Increased right amygdala volume in lithium-treated patients with bipolar I disorder.

OBJECTIVE: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. METHOD: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. RESULTS: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. CONCLUSION: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

Quantitative assessment of 99mTc-depreotide uptake in patients with non-small-cell lung cancer: immunohistochemical correlations.

BACKGROUND: Somatostatin receptor (SSTR) scintigraphy with (99m)Tc-depreotide is used for differential diagnosis of solitary pulmonary nodules. The method is based on SSTR expression in cancer tissue. PURPOSE: To estimate the expression of SSTRs in non-small-cell lung cancer (NSCLC) in vitro, and to determine the correlation between (99m)Tc-depreotide uptake in vivo and different tumor characteristics determined in vitro, such as tumor grade, and presence of SSTR2, MIB-1, and p53. MATERIAL AND METHODS: A total of 127 patients with lung lesions detected on computed tomography (CT) were investigated with SSTR scintigraphy after injection of 740 MBq (99m)Tc-depreotide. This study includes 19 patients with NSCLC with histologically proven diagnosis. The quantitative evaluation of (99m)Tc-depreotide was performed using region-of-interest analysis and includes tumor counts/cm(3), background counts/cm(3), and the ratio between tumor and background counts. RESULTS: 99mTc-depreotide uptake was found in all NSCLC tumors, which expressed SSTR2 defined in vitro by immunochemical methods. SSTR2 expression was negatively correlated to the degree of the tumor's differentiation (P<0.05). 99mTc-depreotide uptake in tumor cells did not correlate with tumor grade, or SSTR2, MIB-1, or p53 expression. CONCLUSION: There is an expression of SSTRs in NSCLC. The degree of tumor differentiation correlates negatively with SSTR2 measured in vitro and positively with MIB-1 expression in tumor tissue. No correlation was found between (99m)Tc-depreotide uptake and possible prognostic factors such as MIB-1 and p53 expression in tumor cells in NSCLC. Lastly, no correlation was found between (99m)Tc-depreotide uptake and tumor grade or SSTR2 expression.

Hepatic ketogenesis and gluconeogenesis in humans.

Splanchnic arterio-hepatic venous differences for a variety of substrates associated with carbohydrate and lipid metabolism were determined simultaneously with hepatic blood flow in five patients after 3 days of starvation. Despite the relative predominance of circulating beta-hydroxybutyrate, the splanchnic productions of both beta-hydroxybutyrate and acetoacetate were approximately equal, totaling 115 g/24 h. This rate of hepatic ketogenesis was as great as that noted previously after 5-6 wk of starvation. Since the degree of hyperketonemia was about threefold greater after 5-6 wk of starvation, it seems likely that the rate of ketone-body removal by peripheral tissues is as important in the development of the increased ketone-body concentrations observed after prolonged starvation as increased hepatic ketone-body production rate. Splanchnic glucose release in this study was 123 g/24 h, which was less than that noted previously after an overnight fast, but was considerably more than that noted during prolonged starvation. Hepatic gluconeogenesis was estimated to be 99 g/24 h, calculated as the sum of lactate, pyruvate, glycerol, and amino acid uptake. This was greater than that observed either after an overnight fast or after prolonged starvation. In addition, a direct relationship between the processes of hepatic ketogenesis and gluconeogenesis was observed.

Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB.

Cyclic AMP mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of transcription factor CREB. We have previously determined that although phosphorylation at Ser-133 is critical for induction, this site does not appear to participate directly in transactivation. To test the hypothesis that CREB ultimately activates transcription through domains that are distinct from the PK-A site, we constructed a series of CREB mutants and evaluated them by transient assays in F9 teratocarcinoma cells. Remarkably, a glutamine-rich region near the N terminus appeared to be important for PK-A-mediated induction of CREB since removal of this domain caused a marked reduction in CREB activity. A second region consisting of a short acidic motif (DLSSD) C terminal to the PK-A site also appeared to synergize with the phosphorylation motif to permit transcriptional activation. Biochemical experiments with purified recombinant CREB protein further demonstrate that the transactivation domain is more sensitive to trypsin digestion than are the DNA-binding and dimerization domains, suggesting that the activator region may be structured to permit interactions with other proteins in the RNA polymerase II complex.

