Taxol-induced neuropathy: chronic effects of local injection

Summary The long-term neurotoxic effects of taxol, a compound known to promote microtubule protein polymerization, injected subepineurially into rat sciatic nerve were studied up to 10 weeks post-injection. At the site of injection, taxol caused local axonal reactions and degeneration which were causally related to the slow progressive accumulation of microtubules and other axoplasmic constituents. This culminated in the appearance of giant axonal spheroids and profiles similar to the retraction bulbs of Wallerian degeneration. From these axonal bulbs, many of which arose at nodes of Ranvier, groups of regenerating sprouts emanated. During the acute phase of taxol neurotoxicity, some swollen axons were divested of their myelin sheaths and remained demyelinated for many weeks. After 4 weeks, remyelination was apparent along some fibres. In addition to the accumulation of profiles usually associated with retraction bulbs, there was a vast increase in microtubules, some of which were aligned in concentric rings and formed channels for mitochondria. Microtubule anomalies were also visualized in distal portions of affected fibres and in regenerating sprouts. In contrast, Schwann cells displayed microtubule abnormalities only at the site of the lesion where excessive microtubule polymerization caused the displacement of ribosomes from rough endoplasmic reticulum. Distally, Schwann cells were essentially normal. Axonal depletion and regenerating sprouts were noted further downstream in the tibial nerve, and the gastrocnemius muscle showed changes similar to denervation atrophy. These results extend previous observations by demonstrating chronic, reparatory and reversible phenomena, the implications of which are discussedvis á vis axoplasmic transport and nerve regeneration.     

Long-term respiratory health effects of the herbicide, paraquat, among workers in the Western Cape

OBJECTIVE: To evaluate the possible effects of paraquat spraying among workers on deciduous fruit farms in the Western Cape, South Africa. Paraquat is a commonly used herbicide world wide and is a well documented cause of pulmonary fibrosis in studies of laboratory animals and in humans after exposure to a high dose (usually accidental or as parasuicide). The respiratory effects of long term, low dose exposure to paraquat have not been fully evaluated. METHODS: A cross sectional study of 126 workers. Administered questionnaires generated information on exposure, respiratory symptoms, and potential confounding variables. Spirometry and gas transfer were measured and chest radiographs performed. Oxygen desaturation on exercise testing was by oximetry during a modified stage one exercise test. RESULTS: No association was found between long term exposure to paraquat and reported symptoms, spirometry (forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC) and gas transfer (TLCO and KCO) or chest radiography. Multivariate analysis showed a significant relation between measures of long term exposure to paraquat and arterial oxygen desaturation during exercise independent of short term exposure. CONCLUSION: Previous studies have not shown a significant relation between measures of exposure to paraquat and standard tests of lung function. Arterial oxygen desaturation during exercise represents a more sensitive test. The findings indicate that working with paraquat under usual field conditions is associated with abnormal exercise physiology in a dose dependent fashion independent of recent exposure and acute poisoning events.

 

     

Acute stages of batrachotoxin-induced neuropathy: a morphologic study of a sodium-channel toxin

Summary The acute effects of batrachotoxin, a steroidal neurotoxin which opens the membrane sodium channel, were observed morphologically at various time points up to 3 h after injection into rat peroneal nerve. Three changes were found. First, there was massive swelling of the axon at the node of Ranvier accompanied by retraction of paranodal myelin. Second, a similar swelling of unmyelinated axons was seen. Third, extracellular fluid accumulated along the internode in the adaxonal space, the intraperiod line of myelin and, rarely, the external mesaxon, with concomitant shrinkage of the axon. The first two changes might be explained on the basis of massive shift of sodium through the batrachotoxin-modified sodium channel into the axon and subsequent osmotic shift of fluid. The reason for the third change is not clear but probably also has a ionic basis.     

Anti-tumor necrosis factor therapy abrogates autoimmune demyelination.

To define a role for the cytokine tumor necrosis factor (TNF) in immune-mediated demyelination, the effect of anti-TNF antibody was investigated with a form of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice induced by the adoptive transfer of myelin basic protein-(MBP)-sensitized T lymphocytes, an animal model of the human disease multiple sclerosis (MS). In three separate experiments, no mouse sensitized for EAE and then treated with anti-TNF by intraperitoneal injection developed signs of central nervous system (CNS) disease. Examination of CNS tissue from anti-TNF-treated animals showed no pathological changes. CNS tissue from control animals demonstrated extensive inflammatory cell infiltration and demyelination. To test whether anti-TNF therapy was inhibitory to encephalitogenic cells, preincubation of MBP-sensitized T lymphocytes with anti-TNF in vitro prior to injection into recipient mice was performed, and resulted in no diminution of their ability to transfer EAE. In addition, spleen cells from anti-TNF-treated mice were capable of serial transfer of EAE, similar to spleen cells from control animals. However, spleen cells from anti-TNF-treated mice did not produce TNF on stimulation with MBP or concanavalin A. This study showed that anti-TNF antibody can inhibit effectively the development of EAE by interfering with the effector, rather than the induction, phase of the disease. Anticytokine therapy may have important applications in the development of new therapeutic strategies for MS.     

