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PubMed1998

Thiol redox modulation of tumor necrosis factor-alpha responsiveness in cultured AIDS-related Kaposi's sarcoma cells.

Both clinical and experimental evidence indicates that AIDS-related Kaposi's sarcoma (AIDS-KS) has a multifactorial pathogenesis with factors such as HIV viral load, latent virus induction, and opportunistic infections contributing to disease progression. However, a consistent feature that unites these apparently diverse putative etiologic agents is sustained serum elevations of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). While virtually every cell responds to TNF-alpha with gene activation, the extent of TNF-alpha-mediated cellular signaling is regulated by a delicate balance between signal activation and signal arresting events. Reactive oxygen intermediates (ROI), which are generated as a consequence of TNF-alpha membrane interaction, are part of this TNF-alpha-initiated cellular activation cascade. Previous studies in our laboratory have shown that AIDS-KS cells possess impaired oxygen intermediate scavenging capacities, thereby establishing conditions permissive for the intracellular retention of ROI. In this study, we used cellular capacity to upregulate the cytoprotective enzyme superoxide dismutase (SOD) to address the extent of cellular response to TNF-alpha. Concurrent with the SOD analyses, nucleotide profiles were obtained to assess cellular bioenergetic responses during TNF-alpha challenge. Proliferative growth levels of mitochondrial (Mn)SOD activities showed an activity spectrum ranging from lowest activity in AIDS-KS cells, to intermediate levels in matched, nonlesional cells from the AIDS-KS donors, to highest activities in HIV normal fibroblasts. In contrast, following TNF-alpha challenge, the AIDS-KS and KS donor nonlesional cells showed a 11.89- and 5.86-fold respective increase in MnSOD activity, while the normal fibroblasts demonstrated a 1.35-fold decrease. Subsequent thiol redox modulation studies showed that only the normal fibroblast cultures showed a potentiation of TNF-alpha-mediated MnSOD upregulation following GSH depletion. In addition, provision of the GSH precursor, N-acetylcysteine during TNF-alpha challenge only diminished MnSOD activity and mitochondrial compartmentalization in the AIDS-KS cells, a finding that likely reflects the lower levels of reduced thiols in this cellular population. Our data, which show that a perturbation in their cellular thiol redox status accentuates AIDS-KS cellular responsiveness to TNF-alpha, suggest a biochemical rationale for the recognized TNF-alpha AIDS-KS clinical correlation.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Paleocortex is specified in mice in which dorsal telencephalic patterning is severely disrupted.

The patterning of the telencephalon is regulated by the concerted action of distinct mechanisms operating in different portions of this structure. Although much progress has been made in understanding the mechanisms underlying the specification of dorsal and ventral structures, little is known about the specification of the paleocortex, the olfactory cortex located at the interface of the dorsal and ventral telencephalon. The paleocortex is thought to be a dorsal, cortical structure, derived from the lateral extreme of the dorsal telencephalon. We examined mutant mice in which dorsal telencephalic patterning is severely disrupted, to ask how these perturbations affect the paleocortex. In the Lhx2-/- telencephalon, where the cortex is greatly shrunken such that medial and dorsal cortical tissue is undetectable, normal expression of several paleocortical markers is observed. The Gli3-/- telencephalon, where the dorsal telencephalon is ventralized, also displays paleocortical markers. In contrast, when the ventral telencephalon is almost completely deleted, such as in the BF1-/- brain, paleocortical markers are undetectable. These results indicate that the specification of the paleocortex can occur in spite of drastic perturbations of dorsal patterning. Furthermore, in the Lhx2 mutant, the paleocortex is juxtaposed to an expanded and mislocated source of Wnt and Bmp signaling, the cortical hem, whereas, in the Gli3 mutant, paleocortical markers arise even though the cortical hem is missing. This indicates that an increase or decrease in cues from this dorsal signaling center does not disrupt the specification of the paleocortex. Finally, by using an in vitro assay, we found that isolated explants of lateral telencephalon up-regulate normal expression of paleocortical markers when maintained in vitro, from as early as embryonic day (E) 10.5. Together, the results reveal that, although the paleocortex is considered to be a cortical structure, it is specified even when dorsal telencephalic patterning is grossly perturbed. Furthermore, our in vitro data reveal that, if mechanisms outside the lateral telencephalon are involved in the specification of the paleocortex, they must act extremely early, prior to E10.5.

