Needle exchange programs: an economic evaluation of a local experience

OBJECTIVE: To determine whether providing a needle exchange program to prevent HIV transmission among injection drug users would cost less than the health care consequences of not having such a program. DESIGN: Incidence outcome model to estimate the number of cases of HIV infection that this program would prevent over 5 years, assuming that the HIV incidence rate would be 2% with the program and 4% without it, and that an estimated 275 injection drug users would use the service over this time. SETTING: Hamilton, Ont. OUTCOME MEASURES: Estimated number of cases of HIV infection expected to be prevented with and without the program over 5 years; estimated lifetime health care costs of treating an AIDS patient. The indirect costs of AIDS to society (e.g., lost productivity and informal caregiving) were not included. Projected costs were adjusted (discounted) to reflect their present value. In a sensitivity analysis, 3 parameters were varied: the estimate of the HIV transmission rate if no needle exchange program were provided, the number of injection drug users participating in the program, and the discount rate. RESULTS: With very conservative estimates, it was predicted that the Hamilton needle exchange program will prevent 24 cases of HIV infection over 5 years, thereby providing cost savings of $1.3 million after the program costs are taken into account. This translates into a ratio of cost savings to costs of 4:1. The sensitivity analysis confirmed that these findings are robust. CONCLUSION: Needle exchange programs are an efficient use of financial resources.     

Mutant adenovirus type 9 E4 ORF1 genes define three protein regions required for transformation of CREF cells.

Human adenovirus type 9 (Ad9) elicits exclusively estrogen-dependent mammary tumors in rats, and an essential oncogenic determinant for this virus is Ad9 E4 open reading frame 1 (9ORF1), which encodes a 125-residue cytoplasmic protein with cellular growth-transforming activity in vitro. In this study, we engineered 48 different mutant 9ORF1 genes in an attempt to identify regions of this viral protein essential for transformation of the established rat embryo fibroblast cell line CREF. In initial assays with CREF cells, 17 of the 48 mutant 9ORF1 genes proved to be severely defective for generating transformed foci but only 7 of these defective genes expressed detectable amounts of protein. To further examine the defects of the seven mutant proteins, we selected individual cell pools of stable CREF transformants for the wild-type and mutant 9ORF1 genes. Compared to cell pools expressing the wild-type 9ORF1 protein, most cell pools expressing mutant proteins displayed decreased growth in soft agar, and all generated significantly smaller tumors in syngeneic animals. The altered amino acid residues of the seven mutant 9ORF1 polypeptides clustered within three separate regions referred to as region I (residues 34 to 41), region II (residues 89 to 91), and C-terminal region III (residues 122 to 125). By using indirect immunofluorescence, we also assessed whether the mutant proteins localized properly to the cytoplasm of cells. The region I and region II mutants displayed approximately wild-type subcellular localizations, whereas most region III mutants aberrantly accumulated within the nucleus of cells. In summary, we have identified three 9ORF1 protein regions necessary for cellular transformation and have demonstrated that C-terminal region III sequences significantly influence the proper localization of the 9ORF1 polypeptide in cells.     

Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase

Galliven, E. A., A. Singh, D. Michelson, S. Bina, P. W. Gold, and P. A. Deuster. Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase.J. Appl. Physiol. 83(6):1822-1831, 1997.Two studies, each utilizing short-term treadmillexercise of a different intensity, assessed the metabolic and hormonalresponses of women to exercise in the morning (AM) and late afternoon(PM). In study 1, plasmaconcentrations of growth hormone, arginine vasopressin, catecholamines,adrenocorticotropic hormone, cortisol, lactate, and glucose weremeasured before, during, and after high-intensity exercise (90%maximal O₂ uptake) in the AM andPM. In study 2, plasma concentrationsof adrenocorticotropic hormone, cortisol, lactate, andglucose were measured before, during, and aftermoderate-intensity exercise (70% maximalO₂ uptake) in the AM and PM in thefollicular (days 3-9), midcycle (days 10-16), and luteal(days 18-26) phases of themenstrual cycle. The results of studies1 and 2 revealed nosignificant diurnal differences in the magnitude of responses for anymeasured variable. In addition, study2 revealed a significant time-by-phase interaction forglucose (P = 0.014). However, netintegrated responses were similar across cycle phases. These datasuggest that metabolic and hormonal responses to short-term,high-intensity exercise can be assessed with equal reliability in theAM and PM and that there are subtle differences in blood glucoseresponses to moderate-intensity exercise across menstrual cycle phase.

