Is Polypharmacy Associated with Cognitive Frailty in the Elderly? Results from the Korean Frailty and Aging Cohort Study.

OBJECTIVES: Cognitive frailty-the coexistence of physical frailty and cognitive impairment-is a phenotype of frailty in the elderly. The coexistence of physical frailty and cognitive impairment, known as cognitive frailty, is one of the phenotypes of frailty in the elderly. Cognitive frailty predicts adverse health outcome more accurately than does physical frailty. In this study, we aim to determine whether the polypharmacy common among the elderly is linked with cognitive frailty. DESIGN, SETTING, AND PARTICIPANTS: The elderly, aged between 70 and 84 years, who participated in the cross-sectional Korean Frailty and Aging Cohort Study were included in the present study. MEASUREMENTS: Polypharmacy and hyperpolypharmacy were defined as the use of at least five and ten medications, respectively. Physical frailty was assessed by the Korean version of the FRAIL scale, and cognitive status was measured by the Trail Making Test part A, word list recall test, the Korean version of the Frontal Assessment Battery, and the Digit Span Backward test. RESULTS: Among the 2,392 participants, 26.8% and 4.1% took more than five and ten prescribed medications, respectively. Polypharmacy and hyperpolypharmacy participants tend to have more cognitive impairment and physical frailty. Participants with cognitive frailty had the highest polypharmacy rate regardless of medication type. After controlling for the potential confounders including severity of comorbidities, frailty was found to be significantly related to polypharmacy, as defined by prescribed as well as total medications, including non-prescribed medications. However, cognitive impairment only showed a linkage to polypharmacy of prescribed medications, which-according to the results of multivariable analysis- could increase cognitive frailty, with an odds ratio of 2.70. CONCLUSION: Although the elderly tend to depend on various medications, they should seriously consider the risk of polypharmacy for better health outcomes.

Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses.

XIAP-associated factor 1 (XAF1) is a new candidate tumor suppressor, which has been known to exert proapoptotic effects by interfering with the caspase-inhibiting activity of XIAP. To explore the XAF1's candidacy for a suppressor in urogenital tumorigenesis, we investigated the XAF1 status in a series of cancer cell lines and primary tumors derived from the bladder, kidney and prostate. Expression of XAF1 transcript was undetectable or extremely low in 60% (3/5) of bladder, 66% (10/15) of kidney, and 100% (3/3) prostate cancer cell lines. Abnormal reduction of XAF1 was also found in 33% (18/55) of primary bladder and 40% (8/20) of primary kidney tumors, and showed a correlation with advanced stage and high grade of bladder tumor. Hypermethylation at 14 CpG sites in the 5' proximal region of the XAF1 promoter was highly prevalent in cancers versus adjacent normal or benign tissues and tightly associated with reduced gene expression. XAF1 expression enhanced the apoptotic response of tumor cells to chemotherapeutic agents, such as etoposide or 5-FU. While XAF1 expression did not influence the subcellular distribution or expression of XIAP, it elevated the protein stability of p53 and its target gene expression. Moreover, the apoptosis-sensitizing and growth suppression function of XAF1 was markedly impeded by blockade of p53 function. Collectively, our study demonstrates that epigenetic alteration of XAF1 is frequent in human urogenital cancers and may contribute to the malignant progression of tumors by rendering tumor cells a survival advantage partially through the attenuated p53 response to apoptotic stresses.

Changes in mucosal immune cells of bladder tumor patient after BCG intravesical immunotherapy.

The Bacillus Calmette-Guerin (BCG) is considered to be at least as effective, and perhaps superior to chemotherapy in the prophylaxis of recurrent superficial tumors. However, the mechanism of the antitumor effect of BCG is still not exactly known. We have conducted investigations to examine changes in bladder mucosal immune cells in patients with superficial bladder carcinoma treated with a first cycle of BCG. The study group included 15 BCG and 5 doxorubicin instillation patients, most in the intermediate or high risk group for recurrent tumor. Grossly normal bladder mucosal cold cup biopsies were performed at initial TUR and one week after six consecutive weekly instillations of BCG or doxorubicin. All specimens underwent immunohistochemical staining, both pre-treatment and post-treatment, including CD20, CD45RO, CD8, CD4 and CD57. Immunoreactive cell counts were evaluated from three different microscopic fields (x400) under the grid. The mean duration of follow-up was 52.8 months. The post-treatment bladder mucosal B-cells (CD20) and T-cells (CD45RO, CD4, CD8) were significantly increased compared to pre-treatment in patients treated with BCG instillation, but NK-cells (CD57) were not changed. However, there was no change in B-cells or T-cells in patient treated with doxorubicin. The CD20 cells in pre-treatment specimens did not correlate with any other cells. However, it was a statistically significant correlation with CD45RO in post-treatment specimens. The CD4 correlated with CD45RO and CD8 in pre-treatment, but it was correlated with CD45RO and CD57 in post-treatment specimens. There was no tumor recurrence in cases with significantly increased B-cells after BCG instillation. The results of these studies suggest that intravesical BCG immunotherapy for superficial bladder tumor induces a significant increase in T-cells as well as B-cells and that B-cells have a preventive effect on tumor recurrence. Further studies with a larger number of patients are needed to confirm the value of the B-cell increment after BCG instillation as a clinically independent prognostic factor.

