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Richard J Kryscio

Publications and source records attributed to Richard J Kryscio.

At least 19 recordsLinked to original sources

Shared random effects analysis of multi-state Markov models: application to a longitudinal study of transitions to dementia.

Multi-state models are appealing tools for analysing data about the progression of a disease over time. In this paper, we consider a multi-state Markov chain with two competing absorbing states: dementia and death and three transient non-demented states: cognitively normal, amnestic mild cognitive impairment (amnestic MCI), and non-amnestic mild cognitive impairment (non-amnestic MCI). The likelihood function for the data is derived and estimates for the effects of the covariates on transitions are determined when the process can be viewed as a polytomous logistic regression model with shared random effects. The presence of a shared random effect not only complicates the formulation of the likelihood but also its evaluation and maximization. Three approaches for maximizing the likelihood are compared using a simulation study; the first method is based on the Gauss-quadrature technique, the second method is based on importance sampling ideas, and the third method is based on an expansion by Taylor series. The best approach is illustrated using a longitudinal study on a cohort of cognitively normal subjects, followed annually for conversion to mild cognitive impairment (MCI) and/or dementia, conducted at the Sanders Brown Center on Aging at the University of Kentucky.

Aged↗

Factors associated with return for routine annual screening in an ovarian cancer screening program.

OBJECTIVE: To identify clinical, demographic, dispositional, and attitudinal variables associated with return for routine, annual transvaginal sonography (TVS) screening for ovarian cancer. METHODS: Asymptomatic, average to high risk, women (n=585) participating in a free university-based ovarian cancer screening program completed a baseline interview prior to undergoing an initial TVS screening test. During the baseline interview, demographic (age, education, partner status, race), clinical (family history of ovarian cancer), dispositional (optimism, health values), and attitudinal (perceptions of personal risk for ovarian cancer and effectiveness of screening, intentions to return for repeat routine screening, discomfort during screening, satisfaction with the screening process, ovarian cancer-specific distress) information was obtained. Return for repeat screening was documented from screening program records. RESULTS: Results from both multivariate proportional hazards and logistic regression analyses indicated that stated intentions to return for a repeat screening test within the next year was the strongest predictor of return for repeat screening. Possessing > or =12 years of education was also associated with a greater likelihood of repeat screening in both the proportional hazards and logistic regression analyses. CONCLUSIONS: Results provide further support for low education as a risk factor for suboptimal participation in cancer screening. Results also highlight the critical link between intentions to perform a health-protective behavior and subsequent performance of that behavior and suggest that repeat screening could be enhanced by eliciting both an intention to return for annual ovarian cancer screening as well as a specific plan for implementing this intention.

Adult↗

The treatment of lateral T1 and T2 squamous cell carcinomas of the vulva confined to the labium majus or minus.

OBJECTIVE: To determine the pattern of lymph node metastases, recurrence rate, and survival of patients with lateral T1 and T2 squamous cell cancer (SCC) of the vulva treated by radical vulvectomy or hemivulvectomy and inguinal lymphadenectomy. METHODS: An institutional review was performed to identify lateral T1 and T2 SCC of the vulva confined to the labium majus and minus. RESULTS: Sixty-one patients with lateral T1 and 61 patients with lateral T2 SCC of the vulva were treated from 1963 to 2003. Radical vulvectomy (RV) was performed in 60 patients, and radical hemivulvectomy (RHV) in 62 patients. Seven of 61 patients (11%) with T1 lesions had ipsilateral superficial inguinal lymph node (SIL) metastases, but none had deep inguinal lymph (DIL) node metastases. Nineteen of 61 patients (31%) with T2 lesions had ipsilateral SIL metastases, and 8 had ipsilateral DIL metastases. No patient had contralateral SIL or DIL metastases. Six patients (10%) with T1 lesions and seven patients (11%) with T2 lesions developed recurrence to the ipsilateral vulva and were treated by re-excision. All patients are alive with no evidence of disease 10-195 months after treatment. One patient with T1 and three patients with T2 SCC developed distant recurrence and died of disease (DOD) 10-15 months after surgery. Disease-free survival of patients with T1 lesions was 98% at 2 years and 98% at 5 years, and with T2 lesions was 95% at 2 years and 93% at 5 years. Local or distant recurrence was not more common in patients treated by RHV than in those treated by RV. CONCLUSION: Lateral T1 and T2 squamous cell cancers of the vulva spread to the ipsilateral inguinal lymph nodes and can be treated effectively with RHV and ipsilateral SIL dissection. Deep inguinal lymphadenectomy is indicated only when the SIL are positive.

