Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.     

Normal-incidence InAs self-assembled quantum-dot infrared photodetectors with a high detectivity

An InAs/AlGaAs quantum-dot infrared photodetector based on bound-to-bound intraband transitions in undoped InAs quantum dots is reported. AlGaAs blocking layers were employed to achieve low dark current. The photoresponse peaked at 6.2 /spl mu/m. At 77 K and -0.7 V bias, the responsivity was 14 mA/W and the detectivity, D*, was 10/sup 10/ cm/spl middot/Hz/sup 1/2//W.     

Differential divalent cation requirements uncouple the assembly and catalytic reactions of human immunodeficiency virus type 1 integrase

Previous in vitro analyses have shown that the human immunodeficiency virus type 1 (HIV-1) integrase uses either manganese or magnesium to assemble as a stable complex on the donor substrate and to catalyze strand transfer. We now demonstrate that subsequent to assembly, catalysis of both 3' end processing and strand transfer requires a divalent cation cofactor and that the divalent cation requirements for assembly and catalysis can be functionally distinguished based on the ability to utilize calcium and cobalt, respectively. The different divalent cation requirements manifest by these processes are exploited to uncouple assembly and catalysis, thus staging the reaction. Staged 3' end processing and strand transfer assays are then used in conjunction with exonuclease III protection analysis to investigate the effects of integrase inhibitors on each step in the reaction. Analysis of a series of related inhibitors demonstrates that these types of compounds affect assembly and not either catalytic process, therefore reconciling the apparent disparate results obtained for such inhibitors in assays using isolated preintegration complexes. These studies provide evidence for a distinct role of the divalent cation cofactor in assembly and catalysis and have implications for both the identification and characterization of integrase inhibitors.     

Reasons for personnel turnover in a private health facility

In this article 1 describe efforts to build a genetically informative, population-based sample of black twins to study physical frailty and aging in the United States. This project involves the use of governmental registries combined with sampling techniques developed to overcome limitations in the registry data. Two analytical approaches to measures of disability are included to illustrate the types of questions that can be addressed with this sample. These results suggest that physical disability in late life has both genetic and environmental determinants. Only with a genetically informative sample can evidence be collected indicating that frailty may be driven by fixed processes (i.e., disability resulting from activation of senescence genes), fluid processes (i.e., disability resulting from changes in the features of the environment), or a combination of both.     

Polymorphonuclear neutrophil granulocyte chemotactic hyperresponsiveness in a case of canine acromegaly

Growth hormone (GH) has recently been shown to affect polymorphonuclear neutrophil granulocyte (PMN) function and to be secreted by mononuclear cells, indicating that the hormone may be active in an immunophysiologic network, acting as an endo- or paracrine priming agent. The purpose of the present study was to evaluate the chemotactic responsiveness of canine peripheral PMN in a dog with acromegaly, caused by spontaneous, progesterone-induced hypersecretion of GH and, secondary to this, a seven-fold increase in insulin-like growth factor I (IGF-I). The chemotactic responsiveness towards zymosan-activated serum (ZAS) and leukotriene B4 (LTB4) was evaluated at a time when the dog suffered from acromegaly and again 57 days after corrective surgery (ovariohysterectomy). The experiments showed that PMN from the patient exhibited enhanced chemotactic migration that appeared to be associated with the hypersomatotropic condition as judged from the reversibility of the phenomenon. The glucose intolerance and elevated serum alkaline phosphatase that were observed in the acromegalic dog were also shown to be reversible following surgery.     

Adherence to pharmacologic management of hypertension

Adherence to pharmacologic therapy of hypertension is low (in the range of 50-70%) and has important implications both for blood pressure control and cardiovascular complications. Based on a review of the literature using the levels of evidence grading technique, determinants of adherence to the pharmacologic therapy of hypertension have been assessed. Additionally, interventions to improve compliance were evaluated. Patient-centred, health care provider-centred and drug-specific factors have all been shown to affect adherence rates. We conclude that the extent of adherence to pharmacologic therapy is modifiable. Measurable improvements in adherence can be obtained from simplified medication regimens and a combination of behaviour strategies, including the tailoring of pill-taking to patients' daily habits and rituals, the advocacy of self-monitoring of pills and blood pressure, and the institution of reward systems.     

