Decrease in muscle glutamine, ribosomes, and the nitrogen losses are similar after laparoscopic compared with open cholecystectomy during the immediate postoperative period

A number of studies have localized CGRP to nerves in the cornea and iris, and it is thought that CGRP, along with other neuropeptides, is involved in pain sensation. It is also possible that CGRP could mediate trophic influences between nerve endings and corneal epithelium. This investigation utilized an in vitro rabbit corneal whole mount preparation to study the effect of topical 2.5 microM CGRP application on epithelial wound healing rates of 5 mm diameter epithelial wounds. CGRP (2.5 microM) was applied topically to 5 mm epithelial wounds at 0, 4, 16, 20, 24, 28, 40, 44, 48, 52, 56, 64, 68, and 72 hours after wounding and healing was visualized with fluorescein. CGRP was found to increase the epithelial wound healing rate by 25%, from 51 +/- 3 microns/hr for the control corneas, to 64 +/- 2 microns/hr for CGRP-treated corneas (mean +/- standard error, n = 10). Histological examination of the corneas following healing showed that the epithelium of the CGRP-treated corneas healed in a similar manner as in the control corneas. These findings may have clinical utility for the understanding and treatment of corneal and other epithelial wounds.     

Distributed interactive simulation in the evolution of DoD warfaremodeling and simulation

Distributed interactive simulation (DIS) is a revolutionary development that is changing permanently many features of Defense Department work. The field of warfare modeling and simulation (M&S) is quite large, however, and this paper reviews its evolution and how DIS fits within it. A few things are clear. First, DIS is exceedingly valuable for training. Second, DIS could be a powerful means for improving the quality of planning and analysis if used wisely for occasional well designed experiments. These could 1) provide insights about real-world processes involving human performance and behavior (including decision making), 2) help inform and calibrate models, and 3) help test plans in a quasioperational environment. Third, distributed war gaming, which depends on DIS technology, is already lowering boundaries among developers, planners, and warfighters. This can shorten development processes and improve the results through virtual prototyping; it can also improve operational readiness. To achieve these potential benefits, however, will require a holistic approach, conceptual breakthroughs, and profoundly difficult model development efforts. The challenges include developing integrated hierarchies of models, developing adaptive decision models and other models of human behavior, developing and using new forms of uncertainty-sensitive analysis, and learning how to use DIS experiments effectively     

Synthesis and antitumor evaluation of 2,5-disubstituted-indazolo[4, 3-gh]isoquinolin-6(2H)-ones (9-aza-anthrapyrazoles)

The synthesis and antitumor evaluation of 2, 5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-aza-APs) are described. The key intermediates in the synthesis are benz[g]isoquinoline-5,10-diones which are substituted at positions 6 and 9 with groups of different nucleofugacity for SNAr displacements. The initial displacement of fluoride by a substituted hydrazine leads to the pyrazole analogues. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs 12. These analogues were converted into their maleate or hydrochloride salts 13. In two cases, namely, 13x and 13z, sidearm buildup was also employed in the synthetic pathway. In vitro evaluation of 9-aza-APs against the human colon tumor cell line LoVo uncovered for most of the compounds a cytotoxic potency lower than that of DuP-941 or mitoxantrone and comparable to that of doxorubicin. Only analogues 13c, 13n, and 13ff were as cytotoxic as DuP-941. Interestingly, while DuP-941 was highly cross-resistant in the LoVo cell line resistant to doxorubicin (LoVo/Dx), the 9-aza-APs carrying a distal lipophilic tertiary amine moiety in both chains were capable of overcoming the MDR resistance induced in this cell line. The 9-aza-APs show outstanding in vivo antitumor activity against both systemic P388 murine leukemia and MX-1 human mammary carcinoma transplanted in nude mice. At their optimal dosages, congeners 13a-c, 13f, 13n, 13q, 13x, and 13dd were highly effective against P388 leukemia with T/C% of 200-381, while the T/C% value of DuP-941 was 147. In the MX-1 tumor model, 24 compounds elicited percentages of tumor weight inhibitions (TWI) ranging from 50% to 99%. Congeners 13d, 13k, 13l, 13x, 13z, and 13ee emerged as the most effective ones, with TWI% 96, simliar to that of DuP-941 (TWI% = 95). On the basis of their efficacy profile in additional experimental tumors and lack of cardiotoxicity in preclinical models, two congeners have surfaced as potential clinical candidates.     