Animals↗
PubMed2000

Modeling plasma virus concentration during primary HIV infection.

During primary HIV infection the viral load in plasma increases, reaches a peak, and then declines. Phillips has suggested that the decline is due to a limitation in the number of cells susceptible to HIV infection, while other authors have suggested that the decline in viremia is due to an immune response. Here we address this issue by developing models of primary HIV-1 infection, and by comparing predictions from these models with data from ten anti-retroviral, drug-naive, infected patients. Applying nonlinear least-squares estimation, we find that relatively small variations in parameters are capable of mimicking the highly diverse patterns found in patient viral load data. This approach yields an estimate of 2.5 days for the average lifespan of productively infected cells during primary infection, a value that is consistent with results obtained by drug perturbation experiments. We find that the data from all ten patients are consistent with a target-cell-limited model from the time of initial infection until shortly after the peak in viremia. However, the kinetics of the subsequent fall and recovery in virus concentration in some patients are not consistent with the predictions of the target-cell-limited model. We illustrate that two possible immune response mechanisms, cytotoxic T lymphocyte destruction of infected target cells and cytokine suppression of viral replication, could account for declines in viral load data not predicted by the original target-cell-limited model. We conclude that some additional process, perhaps mediated by CD8+ T cells, is important in at least some patients.

Cytokines↗
PubMed1980

A mathematical model of canine granulocytopoiesis.

The granulocyte cell renewal system of the dog is represented by a mathematical model consisting of the following compartments: The pool of pluripotential stem cells, the committed stem cell pool, divided into a blood and a bone marrow compartment, the proliferation pool, the maturation pool, the reserve pool and the blood pool of functional granulocytes. This chain of compartments is described by a system of non-linear differential equations. Cell losses anyplace in the system provoke increased production in all pools containing cells capable to divide. A reduced number of granulocytes in the blood pool stimulates production of a "granulocyte releasing factor" which mobilizes a rising number of cells to transit from the marrow reserve into the blood pool. The model was simulated on a digital computer. It was found to be capable to reproduce the steady state conditions and it also fits the data of two distinct experimental perturbations of the system both equally well. These perturbations are a loss of proliferating cells as it occurs after the administration of cytostatic drugs and losses of functional cells as they are induced by leukapheresis experiments of differing leukapheresis rates.

Animals↗
PubMed1983

Effect of chronic ethanol feeding on pancreatic enzyme secretion in rats in vitro.

The effect of long-term ethanol intake on pancreatic digestive enzyme secretion was determined in Sprague-Dawley rats. Weight-matched triplets were fed Lieber-DeCarli diet containing 5% w/v concentration of ethanol, isocaloric amounts of Lieber-DeCarli diet, or rat chow ad libitum for 6, 12, and 18 months. Basal and bethanechol-stimulated secretion of amylase, lipase, trypsinogen, chymotrypsinogen, and pancreatic secretory trypsin inhibitor (PSTI) was determined. In the ethanol-fed group, basal secretion of trypsinogen and chymotrypsinogen was increased at 6, 12, and 18 months. In addition, basal secretion of amylase and lipase was increased and that of PSTI was decreased at 12 and 18 months. Secretion of PSTI was stimulated by bethanechol (10(-4)M), whereas the secretion of digestive enzymes was not stimulated in the ethanol-fed versus two control groups. At 12 months the dose-response curve of amylase and lipase secretion was shifted upwards in the ethanol-fed group with increase in ED50. These data are suggestive of membrane perturbations leading to increased basal secretion and a subsensitivity of the cholinergic receptors in the ethanol-fed group. Increased basal secretion of proteases in the presence of diminished trypsin inhibitor indicates that premature activation of proenzymes could occur resulting in pancreatitis.

Amylases↗
PubMed2000

Dose measurements in the build-up region for the photon beams from Clinac-1800 dual energy medical linear accelerator.