Effects of repeated short versus single long episodes of focal ischemia on somatosensory evoked potentials and development of cerebral infarction in cats.

The effects of repeated short episodes of focal ischemia at 30-minute intervals or a single equivalent long episode of focal ischemia on neuronal function and development of cerebral infarction were compared using somatosensory evoked potential (SEP) recording and 2,3,5-triphenyltetrazolium chloride staining in a cat model. Seventeen cats underwent transorbital occlusion of the middle cerebral artery (MCA), using one of three procedures: sham-operation; single 1-hour occlusion of the MCA, followed by 3 hours of recirculation; or three 20-minute occlusions of the MCA at 30-minute intervals, followed by 3 hours of recirculation. Two of six cats in the single long-term occlusion group showed recovery of SEP, whereas all six cats in the repeated short-term occlusion group showed recovery of SEP at 3 hours after recirculation. All six cats in the single long-term occlusion group had cerebral infarction of various sizes, but only one cat in the repeated short-term occlusion group developed infarction. Repeated short episodes of focal ischemia are relatively less damaging than a single equivalent long episode of focal ischemia, even if the reperfusion interval is extended to 30 minutes.

Molecular cloning of the leuB genes from Mycobacterium bovis BCG and Mycobacterium tuberculosis.

A gene responsible for the biosynthesis of leucine has been cloned by the complementation of the Escherichia coli leuB6 auxotroph mutant after transformation with the Mycobacterium bovis BCG genomic DNA library, which was constructed by ligating the partially digested BCG DNA with Sau3A1 into the pUC19 digested with BamHI. Sequencing of the leuB gene of BCG revealed an ORF (open reading frame) of 1.011 bp encoding isopropylmalate dehydrogenase with a calculated molecular weight of 42 kDa. The leuB gene of Mycobacterium tuberculosis isolated from Korean tuberculosis patient is shown to be identical to that of BCG except one bp.

Efficacy of the platinum analog [Pt(cis-dach)(DPPE)-2NO3] on histocultured human patient bladder tumors and cancer cell lines.

Cisplatinum is currently used as a front line agent in many important tumors, but its dose-limiting nephrotoxicity prevents potential efficacy. There is therefore great interest in developing new platinum agents that have less toxicity. We have synthesized new platinum analogues containing DACH as a carrier ligand and DPPE as a leaving group. Previously we showed that these new platinum complexes have much less nephrotoxicity than cisplatinum. In the present study, the efficacy of one new platinum complex was evaluated with human patient bladder tumor specimens in three-dimensional histoculture as well as with monolayer cultures of cancer cell lines. The efficacy end points used were glucose consumption and thymidine incorporation on the histocultured specimens and MTT reduction on monolayer cell cultures. Our results showed that the new platinum complex was more effective at high concentration (10(-3) M) but less effective at low concentration (10(-4) M) compared to cisplatinum on histocultured bladder tumor specimens. The compound demonstrated higher efficacy than cisplatinum on P-388, and L-1210 leukemic cell lines. The new analog demonstrated similar efficacy to cisplatinum on the MKN-45 human stomach cancer cell line. The PC-14 human lung cancer cell line, MH1C1 rat hepatoma cell line, NIH-OV3, SKOV-3 ovarian cancer cell lines were as sensitive to the new analog as to cisplatinum at high concentrations of the new platinum analogue. The cisplatinum-resistant M-14 melanoma cell line was not sensitive to either the new analog or cisplatinum. Based on these results, this novel platinum compound appears to be a valuable lead compound with high efficacy and low nephrotoxicity.