Adult↗

JC virus detection in bodily fluids: clues to transmission.

JC virus in saliva, oropharyngeal fluid, blood, and urine samples obtained from 58 human immunodeficiency virus-infected persons and 58 matched controls was investigated by performing quantitative polymerase chain reaction. JC virus was rarely present in oropharyngeal fluid and blood samples, even in those obtained from immunosuppressed individuals, but it was commonly detected in urine samples from both groups, suggesting that urine contributes to transmission.

Adult↗

Neuropathologic substrate of mild cognitive impairment.

OBJECTIVE: To define the neuropathologic findings in amnestic mild cognitive impairment (MCI) and early Alzheimer disease (EAD). METHODS: The mean numbers of diffuse plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs) in 4 neocortical regions and 4 ventromedial temporal lobe regions were counted in 10 patients with amnestic MCI and compared with the mean numbers in 23 normal control subjects and 10 patients with EAD, and then were compared with memory performance. All of the controls and patients were followed longitudinally. RESULTS: Patients with MCI showed no significant difference (P>.05) in the number of diffuse plaques from that in normal controls or patients with EAD. In patients with MCI, the number of NPs was significantly elevated in all 4 neocortical regions and amygdala compared with controls (P<.01 to <.001). There were no significant differences (P>.05) in the number of NPs between MCI and EAD cerebral cortex, but significant increases were present for NPs in EAD amygdala and subiculum compared with MCI (P<.01). In patients with MCI compared with controls, the only significant increase in NFTs in the neocortex was in the parietal lobe. However, the number of NFTs was significantly elevated in MCI in all 4 ventromedial temporal lobe structures compared with controls (P<.01 to <.001). In comparing MCI with EAD, there were significant increases in NFTs in EAD in frontal and temporal lobes, amygdala, and subiculum (P<.01). The numbers of NPs and NFTs were significantly elevated in all of the neocortical regions and ventromedial temporal lobe regions in patients with EAD compared with controls (P<.001). Memory function was significantly correlated with NFTs in CA1 of the hippocampus (P<.01) and the entorhinal cortex (P<.05). CONCLUSIONS: In patients with amnestic MCI who were followed longitudinally, the early changes of Alzheimer disease were present. The NFTs were slightly more prominent than beta-amyloid peptide deposition in the progression from normal to MCI to EAD. Ventromedial temporal lobe NFTs probably represent the substrate for memory decline in MCI. From a neuropathologic perspective, it appears that amnestic MCI is, in reality, EAD.

Aged↗

High prevalence of multiple human herpesviruses in saliva from human immunodeficiency virus-infected persons in the era of highly active antiretroviral therapy.

Human immunodeficiency virus (HIV) infection is associated with an increased risk for human herpesviruses (HHVs) and their related diseases. Methods for limiting the transmission of HHVs require a better understanding of the prevalence and infectiousness of oral HHVs in HIV-infected patients. We performed quantitative PCR to investigate the prevalence, quantity, risk, and correlates of salivary HHVs from 58 HIV-seropositive individuals in a case control study. HHVs were significantly more prevalent in the salivas of HIV-seropositive persons than in those of the controls (odds ratios [ORs], 4.2 to 26.2; P<or=0.008). In HIV-infected patients, Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), cytomegalovirus (CMV), and herpes simplex virus type 1 (HSV-1) were detected in 90%, 57%, 31% and 16% of samples, respectively, compared with 48%, 24%, 2%, and 2%, respectively, of samples from controls. Multiple HHVs were observed in 71% of HIV-seropositive persons and only 16% of controls (OR, 13.0; 95% confidence interval, 5.29 to 32.56). HIV-positive patients had significantly higher EBV loads than HIV-negative persons (P<0.0001). HIV-infected patients with CD4 counts above 200 cells/microl had increased probability for having HHV-8 in saliva (P=0.009) compared with patients whose counts were less than 200. In contrast, HSV-1, EBV, and CMV were detected more often when CD4 counts were low. High salivary HHV loads were detected for those (n=7) with oral lesions. These findings suggest that saliva is a potential risk factor for the acquisition of multiple HHVs, and several host factors may function to accelerate HHV reactivation or replication in patients with HIV infection.

