Trends Influencing Future Delivery of Mental Health Services in Large Healthcare Systems

The delivery of mental health services, particularly psychotherapy and other psychosocial care, is being increasingly limited by financial constraints. We briefly review three trends that will play an increasingly important role in the delivery of mental health services in large organizations such as health maintenance organizations. These are (a) an increasing role for self-help and bibliotherapy interventions, both in traditional and electronic formats; (b) mental health services being offered in settings other than mental health specialty clinics; and (c) an increased emphasis on mechanisms for improving the quality and type of services offered, including quality improvement methods and pay-for-performance.     

Effect of smoking cessation on serum apolipoprotein A-I and A-II concentrations.

This study investigated the effects of 6 weeks' smoking cessation on serum levels of total-cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C) and apolipoproteins A-I and A-II (apo A-I and apo A-II) in 64 subjects of both sexes. Smoking cessation was associated with an increase in levels of apo A-II. Concurrent changes in weight and alcohol consumption during attempted smoking cessation, together with change in thiocyanate level, were entered as predictor variables into a multiple regression analysis. The change in apo A-II was found to be best accounted for by change in plasma thiocyanate level, and, in women, change in HDL-C and apo A-I by change in weight. The changes induced by smoking cessation may be due, at least in part, to associated changes in alcohol consumption and/or dietary intake, but in the case of apo A-II there is evidence of a more direct effect.     

Regulation of intracellular Ca concentration by interleukin-1β in rat cortical synaptosomes: an age-related study

The pro-inflammatory cytokine interleukin-1β (IL-1β) is released by cells during injury and stress, and increased neuronal expression of IL-1β is a feature of age-related neurodegeneration. We have recently reported that IL-1β has a biphasic effect on the K⁺-induced rise in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in cortical synaptosomes, exerting an inhibitory effect on the K⁺-induced rise in [Ca²⁺]_i at lower (3.5 ng/mL) concentrations and a stimulatory effect on the K⁺-induced rise in [Ca²⁺]_i at higher (100 ng/mL) concentrations. In the present study, we observed that the K⁺-induced rise in [Ca²⁺]_i was inhibited to a similar extent by the lower concentration of IL-1β in cortical synaptosomes prepared from young (3-month-old), middle-aged (12-month-old) and aged (24-month-old) rats. In contrast, cortical synaptosomes prepared from the aged rats exhibited an increased susceptibility to the higher concentration of IL-1β, resulting in a marked elevation in [Ca²⁺]_i. We propose that the age-related increase in neuronal concentration of IL-1β promotes a dramatic elevation in [Ca²⁺]_i following membrane depolarization, thereby altering Ca²⁺ homeostasis and exacerbating neuronal vulnerability to excitotoxicity.     

BRCA1 and pancreatic cancer: pedigree findings and their causal relationships

Anecdotal reports and series studies indicate that 5-10% of pancreatic cancer (PC) cases are familial. In addition, PC is associated with a variety of hereditary cancer syndromes. PC appears to be an integral cancer in the hereditary breast-ovarian cancer (HBOC) syndrome, with most notice given to the role of BRCA2. Our purpose is to call attention to BRCA1, which also predisposes to PC. Using data from our familial breast cancer registry, we identified 19 BRCA1/2 families that contain PC affecteds in the pedigrees, 15 with BRCA1 mutations and 4 with BRCA2 mutations. The association between BRCA2 and pancreatic cancer is well established; however, a definite link with pancreatic cancer in families carrying a BRCA1 mutation has been far less studied. Thus, the focus of this report is on 9 of the 15 BRCA1 families, in which PC affecteds were either confirmed carriers of the BRCA1 mutation or were inferred as probable obligate BRCA1 mutation carriers. The numbers are small, but nevertheless illustrate the finding of others of an apparent association between PC and BRCA1-mutation-bearing families. Given the dismal prognosis of PC, with the only current hope for survival being through surgical extirpation of the pancreas prior to metastasis, it is prudent that we realize the potential predisposition toward PC via BRCA1, in the hope of early diagnosis and prevention.     

Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma.

We sought to determine whether identification of poor-risk subgroups of diffuse large B-cell lymphoma (DLBCL) using immunohistochemical stains would have practical utility with regard to prognosis and therapeutic decisions. Tissue microarray blocks were created using replicate samples of formalin-fixed, paraffin-embedded tissue from 200 cases of de novo DLBCL. The sections were stained with antibodies to proteins that are expressed by activated or proliferating B cells including MUM1, FOXP1, bcl-2, survivin, protein kinase C-beta (PKC-beta), cyclin D2, cyclin D3, and Ki-67. In univariate analysis, tumor expression of cyclin D2 (P = 0.025) or PKC-beta (P = 0.015) was associated with a worse overall survival, whereas none of the other markers was predictive of overall survival. Patients with DLBCL that expressed either cyclin D2 or PKC-beta had a 5-year overall survival of only 30% as compared to 52% for those who were negative for both markers (P = 0.0019). In multivariate analysis, the expression of cyclin D2 or PKC-beta was an independent predictor of poor overall survival (P = 0.035). Cyclin D2 and PKC-beta expression will be useful in designing a 'biological prognostic index' for patients with DLBCL.     

