Common Damage Mechanism Research Articles

Auditory research involving antioxidants

The role of antioxidants in the management of hearing loss has generated considerable interest over the past several years. Research efforts in this field have yielded many new insights into the molecular and cellular nature of several types of hearing impairment, including age-related, noise-induced, and drug-induced hearing loss. The objective of this paper is to highlight some of the important studies published over the past several years that have further contributed to our understanding of the mechanism of antioxidants in attenuating hearing loss. There is compelling evidence to suggest that antioxidant therapy is beneficial in attenuating, improving, or reversing the effects of several types of acquired hearing loss. Cellular and subcellular changes resulting from these types of hearing impairment are remarkably similar and seem to have a common putative mechanism of oxidative stress and damage. Recent studies have lent further credibility to the notion that antioxidant therapy can be of considerable benefit in the treatment of hearing loss. The increasing body of literature pertaining to human studies will shed further light into this fascinating area of research. This review elucidates the role of antioxidants in hearing loss and illustrates the continued evolution of research efforts in this field.

Neuroimage Findings in 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency

A case of 2-methyl-3-hydroxybutyryl-coenzyme A dehydrogenase deficiency, an X-linked defect of isoleucine degradation, is reported. A 10-month-old male infant with developmental regression, visual impairment, movement disorder, and seizures, he suffered acute deterioration with multiorganic failure after a respiratory infection. Laboratory studies revealed hyperlactacidemia and increased excretion of 2-methyl-3-hydroxybutyric acid (2M3HBA) and tiglylglycine (TG). The diagnosis was established by molecular genetic analysis of the involved X-chromosome gene HADH2. The patient was hemizygous for the mutation R130C (c. 388C>T). Magnetic resonance imaging disclosed frontotemporal atrophy and bilateral signal abnormalities in the putamina. The presence of basal ganglia abnormalities and lactic acidemia, also shared by mitochondrial disorders, suggests a common pathophysiologic mechanism of damage.

Brine Imbibition Damage in the Alpine/Colville River Field, Alaska

Abstract Early exploration well tests in the Colville River Field (also known as Alpine) drilled with water-based mud systems exhibited unexplainably high near wellbore residual skin damage as documented by pressure build-up testing. Typical formation damage echanisms including clay reactions, mechanical damage, and gas trapping could not explain the damage. Between March 1998 and July 2001, laboratory testing determined imbibition-induced water trapping to be the primary formation damage mechanism. In situ water saturation is significantly lower than the residual or connate water saturation, a condition rarely encountered in the field. Lab tests quantified impacts and identified methods to minimize or eliminate formationdamage. This paper documents how successful identification of a unique damage mechanism improved drilling results in a low permeability sandstone. Introduction Exploration drilling results in Colville River prospects consistently demonstrated higher than expected near wellbore skin damage as measured by build-up test analysis. Investigations into more common damage mechanisms such as solids migration and clay swelling could not explain the damage. Early reservoir core studies indicated that residual water saturations from relative permeability curves should be higher than the observed initial water saturations. Later studies with traced core confirmed initial water saturations were considerably less than normal connate water saturations. Further lab work confirmed the water-blocking tendency by measuring water imbibition and permeability recovery during regain permeability tests. Various drilling fluids were tested, with oil-muds consistently delivering lower permeability losses than water-based fluids. For a number of operational reasons, all wells on the first development pad (CD1) were drilled with brine-based fluids. The second pad (CD2) development team accepted the lab results and, after demonstrating the potential benefits of oil-based mud drilling, convinced the drilling team to develop and test a suitable mud program. Initial test results confirmed the lab results and conclusions when Well CD2–47 came in flowing at 300% more than predicted, based on equivalent brine-based mud completions in comparable pay to date. Following this early success, the oil-mud program was expanded and has consistently delivered more productive wells in line with expectations from the lab work. Background The Colville River Field (also known as the Alpine Field) is located approximately 100 km due west of the Prudhoe Bay Field on the north slope of Alaska (see Figure 1)(1, 2). It contains 70 × 106 m3 of recoverable reserves, with approximately 160 x?106 m3 of oil-inplace. Production is from the Alpine Oil Pool, a very fine-grained Jurassic age shallow marine sandstone complex with stratigraphically trapped 40 °API oil. The reservoir is normally pressured and undersaturated. Initial reservoir pressure is approximately 5,500 kPa above the bubble point, and the primary recovery mechanism is solution drive. Figure 2 presents a log and petrophysical overview, and Table 1 provides a summary of key reservoir properties. The field was discovered in 1994 with the drilling of the Bergschrund No. 1. Further delineation confirmed the prospect during subsequent winter seasons, and gravel pad construction began during the 1998 winter season.