Adult↗

Salivary biomarkers of existing periodontal disease: a cross-sectional study.

BACKGROUND: The authors conducted a study to determine if salivary biomarkers specific for three aspects of periodontitis--inflammation, collagen degradation and bone turnover--correlate with clinica features of periodontal disease. METHODS: The relationship between periodontal disease and the levels of interleukin-1 beta (IL-1beta), matrix metalloproteinase (MMP)-8, and osteoprotegerin (OPG) in whole saliva of 57 adults (28 "case" subjects with moderate-to-severe periodontal disease and 29 healthy control subjects) was examined in a case-control trial. RESULTS: Mean levels of IL-1beta and MMP-8 in saliva were significantly higher in case subjects than in controls. Both analytes correlated with periodontal indexes, whereas, after adjustment for confounders, OPG did not. Elevated salivary levels of MMP-8 or IL-1beta (more than two standard deviations above the mean of the controls) significantly increased the risk of periodontal disease (odds ratios in the 11.3-15.4 range). Combined elevated salivary levels of MMP-8 and IL-1beta increased the risk of experiencing periodontal disease 45-fold, and elevations in all three biomarkers correlated with individual clinical parameters indicative of periodontal disease. CONCLUSION: Salivary levels of MMP-8 and IL-1beta appear to serve as biomarkers of periodontitis. CLINICAL IMPLICATIONS: Qualitative changes in the composition of salivary biomarkers could have significance in the diagnosis and treatment of periodontal disease.

Adult↗

Alzheimer's disease and head circumference.

OBJECTIVE: Larger brains may contain more neurons and synaptic connections, providing a greater reserve against cognitive decline in Alzheimer's disease (AD). Larger head circumference (HC) may therefore be associated with later detection and diagnosis of AD. We investigated HC in nondemented individuals and AD patients using cross-sectional and prospective analyses. METHODS: The cross sectional analysis compared mean HC between 592 AD patients and 459 nondemented controls. Prospective analysis was based on the same initially normal controls who were followed longitudinally for conversion to dementia. Diagnosis of AD was made by neurologists using NINDS-ADRDA criteria. RESULTS: When compared to AD patients, controls had a significantly larger mean HC by 0.58 cm in men and by 0.31 cm in women, but these differences were no longer significant after adjustment for age and years of education. HC varied inversely with age and directly with years of education but did not vary with presence/absence of dementia in first-degree relatives or with apolipoprotein-E (ApoE) genotype. In the prospective analysis, the hazard ratio for time to conversion to AD was not significant for HC when adjusted for age at entry, ApoE allele status, family history of dementia, gender, and years of education. ApoE allele status, first degree relative with dementia, and baseline age conferred an increased risk for conversion to AD, consistent with other studies. CONCLUSIONS: We observed a smaller HC in AD patients compared to nondemented individuals, but AD per se accounted for little of this difference. HC was not a statistically significant predictor for conversion to AD in our longitudinal group.

Aged↗

The accuracy of examination under anesthesia and transvaginal sonography in evaluating ovarian size.

OBJECTIVE: To compare pelvic examination under anesthesia to transvaginal sonography (TVS) as a method for ovarian detection and measurement. METHODS: Two hundred and eighty-nine ovaries from 151 women were evaluated. After induction of anesthesia, a complete pelvic examination and TVS were performed, and the ovaries were removed surgically. Ovarian dimensions generated sonographically and estimated on clinical examination were compared to those obtained from the measured surgical specimen. RESULTS: Forty-four percent of ovaries were palpable clinically whereas 85% were visualized sonographically (P < 0.001). Right ovaries were palpable more frequently than left ovaries (P < 0.01). Ovaries were detected clinically in 30% of women > or = 55 years of age versus 51% of women <55 years of age (P < 0.05), in 9% of women weighing > or = 200 lb versus 55% of women weighing <200 lb (P < 0.001), and in 12% of women with a uterine weight > or = 200 g versus 51% of women with a uterine weight <200 g (P < 0.001). TVS was significantly more accurate than clinical examination in detecting ovaries in women with these high risk characteristics. CONCLUSIONS: TVS is significantly more accurate than clinical examination in detecting ovaries and in defining their dimensions. Ovaries frequently are not palpable in women > or = 55 years of age, women who weigh > or = 200 lb, or women with an enlarged uterus (> 200 g). The addition of TVS to annual pelvic examination may be beneficial in women > or = 55 years of age who are overweight and therefore at high risk to develop ovarian cancer.

