Inhibition of hepatitis B virus replication during adenovirus and cytomegalovirus infections in transgenic mice

We have previously demonstrated that hepatitis B virus (HBV) replication and gene expression are abolished in the livers of HBV transgenic mice by cytotoxic T lymphocytes (CTLs) and during lymphocytic choriomeningitis virus (LCMV) infection, stimuli that trigger the production of alpha/beta interferon, gamma interferon, and tumor necrosis factor alpha in the liver. We now report that hepatic HBV replication and gene expression are inhibited by the local induction of these cytokines during adenovirus- and murine cytomegalovirus (MCMV)-induced hepatitis. Further, we show that MCMV also blocks HBV replication and gene expression in the proximal convoluted tubules of the kidney by causing interstitial nephritis and inducing the same cytokines in the renal parenchyma. These results suggest that inflammatory cytokines probably contribute to viral clearance during acute viral hepatitis in humans, and they imply that induction of these cytokines in the liver and other infected tissues of chronically infected patients might have therapeutic value.     

The entry of [D-penicillamine2,5]enkephalin into the central nervous system: saturation kinetics and specificity

The delta opioid receptor-selective, enzymatically stable peptide [D-Penicillamine2,5]enkephalin (DPDPE) has recently acquired special significance with the identification of a saturable uptake system for this analgesic into the CNS. The aim of the present study was to characterize further the entry of [3H]DPDPE into the brain and CSF by means of a bilateral in situ brain perfusion method. Initial experiments revealed a saturable [3H]DPDPE uptake into the brain that followed Michaelis-Menten type kinetics with a K(m) value of 45.5 +/- 27.6 microM, a V(max) value of 51.1 +/- 13.2 pmol x min(-1) x g(-1) and a K(d) value of 0.6 +/- 0.3 microl x min(-1) x g(-1). Uptake of [3H]DPDPE into the CSF could not be inhibited (K(d) = 0.9 +/- 0.1 microl x min(-1) x g(-1)). Entry of [3H]DPDPE into the CNS was not inhibited in the presence of 10 mM 2-aminobicyclo-[2,2,1]-heptane-2-carboxylic acid (BCH) or 50 microM ICI 174,864, which suggests that the saturable mechanism does not involve the large neutral amino acid transporter or binding to opioid receptors. It would also appear that [3H]DPDPE is not in competition with either poly-L-lysine or insulin to enter the CNS. However, both of these substances significantly increased the CNS entry of [3H]DPDPE but not that of the vascular space marker [14C]sucrose, and this may have valuable clinical implications. It is not known at present which saturable uptake mechanism is responsible for the CNS entry of [3H]DPDPE, but overall the results suggest a carrier-mediated transport system.     

Tracking of markers and onset of disease among HIV-1 seroconverters

Repeated measurements on persons infected with HIV-1 indicate that infection has a dynamic impact on several markers of immune suppression and activation. The objectives of this report are: (a) to provide a statistical model for the correlation structure of serial measurements of immunological markers, and (b) to identify features of marker profiles associated with the timing of AIDS diagnoses. We analyse data obtained from 328 seroconverters participating in the Multicenter AIDS Cohort Study on whom the date of HIV-1 seroconversion is known within +/- 4.5 months. Immunological markers considered here are CD4 cell counts, serum beta 2-microglobulin and serum neopterin. The statistical model for HIV-related changes in markers consists of (1) a piecewise linear regression model for the trajectories of markers over time and (2) a two-parameter autocorrelation function that generalizes Markovian and simple random effects autocorrelation structures. Application of this model for marker measurements revealed a high degree of tracking, as the estimated autocorrelation function exhibited sub-exponential decay over time. Though current marker levels are most informative on future values, there is substantial information (memory) in previous measurements. A feature suggested by the analysis of groups formed according to the length of the AIDS-free period, is the sequential divergence of the CD4 trajectories where steeper declines occurred with a two-year lag prior to AIDS onset. For AIDS cases diagnosed 3-5 and 5-7 years after seroconversion, the rates of decline compared with those free of AIDS for at least 4 years were steeper by 95 and 46 per cent respectively at two years prior to AIDS.     

Investigating the numerical effects of ascertainment bias in linkage analysis: development of methods and preliminary results

It is general practice to have nonsingle ascertainment of pedigrees for linkage studies, along with intrafamilial sampling that is dependent on who among the related individuals was initially ascertained (Proband dependent or PD sampling). Vieland and Hodge [1995; 1996] have shown that under these conditions, the likelihood used in calculating the lod score is not strictly correct and can produce asymptotically biased estimates of the recombination fraction, theta. However they speculated that this bias would be small in most applications. This paper presents preliminary work aimed at quantifying the numerical magnitude of the bias introduced by PD sampling and nonsingle ascertainment in linkage analysis. We considered five generating models where we varied the ascertainment procedure, intrafamilial sampling scheme, and the sample size for each model. In this limited initial set of simulations, asymptotic bias in theta appears to be trivial, while PD sampling procedures can increase the efficiency of theta. These preliminary results support the view that the advantages of unsystematic ascertainment may offset any small estimation bias that may arise.     

