Comparative Effectiveness of Behavioral Interventions to Prevent or Delay Dementia: One-Year Partner Outcomes.

BACKGROUND/OBJECTIVE: Various behavioral interventions are recommended to combat the distress experienced by caregivers of those with cognitive decline, but their comparative effectiveness is poorly understood. DESIGN/SETTING: Caregivers in a comparative intervention study randomly had 1 of 5 possible interventions suppressed while receiving the other four. Caregivers in a full clinical program received all 5 intervention components. Care partner outcomes in the study group were compared to participants enrolled in a full clinical program. PARTICIPANTS: Two hundred and seventy-two dyads of persons with amnestic mild cognitive impairment (pwMCI) and care partners enrolled in the comparative intervention study. 265 dyads participated in the full clinical program. INTERVENTION: Behavioral intervention components included: memory compensation training, computerized cognitive training, yoga, support group, and wellness education. Each was administered for 10 sessions over 2 weeks. MEASUREMENTS: A longitudinal mixed-effect regression model was used to analyze the effects of the interventions on partner burden, quality of life (QoL), mood, anxiety, and self-efficacy at 12 months follow-up. RESULTS: At 12 months, withholding wellness education or yoga had a significantly negative impact on partner anxiety compared to partners in the clinical program (ES=0.55 and 0.44, respectively). Although not statistically significant, withholding yoga had a negative impact on partner burden and mood compared to partners in the full clinical program (ES=0.32 and 0.36, respectively). CONCLUSION: Our results support the benefits of wellness education and yoga for improving partner's burden, mood, and anxiety at one year. Our findings are the first to provide an exploration of the impact of multicomponent interventions in care partners of pwMCI.

Undetectable sensitive serum thyroglobulin (<0.1 ng/ml) in 163 patients with follicular cell-derived thyroid cancer: results of rhTSH stimulation and neck ultrasonography and long-term biochemical and clinical follow-up.

CONTEXT: Surveillance of patients with differentiated thyroid cancer (DTC) is achieved using serum thyroglobulin (Tg), neck ultrasonography (US), and recombinant human TSH (rhTSH)-stimulated Tg (Tg-stim). OBJECTIVE: Our primary aim was to assess the utility of rhTSH Tg-stim in patients with suppressed Tg (Tg-supp) below 0.1 ng/ml using a sensitive assay. Our secondary aims were to assess the utility of US and to summarize the profile of subsequent Tg-supp measures. DESIGN: This is a retrospective study conducted at two sites of an academic institution. PATIENTS: A total of 163 patients status after thyroidectomy and radioactive iodine treatment who had Tg-supp below 0.1 ng/ml and rhTSH Tg-stim within 60 d of each other were included. RESULTS: After rhTSH stimulation, Tg remained below 0.1 ng/ml in 94 (58%) and increased to 0.1-0.5 in 56 (34%), more than 0.5-2.0 in nine (6%), and above 2.0 ng/ml in four (2%) patients. Serial Tg-supp levels were obtained in 138 patients followed over a median of 3.6 yr. Neck US were performed on 153 patients; suspicious exams had fine-needle aspiration (FNA). All positive FNA were identified around the time of the initial rhTSH test. Six of seven recurrences were detected by US (Tg-stim >2.0 ng/ml in one, 0.8 in one and ≤ 0.5 in four). One stage IV patient had undetectable Tg-stim. CONCLUSION: In patients with DTC whose T(4)-suppressed serum Tg is below 0.1 ng/ml, long-term monitoring with annual Tg-supp and periodic neck US are adequate to detect recurrences. In our experience, rhTSH testing does not change management and is not needed in this group of patients.

A comparison of high definition-image enhanced colonoscopy and standard white-light colonoscopy for colorectal polyp detection.