Adult↗

Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment.

Multiple studies demonstrate that the brain in Alzheimer's disease (AD) contains extensive oxidative damage. Most of these studies used advanced-stage AD patients raising the question of whether oxidative damage is a late effect of neurodegeneration or precedes and contributes to the pathogenesis of AD. Here we describe F(2)-isoprostane (F(2)-IsoP) and F(4)-neuroprostane (F(4)-NP) levels in longitudinally followed, well documented autopsied normal control subjects and patients with amnestic mild cognitive impairment (MCI), and late-stage AD. Gas chromatography/negative ion chemical ionization/mass spectrometry was used to determine F(2)-IsoP and F(4)-NP levels. Significant increases in F(2)-IsoP levels were found in frontal, parietal and occipital lobes in MCI and late AD compared to controls but no significant differences were present between MCI and late AD. A significant increase in F(4)-NPs was present in parietal and occipital lobes in MCI compared to controls and a significant increase was present in these regions and hippocampus in late AD compared to controls. The only difference between MCI and late AD was significantly increased F(4)-NP in hippocampus in late AD. Our data indicate that lipid peroxidation is present in the brain of MCI patients and suggest that oxidative damage may play a role in the pathogenesis of AD.

Aged↗

Effect of prophylactic valacyclovir on the presence of human herpesvirus DNA in saliva of healthy individuals after dental treatment.

Human herpesviruses (HHVs) are ubiquitous pathogens that intermittently reactivate from latency. Transmission is believed to be facilitated by their frequent appearance in saliva. This study sought to understand the factors that influence the appearance of these viruses in saliva by examining the prevalence, pattern, and quantity of all eight HHVs in saliva of immunocompetent adults with a history of recurrent oral herpes simplex virus (HSV) infections following dental treatment and antiviral therapy. Valacyclovir or matched placebo was given (2 g twice on the day of treatment and 1 g twice the following day) to 125 patients in a randomized, double-blind controlled trial. Saliva, collected on the day of dental treatment and 3 and 7 days later, was analyzed using real-time quantitative PCR. At all visits, HHVs coinfected saliva. Over the course of the week, the DNAs of HHV-6 and HHV-7 were detected significantly more often (97% to 99% of patients) than Epstein-Barr virus (EBV; 64.8%), HSV-1 (13.0%), HHV-8 (3.2%), cytomegalovirus (2.4%), HSV-2 (0%), and varicella-zoster virus (0%), irrespective of drug treatment (P < 0.002). Mean genome copy numbers were highest for HSV-1 and HHV-6. Dental treatment did not influence asymptomatic viral shedding patterns. However, valacyclovir treatment resulted in significantly fewer patients shedding EBV at both postoperative visits compared with placebo (P < 0.008). These results suggest that HHVs are simultaneously present in the saliva of healthy adults at levels that could facilitate transmission, and valacyclovir therapy decreases the prevalence of EBV in saliva but has little effect on HHV-6 and HHV-7.

Acyclovir↗

Designing a large prevention trial: statistical issues.

Recent research in Alzheimer's disease (AD) is centred about the early detection and prevention of this disease. Several recent moderate size clinical trials targeted at high risk cohorts have been designed along this theme. There have been few attempts to design a large trial to prevent this disease in elderly individuals at low risk for the disease. The purpose of this paper is to suggest a framework for designing a simple, large AD prevention trial. This framework uses a discrete time hazard model for decreasing the incidence of AD when participants are randomly assigned to one or more active prevention agents or placebo. This design allows for differential incidence among participants due to age, family history, genetic disposition, and ethnicity. It takes into account the length of the follow-up period, participant mortality, drop-outs, drop-ins, and loss to follow-up. This framework is illustrated by PREADVISE, a recently initiated large add-on prevention trial investigating the use of anti-oxidants for preventing AD among men enrolled in a even larger prostate cancer prevention study, SELECT.