The effect of systemic d-amphetamine on motor versus motivational processes in the rat

Reflective practice has emerged in the U.K. and beyond as an important issue not just in nursing but in many other professions. However, it remains problematic; it is difficult to conceptualize and many aspects of it are open to debate. Reflective practice is also contentious because, at a fundamental level, it raises a number of important issues for professional practitioners and the way they view their practice. The intention of this paper is to: explore some of the issues that have emerged as the profession of nursing and other professions have gained a better understanding of reflective practice; broaden the scope of the debate and refocus it; raise issues which are in need of further research.     

Maintaining ambulation in the frail nursing home resident: a nursing administered walking program

This article describes a walking program that was implemented at a 550-bed long-term care facility. The program was developed in order to promote functional mobility in the frail nursing home population. The aim of the program is to establish a nursing procedure that focuses on the individual resident's need to walk, and to improve or maintain the ambulatory status of the frail elderly. Twenty nursing home residents from the first three units on which the program was implemented were evaluated before and after the implementation of the program. The data show that the participants improved their ambulatory status after participating in the walking program. This improvement was accompanied by a decrease in the proportion of residents falling.     

Antimicrobial susceptibility of periodontopathic bacteria associated with failing implants

Histological, immunohistochemical, and flow cytometric characteristics of three unusual parotid gland tumors are described. The patients were adult white men with carcinoma ex pleomorphic adenoma, true malignant mixed tumor, and primary parotid gland chondrosarcoma. The carcinoma ex pleomorphic adenoma showed evidence of simultaneous epithelial, myoepithelial, and mesenchymal differentiation by immunohistochemistry. The true malignant mixed tumor exhibited variable positivity for two keratins, vimentin, proliferating cell nuclear antigen, Ki67, and p53. The chondrosarcoma initially stained for vimentin, S100, muscle-specific actin, proliferating cell nuclear antigen, and Ki67, but it lost actin expression in its first recurrence, accompanied by more extensive Ki67 staining. DNA ploidy varied from diploid to aneuploid with intratumoral variation in the carcinosarcoma. S-phase fractions ranged from 2.43% to 13.9%. The findings underscore the diversity of tumors that may be pathogenetically related to, and at times derived from, pleomorphic adenoma.     

Assessment of the anti-G straining maneuver (AGSM) skill performance and reinforcement program

Retractions of the pars flaccida (PF) and the pars tensa (PT) were assessed in 250 atelectatic ears in an attempt to find out the way in which the differences in mechanical properties of the two parts of the tympanic membrane are reflected clinically. Retraction of PF was found in 217 ears (86.8 per cent) and retraction of PF in 150 (60 per cent). The concomitant presence of both types of retraction was observed in 117 ears (46.8 per cent) while 133 (53.2 per cent) had only one type, 100 of them (75.1 per cent) PF retraction and 33 (24.9 per cent) PT retraction. When only one type of retraction was present, the empirical probability of having a PF retraction was 75.1 per cent, while the probability of having a PT retraction was only 24.9 per cent. Clinically, the more frequent occurrence of PF retraction in the absence of PT retraction than vice versa reflects the greater collapsibility of the PF. When both types of retractions were present, we found a positive correlation between their severity.     

Evaluation of the AMPLICOR cytomegalovirus test with specimens from human immunodeficiency virus-infected subjects

The AMPLICOR cytomegalovirus (CMV) test, a new qualitative assay for the detection of CMV DNA in plasma, was compared to conventional methods and quantitative PCR (Q-PCR) assays by using leukocytes and plasma from 179 blood samples from subjects with AIDS. For the diagnosis of CMV disease, cell-based assays such as a Q-PCR with polymorphonuclear leukocytes (Q-PCR-PMNL) and a pp65 antigenemia assay had the highest sensitivities but suffered from a lack of specificity. The best agreement between the results of the Q-PCR-PMNL assay and those of the AMPLICOR test was found when a threshold diagnostic value of 690 copies per 10(5) cells was selected for the Q-PCR-PMNL assay. In that context, the AMPLICOR CMV test had a sensitivity of 96.4% and a specificity of 95.3% when results were compared to results of the cell-based PCR assay. This threshold was close to the one described as associated with the best sensitivity and specificity for the diagnosis of CMV disease in a recently published study (4). Blood samples that tested positive by the Q-PCR-PMNL assay but negative by the AMPLICOR CMV test were associated with viral loads (mean, 785 copies, median, 96 copies per 10(5) leukocytes) lower than the viral loads of blood samples that tested positive by both assays (mean, 21,452 copies; median, 9,784 copies per 10(5) leukocytes) (P = 0.003). The AMPLICOR CMV test gave positive results at least 48 days before the development of symptomatic CMV disease in a longitudinal analysis of a limited subset of patients (n = 6) from whom sequential specimens were available for testing. In conclusion, the AMPLICOR CMV test is a very convenient assay combining rapidity, simplicity, and the possibility of batch testing. A positive result by this test seems particularly important since this implies, in most instances, the presence or the imminence of CMV disease, although a negative test result does not rule out disease.