AIM: Since the skin dose becomes the limiting factor while deciding the tumorcidal dose, the detailed analysis of dose distribution in the build-up region is necessary for high-energy photon beams. In this study the beam characteristics affecting the build-up and skin dose for 6- and 18-MV photons are analyzed. MATERIALS AND METHODS: Measurements were made with 6- and 18-MV photons using a PTW parallel-plate ionization chamber (B 23344-036) and a RDM-1F electrometer. Build-up ionization measurements were made with the chamber fitted into a 25 x 25 x 25 cm polystyrene phantom with a fixed SSD of 100 cm. The entrance and build-up dose measurements were made with a polycarbonate and a mesh type metallic shielding tray and a 45 degrees wedge. Exit dose measurements were carried out for the graphite patient supporting assembly table top, 1.0 cm thick piece of wood and the 1.0 cm thick patient supporting perspex base frame for head and neck treatments. RESULTS: It was observed that the dmax decreased slightly with field size as with other accelerators. For both photon energies the surface dose was observed to increase with increase in field size. It was also noticed that the dose in the build-up region increases slightly when the polycarbonate secondary blocking tray is introduced with the increase in surface dose. The data show that the tray perturbation factor (TPF) at surface decreases steadily with tray-surface distance for both photon beams for all field sizes. It was noted that the TPF was more when the polycarbonate tray was introduced at shorter tray-surface distances for both energies. At tray-surface distances above 60 cm the TPF almost remained close to unity for 6-MV photons for all field sizes, whereas the continuous decrease in TPF could be noted for 18-MV photon beams even after the TPF reached unity. CONCLUSION: The increase in surface dose with field size for both photon energies is due to the electron scattering from the intervening materials. The use of wedge filters absorbs low-energy scattered electrons significantly and hence, the relative surface dose (RSD) is always less than unity. The increase in dose enhancement percentage with graphite compared to perspex supporting assembly indicates that the electron backscatter is proportional to the atomic number of the medium.

Electrons↗
PubMed2005

Perturbation-enhanced neuromuscular training alters muscle activity in female athletes.

Female athletes involved in jumping and cutting sports injure their anterior cruciate ligaments (ACL) 4-6 times more frequently than their male counterparts in comparable sports. Neuromuscular factors, including quadriceps dominance, has been incriminated as contributing to the higher rates of injury in women. Currently, the most effective form of intervention developed to reduce female ACL injury rates has been neuromuscular training. The purpose of this study was to (1) identify gender based muscle activity patterns during disturbed walking that may contribute to ACL injury, and (2) determine if a novel training program could positively influence patterns among healthy female athletes utilizing a disturbed gait paradigm. Twenty healthy athletes (female=10, male=10) were tested. All subjects participated in five trials during which a platform translated horizontally in a lateral direction at heel contact before and after completing ten sessions of a perturbation training program. Electromyographic (EMG) data from the vastus lateralis, medial and lateral hamstrings, and medial gastrocnemius were collected. Trials were analyzed for the muscle onset, termination of activity, peak amplitude, time to peak amplitude, and integrated EMG activity. Muscle cocontraction, the simultaneous activation of antagonistic muscles (lateral hamstrings-vastus lateralis, and medial gastrocnemius-vastus lateralis), was calculated as indicators of active knee stiffness in preparation for heel strike, during weight acceptance and midstance. Prior to training, women had significantly higher peak quadriceps activity and higher integrated quadriceps activity during midstance than men. Both medial and lateral hamstring integrals during midstance increased from pre to posttraining. Onset times to peak activities for hamstrings and quadriceps were similar before training except for medial hamstring time to peak which occurred after heel strike in most women. Time to peak medial hamstring activity moved from after to just before heel strike after training. Women had higher medial gastrocnemius-vastus lateralis cocontraction indices in the preparatory and weight acceptance phases of gait than men after training. Prior to training, the athletic women in our sample demonstrated characteristic quadriceps dominance and decreased active knee stiffness when compared to male athletes. Modulation of activity and timing of ACL agonist musculature (hamstrings and gastrocnemius) from before to after training resulted in normal quadriceps-hamstring balance and increased active stiffness. These alterations in ACL agonist muscle activation patterns may reduce the risk of biomechanical strain injury among a high risk population.