BACKGROUND AND STUDY AIMS: Colonoscopy is widely used to detect and remove precancerous polyps, but fails to detect some polyps. Recent studies evaluating different image-enhanced methods have revealed conflicting results. The efficacy of colonoscopy imaging with simultaneous use of commercially available improvements, including high definition narrow band imaging (HD-NBI), and monochromatic charge-coupled device (CCD) video, was compared with a widely used standard definition white light (SDWL) colonoscopy system for detecting colorectal polyps. The primary aim was to determine whether the combination of image-enhanced colonoscopy systems resulted in fewer missed polyps compared with conventional colonoscopy. PATIENTS AND METHODS: In a randomized controlled trial (Clinicaltrials.gov. study number NCT00825292) patients having routine screening and surveillance underwent tandem colonoscopies with SDWL and image-enhanced (HD-NBI) colonoscopy. The main outcome measurement was the per-polyp false-negative ("miss") rate. Secondary outcomes were adenoma miss rate, and per-patient polyp and adenoma miss rates. RESULTS: 100 patients were randomized and 96 were included in the analysis. In total, 177 polyps were detected; of these, 72 (41 %) were adenomatous. Polyp and adenoma miss rates for SDWL colonoscopy were 57 % (60/105) and 49 % (19/39); those for image-enhanced colonoscopy were 31 % (22/72) and 27 % (9/33) (P = 0.005 and P = 0.036 for polyps and adenomas, respectively). Image-enhanced and SDWL approaches had similar per-patient miss rates for polyps (6/35 vs. 9/32, P = 0.27) and adenomas (4/22 vs. 8/20, P = 0.11). CONCLUSIONS: Utilization of multiple recent improvements in image-enhanced colonoscopy was associated with a reduced miss rate for all polyps and for adenomatous polyps. It is not known which individual feature or combination of image-enhancement features led to the improvement.

Association of surgeon with surgical site infection after liver transplantation.

Surgical site infection (SSI) after liver transplantation has been associated with increased risk of allograft loss and death. Identification of modifiable risk factors for these infections is imperative. To our knowledge, intraoperative practices associated with transplant surgeons have not been assessed as a risk factor. A retrospective cohort study of risk factors for SSI after 1036 first liver transplantations completed by seven surgeons at a single center between 2003 and 2008 was undertaken. Cox proportional hazards models were used to evaluate the association between surgeons and SSIs. SSIs were identified in 166 of 1036 patients (16%). Single variable analysis showed strong evidence of an association between surgeon and SSI (p = 0.0007); the estimated cumulative incidence of SSI ranged from 7% to 24%. This result was consistent in multivariable analysis adjusting for potentially confounding variables (p = 0.002). The occurrence of organ-space or deep SSI varied significantly among surgeons in both single variable analysis (p = 0.005) and multivariable analysis (p = 0.006). These findings provide evidence that differences in the surgical practices of individual surgeons are associated with risk for SSI after liver transplantation. Identification of specific surgical practices associated with risk of SSI is warranted.

SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study.

BACKGROUND AND PURPOSE: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS: Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS: Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS: In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.

Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease.

BACKGROUND: Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels. METHODS: We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD. Using the genotypes from our LOAD genome-wide association study for the cis-single nucleotide polymorphisms (SNPs) (n = 619) of these 12 LOAD candidate genes, we tested for associations with expression levels as endophenotypes. The strongest expression cis-SNP was tested for AD association in 7 independent case-control series (2,280 AD and 2,396 controls). RESULTS: We identified 3 SNPs that associated significantly with IDE (insulin degrading enzyme) expression levels. A single copy of the minor allele for each significant SNP was associated with approximately twofold higher IDE expression levels. The most significant SNP, rs7910977, is 4.2 kb beyond the 3' end of IDE. The association observed with this SNP was significant even at the genome-wide level (p = 2.7 x 10(-8)). Furthermore, the minor allele of rs7910977 associated significantly (p = 0.0046) with reduced LOAD risk (OR = 0.81 with a 95% CI of 0.70-0.94), as expected biologically from its association with elevated IDE expression. CONCLUSIONS: These results provide strong evidence that IDE is a late-onset Alzheimer disease (LOAD) gene with variants that modify risk of LOAD by influencing IDE expression. They also suggest that the use of expression levels as endophenotypes in genome-wide association studies may provide a powerful approach for the identification of disease susceptibility alleles.

Safety and efficacy of cytology brushings versus standard fine-needle aspiration in evaluating cystic pancreatic lesions: a controlled study.

