On epidemiology and geographic information systems: a review and discussion of future directions

Leu-enkephalin radiolabelled at the N-terminal tyrosine by two different methods was presented to isolated perfused rat livers. Approximately 10% of a pulse of tritiated Leu-enkephalin was taken up first-pass; this was increased to 62% when the peptide was iodinated with Bolton and Hunter reagent. Uptake of both forms of radiolabelled Leu-enkephalin was inhibited by taurocholate in a concentration-dependent manner. The proportion of internalised radioactivity secreted into bile also differed but in both cases showed a very rapid time-course similar to that of [24-(14)C]taurocholate and suggestive of non-endocytic transfer via membrane transport proteins. Pre-perfusion with the aminopeptidase inhibitor bestatin increased uptake of 3H-labelled Leu-enkephalin from 10% to 23%; no further increase occurred when the endopeptidase 24.11 inhibitor thiorphan was also present. On infusion of the native peptide into rat livers, 80% of Leu-enkephalin immunoreactivity was lost between the pre- and post-hepatic perfusate; this was reduced to 65% in the presence of 10(-5) M bestatin. The almost total release of the N-terminal tyrosine from 3H-labelled Leu-enkephalin which escaped first-pass uptake confirmed that substantial sinusoidal metabolism had occurred. Low levels of aminopeptidase N were visualised in the sinusoidal membrane using a specific monoclonal antibody coupled to peroxidase staining. Thus, hepatic inactivation of Leu-enkephalin is primarily via hydrolysis mediated by cell surface peptidase (including aminopeptidases) whilst uptake of the intact peptide, probably by a bile salt transport protein, is quantitatively minor unless the N-terminus is blocked by Bolton and Hunter reagent or peptidase inhibitors are present.     

Buspirone: future directions

Glucagon-like peptide 1(7-36) amide (GLP-1) is postulated to be the major physiological incretin in humans, but evidence is indirect. We report the first studies examining the physiological role of GLP-1 in the postprandial state in humans using the GLP-1 antagonist exendin 9-39. Exendin 9-39 completely blocked GLP-1-induced glucose-stimulated insulin release from perifused human islets of Langerhans. In healthy fasted volunteers, intravenous infusion of exendin 9-39 at 500 pmol x kg(-1) x min(-1) in the hyperglycemic state abolished the insulinotropic effect of a physiological dose of GLP-1 and fully reversed the glucose-lowering effect of GLP-1. Nine healthy subjects consumed a 150-g oral glucose tolerance test and were infused with 500 pmol x kg(-1) x min(-1) exendin 9-39 or saline. Exendin 9-39 increased the peak postprandial glucose level (exendin 9-39, 8.67 +/- 0.35 vs. saline, 7.67 +/- 0.35 mmol/l, P < or = 0.005) and increased postprandial plasma glucose incremental area under the curve by 35% (exendin 9-39, 152 +/- 19 vs. saline, 113 +/- 16 mmol x min x l(-1), P < or = 0.05). This could be explained as partly secondary to the blockade of glucose-induced suppression of glucagon and maybe also to an increased rate of gastric emptying. Thus, in humans exendin 9-39 acts as an antagonist of GLP-1 both in vitro and in vivo. When infused alone, exendin 9-39 causes a deterioration in postprandial glycemic control, suggesting that GLP-1 may be important for maintenance of normal postprandial glucose homeostasis in humans.     