Adult↗
PubMed1984

Interaction of dolichol and dolichyl phosphate with phospholipid bilayers.

The thermotropic phase transition of dipalmitoylphosphatidylcholine vesicles reconstituted with dolichol or dolichyl phosphate was investigated as a function of the lipid-to-polyisoprenoid ratio by means of differential scanning calorimetry and fluorescence depolarization of the embedded probe 1,6-diphenyl-1,3,5-hexatriene. At the concentrations studied, dolichol and dolichyl phosphate lowered and broadened the transition temperature of dipalmitoylphosphatidylcholine bilayers. Dolichol was found to increase the motional freedom of the bilayer both below and above the transition temperature as determined by fluorescence depolarization. In contrast, low concentrations of dolichyl phosphate decreased the bilayer motional freedom below the transition temperature while high concentrations increased the motional freedom. Above the transition temperature, dolichyl phosphate decreased bilayer 'fluidity' at all concentrations. The data suggest that these polyisoprenoids perturb the bilayer lattice, with the neutral species dolichol increasing membrane 'fluidity', while dolichyl phosphate acts to 'stiffen' the membrane.

Calorimetry, Differential Scanning↗
PubMed1996

Studies on the thermotropic effects of cannabinoids on phosphatidylcholine bilayers using differential scanning calorimetry and small angle X-ray diffraction.

We have studied the thermotropic properties of a wide variety of cannabinoids in DPPC bilayers. The molecules under study were divided into four classes: (a) classical cannabinoids possessing a phenolic hydroxyl group; (b) delta9-THC metabolites with an additional hydroxyl group on the C ring; (c) non-classical cannabinoids, and (d) cannabinoids with a protected phenolic hydroxyl group. The results showed that the first three groups have similar effects on the thermotropic properties of DPPC bilayers up to x = 0.05 (molar ratio) and that these effects do not parallel their biological activity. For concentrations less than x = 0.01, cannabinoids affect mainly the pretransition temperature in a progressive manner until its final abolishment. At x = 0.05, they further affect the main phase transition by lowering its phase transition temperature and broadening its half width. At high concentrations the thermograms have multiple components, indicating that membranes are no longer homogeneous but rather consist of different domains. At these concentrations cannabinoids with more hydroxyl groups give simpler thermograms. Low concentrations of cannabinoids in group d affect significantly the pretransition temperature, while high concentrations affect only marginally the main phase transition by slightly lowering its temperature and broadening its half width. These results point out the importance of the phenolic hydroxyl group in inducing membrane perturbations. The d-spacing data from our small angle X-ray diffraction experiments show that delta8-THC produces significant structural changes in the lipid bilayer, including the gel-phase tilting angle, the intermolecular cooperativity and the gauche:trans conformer ratio. Conversely, the inactive analog Me-delta8-THC does not cause drastic changes to the bilayer structure.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1978

Changes in conformation and immunological activity of ovalbumin during its modification with different acid anhydrides.