Eph receptors and ephrins demarcate cerebellar lobules before and during their formation.

The formation of the ten cerebellar lobules is an unsolved problem in brain development. We report a screen for the four subfamilies of Eph receptors and their ligands (ephrins) in developing mouse cerebellum, using soluble receptor-immunoglobulin and ligand-immunoglobulin fusion proteins, and antibodies against EphA and ephrin-B proteins. Our results identify Eph receptors and ephrins as the first molecules known to demarcate individual lobules during development. Staining for ephrin-A ligands is in lobule VIII as it forms, across the whole width of the cerebellum. Staining for three EphA receptors approximately coincides with presumptive lobules VI and/or VII before and just after birth, whereas a fourth EphA receptor (EphA4, which binds ligands of both subfamilies) has more widespread expression. Staining for EphB receptors is in lobules VII, VIII, and IX. Staining for ephrin-B ligands is much weaker, becomes detectable only after birth, and does not appear to be lobule-specific. Staining for all subfamilies spreads to at least some adjacent lobules as maturation proceeds. The lobule-specific patterns appear before the lobules form, and initially extend across the width of the cerebellum, in spite of the lesser conservation of the lateral extensions of the lobules. These expression patterns define previously unknown developmental units and suggest that Eph family proteins may contribute to cerebellar morphogenesis.

Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer.

We have constructed recombinant human adenoviruses that express wild-type human p53 under the control of either the Ad 2 major late promoter (MLP) or the human cytomegalovirus (CMV) immediate early gene promoter. Each construct replaces the Ad 5 E1a and E1b coding sequences necessary for viral replication with the p53 cDNA and MLP or CMV promoter. These p53/Ad recombinants are able to express p53 protein in a dose-dependent manner in infected human cancer cells. Tumor suppressor activity of the expressed p53 protein was assayed by several methods. [3H]Thymidine incorporation assays showed that the recombinant adenoviruses were capable of inhibiting DNA synthesis in a p53-specific, dose-dependent fashion. Ex vivo treatment of Saos-2 tumor cells, followed by injection of the treated cells into nude mice, led to complete tumor suppression using the MLP/p53 recombinant. Following a single injection of CMV/p53 recombinant adenovirus into the peritumoral space surrounding an in vivo established tumor derived from a human small cell lung carcinoma cell line (NIH-H69), we were able to detect p53 mRNA in the tumors at 2 and 7 days post-injection. Continued treatment of established H69 tumors with MLP/p53 recombinant led to reduced tumor growth and increased survival time compared to control treated animals. These results indicate that recombinant adenoviruses expressing wild-type p53 may be useful vectors for gene therapy of human cancer.

Attitudes of Olmsted County, Minnesota, residents about tobacco smoke in restaurants and bars.

OBJECTIVE: To determine the attitudes of Olmsted County, Minnesota, adults about environmental tobacco smoke in restaurants, bars, and nightclubs. SUBJECTS AND METHODS: In this population survey,2014 adults were contacted by random digit dial methods between February 28 and May 5, 2000, and asked to participate in a telephone survey; 1224 (61%) consented. RESULTS: For the 57% (95% confidence interval [CI], 54%-60%) of the study population that reported exposure to environmental tobacco smoke, the most frequently reported sites of exposure were restaurants (44% [95% CI, 41%-48%]), work (21% [95% CI, 18%-24%]), and bars (19% [95% CI, 16%-22%]). Seventy-two percent (95% CI, 69%-74%) of respondents said that they would select a smoke-free restaurant over one where smoking is permitted, and 70% (95% CI, 67%-72%) said that they would select a smoke-free bar over one where smoking is permitted. The majority of respondents said that they would not dine out or visit bars or nightclubs more often or less often if all restaurants, bars, and nightclubs were smoke-free. CONCLUSIONS: Olmsted County residents prefer smoke-free restaurants, bars, and nightclubs.

The CardioVision 2020 baseline community report card.