Interlaboratory validation of a CD71-based flow cytometric method (Microflow) for the scoring of micronucleated reticulocytes in mouse peripheral blood

An interlaboratory study was performed to validate an anti-CD71/flow cytometry-based technique for enumerating micronucleated reticulocytes (MN-RETs) in mouse peripheral blood. These experiments were designed to address International Workshop on Genotoxicity Test Procedures validation criteria by evaluating the degree of correspondence between MN-RET measurements generated by flow cytometry (FCM) with those obtained using traditional microscopy-based methods. In addition to these cross-methods data, flow cytometric MN-RET measurements for each blood sample were performed at two separate sites in order to evaluate the reproducibility of data between laboratories. In these studies, groups of male CD-1 mice were treated with vehicle (saline or vegetable oil), a negative control (saline or vegetable oil), or four dose levels of five known genotoxicants (clastogens: cyclophosphamide, benzo[a]pyrene, 5-fluorouracil, methotrexate; aneugen: vincristine sulfate). Exposure occurred on 3 consecutive days via intraperitoneal injection, and blood samples were obtained approximately 24 hr after the final treatment. MN-RET frequencies were determined for each sample based on the analysis of 2,000 (microscopy) and 20,000 (FCM) reticulocytes. Regardless of the method utilized, each genotoxic agent was observed to cause statistically significant increases in the frequency of MN-RETs, and each response occurred in a dose-dependent manner. Spearman's correlation coefficient (rs) for FCM versus microscopy-based MN-RET measurements (nine experiments, 252 paired measurements) was 0.740, indicating a high degree of correspondence between methods. The rs value for all flow cytometric MN-RET measurements performed at the two independent sites was 0.857 (n = 248), suggesting that the automated method is highly transferable between laboratories. Additionally, the flow cytometric system offered advantages relative to microscopy-based scoring, including a greater number of cells analyzed, much faster analysis times, and a greater degree of objectivity. Collectively, data presented in this report suggest that the overall performance of mouse peripheral blood micronucleus tests is enhanced by the use of the flow cytometric scoring procedure.     

A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred

Genomic deletions of the MSH2 gene are a frequent cause of hereditary nonpolyposis colorectal cancer (HNPCC), a common hereditary predisposition to the development of tumors in several organs including the gastrointestinal and urinary tracts and endometrium. The mutation spectrum at the MSH2 gene is extremely heterogeneous because it includes nonsense and missense point mutations, small insertions and deletions leading to frameshifts, and larger genomic deletions, the latter representing approximately 25% of the total mutation burden. Here, we report the identification and molecular characterization of the first paracentric inversion of the MSH2 locus known to cause HNPCC. Southern blot analysis and inverse PCR showed that the centromeric and telomeric breakpoints of the paracentric inversion map within intron 7 and to a contig 10 Mb 3' of MSH2, respectively. Pathogenicity of the paracentric inversion was demonstrated by conversion analysis. The patient's lymphocytes were employed to generate somatic cell hybrids to analyze the expression of the inverted MSH2 allele in an Msh2-deficient rodent cellular background. The inversion was shown to abolish MSH2 expression by both northern and western analysis. This study confirms that Southern blot analysis still represents a useful and informative tool to screen for and identify complex genomic rearrangements in HNPCC. Moreover, monoallelic expression analysis represents an attractive approach to demonstrate pathogenicity of unusual mutations in autosomal dominant hereditary conditions.     

Apolipoprotein A-I and A-II levels in an Australian population

Values for apolipoproteins A-I and A-II (apo A-I and apo A-II) are reported for 389 women and 390 men in the town of Busselton, Western Australia. Apo A-I levels were found to be relatively constant with age in men but to rise with age in women. Apo A-II levels remained constant with age in men until older age, when they declined, but rose with age in women, showing a fall in the oldest age group. Apo A-I levels were greater in women than in men, but apo A-II levels were lower in younger women than in younger men, and higher in older women than in older men. On stepwise multiple regression analysis, neither apo A-I nor apo A-II levels showed an independent relationship with age in women; the same was true for apo A-I in men. Alcohol consumption was directly associated with apo A-I and A-II levels in both sexes; adiposity was inversely associated with apo A-I levels in both sexes but with apo A-II only in women. Triglyceride levels showed an inverse association with apo A-II in women. Frequency of exercise was independently and directly associated with apo A-I and A-II levels in women only.