitrypsin (AAT) protects elastic tissue and may play a role in atherogenesis. The association of atherosclerosis progression with common AAT variants was considered in 2 clinical trials. METHODS AND RESULTS: We examined the association of AAT V213A, S and Z deficiency alleles, and the functional 3' UTR 11478G>A with change in minimal luminal diameter, a measure of focal disease, in the Lopid Coronary Angiography Trial gemfibrozil study of post-bypass men. S or Z carriers (n=14) showed strong progression of disease on placebo (11.5%) but responded well to treatment (3% regression). 11478A carriers treated with placebo or gemfibrozil showed significantly more disease progression (n=8, -14.5% and n=16, -4.0%, respectively) than 11478GG men (n=107, -7.0% and n=108, -1.4%, respectively; overall, P=0.003). VV213 men treated with gemfibrozil (n=68) showed -4.8% progression, whereas A213 carriers (n=55) showed +1.4% regression of disease (P=0.001). No V213A effect was seen on placebo (P=0.11). In the Diabetes Atherosclerosis Intervention Study fenofibrate trial of angiographic progression in type 2 diabetes, the association of 11478A with increased disease progression was confirmed in the treatment group, but not the gemfibrozil-treated A213 association with regression, suggesting a pharmacogenetic difference. CONCLUSIONS: Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis.

3' Untranslated Regions↗
PubMed2002

Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease.

BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of genes involved in lipid metabolism and inflammation, making it a candidate gene for atherosclerosis and ischemic heart disease (IHD). METHODS AND RESULTS: We investigated the association between the leucine 162 to valine (L162V) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the Lopid Coronary Angiography Trial (LOCAT), a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study (NPHS2), a prospective study of healthy middle-aged men in the United Kingdom. There was no association with plasma lipid concentrations in either study. Both polymorphisms influenced progression of atherosclerosis and risk of IHD. V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis. Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes. The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele. Homozygotes for the intron 7 C allele had increased risk of IHD, an effect modulated by the L162V polymorphism CONCLUSIONS: The PPARalpha gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall.

Aged↗