Texas Medical Center

About: Texas Medical Center is a healthcare organization based out in Houston, Texas, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 2845 authors who have published 2394 publications receiving 79426 citations.

Off-label use of second-generation antipsychotic agents among elderly nursing home residents.

Abstract: Objective: This study examined off-label and evidence-based use of second-generation antipsychotic agents among elderly nursing home residents and factors associated with off-label use. Methods: This study involved a retrospective, cross-sectional analysis of data from the 2004 National Nursing Home Survey (NNHS). The sample included nursing home residents 65 years and older who received second-generation antipsychotic agents. This study used an indication-based definition of offlabel use established by the U.S. Food and Drug Administration (FDA). Evidence-based use included FDA-approved indications and indications for which the Agency of Healthcare Research and Quality found at least moderate strength of evidence of effectiveness. Descriptive statistics were used to examine the prevalence of off-label and evidencebased use. Multiple logistic regression was used to examine the patient and facility factors associated with off-label use of second-generation antipsychotics. Results: According to the 2004 NNHS, 308,990 (23.5%) elderly nursing home residents received at least one second-generation antipsychotic agent. Of those using second-generation antipsychotics, 86.3% received them for off-label indications and 56.9% received them for an evidence-based use. Multivariate analysis found that age (≥75 years), self-pay for nursing home care, diagnosis of dementia, and residing in a nonprofit nursing home were positively associated with offlabel use, whereas receiving Medicaid benefits was negatively associated with such use. Conclusions: Although second-generation antipsychotics were frequently used for off-label indications, most of the usage was evidence based among elderly nursing home residents. However, the high level of non–evidence-based use combined with recent safety and efficacy data suggests an urgent need to address the evidence base for this vulnerable population. (Psychiatric Services 61:130–136, 2010)

PKC isozyme S -cysteinylation by cystine stimulates the pro-apoptotic isozyme PKCδ and inactivates the oncogenic isozyme PKCε

Abstract: Protein kinase C (PKC) is a family of ten isozymes that play distinct and in some cases opposing roles in cell growth and survival. We recently reported that diamide, a diazene carbonyl derivative which oxidizes thiols to disulfides through addition/displacement reactions at the diazene bond, induces potent GSH-dependent inactivation of several PKC isozymes, including the oncogenic isozyme PKCe, via S-glutathiolation. PKCδ, a pro-apoptotic isozyme, was distinguished by its resistance to inactivation. In this report, we show that PKC-regulatory S-thiolation modifications produced by physiological disulfides elicit opposing effects on PKCδ and PKCe activity. We report that PKCδ is stimulated 2.0–2.5 fold by GSSG, (Cys–Gly)2 and cystine, under conditions where PKCγ and PKCe are fully inactivated by cystine, and PKCα activity is affected marginally or not at all by the disulfides. Focusing on cystine, we show that DTT quenches cystine-induced PKCδ stimulation and PKCγ and PKCe inactivation, indicative of oxidative regulation. By analyzing DTT-reversible isozyme radiolabeling by [ 35 S]cystine, we demonstrate that PKCγ, PKCδ and PKCe are each [ 35 S] S-cysteinylated in association with the concentration-dependent regulation of isozyme activity by cystine. The restricted reactivity of cystine, together with the effects of DTT and thioredoxin on cystineinduced PKC isozyme regulation reported here, indicate that the cystine-induced PKC-regulatory effects entail isozyme S-cysteinylation. We recently hypothesized that antagonism of tumor promotion/progression by small cellular thiols may involve PKC regulation via oxidant-induced Sthiolation reactions with PKC isozymes. The findings of cystine-induced PKC isozyme regulation by S-cysteinylation reported here offer correlative support to the hypothetical model. Thus, PKCδ, a potent antagonist of DMBA– TPA-induced tumor promotion/progression in mouse skin, is stimulated by S-cysteinylation, PKCe, an important mediator of the tumor promotion/progression response, is inactivated by S-cysteinylation, and PKCα, which is not influential in DMBA–TPA-induced tumor promotion/progression, is not regulated by cystine. Furthermore, PKCγ has oncogenic activity, and S-cysteinylation inactivated PKCγ and PKCe similarly. These findings provide evidence that S-cysteinyl acceptor-sites in PKC isozymes may offer attractive targets for development of novel cancer preventive agents.