Breast cancer immunotherapy: current status and future prospects

The development of an immunotherapeutic approach to cancer is the concern for many immunologists, but despite the impressive progress over the past decade, such as the identification of tumour antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. Mucins have attracted interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucin1 (MUC1; e.g. breast, pancreas, ovary etc.). All of the identified targets for cancer, including MUC1, are normal proteins; however MUC1 expressed on tumours can be considered as tumour specific due to their overexpression, altered glycosylation and its ubiquitous distribution on the cell surface rather than at the secretory pole in adenocarcinomas. These observations have led to the development of several different approaches to immunize against breast cancer using synthetic carbohydrates or peptides conjugated to carriers and given together with a variety of adjuvants to elicit the appropriate immune response. Mannan, a polymannose carbohydrate isolated from the cell wall of yeast, is an appropriate and effective protein carrier for eliciting a cellular (T1-type) or humoral (T2-type) immune response depending on the mode of conjugation (oxidized or reduced). In addition, mannan holds promise and opens many avenues as a carrier for vaccine development for other antigens. Several clinical trials are in progress to evaluate the immunogenicity of MUC1 and its suitability as to use for immunotherapy/vaccine for breast cancer.     

Oral chemotherapy: rationale and future directions

PURPOSE AND METHODS: The expanding role of oral chemotherapy in oncology is suggested by the abundance of orally formulated agents currently in development. The pharmacoeconomic principles that drive oral drug formulation are discussed. Patient preference for oral therapy is identified as a second major impetus for the design of oral cytotoxics. While the rationale for oral formulations is apparent, substantial patient compliance and pharmacokinetic limitations have been identified for this route of administration. Specific aspects of bioavailability limitations and patient compliance are discussed. Relevant pharmacokinetic data for each orally formulated chemotherapy agent are compared and selected novel oral cytotoxics and cytotoxic modulators are discussed. RESULTS: A review of pharmacokinetic literature suggests substantial variability in bioavailability for many orally formulated cancer cytotoxics. While these findings are observed for all classes of oral drugs, the issue is especially critical for cancer chemotherapy, in which a narrow therapeutic index is frequently observed. Improved bioavailability and reduced interpatient biovariability are therefore desirable for new cytotoxic formulations. Pharmacologic manipulations to improve bioavailability and reduce costs are examined. CONCLUSION: Oral chemotherapy represents a fundamental change in contemporary oncology practice, driven by pharmacoeconomic issues, patient convenience, and the potential for improved patient quality of life. Novel cytostatic therapies that require protracted drug administration periods will also favor an oral formulation. While the use of oral chemotherapy may initially be limited to metastatic disease palliation, demonstration of equivalent efficacy would allow for its subsequent use in adjuvant settings. This efficacy is contingent on circumventing bioavailability limitations and patient noncompliance. The development of specific, low-toxicity inhibitors of CYP3A4, P-glycoprotein (P-gp), and other drug metabolizing enzymes such as dihydropyrimidine dehydrogenase represents a major innovative step in the successful formulation of oral chemotherapy.     

What causes prostate cancer? A brief summary of the epidemiology

Epoetin alfa is the cornerstone of anemia therapy in patients with end-stage renal disease. In addition to stimulating erythropoiesis, Epoetin alfa has been demonstrated to affect hemostasis. Such effects may be important because patients with chronic renal failure have a bleeding diathesis that is multifactorial in origin. Therefore, a computer literature search on the relationship between Epoetin alfa therapy for anemia in patients with end-stage renal disease and platelets, coagulation, coagulation inhibitors, and fibrinolysis was performed. All articles and abstracts reporting original data in the English language on Epoetin alfa and its effect on hemostasis were reviewed. The literature suggests that the effects of Epoetin alfa on the coagulation cascade are of minimal clinical importance. However, Epoetin alfa transiently increases the number of circulating platelets and improves platelet function, and these effects are associated with a return of the bleeding time towards normal.     

Philosophy of nursing: future directions

At a time when psychiatric nurses in Australia face the changes brought about by the transfer of nursing education to the universities, it is timely to reconsider the knowledge base of the profession, not from the perspective of any one theoretical position, but by reflecting on a fundamental division in the way nursing is thought about. Many nurse theorists argue for a shift away from conceptions of nursing based on medicine and science. The alternative, idealism, brings with it a new set of problems, particularly the tendency to react against the perceived dominance of the medical profession instead of positing a philosophy of nursing that reflects a more considered response. The argument developed here begins by aligning medicine and related conceptions of nursing with materialism. This leads to a consideration of the relevance of philosophical positions on the nature of body and mind, that is then linked to the assumptions of medicine and nurse theorists. Introduction of the concepts of holism and interactionist dualism follows. The implications of these concepts for psychiatric nursing are drawn out by using conceptions of the objective and rational. Finally, it is argued that interactionist dualism enables psychiatric nurses to be sensitive to the experiences of patients while still acknowledging the importance of objective knowledge.     