In order to probe the cause and nature of conformational changes induced by the chemical modification of amino groups in proteins, five acylated derivatives of ovalbumin namely 21% acetylated, 32% succinylated, 90% butyrated 92% succinylated, and 95% acetylated ovalbumins were prepared and their molecular and immunological properties were systematically investigated. As evidenced by the ultraviolet difference spectral, solvent perturbation, gel filtration, and viscosity data, acylation of the amino groups produced a definite conformational change in native ovalbumin whose extent was higher for higher degrees of chemical modification. The solvent pertubation data showed an exposure of 0.5 tryptophan and 3 tyrosine residues in native ovalbumin; the exposure increased to 1 tryptophan and about 5 tyrosine residues in the maximally modified proteins (i.e. 90% butyrated, 92% succinylated, and 95% acetylated ovalbumins). The Stokes radius (2.7 nm) and intrinsic viscosity (3.9 ml/g) of ovalbumin increased, respectively, to about 3.4 nm and 7.7 ml/g upon acylation of its 18 lysine residues; the intrinsic viscosity of 95% acetylated ovalbumin was 7.2 ml/g. The reduced viscosity of ovalbumin (4.2 ml/g) which remained unaltered on raising the pH to pH 11.2, increased to 7.9 ml/g on succinylation of 18 lysine residues. On raising the ionic strength from 0.15 to 1.0, the value decreased from 7.9 to 6.2 ml/g. These observations taken together with the fact that the intrinsic viscosities of 92% succinylated and 90% butyrated ovalbumins are identical, argue against the presently prevalent proposal that electrostatic effects alone are responsible for the disruption of native protein conformation during chemical modification. The immunological activity of ovalbumin towards rabbit anti-ovalbumin expectedly decreased with acylation of its amino groups but the three maximally modified ovalbumins retained 40% immunological activity. This taken along with the spectral and viscosity data showed substantial native structure (format) in the three maximally acylated derivatives. The rabbit antiserum against 95% acetylated ovalbumin did not cross-react with acetylated lysozyme and reacted poorly with the native and 92% succinylated ovalbumins suggesting that the antigenic make-up of the three maximally modified ovalbumins is different.

Acylation↗
PubMed1986

Augmentation of interleukin-2 release by cytochalasins.

Augmentation of mitogen-induced release of the T cell lymphokine interleukin-2 (IL-2) occurred using several cytochalasins in coculture with a T cell lymphoma line (JM) or with purified T cells. When added concurrently with mitogen, cytochalasins had no apparent negative effect either on the ability of mitogen to signal IL-2 production or on the total amount produced. Use of cytochalasins that affect submembranous actin in peripheral lymphocytes established a link between cytoskeletal alterations and lymphokine release, although direct membrane perturbation cannot be excluded. These data indicate that an intracellular pool of IL-2 may accumulate in both T cell lines and in purified peripheral T cells and that maintenance of that pool may be affected by alterations of the cytoskeletal elements. Cytochalasins not only increased IL-2 release, but could substitute for phorbol myristic acetate (PMA) in supporting mitogen-signaled IL-2 production. We interpret these data also to indicate that cytoskeletal attachment to the surface molecules that signal IL-2 production is not needed for the activation.

Animals↗
PubMed1996

Specific characteristics of phosphofructokinase-microtubule interaction.

Muscle phosphofructokinase interacts with microtubule-associated protein-free microtubules resulting in a reduction of the overall activity of the enzyme [Lehotzky et al. (1993) J. Biol. Chem. 268, 10888-10894] and periodical cross-linking of the tubules [Lehotzky et al. (1994) Biochem. Biophys. Res. Commun. 204, 585-591]. Microtubule polymers of 'tail-free' tubulin obtained by removal of the carboxy-termini with limited subtilisin digestion retain the binding domains for phosphofructokinase that cross-bridges microtubule 'bodies'. Microtubule-associated proteins bound on tubulin 'tails' do not perturb the kinase binding. These data suggest that the tubulin carboxy-terminal domain is not involved in microtubule-phosphofructokinase interactions and phosphofructokinase and microtubule-associated proteins have distinct binding domains on microtubules. Of different isoforms of phosphofructokinase, occurring mainly in brain and tumor cells, the muscle isoform exhibits selective adsorption behaviour on microtubules. Phosphofructokinase M and C isoforms with different associative and allosteric properties may represent an auxiliary pathway to modulate energy production via glycolysis.

Animals↗
PubMed1992

Disruption of endothelial barrier function by lipolytic remnants of triglyceride-rich lipoproteins.