Non‐Hodgkin's lymphoma of the tonsil .A clinicopathologic study of 65 cases

Abstract: Sixty-five patients presenting to M. D. Anderson Hospital and Tumor Institute with Stages IE and IIE primary tonsillar lymphoma between 1954 and 1981 were reviewed. All cases were non-Hodgkin's lymphomas, with the majority being diffuse large cell lymphoma (85%). Initial therapy was radiotherapy alone in 54 patients, radiotherapy combined with chemotherapy in 8 patients, and chemotherapy alone in 3 patients. Stage was the most important prognostic factor, with 86% and 41% 5-year survivals for Stages IE and IIE, respectively (P = 0.006). Lymphangiography was crucial in staging patients with clinically positive cervical lymph nodes because 94% of clinically staged IIE patients developed recurrent disease, in comparison with only 50% of lymphangiogram-staged IIE patients. The incidence of large cell lymphoma was so high as to preclude analysis of survival by histologic type. From this limited series, radiotherapy alone would appear to be sufficient initial therapy for Stage IE patients, whereas Stage IIE patients probably benefit from the addition of prophylactic chemotherapy. Relapses were most common in nonirradiated lymph-node-bearing areas, with the majority presenting in the first 2 years following initial therapy. The salvage of relapsing patients has been disappointing, with the best hope residing in combination chemotherapy.

A comparison of DNA adduct formation in white blood cells and internal organs of mice exposed to benzo[a]pyrene, dibenzo[c,g]carbazole, safrole and cigarette smoke condensate.

Abstract: Measurement of tissue/cell DNA adducts represents a suitable monitor of carcinogen exposure because the majority of chemical mutagens/carcinogens react with DNA, forming covalent adducts, a key event in the initiation of chemical carcinogenesis. Investigations of DNA-adduct formation in vivo in white blood cells (WBC) versus target tissues, i.e. internal organs for most carcinogens, is expected to yield useful information about the suitability of WBC for biomonitoring and risk assessment. For this purpose, female ICR mice were given 0.4 mmole/kg benzo[a]pyrene (BP), 0.045 mmole/kg dibenzo[c,g]carbazole (DBC) or 2.47 mmole/kg safrole by oral gavage or 4 daily doses (equivalent to 3 cigarettes) of cigarette-smoke condensate (CSC) by topical application. At 24 h after dosing, DNA adducts were detected by a nuclease P1-enhanced 32P-postlabeling assay [M.V. Reddy and K. Randerath, Carcinogenesis, 7 (1986) 1543] in WBC and internal tissues treated with individual carcinogens, while CSC treatment elicited aromatic adducts in most tissues but not in WBC. Adduct patterns of WBC DNA were qualitatively similar to those of internal organs, but adduct amounts varied. BP, a systemic carcinogen, bound nearly as much to WBC DNA as to target-tissue DNA samples; whereas the liver carcinogens, DBC and safrole, bound to WBC DNA considerably less (22- and 51-fold, respectively) compared with liver DNA. The number of adducts in 10(7) nucleotides of WBC, liver, lung, kidney and spleen DNA, respectively, were: 2, 5, 3, 2 and 3 with BP; 6, 131, 6, 14 and 4 with DBC; 5, 238, 3, 5 and 0.6 with safrole. For CSC, these values were 0, 1 and 0.02 in WBC, lung and spleen, respectively. Our results show that carcinogen binding to WBC DNA does not reflect binding to target-tissue DNA in a quantitative sense for the carcinogens studied except for BP, and that WBC are not suitable surrogates for monitoring CSC exposure by DNA-adduct measurement after topical application. The CSC data in mice was consistent with the previous findings in humans that smokers' tissues but not WBC show smoking-related bulky/aromatic DNA adducts, as measured by 32P-postlabeling.