Estimation of dynamical model parameters taking into account undetectable marker values

Background  

Mathematical models are widely used for studying the dynamic of infectious agents such as hepatitis C virus (HCV). Most often, model parameters are estimated using standard least-square procedures for each individual. Hierarchical models have been proposed in such applications. However, another issue is the left-censoring (undetectable values) of plasma viral load due to the lack of sensitivity of assays used for quantification. A method is proposed to take into account left-censored values for estimating parameters of non linear mixed models and its impact is demonstrated through a simulation study and an actual clinical trial of anti-HCV drugs.     

Age-related changes in respiration coupled to phosphorylation. I. Hepatic mitochondria

Age-related changes affecting mitochondrial adenine nucleotide metabolism may underlie age-related decreases in hepatic metabolic activities. Oxidative activity coupled with phosphorylation, the apparent Km and Vmax of the adenine nucleotide translocase (AdNT), the adenine nucleotide pool size and membrane lipid composition were determined for hepatic mitochondria from young (3 months), mature (12 months) and aged (24 months) Fischer 344 male rats which had been fed NIH-31 diet. The age-related decreases in state 3 respiration supported by NAD-linked substrates were 2-4-fold greater than that of an FAD-linked substrate. The 32% (P less than 0.05) decrease in the AdNT Vmax calculated for the aged rats was accompanied by a 17% decrease in the AdNT Km. The exchangeable pool of adenine nucleotides in mitochondria from aged rats was 72% (P less than 0.05) that in the young rats. While the age-related increase in the cholesterol/phospholipid-Pi ratio and changes in the phospholipid head group pattern were not significant, the overall change in the fatty acid pattern effected a 20% (P less than 0.05) decrease in the n-6/n-3 fatty acid ratio. These data suggest that the reduced Vmax of the AdNT is a consequence of a diminished pool of exchangeable adenine nucleotides. The lower AdNT velocity may reflect the effect of changes in the lipid environment of the membrane in which it is embedded. The major shifts in these parameters occurred during the second year of life.     

Chromium-induced pulmonary cancer. Report of a case and a review of the literature

A 57-year-old man, whose occupational history was that of a chromate worker for about 35 years, suffered nasal perforation during and died due to pulmonary cancer. In the autopsy materials, the concentration of chromium in the lung tissues was very high, being about 90 times the amount found in normal lungs. The chromium particles in the lung tissues could not be detected by analytical electron microscope, but they could be found in the anthoracotic lesions of the lungs by means of an X-ray microanalyser. The present case was judged to be a case of chromium-induced pulmonary cancer since all the pathologic data obtained were similar to those found in similar cases reported in the literature.     

Donor origin Rh antibodies as a cause of significant hemolysis following ABO-identical orthotopic liver transplantation

A group A, D-positive patient underwent orthotopic liver transplantation from a group A, D-negative (cde/cde) donor. Anti-D and -E were eluted from the recipient's red cells and were found in the recipient's serum 13 days later, at which time significant hemolysis developed. These Rh antibodies appear to he secondary to passive transfer of sensitized donor lymphocytes, a rare finding following liver transplantation.     

Influence of encapsulation on staphylococcal opsonization and phagocytosis by human polymorphonuclear leukocytes

In previous studies, encapsulated Staphylococcus aureus strains have been shown to resist phagocytosis. In this investigation, the nature of the interference with phagocytosis by human polymorphonuclear leukocytes was examined by studying the opsonization of two pairs of unencapsulated (Smith compact and M variant) and encapsulated (Smith diffuse and M) S. aureus strains. The uptake of [3H]glycine-labeled bacteria by normal leukocytes was quantitatively measured after incubation of bacteria in pooled serum, C2-deficient serum, immunoglobulin-deficient serum, and serum from a rabbit immunized with S. aureus M. The presence of a capsule was found to interfere with opsonization by both the classical and alternative pathways of complement as well as by heat-stable opsonic factors in nonimmune human serum. This interference was significantly greater in the case of the S. aureus M strain than in the case of the Smith diffuse strain. The only effective opsonic source for S. aureus M was immune rabbit serum. It is proposed that encapsulation of S. aureus strains interferes with phagocytosis by preventing effective bacterial opsonization.     