Aged↗

Use of a T cell-specific monoclonal antibody, T10B9, in a novel allogeneic stem cell transplantation protocol for hematologic malignancy high-risk patients.

To reduce the toxicity of traditional conditioning regimens for allogeneic stem cell transplantation (allo-SCT), we used single-agent chemotherapy conditioning with either busulfan (total cumulative dose, 16 mg/kg) or melphalan (200 to 240 mg/m 2 ), followed by the anti-T cell-specific monoclonal antibody T10B9 (MEDI-500) daily for 3 days. T cell-replete SCT was performed from HLA-identical sibling donors. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of 7 additional days of T10B9 and delayed onset of cyclosporine (ie, on day +4 or +5). Twenty-six high-risk hematologic malignancy patients were entered onto this study. All 24 patients who survived longer than 8 days engrafted, although 1 patient experienced late graft failure. Deaths occurred in 21 of 26 patients because of infection (n = 7), progression/recurrence of primary disease (n = 6), aGVHD (n = 4), regimen-related toxicity (n = 1), and other causes (n = 3). Five of these patients are enjoying disease-free survival with a median survival of 1193 days after allo-SCT. The conditioning regimen induced modulation of surface expression of CD3 (but not CD4 or CD8) and was associated with decreasing tumor necrosis factor-alpha (but not interleukin-6) serum levels. In conclusion, single-agent chemotherapy conditioning with T10B9 produced durable engraftment and long-term survival in some patients who would not have qualified for a traditional allo-SCT.

Adult↗

Tamoxifen-associated malignant endometrial tumors: pathologic features and expression of hormone receptors estrogen-alpha, estrogen-beta and progesterone; a case controlled study.

OBJECTIVE: Expression analysis of estrogen receptor-beta (ER-beta) and estrogen receptor-alpha (ER-alpha) in tamoxifen-associated malignant endometrial tumors (TAMET) has not previously been published. Antiestrogens complexed with ER-beta have been reported to result in activation of the activator protein-1 (AP-1) pathway that may result in cell proliferation and tumor growth. In this study, the pathologic features and expression of ER-alpha, ER-beta and progesterone receptor (PR) in TAMET were determined and compared to matched cases of non-tamoxifen-associated endometrial cancers. METHODS: TAMET (n = 33) were evaluated for pathologic features (tumor type, grade, depth of myometrial invasion, lymphvascular space invasion and lymph node status), expression of ER-alpha, ER-beta and PR, and survival data (mean follow-up: 28.7 months). Each case was matched to two control patients with spontaneous endometrial cancers according to tumor type, grade and stage as well as patient age and weight (mean follow-up: 51.5 months). Formalin-fixed paraffin-embedded tissue sections were immunostained with anti-ER-alpha (1D5, Dako, Carpinteria, CA) and anti-PR (PgR636, Dako). Expression scores were determined as a sum of the product of staining intensity and proportion of cells staining (H-score). Deparaffinized sections of tumor were microdissected followed by RNA isolation. Quantification of ER-beta mRNA was performed by real-time quantitative RT-PCR with results expressed as a percentage of beta-actin mRNA. RESULTS: Of the 33 cases 20 were endometrioid (8 grade 1, 10 grade 2, 2 grade 3), 9 papillary serous and 4 malignant mullerian mixed tumors. Using a multivariate conditional regression model, TAMET had lower ER-alpha expression (P = 0.018), higher PR expression (P = 0.029), and more frequent expression of ER-beta (P = 0.032) as compared to control cases. Cases with TAMET had more deaths from cancer and significantly worse survival from disease than controls (P = 0.01 by a log rank test). CONCLUSION: TAMET are characterized by a lower expression of ER-alpha, higher expression of PR and more frequent expression of ER-beta as compared to spontaneous tumors. Differential expression of ER-alpha and ER-beta may alter the expression of key target genes (such as those induced by AP-1-dependent gene transcription), and contribute to the pathogenesis and clinical behavior of these tumors. Survival from disease was significantly worse for cases with TAMET as compared to controls.