     

Monophyly of the order Rodentia inferred from mitochondrial DNA sequences of the genes for 12S rRNA, 16S rRNA, and tRNA-valine

A recent analysis of amino acid sequence data (Graur et al.) suggested that the mammalian order Rodentia is polyphyletic, in contrast to most morphological data, which support rodent monophyly. At issue is whether the hystricognath rodents, such as the guinea pig, represent an independent evolutionary lineage within mammals, separate from the sciurognath rodents. To resolve this problem, we sequenced a region (2,645 bp) of the mitochondrial genome of the guinea pig containing the complete 12S ribosomal RNA, 16S ribosomal RNA, and transfer RNA(VAL) genes for comparison with the available sciurognath and other mammalian sequences. Several methods of analysis and statistical tests of the data all show strong support for rodent monophyly (91%-98% bootstrap probability, or BP). Calibration with the mammalian fossil record suggests a Cretaceous date (107 mya) for the divergence of sciurognaths and hystricognaths. An older date (38 mya) for the controversial Mus- Rattus divergence also is supported by these data. Our neighbor-joining analyses of all available sequence data (25 genes) confirm that some individual genes support rodent polyphyly but that tandem analysis of all data does not. We propose that the conflicting results are due to several compounding factors. The unique biochemical properties of some hystricognath metabolic proteins, largely responsible for generating this controversy, may have a single explanation: a cascade effect resulting from inactivation of the zinc-binding abilities of insulin. After excluding six genes possibly affected by insulin inactivation, analyses of all available sequence data (7,117 nucleotide sites, 3,099 amino acid sites) resulted in strong support for rodent monophyly (94% BP for DNA sequences, 90% for protein sequences), which lends support to the insulin-cascade hypothesis.      

A freeze-fracture study of the nuclear envelope during spermiogenesis inMarsilea. Formation of a pore-free zone associated with the microtubule ribbon

Summary The nuclear envelope was freeze-fractured at different stages during spermiogenesis inMarsilea. Nuclear pores were seen at all stages of development, but were excluded from a specialized region of the nuclear envelope that is in contact with the microtubule ribbon. The microtubule ribbon is associated with one edge of the nuclear envelope throughout nuclear shaping and chromatin condensation and the pore-free zone may be a region of the nuclear envelope that is important in these processes.     

Phanerochaete chrysosporium beta-Glucosidases: Induction, Cellular Localization, and Physical Characterization

Phanerochaete chrysosporium produces intracellular soluble and particulate beta-glucosidases and an extracellular beta-glucosidase. The extracellular enzyme is induced by cellulose but repressed in the presence of glucose. The molecular weight of this enzyme is 90,000. The K(m) for p-nitrophenyl-beta-glucoside is 1.6 x 10 M; the K(i) for glucose, a competitive inhibitor, is 5.0 x 10 M. The K(m) for cellobiose is 5.3 x 10 M. The intracellular soluble enzyme is induced by cellobiose; this induction is prevented by cycloheximide. The presence of 300 mM glucose in the medium, however, had no effect on induction. The K(m) for p-nitrophenyl-beta-glucoside is 1.1 x 10 M. The molecular weight of this enzyme is approximately 410,000. Both enzymes have an optimal temperature of 45 degrees C and an E(act) of 9.15 kcal (ca. 3.83 x 10 J). The pH optima, however, were approximately 7.0 and 5.5 for the intracellular and extracellular enzymes, respectively.     

Relationship between microsomal membrane permeability and the inhibition of hepatic glucose-6-phosphatase by pyridoxal phosphate.

Arion et al; (Arion, W. J., Wallin, B. K., Lange A. J., and Ballas, L. M. (1975) Mol. Cell. Biochem. 6, 75-83) propsed a model for glucose-6-phosphatase in which the substrate was transported across the microsomal membrane by a carrier before hydrolysis on the cisternal side. Evidence to support this model has been obtained by studying the inhibition of the enzyme by pyridoxal-P. Pyridoxal-P was a linear noncompetitive inhibitor of glucose-6-phosphatase (EC 3.1.3.9) in freshly isolated ("intact") microsomes from rat liver. Pyridoxol-P was a much less effective inhibitor and no inhibition was observed with pyridoxamine-P. When microsomes were subjected to nitrogen cavitation, treatment with solium deoxycholate, or glutaraldehyde fixation, the Km of glucose-6-phosphatase for glucose-6 P decreased from approximately 6 mM to approximately 2.5 mM; the corresponding change in the Vmax ranged from-10% to +40%. The same procedures decreased the inhibition of glucose-6-phosphatase by pyridoxal-P several-fold. No inhibition by pyridoxal-P was observed in a preparation of glucose-6-phosphatase purified approximately 20 fold (on the basis of Vmax) from micoromes. A nondialyzable inhibitor was apparently formed when intact microsomes were reacted with pyridoxal-P and NaBH4; this inhibition was also reversed by procedures which changed the kinetic properties of glucose-6-phosphatase.