Remnants, resulting from the lipolysis of triglyceride-rich lipoproteins, injured cultured endothelial cells and resulted in decreased barrier function of the vascular endothelium. Endothelial cells were cultured on micropore filters. Albumin transfer across endothelial cell monolayers was measured after a 24-h exposure to media enriched with control or in vitro-lipolyzed samples of various hypertriglyceridemic (HTG) sera and its isolated lipoprotein (VLDL, LDL and HDL) and serum free protein (d greater than 1.21 g/ml) fractions. Compared with control cultures, neither control HTG serum nor its isolated lipoprotein and serum-free protein fractions had any effect on albumin transfer. In contrast, lipolyzed HTG (L-HTG) serum and all of its isolated lipoprotein fractions (L-VLDL, L-IDL, L-LDL and L-HDL) caused a marked decrease in endothelial barrier function, evidenced by a significant increase in albumin transfer across endothelial monolayers. The L-IDL and L-HDL fractions were more effective in increasing albumin transfer than the L-VLDL and L-LDL fractions. The extent of the L-IDL and L-HDL mediated increases in albumin transfer was concentration dependent. An exposure of 12 h was required for L-HDL to increase albumin transfer. The L-HDL mediated increase in albumin transfer was reversible only after a 12-h exposure at low concentrations. The free protein fraction from L-HTG serum had no significant effect on the barrier function of endothelial cells. The presence of normolipidemic HDL in culture medium prevented disruption of the endothelial barrier induced by L-IDL but not by L-HDL. The decrease in endothelial barrier function induced by lipolyzed samples of HTG serum or lipoproteins appeared to be correlated with the level of free fatty acids contained in lipolytic remnants. Enrichment of LDL, and in particular HDL, with fatty acid significantly increased albumin transfer. Compared with lipolyzed samples, sera/lipoproteins oxidized in vitro by Cu2+ ions had little effect on endothelial barrier function, which did not correlate with their respective thiobarbituric acid-reacting substance (TBARS) values. TBARS remained within normal range after L-HDL incubation with endothelial cells for up to 48 h. At most concentrations tested, exposure to lipolyzed but not oxidized lipoproteins resulted in morphological perturbations of cell monolayers. These data suggest that lipolytic remnants of triglyceride-rich lipoproteins may play an important role in the development of atherosclerosis by decreasing the barrier function of the vascular endothelium. The remnant-induced injury of the arterial wall may permit the entry of cholesterol-rich lipolytic remnants as well as LDL into the arterial wall.

Animals↗
PubMed1984

Dependence of jumping performance on muscle properties when humans use only calf muscles for propulsion.

Using optimal control techniques, maximum height jumps were simulated for humans who held their body rigid except for the ankle. Three dynamic models of ankle torque generation based on known calf muscle properties were used. Force and kinematics obtained from the simulations using nominal and perturbed parameters were compared with data obtained from humans who had performed this type of jump. One torque model incorporated the series elastic, force-length and force-velocity properties of muscle. Our results suggest that higher jumps would be achieved by those who have the most compliant and fastest contracting muscles. It was also found that height attained depended much more on the ability of muscles to generate isometric force at long lengths than at short lengths. Studies of forward and strictly vertical jumps using similar computer methods suggest that for any maximal jump the optimal strategy is first to achieve a unique state (position, velocity and acceleration) with the feet flat on the ground, and then to maximally activate one's calf muscles until lift-off.

Adult↗
PubMed1986

Pineal function during ethanol intoxication, dependence, and withdrawal.

Pineal melatonin and serotonin content were determined during one to four days of continuous intoxication, and during the alcohol withdrawal syndrome. The nocturnal rise in pineal melatonin was blunted in continuously intoxicated animals, however this was found to be unrelated to duration of treatment. The initial dependent-intoxicated phase of the alcohol withdrawal syndrome produced a reduction of nocturnal pineal melatonin content with a concomitant elevation in pineal serotonin. The overt withdrawal phase of the alcohol withdrawal syndrome had no effect on pineal melatonin or serotonin content. This data suggests that ethanol may perturb pineal melatonin synthesis either directly, or indirectly by altered receptor function. Contrary to our expectations the pineal may not be a useful model to probe the physiology of increased noradrenergic neurotransmission produced by ethanol withdrawal.

Alcohol Withdrawal Delirium↗
PubMed1983

Immunologic aberrations in asbestos cement workers: dissociation from asbestosis.