Melting of a DNA hairpin without hyperchromism

UV absorbance spectroscopy is the most common method for detecting nucleic acid structural transitions and obtaining thermodynamic parameters. UV-detected melting has been used to determine stabilities of nucleic acid hairpins, duplexes, triplexes, and higher order structures and to determine thermodynamic effects of unusual or modified bases and mismatched base-pairs. We report that in some cases UV absorbance spectroscopy is an inadequate analytical technique for these purposes. Some critical transitions are invisible to UV absorbance spectroscopy. For example, the conversion of dodecamer d(CGCAAATTCGCG) from hairpin to random coil is not accompanied by hyperchromism. Circular dichroism (CD) spectroscopy (263 nm) clearly detects two transitions for this dodecamer, each giving a pronounced change in ellipiticity. The concentration dependence of the low-temperature transition and the concentration independence of the high-temperature transition indicate that the predominant state converts from duplex to hairpin to random coil as the temperature increases. These assignments are confirmed by comparison to oligonucleotides of similar sequence that undergo a hairpin to coil transition only. In contrast to CD spectroscopy, UV absorbance spectroscopy shows only a single transition. The transition detected by UV absorbance spectroscopy corresponds to the low-temperature transition detected by CD. UV absorbance spectroscopy does not detect the second transition at any wavelength (from 218 to 310 nm) (by changes) in either absorbance or its derivative with temperature.     

Non-transferrin iron uptake by trophoblast cells in culture. Significance of a NADH-dependent ferrireductase

BACKGROUND: Glucocorticoids have been linked to self-administration of a wide range of drugs in animals and are increased endogenously by chronic nicotine intake. Corticosteroids have also been shown to regulate nicotine receptor sensitivity and to be involved in behavioral sensitization to nicotine. METHODS: Cortisol levels and cortisol suppression in response to dexamethasone were measured in a sample of smokers participating in a smoking cessation treatment trial. RESULTS: Cortisol levels dropped significantly during the early quitting process (2 weeks post-quit) and returned to a level below baseline 1 month post-quit. The magnitude of the initial drop in cortisol was strongly related to post-quit distress and marginally predictive of abstinence. Neither baseline nor post-quit changes in percent cortisol suppression after dexamethasone were related to abstinence success or withdrawal distress. CONCLUSIONS: Withdrawal from cigarette smoking is marked by a reduction in cortisol levels that appears to be related to the degree of distress experienced during the early quitting period. Further work is needed to determine whether withdrawal-related cortisol changes or distress are predictive of abstinence success.     

Progressive familial leukodystrophy of late onset

We report a family in which three siblings developed dementia between the ages of 40 and 70 years. Two of the siblings developed symptoms of depression, abnormal behavior, and an inability to function, progressing to severe dementia. The third sibling had a severe dementia, the clinical details of which are not available. In the two deceased siblings neuropathologic examinations demonstrated severe demyelination, axon loss, and gliosis in cerebral white matter. Cerebellar and brainstem white matter were unaffected. Cerebral gray matter was negligibly affected. The disorder, histopathologically classified as a pigmented orthochromatic leukodystrophy, is extremely rare. Its etiology is unknown, but the pathology and familial occurrence imply that it represents a genetic defect in a function localized in the cerebral white matter.     

Ethical and practical issues involved in behavioral pharmacology research that administers drugs of abuse to human volunteers

Researchers carrying out non-therapeutic research that involves the administration of drugs of abuse to human volunteers can be faced with many ethical and practical questions. The history of this type of research is relatively brief, with little in the way of published information relevant to carrying out behavioral pharmacological research with human participants. The aim of this article is to raise issues that occur in most studies of this type and to provide solutions that we have found acceptable and which have been approved by a variety of institutions and regulatory agencies. Clearly, there are other approaches that would work equally as well, and we are not attempting to provide 'the' answer to many of the issues raised. We believe that raising these issues and providing our perspectives is important for stimulating others to discuss them and for all of us to strive, where possible, to reach a consensus concerning ethical practices and to become aware of gaps and pitfalls. The topics discussed range from the nuts and bolts of acquiring and keeping track of drugs, to selecting research participants and designing ethical studies that protect our volunteers while still collecting scientifically useful data.     

Recruitment strategies in the women's health trial: feasibility study in minority populations. WHT:FSMP Investigators Group. Women's Health Trial:Feasibility Study in Minority Populations

The Women's Health Trial:Feasibility Study in Minority Populations (WHT:FSMP) examined the feasibility of recruiting postmenopausal women from a broad range of racial and socioeconomic backgrounds into a primary prevention trial requiring marked reductions in dietary fat. Postmenopausal women aged 50-79 yr who had no history of cardiovascular disease or cancer and who consumed 36% or more total energy from fat qualified to participate. We randomized the women into dietary intervention (60%) or control (40%) groups; we aimed to randomize 750 women in 18 months in each of the three clinical centers. All centers achieved goals for randomization based on ethnicity, and two centers exceeded overall recruitment goals. The greatest source of randomized participants was mass mailing, followed by items in the media, referrals, and community outreach. Recruitment yields were generally similar for the ethnic groups but lower for less-educated participants. The experience of WHT:FSMP indicates that postmenopausal women from the African-American, Hispanic, and non-Hispanic white communities can be recruited into dietary intervention studies for the prevention of disease.