Adult↗

Recursive partitioning analysis classifications I and II: applicability evaluated in a randomized trial for resected single brain metastases.

PURPOSE: Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) prognostic classes I and II for patients with brain metastases is derived from a database made up primarily of patients with unresected and multiple metastases. An analysis of a previously published randomized trial was performed to determine the applicability of these RPA prognostic classes in the setting of resection of single metastases to the brain. PATIENTS AND METHODS: Ninety-five patients with single metastases to the brain that were treated with complete surgical resection entered this study. Patients were randomly assigned to treatment with postoperative whole brain radiotherapy (WBRT) (n = 49 patients) or no further brain treatment (n = 46 patients). All patients entered on this study had a Karnofsky performance status of > or =70. Therefore, although the RTOG RPA has 3 classes, only patients with RPA classes I (n = 26) or II (n = 69) were eligible for this study analysis. RESULTS: For RPA class I, the median survival was 10.9 months versus 9.8 months for class II patients (P = 0.45). Multivariate analysis showed that only postoperative WBRT, independent of RPA class I or II, lessened the risk of brain tumor recurrence (P < 0.0001). CONCLUSION: This analysis of a randomized trial evaluating postoperative WBRT in the treatment of single metastases to the brain showed no difference in survival between RPA class I or II patients. In addition, the use of postoperative WBRT after complete surgical resection of single brain metastases results in substantially better control of disease in the brain independent of RPA classes I or II.

Adult↗

Patterns of colorectal cancer incidence, risk factors, and screening in Kentucky.

BACKGROUND: Colorectal cancer incidence rates are higher in Kentucky than in the United States in general, and there are regional variations within the state. METHODS: This study investigates these variations in relation to lifestyle and health behaviors, combining data from the Kentucky Behavioral Risk Factor Surveillance System (BRFSS), and from the Kentucky Cancer Registry. We used Kentucky's fifteen Area Development Districts (ADDs) as units of analysis across a five-year period from 1993 to 97. RESULTS: Differences were observed across ADDs. ADDs with a higher prevalence of risk factors, with the exception of chronic alcohol drinking, had lower CRC rates. ADDs with a higher proportion of respondents having had recent routine check-ups had higher CRC incidence rates. CONCLUSIONS: In general, healthier lifestyles and positive health-related behaviors were associated with increased colorectal cancer incidence. This may be explained by the tendency for healthier individuals to receive regular check-ups and screening, thus increasing the detection rate of colorectal cancer.

Alcohol Drinking↗

Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with APOE.

Oxidative stress enhanced by transition metals such as iron forms an attractive hypothesis for neurodegeneration in Alzheimer's Disease (AD). Iron is increased in the brain in AD, but whether this is a primary abnormality or the result of secondary accumulation is unclear. Among several genetic loci associated with AD, the locus at chromosome 6p21 contains the hereditary hemochromatosis gene HFE. To determine whether a genetic predisposition to iron accumulation is associated with AD, we evaluated three hemochromatosis-associated HFE mutations and APOE in cognitively and histopathologically evaluated subjects with AD, mild cognitive impairment (MCI), non-demented controls with AD-like pathologic changes defined by Braak stage > or = 3 (high pathology controls (HPC)), and non-demented controls without significant histologic changes (low-pathology controls (LPC)). In a subset, we examined ventricular (CSF) fluid F(2)-isoprostane (F(2)-IsoP) levels, a marker of lipid peroxidation. Seventeen subjects demonstrated homozygous or compound heterozygous HFE mutations, 13 (9.4%) in the AD/MCI group (P = 0.019 vs. LPC) and four (20%) in the HPC group (P = 0.006, P < 0.05 with Bonferroni correction vs. LPC). In contrast, the APOE4 allele frequency was increased only in the AD/MCI patients (P < 10(-3) vs. HPC, P < 10(-6) vs. LPC). F(2)-IsoP levels were increased in AD subjects with any HFE mutation versus wild type HFE (P = 0.027). Although confirmation is required, these findings suggest that HFE mutations are associated with increased oxidative stress and Braak stage, and that HFE and APOE genotypes are different between AD patients, high pathology and low pathology controls.

Alzheimer Disease↗