Activation of extracellular signal-regulated kinases in the sciatic nerves of rats with experimental autoimmune neuritis

To investigate whether the phosphorylation of extracellular signal-regulated kinase (ERK) is involved in autoimmune injury of the peripheral nervous system (PNS), the expression of phosphorylated ERK (p-ERK) was analyzed in experimental autoimmune neuritis (EAN) in rats. Western blot analysis showed that the level of p-ERK was increased significantly in the sciatic nerves of rats on days 14 (p<0.05) and 24 (p<0.01) post-immunization, compared with controls, and its reaction declined at day 30 post-immunization. Immunohistochemistry showed that p-ERK protein was weakly expressed in Schwann cells and vascular endothelial cells in the sciatic nerves of CFA-immunized control rats. In EAN-affected sciatic nerves, p-ERK immunoreactivity was found mainly in ED1-positive macrophages on days 14 and 24 post-immunization. Moreover, on days 24 and 30 post-immunization, p-ERK immunoreactivity increased gradually in the Schwann cells of rat sciatic nerves with EAN. Based on these results, we postulated that the phosphorylation of ERK has an important role in the differentiation and survival of cells, including inflammatory cells and Schwann cells, in the rat sciatic nerve in EAN. Specifically, the activation of ERK in the recovery phase of EAN paralysis seems to be related in the survival of Schwann cells.     

Background nonselective cationic current and the resting membrane potential in rabbit aorta endothelial cells

The ion channel conductances that regulate the membrane potential was investigated by using a perforated patch-clamp technique in rabbit aorta endothelial cells (RAECs). The whole-cell current/voltage (I-V) relation showed a slight outward rectification under physiological ionic conditions. The resting membrane potential was -23.3 +/- 1.1 mV (mean +/- SEM, n = 19). The slope conductances at the potentials of -80 and 50 mV were 31.0 +/- 4.0 and 62.8 +/- 7.1 pS pF(-1), respectively (n = 15). Changes in the extracellular and intracellular Cl(-) concentrations did not affect the reversal potential on I-V curves. The background nonselective cationic (NSC) current was isolated after the K(+) current was suppressed. The relative permeabilities calculated from the changes in reversal potentials using the constant-field theory were P(K):P(Cs):P(Na):P(Li) = 1:0.87:0.40:0.27 and P(Cs):P(Ca) = 1:0.21. Increases in the external Ca(2+) decreased the background NSC current in a dose-dependent manner. The concentration for half block by Ca(2+) was 1.1 +/- 0.3 mM (n = 7). Through the continuous recording of the membrane potential in a current-clamp mode, it was found that the background NSC conductance is the major determinant of resting membrane potential. Taken together, it could be concluded that the background NSC channels function as the major determinant for the resting membrane potential and can be responsible for the background Ca(2+) entry pathway in freshly isolated RAECs.     

Climbing fiber afferent modulation during treadmill locomotion in the cat

The relationship of the climbing fiber afferent discharge to the unperturbed and perturbed step cycle was evaluated in the cat. Following a precollicular-premamillary decerebration, cats walked spontaneously on a motorized treadmill. Purkinje cells were recorded extracellularly and simple and complex spikes were discriminated. Right forelimb displacement, biceps and triceps EMG activity, as well as treadmill velocity, were also monitored. In some animals pressure measurements of the contact of the footpad with the treadmill were obtained. Cells were studied during both "normal" and perturbed locomotion. The perturbation consisted of a braking of the treadmill at different phases in the step cycle. Histograms of the simple and complex spike activity, and averages of the right forelimb displacement, biceps, and triceps EMG activity and treadmill velocity were constructed. The complex spike activity of 163 Purkinje cells was averaged through a minimum of 50 sweeps in either normal and/or perturbed locomotion. Statistical analysis revealed that the probability of the climbing fiber afferent discharge in 54% of the cells (36/67) studied during normal locomotion was significantly modulated with the step cycle. For most Purkinje cells the onset of the increase in climbing fiber afferent discharge was coupled to triceps activity and the onset of stance phase. A group of cells exhibited complex spike discharge in association with biceps onset and swing. These observations suggest that complex spike discharge occurs preferentially at the phase transition periods in the step cycle when the trajectory of the forelimb changes from swing to stance or stance to swing. During treadmill braking 51% of the cells exhibited complex spike modulation (70/137). A number of different patterns of climbing fiber afferent modulation occurred. The most common pattern was an increase in complex spike discharge with the resumption of the treadmill movement and locomotion. Analysis of the time of these periods of increased climbing fiber activity suggests that, although in some cells the response is coupled to the treadmill onset, in other cells the modulation occurs at longer latencies. Subsequent analysis aligning the EMG, displacement, and treadmill velocity signals with the times of the climbing fiber afferent discharge suggested some responses were coupled to the reinitiation of the locomotor cycle. The second most common pattern was an increase in climbing fiber afferent discharge at the onset of the perturbation. Also, in some cells, complex spike discharge decreased during the period in which the step cycle was arrested.(ABSTRACT TRUNCATED AT 400 WORDS)