BACKGROUND AND STUDY AIMS: Cystic pancreatic lesions (CPLs) are increasingly detected by various imaging studies. Mucinous CPLs carry a risk of malignant transformation but this is often difficult to diagnose preoperatively. In a previous report of 10 suspected mucinous CPLs, the cellular yield of endoscopic ultrasonography (EUS)-guided cytology brushings was found to be superior to the yield from standard fine-needle aspiration (FNA). The aim of this prospective and blinded study was to compare the cytology yield of mucinous epithelium from brushing with FNA in suspected mucinous CPLs. PATIENTS AND METHODS: In total, 37 patients with 39 CPLs measuring at least 20 mm were enrolled between June 2006 and July 2008 for EUS-cytobrushing and EUS-FNA of CPLs. Demographic, clinical, EUS, cytopathologic, and surgical data were recorded whenever available. Yield of cytology brushings was compared with that of FNA. Procedure morbidity was evaluated after 30 days. The main outcome assessed was yield of intracellular mucin (ICM) on cytobrushing specimens compared with EUS-FNA for the diagnosis of suspected mucinous CPL. RESULTS: Cytobrushings were more likely to detect ICM than the EUS-FNA method ( P = 0.001). In three patients with hypocellular FNA, dysplasia was found on cytology brushing and later confirmed by surgical pathology. Significant complications occurred in three patients (8 %): one postbrushing bleeding and two acute pancreatitis. CONCLUSIONS: Cytology brushings are more likely to provide an adequate mucinous epithelium specimen than standard FNA and could aid the diagnosis of CPLs in a selective group of patients.

Family history of dementia is a risk factor for Lewy body disease.

Genetic factors are important in Alzheimer disease (AD) and Parkinson disease but have not been well characterized in Lewy body dementia (LBD). The authors obtained family history in patients from an autopsy series of AD and LBD and in living healthy controls. A family history of dementia was more common in both LBD and AD compared with controls, suggesting that genetic factors are as important in LBD as they are in AD.

Comparison of five bifunctional chelate techniques for 90Y-labeled monoclonal antibody CO17-1A.

Monoclonal antibody CO17-1A was radiolabeled with 90Y by five bifunctional chelate techniques. Radiation absorbed dose estimates for normal organs and tumor were calculated for each preparation based on timed tissue distribution studies in nude mice bearing SW 948 human colorectal carcinoma xenografts. The cyclic DTPA anhydride technique was inferior to the four other techniques studied. Data for SCN-Bz-DTPA and SCN-Bz-Mx-DTPA, which were conjugated to epsilon-lysyl amino groups, were similar to those for NH2-Bz-DTPA and NH2-Bz-Mx-DTPA, which were conjugated site specifically to oligosaccharides.

Radioimmunotherapy of human colorectal carcinoma xenografts using 90Y-labeled monoclonal antibody CO17-1A prepared by two bifunctional chelate techniques.

Monoclonal antibody CO17-1A, which has specificity for colorectal and pancreatic carcinomas, was radiolabeled with the pure beta emitter, 90Y, by either the cyclic diethylenetriaminepentaacetic acid (DTPA) anhydride technique or by a site-specific bifunctional chelate technique using 1-(p-aminobenzyl)DTPA (p-NH2-Bz-DTPA). Female nude mice bearing SW 948 human colorectal carcinoma xenografts were given injections i.v. of 90Y-labeled monoclonal antibody CO17-1A at dosages of 100, 150, and 200 muCi/25 g body weight. Unlabeled CO17-1A (100 micrograms/25 g body weight) was coadministered. In animals receiving 90Y-CO17-1A prepared by the cyclic DTPA anhydride technique, tumor volume was unchanged from base line at a dose of 200 microCi/25 g. As the dosage of 90Y-CO17-1A increased, the rate of tumor growth decreased, but all experimental animals in this group died between 14 and 21 days. In contrast, CO17-1A radiolabeled with 90Y by the site-specific p-NH2-Bz-DTPA bifunctional chelate technique produced a maximum tumor volume reduction of 87% in the 200 microCi/25 g group by day 15, and no deaths were noted in any of the 90Y-CO17-1A-treated groups for 71 days. Dose-response curves again showed increased tumoricidal effects with increased dosages of 90Y-CO17-1A. S-2-(3-Aminopropylamino)ethylphosphorothioic acid, commonly known as WR-2721, is a radioprotective drug which has been shown to protect against bone marrow depression in irradiated humans. No protection was observed when WR-2721 was used as an adjunct to treatment with 90Y-CO17-1A prepared by either the cyclic DTPA anhydride technique or the site-specific p-NH2-Bz-DTPA technique. When the site-specific p-NH2-Bz-DTPA technique was used, the reduction in WBC and hemoglobin levels correlated with increasing bone marrow toxicity at higher doses. We conclude that CO17-1A labeled with 90Y via the site-specific p-NH2-Bz-DTPA technique has potential for radioimmunotherapy of human colorectal carcinoma.

Analysis of T lymphocyte subsets in tamarins with colitis and colon cancer.