Immunoregulatory disorders have been implicated in the pathogenesis of asbestosis. We therefore compared the immunologic status of a well-characterized group of 31 current and former asbestos-cement workers with that of a group of 52 healthy controls, after adjustments had been made for the possible confounding effects of age, race, and smoking. The asbestos workers had significantly decreased percentages and numbers of both B and T lymphocytes in peripheral blood and a paradoxical IgG hypergammaglobulinemia. Analysis of T-lymphocyte subpopulations revealed that total T-cell numbers (OKT3+), helper-inducer T-cell numbers (OKT4+), and suppressor-cytotoxic T cell numbers (OKT8+) were decreased by similar proportions. These decreases were negatively correlated with time elapsing since the end of exposure to asbestos. In both workers and controls, lymphocyte proliferative responses to phytohemagglutinin (PHA) were correlated positively with the number of OKT4+ cells and negatively with age and serum IgG levels. When adjustments had been made for these confounding variables, no differences in PHA responses were noted between workers and controls. No relationship was detected in the workers between any of the immunologic aberrations noted and (1) radiographic category of pneumoconiosis, (2) estimates of cumulative asbestos exposure, or (3) abnormalities of pulmonary function. These data suggest that the immunologic perturbations we have noted in asbestos-exposed individuals are epiphenomena, unrelated to the pathogenesis of asbestosis itself.

Adult↗
PubMed1990

The conformational flexibility of class I H-2 molecules as revealed by anti-peptide antibodies specific for intracytoplasmic determinants: differential reactivity of beta 2-microglobulin "bound" and "free" H-2Kb heavy chains.

Immunoprecipitation experiments using anti-peptide antisera prepared against exon 6, exon 7 and exon 8-encoded intracytoplasmic regions of the H-2Kb gene product indicated that approximately 1/3 of the H-2Kb heavy chains in a cell surface-labelled glycoprotein fraction from EL-4 cells, or H-2b spleen cells, is not associated with beta 2-microglobulin (beta 2-m). This population of "free" H-2Kb heavy chains failed to react with alloantisera or monoclonal antibodies specific for conventional H-2Kb serological determinants, suggesting that significant conformational alterations were induced in the extracellular domains upon dissociation of beta 2-m. In addition, although antibodies to intracytoplasmic peptide 8 were able to react with both "free" and beta 2-m "bound" heavy chains, the determinants seen by anti-peptide 6 and anti-peptide 7 were only recognized in the "free" heavy chain. These data suggest that the conformational perturbation of the extracellular domains induced by beta 2-m dissociation can be "transmitted" to the intracytoplasmic region of the heavy chain. These results indicate the potential for a class I heavy chain-mediated transmembrane signalling event, and suggest that the "free" class I heavy chain might have a role to play in the major histocompatibility complex (MHC)-restricted presentation of T-cell determinants to cytotoxic T-lymphocytes.

Animals↗
PubMed2007

Physiologically important secondary modifications of red cell membrane in hereditary spherocytosis-evidence for in vivo oxidation and lipid rafts protein variations.

Hereditary spherocytosis (HS) is a heterogeneous group of disorders. The abnormal red cell morphology (resulting in shortened cell survival) is due to a primary deficiency in spectrin, ankyrin-1, band 3 or protein 4.2. Secondary protein deficiencies are often observed and may be involved in the outcome of the disease. In the present study, we searched for secondary erythrocyte membrane protein alterations in HS, including the lipid raft associated proteins and the oxidative index. For this purpose, 12 patients with clinical and laboratory diagnosis of mild to typical HS were examined. Erythrocyte membrane ghosts and skeletons were subjected to SDS-PAGE and immunoblotting analysis using antibodies against red cell membrane proteins and DNP moiety, after 2,4-dinitrophenylhydrazine derivatization. Protein deficiencies, degradation, aggregation and enhanced binding of cytoplasmic components, band 8, hemoglobin and immunoglobulins G to the membrane as well as increased oxidative index, were found in the majority of the HS patients. Proportion of the membrane- and skeleton-bound globin was oxidized/denatured Hb or hemichromes and crosslinkings. Some HS membranes are deficient in lipid rafts proteins and contain sorcin. A context of these distortions is more pronounced in typical HS cases compared to the mild ones. Similar defects in thalassemia and senescent RBCs are dictated by increased oxidative stress and are positively correlated with perturbations in membrane properties. These data add some new insight in the field of HS pathophysiology and clinical variability.

Adolescent↗