Ischaemic preconditioning: present position and future directions

Antibodies generated against a synthetic growth hormone (GH) peptide in a number of animal species were shown to enhance the efficacy of GH. However, the ability to produce the effective antibodies diminished over the time and repeated boosters failed to overcome the hurdle. Therefore, this study was designed to address the issue on the fallen antibody responses by employing different GH peptide antigen preparations in cattle. Holstein steers were repeatedly immunized with a synthetic peptide corresponding to an amino acid sequence 54-95 of porcine GH (pGH). The peptide was conjugated to ovalbumin (OVA) as a carrier. Animals initially responded to the antigen well and elicited antibodies specific to the peptide. However, the 4th challenge with the same OVA-peptide antigen rendered animals unresponsive, resulting in a decline in antibody production. This unresponsiveness was overcome by switching the antigen at the 5th immunization from OVA-peptide to a recombinant peptide preparation which was composed of maltose binding protein (MBP) as a carrier. Antibodies generated in cattle after the 5th immunization recognized not only the pGH(54-95) peptide, but also bovine GH (bGH) and pGH. These antibodies were not immunoreactive with an unrelated control peptide. Hypophysectomized (hypox) rats were used for functional analysis and bGH was active in promoting the growth of these GH-deficient rats. The growth-promoting effect of bGH was significantly enhanced by mixing with bovine anti-peptide antibodies prior to administration. Therefore, the present findings suggest that peptide 54-95 induces cattle to elicit antibodies capable of not only recognizing bGH but also augmenting the somatogenic effectiveness of bGH in hypox rats.     

Historical aspects and future directions

A stratified random sample of 750 males aged 18 to 27 in Calgary, Canada included questions on sexual activity and orientation. A computerized response format (established as a good method for eliciting sensitive personal data) ensured anonymity. Three measures of homosexuality were employed: (1) voluntary, same-gender sexual contact from age 12 to 27: 14.0%; (2) overlapping homosexual (5.9%) and/or bisexual (6.1%) self-identification: 11.1%; and (3) exclusive (4.3%) and non-exclusive (4.9%) same-gender sexual relationships in past 6 months: 9.2%. On the basis of one or more of the three often overlapping measures, 15.3% of males reported being homosexual to some degree. CES-D depression scores did not differ significantly for sexually active homosexual (mean 14.6), bisexual (mean 15.7), and heterosexual (mean 13.7) males. The elevated depression scores for celibate homosexual (mean 27.1) and heterosexual (mean 23.6) males permit various interpretations, but are not supportive of beliefs and related institutional policies recommending or requiring that young adult homosexual males be celibate.     

Bispecific antibody targeted T cell therapy of ovarian cancer: clinical results and future directions

The high frequency of relapse after induction chemotherapy in advanced ovarian carcinoma patients calls for new therapeutic modalities. Retargeted T cell-mediated lysis can be achieved using the bispecific antibody (BsmAb) OCTR, directed to CD3 on T cells and to the folate receptor on ovarian carcinoma cells. Twenty-eight patients with limited intraperitoneal disease after first-line therapy entered a phase II study. They received two i.p. 5 day cycles of activated PBMC retargeted with OCTR. Despite unfavorable tumor characteristics, 7 of 26 patients (27%) showed complete or partial intraperitoneal responses with strict surgicopathologic evaluation. In most cases, the disease relapsed outside the peritoneal cavity, and in 1 case complete intraperitoneal response was accompanied by progression in retroperitoneal lymph nodes. The morbidity was mild to moderate and transient. Combination of i.v. and i.p. administration of OCTR-retargeted lymphocytes will possibly lead to extraperitoneal cure. Ongoing clinical studies indicate that the i.v. infusion of up to 8 x 10(8) OCTR-retargeted T lymphocytes does not induce a higher toxicity than the i.p. treatment. To avoid PBMC preactivation, new approaches for delivering accessory signals are under investigation. Preliminary results indicate that nonactivated PBMC retargeted by OCTR in the presence of an anti-CD28 monoclonal antibody (mAb) are able to significantly inhibit tumor growth.     