The cotton-top tamarin, Saguinus oedipus, serves as an animal model for the study of human colon cancer. This New World monkey has a high incidence of colitis and colon cancer that develops spontaneously. Evidence suggests that these diseases may be the result of a virally induced immunodeficiency. We have shown that T4+/T8+ cell ratios are significantly altered in tamarins with acute colitis and colon cancers. The T4+/T8+ ratios were 1.50 +/- 0.09, 0.70 +/- 0.05, and 0.48 +/- 0.05 for negative controls, acute colitis, and cancer positive tamarins, respectively. Statistical analysis showed a significant difference (p less than or equal to .0005) between negative controls vs. acute colitis and cancer positive groups.

Colon cancer cells in peripheral blood of cancerous tamarins.

Diagnosing colon cancer in its early stages would lower the mortality rate. The cotton-top tamarin, Saguinus oedipus, serves as a model for the study of human colon cancer. This New World monkey has a high incidence of colitis and colon cancer. The mouse anti-human monoclonal antibody BR55.2, with specificity for human colon adenocarcinoma, was biotinylated. Peripheral blood mononuclear cells (PBMC) from animals with colon cancer were fluorescently stained with the biotinylated BR55.2. These results showed the cross-reactivity of mouse anti-human colon cancer monoclonal antibody to the PBMC of cancerous tamarins. Antibodies from either cancerous or chronic colitis tamarins were also biotinylated. Fluorescently labeled cells were detected when PBMC from cancerous tamarins were incubated with biotinylated antibodies from cancerous tamarins. Cytofluorographic analysis also showed a significant 4.5-fold difference in the percentage of fluorescently labeled PBMC between cancerous and chronic colitis tamarins when stained with biotinylated antibodies from cancerous tamarins. DNA flow cytometry analysis showed that PBMC from cancerous tamarins have a higher percentage of aneuploid cells than PBMC from chronic colitis tamarins.

Preclinical assessment of 90Y-labeled monoclonal antibody CO17-1A, a potential agent for radioimmunotherapy of colorectal carcinoma.

Monoclonal antibody CO17-1A was radiolabeled with 90Y using the cyclic DTPA anhydride technique and administered intravenously to athymic nude mice bearing SW 948 human colorectal carcinomas. The tumor specificity of 90Y-CO17-1A was improved by coadministration of 100 micrograms of the unlabeled antibody per animal and by purification using HPLC instead of column gel filtration chromatography. Absorbed radiation dose estimates for 90Y-CO17-1A were calculated. The radiation dose to the bone marrow will limit the amount of 90Y-CO17-1A that can be administered for cancer therapy.

90Y-labeled monoclonal antibodies for cancer therapy.

Monoclonal antibody 17-1A, which has specificity for colorectal carcinoma, was labeled with 90Y (10-20% radiolabeling yield). Tissue distribution studies in tumor-bearing nude mice were carried out. 90Y-labeled 17-1A showed good uptake in the SW 948 colon carcinoma cell line. However, 90Y-labeled A5C3, a monoclonal antihepatitis virus antibody studied as a control, showed similar uptake in this tumor. Neither antibody was taken up well by a WM-9 melanoma. It is believed that the loss of specificity observed is due to the low specific activity of the 90Y-labeled monoclonal antibody preparations used. This hypothesis is supported by radioimmunoassay data.

Prostaglandin suppression: inability to correct severe idiopathic orthostatic hypotension.

A 70-year-old man with classic severe idiopathic orthostatic hypotension received three different indomethacin dose regimens. Baseline urinary prostaglandin concentrations were modestly elevated. Although indomethacin greatly lowered prostaglandin production, no sustained improvement in blood pressure or symptoms occurred. It is proposed that the interindividual variations in vascular reactivity and circulating prostaglandin levels may account for the beneficial responses to indomethacin of some patients and the modest responses of others.

Compulsive water drinking treated with high dose propranolol.

A patient with recurrent, life-threatening water intoxication secondary to compulsive water drinking is described. This patient responded well to nearly 1 g of propranolol daily with a decrease in her drinking behavior, reduced sensation of thirst, and a reduction in her delusional thinking. The rationale for the choice of propranolol with this patient is reviewed.

Agranulocytosis during combined procainamide and phenytoin therapy.

We have presented two cases of agranulocytosis occurring in patients receiving a combination antiarrhythmic regimen. As multiple drug therapy for ventricular arrhythmias becomes more commonplace, increased scrutiny should be given to agents chosen, in an effort to prevent any possible adverse interactions. When future cases are encountered, the acetylator pheontype should be determined. This information would aid in assessing the predicative value of the acetylator phenotype in the development of agranulocytosis. Due to the inherent danger, neither patient was rechallenged with procainamide nor phenytoin.