Probabilistic Sensitivities for Fatigue Analysis of Turbine Engine Disks

A methodology is developed and applied that determines the sensitivities of the probability-of-fracture of a gas turbine disk fatigue analysis with respect to the parameters of the probability distributions describing the random variables. The disk material is subject to initial anomalies, in either low- or high-frequency quantities, such that commonly used materials (titanium, nickel, powder nickel) and common damage mechanisms (inherent defects or surface damage) can be considered. The derivation is developed for Monte Carlo sampling such that the existing failure samples are used and the sensitivities are obtained with minimal additional computational time. Variance estimates and confidence bounds of the sensitivity estimates are developed. The methodology is demonstrated and verified using a multizone probabilistic fatigue analysis of a gas turbine compressor disk analysis considering stress scatter, crack growth propagation scatter, and initial crack size as random variables.

Irreversible cellular senescence induced by prolonged exposure to H 2O 2 involves DNA-damage-and-repair genes and telomere shortening

H 2O 2 has been the most commonly used inducer for stress-induced premature senescence (SIPS), which shares features of replicative senescence. However, there is still uncertainty whether SIPS and replicative senescence differ or utilize different pathways. ‘Young’ human diploid fibroblasts (HDFs), treated with prolonged low doses of hydrogen peroxide, led to irreversible cellular senescence. Cells exhibited senescent-morphological features, irreversible G1 cell cycle arrest and irreversible senescence-associated β-galactosidase positivity. The appearance of these cellular senescence markers was accompanied by significant increases of p21, gadd45 expression and p53 binding activity, as well as a significant decline in DNA repair capability and accelerated telomere shortening. Our results suggest that multiple pathways might be involved in oxidative SIPS, including genes related to DNA-damage-and-repair and telomere shortening, and that SIPS shares the same mechanisms with replicative senescence in vivo. Our findings indicate that several aging theories can be merged together by a common mechanism of oxidative damage, and that the level of oxidative DNA-damage-and-repair capacity may be exploited as reliable markers of cell senescence.

Finite element analysis of low-velocity impact damage in composite laminated plates

Matrix cracking and delamination are the most common damage mechanisms in laminated fiber reinforced composites due to low velocity impact. An approach to predict the initiation and propagation of damage in composite laminated plates is brought forward in this paper, which is based on contact constraint introduced by penalty function method. The potential delamination and matrix cracking areas are considered as cohesive zone and the damage process as contact behavior between the interfaces. A scalar damage variable is introduced and the degradation of the interface stiffness is established. A damage surface which combines stress-based and fracture-mechanics-based failure criteria is set up to derive the damage evolution law. The damage model is implemented into a commercial finite element package, ABAQUS, via its user subroutine VUINTER. Numerical results on (0 4, 90 4)s carbon-epoxy laminate plates due to transversely low velocity impact are in good agreement with experimental observations.

Effect of Pentoxifylline on Antioxidant Status of Healthy and Endotoxemic New Zealand White Rabbits