大丁草中抗菌活性成分的研究Ⅳ

从秋季采收的菊科植物大丁草Gerbera anandria(L.)Sch Bip.全草中共分出十三种成分。本文报道其中三个新化合物的结构鉴定.它们分别是3,8-dihydroxy-4-methoxy-coumarin(ⅪⅩ),3,8-dihydroxy-4-methoxy-2-oxo-2 H-1-benzopyran-5-carboxylic acid(ⅩⅦ),和5,8-dihydroxy-7-(4-hydroxy-5-methyl-coumarin-3-)-coumarin(ⅩⅪ)。     

Total radical trapping antioxidant potential (TRAP) and exercise

The relationship between physical activity, physical fitness and total radical trapping antioxidant potential (TRAP) was examined in the Northern Ireland Health and Activity Survey. This was a cross-sectional population study (n = 1600) using a two-stage probability sample of the population. TRAP was calculated using the sum of the individual serum antioxidant concentrations (urate, protein thiols, ascorbate, alpha tocopherol and bilirubin) multiplied by their respective stoichiometric values. Physical fitness was determined by estimation of VO2max by extrapolation from submaximal oxygen uptake, and physical activity was recorded by computer-assisted interview. Mean serum TRAP concentrations were significantly higher in males (653 +/- 8.2 mumol/l, mean +/- SEM) compared to females (564 +/- 8.0 mumol/l) (p < 0.0001). Both male and female smokers had significantly lower TRAP values than non-smokers (males p < 0.0001, females p = 0.02). In females, there was a positive relationship of TRAP with age (p < 0.001) and body mass index (p < 0.001) but a negative relationship with physical fitness (p < 0.05). The known beneficial effects of exercise and activity do not appear to be directly mediated through increased antioxidant status.      

Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death

Fas is a cell surface receptor that transduces cell death signals when cross-linked by agonist antibodies or by fas ligand. In this study, we examined the potential of fas to contribute to oligodendrocyte (OL) injury and demyelination as they occur in the human demyelinating disease multiple sclerosis (MS). Immunohistochemical study of central nervous system (CNS) tissue from MS subjects demonstrated elevated fas expression on OLs in chronic active and chronic silent MS lesions compared with OLs in control tissue from subjects with or without other neurologic diseases. In such lesions, microglia and infiltrating lymphocytes displayed intense immunoreactivity to fas ligand. In dissociated glial cell cultures prepared from human adult CNS tissue, fas expression was restricted to OLs. Fas ligation with the anti-fas monoclonal antibody M3 or with the fas–ligand induced rapid OL cell membrane lysis, assessed by LDH release and trypan blue uptake and subsequent cell death. In contrast to the activity of fas in other cellular systems, dying OLs did not exhibit evidence of apoptosis, assessed morphologically and by terminal transferase–mediated d-uridine triphosphate-biotin nick-end-labeling staining for DNA fragmentation. Other stimuli such as C2-ceramide were capable of inducing rapid apoptosis in OLs. Antibodies directed at other surface molecules expressed on OLs or the M33 nonactivating anti-fas monoclonal antibody did not induce cytolysis of OLs. Our results suggest that fas-mediated signaling might contribute in a novel cytolytic manner to immune-mediated OL injury in MS.     

Sodium and lithium handling in the isolated hypertensive rat kidney

1. Isolated kidneys taken from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were perfused over a range of perfusion pressures. 2. Lithium clearance was used as an index of proximal tubule sodium handling. 3. When the perfusate contained an oncotic agent (albumin, 6.7 g/dl) the SHR kidneys performed differently from the WKY kidneys with a reduction in inulin clearance, sodium excretion, fractional sodium excretion and fractional lithium excretion [at 105 mmHg (14 kPa) perfusion pressure, SHR 6.0 +/- 1.1% vs WKY 12.6 +/- 2.4% (mean +/- SEM); at 150 mmHg (20 kPa), SHR 17.1 +/- 1.6% vs WKY 27.0 +/- 2.3%]. Calculated indices of distal tubular function showed no major differences between SHR and WKY. 4. When kidneys were perfused without oncotic agent in the perfusate the differences between SHR and WKY in tubular handling of sodium and lithium were largely abolished. 5. These findings are consistent with the hypothesis that increased sodium reabsorption occurs in the proximal tubules of the kidneys of SHR and suggest that this is an intrinsic property of the kidney, not immediately dependent on neural or humoral factors. Increased sodium reabsorption in the proximal tubule may contribute significantly to the existence of hypertension in the SHR.