Lupus nephritis: novel immunosuppressive modalities and future directions

This study reports the effects of mannitol on nerve conduction when used as a therapeutic agent in mammals following the administration of ciguatoxin. Electrophysiological studies were performed in vivo on the rat ventral coccygeal nerve. The absolute and relative refractory periods, conduction velocity and the supernormal response were measured in rats treated with i.p. ciguatoxin, both prior to, and following, the infusion of i.v. mannitol. Ciguatoxin induced significant prolongation of the absolute refractory period as well as significant slowing of the compound nerve conduction velocity. The magnitude of the supernormal response was significantly increased and the duration of the supernormal period extended in ciguatoxin-treated animals. Recordings collected following the infusion of mannitol in these ciguatoxin-treated animals showed that mannitol did not reverse the effects of ciguatoxin on nerve conduction in any of the parameters measured.     

Evaluating the diagnostic interview: obstacles and future directions

The diagnostic interview plays a prominent role within the field of clinical psychology and occupies a fundamental component in graduate training. Educators seem to be focusing less on objective measures to evaluate student skill performance and the overall quality of the interview. The authors review the current methods for evaluating the diagnostic interview in psychology training and identify some of the major obstacles in accurately assessing student interview proficiency. Recommendations are made to address these difficulties, and the authors note some promising future directions.     

Transmyocardial laser revascularization: historical background and future directions

Transmyocardial laser revascularization (TMLR) was investigated as a possible treatment alternative for patients with refractory coronary artery disease. This paper is a summary of nearly four decades of research by the authors. Beginning in 1969 experimental studies were conducted on the beating heart. A prototype 450 W carbon dioxide laser was used to create channels in the ischemic myocardium. Initial clinical studies began in 1984. A protocol was developed for TMLR as an adjunct to CABG in those patient who had at least one vessel which could be bypassed and areas of ischemia which were not amenable to bypass. In the early 1990's the development of a 850 W CO2 laser for clinical use allowed us to begin investigation of TMLR on the beating heart. Patients with end stage coronary artery disease who were not candidates for other forms of treatment were selected. The early results are encouraging with patient followup of from 3 months to 5 years. There are numerous controversies regarding the effects of TMLR on myocardial function and perfusion. To quantify these effects the authors have performed acute and chronic studies on swine using sophisticated techniques with 3D cine magnetic resonance imaging. We concluded TMLR improved left ventricular function and perfusion in acute and chronic ischemia.     

Comorbidity and treatment planning: Summary and future directions.

Blends the commentaries from T. A. Brown and D. H. Barlow, K. T. Mueser et al, M. T. Shea et al, P. C. Kendall et al, H. Abikoff and R. G. Klein, and S. P. Hinshaw (see PA, Vol 80:13821, 13794, 14471, 13663, 13603, and 13616, respectively). Included is a discussion of various definitions of comorbidity, the merits and demerits of a hierarchical diagnostic system, and consideration of the extent, patterning, and nature of comorbidity. Directive comments with reference to future intervention planning mention both assessment (distinguishing overlapping constructs) and treatment (sequencing and treatment manuals) issues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

School consultation research: Past trends and future directions.

Reviews and evaluates school consultation research conducted during the past decade. Attention is given to the breadth and quality of the present consultation knowledge base, the appropriateness of data analysis procedures, and the impact of consultation research findings on consultation training. Recommendations for future directions in school consultation research are offered from both methodological and substantive perspectives. (41 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)