Synthesis and proapoptotic properties of new casein kinase II inhibitors

Casein kinase II (CK2) is the most pleiotropic of all protein kinases with more than 300 substrates implicated in a wide variety of cellular functions as signal transduction, proliferation and cell survival. Increased levels of CK2 has been demonstrated in a number of cancers, where it regulates the activity of various oncoproteins and tumor suppressor proteins. Therefore, CK2 inhibitors could be considered as potential anticancer drugs in monotherapy or in combination with known cytostatics. In this study, we examined proapoptotic activity of new strong CK2 inhibitor - 4,5,6,7-tetraiodobenzimidazole (TIBI) (IC50 = 38 nM) as well as new derivatives of 4,5,6,7-tetrabromobenzimidazole and 4,5,6,7-tetraiodobenzimidazole. All the tested compounds induced apoptosis and cytostatic effects in the promyelocytic leukemia cell line (HL-60). The proapoptotic effect was concentration and time dependent. The changes of the mitochondrial membrane potential and cell cycle progression were also observed.     

Primary non-Hodgkin's lymphoma of the uterine cervix mimicking leiomyoma: case report and review of the literature

Primary malignant lymphoma occurring in the uterine cervix is a rare event. We report a case of primary non-Hodgkin's lymphoma of the uterine cervix mimicking leiomyoma. The immunophenotype of the tumor and the differential diagnostic approach to this uncommon malignancy also are presented.     

Impaired beta-cell function in human aging: response to nicotinic acid-induced insulin resistance

CONTEXT: Glucose tolerance declines with age and may involve impaired beta-cell sensitivity to glucose and beta-cell compensation for insulin resistance. OBJECTIVE: We investigated beta-cell sensitivity to glucose and beta-cell compensation for nicotinic acid-induced insulin resistance in young (age <35 yr) people with normal glucose tolerance (NGT) and old (age >60 yr) people with NGT and impaired glucose tolerance (IGT). DESIGN/PATIENTS/SETTING/INTERVENTION: Fifteen young NGT, 16 old NGT, and 14 old IGT were randomized to 2-wk treatment with nicotinic acid or placebo in a double-blind, crossover study in a university medical setting. At the end of each treatment period, participants had a frequently sampled iv glucose tolerance test and ramp clamp, in which insulin secretion rates (ISR) were determined in response to a matched 5-10 mm glucose stimulus. MAIN OUTCOME MEASURES: Insulin sensitivity (S(I)), acute insulin response to iv glucose (AIRg), and disposition index (AIRg x S(I), or beta-cell compensation for insulin resistance) from frequently sampled iv glucose tolerance testing, and ISR area under the curve (or beta-cell sensitivity to glucose) from ramp clamp were determined. RESULTS: Progressive impairments in insulin secretion as assessed by AIRg, disposition index, and ISR area under the curve were identified in older people with NGT, with more marked defects in older people with IGT. Nicotinic acid treatment significantly reduced S(I) in all groups. beta-Cell compensation for nicotinic acid-induced insulin resistance was incomplete in all three groups, with greater defects in the two older groups. CONCLUSIONS: Human aging is associated with impaired beta-cell sensitivity to glucose and impaired beta-cell compensation to insulin resistance.     

Limitation of the homeostasis model assessment to predict insulin resistance and beta-cell dysfunction in older people

CONTEXT: Studies in older people have shown inconsistent agreement between homeostasis model assessment of insulin resistance (HOMA-IR) and dynamic measures of insulin action and have not evaluated HOMA beta-cell. OBJECTIVE: We compared measures of insulin sensitivity and beta-cell function from the frequently sampled iv glucose tolerance test (FSIGT) to HOMA models. DESIGN/PATIENTS/SETTING/INTERVENTION: Two hundred fourteen young and old with normal glucose tolerance (NGT) and old with impaired glucose tolerance (IGT) participated in a retrospective analysis of FSIGT data in a university medical setting. MAIN OUTCOME MEASURE: Sensitivity to insulin (S(I)) and acute insulin response to glucose (AIRg) from FSIGT were compared with HOMA models. RESULTS: S(I) and HOMA-IR measures identified similar patterns of increasing insulin resistance in the two older groups, compared with younger people with NGT, with the greatest degree of insulin resistance in older people with IGT (P < 0.05 vs. young and old NGT for both S(I) and HOMA-IR). Agreement between HOMA-IR and S(I) was moderate (weighted kappa = 0.51). AIRg was similar in young and old NGT but was markedly decreased in old IGT (P < 0.05 vs. young and old NGT). HOMA-beta-cell was similar in the three groups. Agreement between HOMA beta-cell and AIRg was weak (weighted kappa = 0.35). CONCLUSIONS: HOMA-IR may detect age-related insulin resistance when comparing large populations of older people. However, dynamic testing appears to be necessary to quantitate diminished insulin secretion in older people.     

Biventricular pacing demonstrates similar effects in elderly and younger patients with advanced heart failure in the mid-term follow-up

BACKGROUND: Biventricular (BIV) pacing has been shown to improve haemodynamics and functional status of patients (pts) with advanced chronic heart failure (CHF). No study has determined the effects of BIV in relation to the age of pts. AIM: To compare the clinical outcome in two groups of pts: > or =65 years (yrs) and <65 yrs referred for BIV pacing in our centre with at least 6 months of follow-up. METHODS: Among 15 pts > or =65 yrs and 16 pts <65 yrs successfully implanted with a BIV pacemaker, 12 and 15 pts, respectively, completed 6-month follow-up. Evaluation included change of NYHA class, 6-minute walking distance (6-minWD), drug therapy, QRS duration and echocardiographic parameters. The need for hospitalisation due to the worsening of CHF symptoms, assessed 6 months before and 6 months after BIV pacing, was compared. During long-term follow-up survival and complications related to this therapy were analysed. RESULTS: In both groups after 6 months of BIV pacing clinical improvement was observed, as demonstrated by the reduction in NYHA class (p <0.005), average duration of hospitalisation due to CHF (p <0.05) and diuretics doses (p <0.05). The comparison of changes in these parameters between the two groups, as well as of changes in 6-minWD and echocardiographic parameters, did not show significant difference. BIV pacing enabled an increase in the dosage of beta-blockers (in 50% pts > or =65 yrs and 60% pts <65 yrs), as well as of ACEI or ARB (25% and 40% pts, respectively). Survival was 80% in 15 pts > or =65 yrs during 16+/-15 months of follow-up and 81% in 16 pts v65 yrs during 22+/-14 months. All complications occurred in the 30-day post-operative period with similar frequency in both groups, also when LV lead-related complications were compared. CONCLUSIONS: In the mid-term follow-up BIV pacing demonstrates similar improvement in clinical status and exercise tolerance in elderly pts > or =65 yrs, as compared with pts <65 yrs. In both groups BIV pacing reduced the need for hospitalisation due to worsening of CHF symptoms, and enabled beneficial changes in the pharmacological treatment. Elderly patients are not at risk of more frequent complications associated with BIV pacing.