Keskin E. , E. Oztekin (Menevse) , R. Col , A. Sivr ikaya, K. Uney, E. Yazar: Effect of Pentoxifylline on Antioxidant Status of Healthy and Endotoxemic New Zealand White Rabbits. Acta Vet. Brno 2005, 74: 17-21. In this study, effect of pentoxifylline on antioxidant status of healthy and endotoxemic rabbits was investigated. Endotoxemia was induced with E. coli lipopolysaccharide in New Zealand white rabbits. Forty rabbits were randomly divided into four equal groups. Group 1 served as control. Animals in Group 2 were given lipopolysaccharide (400 μg/kg) intravenously, in Group 3 pentoxifylline (50 mg/kg) was injected intraperitoneally. In Group 4; pentoxifylline (50 mg/kg intraperitoneally) and lipopolysaccharide (400 μg/kg, intravenously) were injected simultaneously. Animals were killed, and liver, heart and kidney samples were taken at 6 hours after administrations. Malondialdehyde, superoxide dismutase, glutathione peroxidase and reduced glutathione levels of heart, liver and kidney tissues were measured. Lipopolysaccharide caused significant increases (p < 0.05) in hepatic malondialdehyde, and cardiac, hepatic and renal glutathione peroxidase activities. It however, caused significant (p < 0.05) decrease in hepatic superoxide dismutase activity when compared to control group. Pentoxifylline caused significant (p < 0.05) increases of cardiac and hepatic malondialdehyde levels, cardiac superoxide dismutase and renal glutathione peroxidase activities, and cardiac, hepatic and renal reduced glutathione levels when compared to control group. As a result, pentoxifylline has no exactly beneficial effect on the antioxidant status of healthy and endotoxaemic New Zealand white rabbits at the administered dose and route. Although it was stated that pentoxifylline may be beneficial in endotoxaemia, its antioxidant effect may be dependent on dose, administration route and animal species. For this reason, when pentoxifylline is used in endotoxaemia, a treatment protocol should be done for each animal species. Pentoxifylline, lipopolysaccharide, antioxidant status, rabbits Lipopolysaccharide (LPS), a major component of the outer membranes of gram (-) bacteria, is released during infection and induces a number of pathological reactions leading to cardiovascular failure and damage to numerous organs. LPS can elicit a systemic inflammatory response syndrome defined as sepsis. When sepsis is accompanied by hypotension plus organ dysfunction, the condition is known as septic shock and the mortality of animals in septic shock has remained high. The common mechanism of tissues damage in the septic shock may be related to widespread vascular endothelial injury and microthrombosis. Homeostasis fails and dysfunction of major organs (heart, kidney, liver) may occur (Hardaway 2000; Cadenas and Cadenas 2002). There is convincing evidence of severe oxidative stress in sepsis. Oxidative stress occurs when antioxidant balance is disrupted by excessive production of reactive oxygen species (ROS) such as superoxide radical, hydroxyl radical, hydrogen peroxide, singlet oxygen and/or by inadequate antioxidant defense mechanisms such as superoxide dismutase (SOD) ACTA VET. BRNO 2005, 74: 17–21 Address for correspondence: Dr. Enver Yazar Department of Pharmacology and Toxicology Faculty of Veterinary Medicine University of Selcuk 42031, kampus Konya, Turkey Phone: +903 322 410 041 Fax: +903 322 410 063 e-mail: eyazar@selcuk.edu.tr http://www.vfu.cz/acta-vet/actavet.htm

Effect of 0.25 ppm Ozone exposure on pulmonary damage induced by bleomycin

To study the effect of ozone in a chronically damaged lung, we used a bleomycin (BLM) induced pulmonary fibrosis model. Both endotracheal instillation of BLM and O3 exposure both produce lung inflammation and fibrosis. Oxidative stress would be a common mechanism of damage for both BLM and O3. Our aim was to assess lung injury induced by 5 and 60 days of intermittent exposure to 0.25 ppm O3 in rats with bleomycin-induced pulmonary fibrosis. Thirty-day-old Sprague Dawley rats were endotracheally instilled with BLM (1 U/100 g body weight) and, 30 days later, exposed to 0.25 ppm 03 (0.25 ppm 4 h per day, 5 days a week). Histopatology controls were instilled with saline and breathing room air. Histopathological evaluation of lungs was done 5 and 60 days after O3 exposure. BLM-induced lung damage did not change after 60 days of intermittent O3 exposure. Five days of O3 exposure increased the mean score of BLM-induced pulmonary inflammation and fibrosis (p=0.06). Frequency of bronchopneumonia increased from 1/7 to 6/6 (p <0.001), suggesting that a short-term exposure to O3 in a previously damaged lung might be a risk factor for developing further lung injury.