Transmission electron microscopic analysis of kidney glomeruli obtained by fine-needle aspiration

Aspiration biopsy of tumors and transplanted organs is a popular atraumatic method for diagnosis and also for the management of patients. Apart from the cytological analyses, it is clear that large aggregates of cells are obtained and these may be examined by electron microscopy. A study was carried out with dogs to assess the yield of intact glomeruli and tubules, resulting from a standard fine-needle aspiration procedure. Employing a 20-gauge needle, yields of approximately ten intact glomeruli were obtained with a tissue processing protocol that utilized filtration through a nylon mesh and backwashing, to resuspend the trapped aggregates. Processing for electron microscopy was carried out in microcentrifuge tubes. The ultrastructural preservation was excellent and the extension of these studies to investigations of not only renal transplantation, but also for diagnosis in human renal diseases of a broad spectrum, is suggested.     

Microstructural engineering applied to the controlled cooling of steel wire rod: Part I. Experimental design and heat transfer

The goal of this study was to develop a mathematical model which incorporates heat flow, phase transformation kinetics, and property-structure-composition relationships to predict the mechanical properties of steel rod being control cooled under industrial conditions. Thus, the principles of microstructural engineering have been brought to bear on this interdisciplinary problem by combining computer modeling with laboratory measurements of heat flow, austenite decomposition kinetics, microstructure and mechanical properties, and industrial trials to determine heat transfer and obtain rod samples under known conditions. Owing to the length and diversity of the study, it is reported in three parts,_[8191]the first of which is concerned with the heat flow measurements. A relatively simple and reliable technique, involving a preheated steel rod instrumented with a thermocouple secured at its centerline, has been devised to determine the cooling rate in different regions of the moving bed of rod loops on an operating Stelmor line. The measured thermal response of the rod has been analyzed by two transient conduction models (lumped and distributed parameter, respectively) to yield overall heat-transfer coefficients for radiation and convection. The adequacy of the technique has been checked by cooling instrumented rods under well-defined, air crossflow conditions in the laboratory and comparing measured heat-transfer coefficients to values predicted from well-established equations. The industrial thermal measurements have permitted the characterization of a coefficient to account for radiative interaction among adjacent rod loops near the edge and at the center of the bed. Formerly Graduate Student, The University of British Columbia.     

Acetohydroxy acid synthase and threonine deaminase activities, and the biosynthesis of isoleucine-leucine-valine in Streptococcus bovis

Acetohydroxy acid synthase (AHAS) and threonine deaminase (TD) activities were found in Streptococcus bovis and shown to be involved in the biosynthesis of the branched chain amino acids isoleucine, leucine and valine. Apparent lack of repression of AHAS synthesis by the end-products and reduced sensitivity of S. bovis growth to analogues of the branched chain amino acids suggested that secretion of isoleucine, leucine and valine in the growth medium may be a consequence of the regulatory features of AHAS. A glycyl-leucine-resistant mutant with reduced TD activity secreted a reduced amount of isoleucine and an increased amount of valine, which might be a result of the reduced rate of synthesis of the isoleucine precursor alpha-ketobutyrate and of a consequent preferential carbon flow through the valine branch of the pathway.     

Ethnic differences in the length of the menstrual cycle during the postmenarcheal period

In 1989, 125 African-American and 123 European-American girls aged 12-14 years were enrolled in a 2-year study in which they maintained a menstrual calendar, recording the date and amount of menstrual bleeding. Weight, exercise, and stress during the previous week were recorded at the start of each menstrual cycle. Although only minor ethnic differences were observed in expected cycle length (29.3 vs. 28.8 days for European-American and African-American girls, respectively), more prominent differences were observed in the between-subjects standard deviation of cycle length (2.9 vs. 2.2 days, respectively) and in the odds of having a cycle longer than 45 days (odds ratio=1.86, 95% confidence interval 1.17-2.97) for European-American compared with African-American girls. Low weight for height and high levels of exercise increased the probability of having a cycle longer than 45 days and decreased expected cycle length of 13- to 45-day cycles. Additional investigation of potential ethnic differences in menstrual cycle characteristics is warranted.