OBJECTIVE: To establish baseline data for the CardioVision 2020 program, a collaborative project in Olmsted County, Minnesota, organized to reduce cardiovascular disease rates by altering 5 health-related items: (1) eliminating tobacco use and exposure, (2) improving nutrition, (3) increasing physical activity, (4) lowering serum cholesterol level, and (5) controlling blood pressure. SUBJECTS AND METHODS: Data about tobacco use, diet, and physical activity were collected by random digit dial interview and follow-up questionnaire from a sample of the population. Blood pressure data were collected from medical records at Mayo Clinic, and serum cholesterol data were derived from the Mayo Clinic laboratory database. Data were stratified into 6 age groups. RESULTS: A total of 624 women and 608 men responded to the questionnaire. Population blood pressure data were available for 1,956 women and 1,084 men. Population serum cholesterol data were available for 17,042 women and 12,511 men. Except for women in the 30- to 39-year-old age group, less than 10% of the population sampled met 4 or 5 goals. Conversely, about 90% of the population met at least 1 goal, and about 80% met 1, 2, or 3 of the goals. CONCLUSION: The data from the Olmsted County population indicate considerable opportunity to reduce this population's burden of cardiovascular disease.

Double agency and the ethics of rationing health care: a response to Marcia Angell.

The arguments against doctors as "double agents" that are presented by Marcia Angell in the preceding article do not defeat the core justification for rationing some relatively high-expense, low-benefit care, and they do not enable us to conclude that clinicians should be barred from any active, substantive role in decisions to limit that care. They do, however, reveal several important conditions that need to govern cost-conscious medial practice in order to preserve an ethic of fidelity to patients: insurers' profits and providers' incomes must be fair, providers must inform patients of any economic reasons that lead to the foregoing of care, and "direct incentive" arrangements must not be used to contain costs.

Risk perception, addiction, and costs to others: an assessment of cigarette taxes and other anti-smoking policies.

This paper offers a relatively comprehensive assessment of government anti-smoking policies (both taxation and other regulatory measures). I conclude that interventions to engender in smokers and prospective smokers an accurate perception of tobacco's health risks are justified, that except in the case of adolescents addiction by itself does not justify intervention beyond providing adequate information, that the proper goal of tobacco taxation policy should be to recoup only the extra costs that smokers place on others (at most a $1/pack tax on cigarettes), and that passive smoke's imposition of harm on unconsenting others strongly supports at least the development of a safe-to-others smokeless cigarette, if not direct intervention.

Equality, autonomy, and efficiency: what health care system should we have?

The U.S. has a wide range of options in choosing a health care system. Rational choice of a system depends on analysis and prioritization of the basis moral goals of equitable access to all citizens, the just sharing of financial costs between well and ill, respect for the values and choices of subscribers and patients, and efficiency in the delivery of costworthy care. These moral goals themselves, however, tell us little about what health care system the United States should have. Equitable access does not demand a level and scope of care for the poor equal to that rationally chosen by the middle class, and there are ways within mixed systems, though not easy ways, to achieve a fair distribution of costs between well and ill. Despite pluralistic systems' apparent advantage in allowing subscribers to choose their own forms of rationing, problems in translating serious long-term subscriber choices into actual medical practice may be greater in pluralistic than in unitary systems. Final choice of a system hinges primarily on peculiar historical facts about U.S. political culture, not on moral principle.

Public philosophy: distinction without authority.

An assumed core of normative ethical principles may constitute a philosophically proper framework within which public policy should be formulated, but it seldom provides any substantive solutions. To generate public policy on bioethical issues, participants still need to confront underlying philosophical controversies. Professional philosophers' proper role in that process is to clarify major philosophical options, to press wider-ranging consistency questions, and to bring more parties into the philosophical debate itself by arguing for particular substantive claims. Though questions of fact that mediate final policy conclusions frequently fall outside philosophical competence, one sort of fact, lack of political support, should seldom cause philosophers to stand aside; philosophers still have an important role as critics of culture, politics, and profession. They have no authority, however, on even the philosophical presuppositions of public policy.