Apoptotic cardiomyocyte death in fatal myocarditis

Acute myocarditis is often a self-limited process with a good outcome. Experimental animal studies have found that cardiomyocyte apoptosis occurs in severe forms of myocarditis. We studied whether cardiomyocyte apoptosis plays a role in the development of fatal acute human myocarditis. Myocardial autopsy samples from subjects who died of acute myocarditis in Finland between 1970 and 1998 were studied. Thirty-three of these cases(16 men and 17 women; 45 +/- 6 years old) were randomly selected for this study. All cases fulfilled the histopathologic Dallas criteria for myocarditis. Eight subjects who had died accidentally served as controls. Apoptotic DNA fragmentation (terminal transferase-mediated DNA nick end labeling) and activation of caspase-3 (immunohistochemistry) were detected. The mode of death was determined retrospectively from all available clinical data. In fatal myocarditis, large amounts of cardiomyocytes showed apoptotic DNA fragmentation or contained active caspase-3 (2.0 +/- 0.3% and 2.8 +/- 0.4%, respectively). In the controls, few apoptotic cardiomyocytes were found (0.008 +/- 0.003% by terminal transferase-mediated DNA nick end labeling and 0.009 +/- 0.003% by detection of active caspase-3, p <0.001 vs myocarditis). The amount of apoptosis did not correlate with the age or gender of the cases, recognized viral etiology, histologic features, or duration of disease. However, more apoptotic cardiomyocytes were detected in the subjects who had myocarditis and had died of heart failure (n = 18) than in those who had myocarditis and died suddenly of cardiac arrest (n = 15; 2.6 +/- 0.4% vs 1.1 +/- 0.2%, p <0.001). In conclusion, cardiomyocyte apoptosis is a common mechanism of myocardial damage in severe acute human myocarditis. Moreover, higher rates of cardiomyocyte apoptosis are associated with the development of fatal heart failure in acute myocarditis.

Fatigue behavior of polycrystalline thin copper films

Abstract Fatigue, a common damage and failure mechanism in bulk metals, is largely unexplored for thin films. In the present paper, we report on the fatigue behavior of Cu films with thicknesses in the range 0.4–3.1 μm on deformable substrates. Films thicker than 1 μm seem to behave like bulk Cu and follow a Manson-Coffin relationship with a fatigue exponent and ductility of about 0.5 and 20 %, respectively. For the sub-micron thick films, a clear size effect is observed: the damage morphology changes and the lifetime increases signaficantly. Based on a microscopical damage analysis, the following sequence for the fatigue damage evolution in the Cu films is suggested: (i) in large grains, extrusions at the film surface and voids at the interface to the substrate are formed, (ii) cracks are nucleated at these voads and grow towards the film surface, and (iii) cracks connect intergranularly to form a continuous pattern of cracks and extrusions in the film. It is argued that void nucleation is the result of ...

Using Underbalanced Drilling to Reduce Invasive Formation Damage and Improve Well Productivity-An Update

Abstract Underbalanced drilling (UBD) is becoming increasingly used as a technique to reduce significant invasive formation damage in vertical and horizontal wells to improve production rates of oil and gas, and enhance injectivity in gas and water injection situations. UBD may be a technically demanding procedure to execute in certain reservoirs and much of the benefit with respect to mitigation of formation damage may be compromised if the underbalanced drilling operation is not screened, designed and conducted in an appropriate fashion. This paper reviews common formation damage mechanisms which may occur in reservoirs and how, in certain situations, these types of damage may be reduced or eliminated through the appropriate use of underbalanced drilling technology. Various situations in which underbalanced drilling technology may result in potential significant formation damage are also discussed. Introduction Underbalanced drilling is utilized worldwide for the drilling of horizontally and vertically oriented wells to increase rates of penetration, reduce invasive formation damage and reduce problems with drilling due to lost circulation and differential sticking. Many successful descriptions of underbalanced drilling are present in the literature(1–8). However, underbalanced drilling is not a panacea for all formation damage problems in that inappropriately designed underbalanced drilling jobs may actually result in more formation damage than if a well-designed and contemplated overbalanced job had been used in the same circumstances. This paper reviews some of the technology in use at the present time in underbalanced drilling, and illustrates some of the points which operators should be aware of before embarking on an underbalanced drilling operation. What Is Underbalanced Drilling (UBD)? A rigorous definition of UBD is a condition where the circulating pressure of the drilling fluid in contact with the formation is less than the effective pore pressure in the adjacent matrix. The desirable course of action is to have this occur along the entire exposed section of the productive pay of the reservoir, resulting in an inflow of oil, water or gas (which may be contained in the matrix) into the wellbore. The produced fluids are returned to the surface along with the circulating drilling fluid. A number of descriptions of UBD exist in the literature. They can be described as follows: Overbalanced Drilling A situation in which the equivalent circulating density of the drilling mud is sufficient that, at bottomhole conditions, the drilling fluid pressure is greater than the formation pressure, resulting in an effectively "killed" state (where no inflow of formation of fluids occurs). This has been the most common technique utilized to drill wells in the past and is still the dominant technology currently used to drill many wells. Low Head Drilling Low head drilling refers to a situation where an overbalance pressure condition, similar to that described above, is maintained but with the use of lower density oil-based fluids or possibly gasified fluids to reduce the magnitude of the overbalance pressure exerted on the formation. The prime motivation is to reduce formation damage and the potential for severe invasive losses and to increase ROP. Low head drilling is still classified as a form of overbalanced drilling.

Academic achievement in individuals with infantile nephropathic cystinosis.

The present study examined academic skills in children and young adults with infantile nephropathic cystinosis. Cystinosis is a genetic metabolic disorder in which the amino acid cystine accumulates in various tissues and organs, including the kidney, cornea, thyroid, and brain. Individuals with cystinosis have normal intelligence but subtle visual processing impairments. Subjects were 19 children and young adults with cystinosis and 19 age-, sex-, and IQ-matched controls. All subjects had IQs within the normal range. On a test of academic achievement, mean standard scores for cystinosis and control subjects, respectively, were as follows: arithmetic 89.95 +/- 13.77 vs. 102.16 +/- 9.62; spelling 90.68 +/- 18.81 vs. 98.00 +/- 10.96; reading 97.47 +/- 15.59 vs. 98.58 +/- 12.41. Multivariate analysis of variance revealed a significant main effect for Group (P = .009); there was no main effect for Sex, nor was there a Group x Sex interaction. Univariate follow-up tests indicated that the cystinosis group performed significantly more poorly than did controls on the arithmetic subtest (P = .001) and that there was a trend (P = .085) toward poorer performance by the cystinosis group on the spelling subtest. Regression analyses revealed no evidence of a developmental lag or deterioration of function with age. The visual processing deficits previously identified in these individuals may underlie the academic difficulties observed here. It is possible that both visual processing and academic difficulties may reflect a common mechanism of selective cortical damage by this genetic defect.

Comparison of photosensitized plasma membrane damage caused by singlet oxygen and free radicals

The efficiency and selectivity of photosensitized damage to membrane functions may be influenced strongly by the identity of the initial reactive species formed by the photosensitizer. To test this possibility, a photosensitizer, rose bengal (RB), was used that resides in the plasma membrane and which generates singlet molecular oxygen ( 1O 2 ∗) upon excitation with visible light, and radicals plus 1O 2 ∗ upon excitation with UV radiation. With this approach, 1O 2 ∗ and radicals are formed at the same locations in the plasma membrane. The response of three plasma membrane functions, namely, proline transport, membrane potential, and membrane impermeability to charged dye molecules, was assessed. The efficiencies of the responses in the presence and absence of oxygen were compared per photon absorbed by RB at two wavelengths, 355 nm (UV excitation) and 532 nm (visible excitation). The efficiency of oxygen removal before irradiation was assessed by measuring the RB triplet lifetime. The three membrane functions were inhibited more efficiently at 355 nm than at 532 nm in the presence of oxygen indicating that the radicals are more effective at initiating damage to membrane components than 1O 2 ∗. The ratio of photosensitized effects at the two wavelengths in the presence of oxygen was the same for two membrane functions but not for the third suggesting that 1O 2 ∗ and radicals initiate a common mechanistic pathway for damage to some membrane functions but not to others. Removing oxygen reduced the efficiency of 355 nm-induced photosensitization by factors of 1.4 to 7. The sensitivity of the three membrane functions to 1O 2 ∗-initiated damage varied over a factor of 50 whereas radical initiated damage only varied by a factor of 15. In summary, these results indicate that radicals and 1O 2 ∗ formed at the same locations in the plasma membrane vary in their efficiency and specificity for membrane damage but may, in some cases, operate by a common secondary damage mechanism in the presence of oxygen.

Strength and Damage Mechanisms of Notched Two-Dimensional Triaxial Braided Textile Composites and Tape Equivalents Under Tension

The unnotched and notched (open hole) tensile strength and failure mechanisms of two-dimensional (2D) triaxial braided composites were examined. The effect of notch size and notch position were investigated. Damage initiation and propagation in notched and unnotched coupons were also examined. Four different fiber architectures were considered; braid angle, yarn and braider size, and percentage of longitudinal yarns, and braider angle varied. Tape laminates equivalent to textile composites were also constructed for comparison. Unnotched tape equivalents were stronger than braided textiles but exhibited greater notch sensitivity. Notched textiles and tape equivalents have roughly the same strength at large notch sizes. Two common damage mechanisms were found: braider yarn cracking and near notch longitudinal yarn splitting. Cracking was found to initiate in braider yarns in unnotched and notched coupons, and propagate in the direction of the braider yarns until failure. Longitudinal yarn splitting occurred in three of four architectures that were longitudinally fiber dominated. Damage initiation stress decreased with increasing braid angle.

Stress tolerance and membrane lipid unsaturation in Saccharomyces cerevisiae grown aerobically or anaerobically

Saccharomyces cerevisiae cells grown either aerobically or anaerobically were tested for tolerance to a brief heat stress (52 degrees C, 5 min) or oxidative stress (20 mM H2O2, 15 min). Tolerance was related to growth phase, in that stationary phase cells were intrinsically more resistant to heat or oxidative stress than exponential phase cells. A mild heat shock (37 degrees C, 30 min) induced thermotolerance and oxidative tolerance in both aerobic and anaerobic cells. However, prior exposure to a low concentration of H2O2 (0.1 mM, 60 min) induced protection against the lethal concentration of H2O2 but not against the lethal temperature. Sensitivity to both heat and oxidative stress was dependent on membrane lipid composition. In the case of anaerobic cells, the most stress resistant had membranes enriched in saturated fatty acids, followed in order by cells enriched in oleic and linolenic acids. Aerobic cells with membranes enriched in palmitoleic and oleic acids showed the highest resistance to stress under all conditions. In both aerobic and anaerobic cells, a mild heat shock or oxidative shock induced markedly increased levels of thiobarbituric acid reactive substance (TBARS), indicative of malondialdehyde formation and lipid damage. Anaerobic cells with membranes enriched in linolenic acid had the highest TBARS, followed by cells enriched in oleic acid, with cells enriched in saturated fatty acids showing the lowest TBARS. The results suggest that heat and oxidative stress may share a common mechanism of damage through induction of oxygen-derived free radicals, resulting in membrane lipid damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD mice by syngeneic splenocytes treated with cytotoxic drugs.

Infusions of syngeneic T-cells, lethally damaged with ultraviolet A light (UVA) and 8-methoxypsoralen (8-MOP), have been reported to prevent or ameliorate a number of autoimmune diseases in humans and in animal models of autoimmune disease. We previously demonstrated that the combination of UVA/8-MOP, or deoxycoformycin and deoxyadenosine (dCF/dAdo), damaged human lymphoid cells by inducing DNA strand breakage and stimulating poly (ADP-ribosyl)ation. These cells subsequently underwent programmed cell death ("apoptosis"). These findings suggested a common mechanism of lymphocyte damage, and that in vitro treatment of T-cells with cCF/dAdo might substitute for UVA/8-MOP. This hypothesis was tested in a model of autoimmune diabetes in the NOD mouse. Young adult female NOD/Wehi mice were given 350 mg/kg cyclophosphamide (CP) on day 1 to induce rapid-onset diabetes and divided into five treatment groups. Four groups received approximately 50 x 10(6) syngeneic mouse splenocytes that had been treated with various cytotoxic agents. 27/40 (68%) of the CP-only control group and 14/30 (48%) of the group given untreated splenocytes developed diabetes. By contrast, only 2/20 (10%) mice of UVA/8-MOP and 3/23 (14%) of dCF/dAdo-treated splenocyte groups developed diabetes (P < 0.01). Diabetes in high spontaneous-diabetes incidence NOD/Lt female mice was also greatly reduced (4/8 untreated vs 1/7 treated; (< 0.05). We postulate that cytotoxic damage to activated splenic T-cells allows their recognition by host T-cells and results in a protective response against autoreactive cells as a form of T-cell vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)

The pathology of early leprous neuropathy

A qualitative and quantitative study was made of early changes in nerves from 10 patients with tuberculoid or lepromatous type of leprosy. Five nerve biopsies, taken from sites remote from skin lesions, were considered to be unaffected when examined by paraffin histology but showed abnormalities in semi-thin resin sections and by electron microscopy; 5 showed mild to moderate involvement by paraffin histology. Changes in ‘unaffected’ nerves in both types of leprosy included the presence of subperineurial oedema; occasional evidence of fibre regeneration, sometimes with atypical features; increased numbers of small myelinated fibres, possibly a consequence of axonal atrophy; a few thinly remyelinated fibres, probably due to secondary demyelination, and some loss of unmyelinated axons. In more affected nerves there was variable loss of axons, both myelinated and unmyelinated. Demyelination was not a conspicuous feature; there was evidence of axonal atrophy in some fibres. Similarities in some of the changes observed in tuberculoid and lepromatous types of leprosy suggest a common mechanism of nerve damage, at least in the early stages. The presence of abnormalities in nerves at a distance from skin lesions implies a more diffuse nerve involvement than might have been expected in both types of leprosy.

Mechanisms of neurotoxicity related to selective disruption of microtubules and intermediate filaments

The neuronal response to several neurotoxic chemicals includes disruption of the cytoskeleton such as interactions with microtubules and altered distribution of neurofilaments. Methylmercury (microtubule disrupting) and acrylamide and 2,5-hexanedione (neurofilament disrupting) have been used in a cell culture (PtK 2) system to distinguish the cytoskeletal targets of these compounds. Methylmercury caused disassembly of microtubules with secondary collapse of vimentin filaments (epithelial cell equivalent of neurofilaments) at higher concentrations; actin filaments were unaltered. This confirms that disruption of actin does not contribute to methylmercury-induced interference with mitosis. In contrast, both acrylamide and 2,5-hexanedione caused a perinuclear redistribution of vimentin filaments with sparing of microtubules. Biochemical studies revealed that 2,5-hexanedione treatment resulted in high molecular weight vimentin-immunoreactive species, presumably by cross-linking of proteins. Selective action of both acrylamide and 2,5-hexanedione on vimentin filaments and the similarity of effects suggest that a common mechanism of damage may occur whereby these compounds act directly on both vimentin and neurofilaments.

Radiation sensitization of E. coli B/r by mixtures of oxygen and nitrous oxide.

Oxygen (O2) sensitizes bacterial cells in at least two mechanistically different ways, depending on the specific O2 concentration present during irradiation. Based on previous work from this laboratory, it has been proposed that nitrous oxide (N2O) and low concentrations of O2 share a common mechanism for damage. This mechanism, involving the production of superoxide anion radicals (O2-), is different from that which causes damage at high O2 concentrations. Others, however, have presented evidence that N2O and O2 (usually tested only at high concentrations) act in different ways to sensitize bacterial cells. We have now measured the radiation sensitivity in mixtures of N2O and O2 to observe additivity patterns and to determine if these two agents have any common processes for sensitization. We found that some low O2 concentrations do not increase the response in N2O, although they can have significant sensitizing effects in N2. This lack of additivity is taken as evidence for a common mechanism of damage from N2O and low concentrations of O2. In contrast, damage from high concentrations of O2 is additive to the damage from N2O. The greatest sensitivity, observed with a gas mixture of about 15 per cent O2/85 per cent N2O, is equivalent to the response in 100 per cent N2 plus the maximum amount of damage O2 can cause plus the maximum amount of damage N2O can cause. This additivity is taken as evidence that N2O and high concentrations of O2 sensitize in different ways. Thus, O2 is known to sensitize these bacteria in at least two different ways; one of these is apparently also the way N2O sensitizes.

Radiation sensitization of bacteria and bacterial spores by nitrous oxide and low concentrations of oxygen: evidence for a common mechanism of damage.

Radiation sensitization of bacteria and bacterial spores by nitrous oxide and low concentrations of oxygen: evidence for a common mechanism of damage.