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Exertion-induced heat stroke is a relatively rare disorder in the moderate maritime climate of The Netherlands. Serious complications of excessive physical activity rarely occur. We describe a marathon runner with multi-organ failure after exertion-induced heat stroke. The patient developed shock, diarrhoea, coma, rhabdomyolysis, acute renal failure, liver cell damage and disseminated intravascular coagulation but recovered completely.
The anterior or posterior drawer force exerted on the tibia by the separate isometric contractions of the quadriceps or hamstrings at various angles of knee flexion was examined in 20 healthy males. A two-dimensional model was analyzed using roentgenographic films. In separate isometric contractions of the quadriceps, the mean value of the anterior drawer force was equivalent to 14% of the tension of the quadriceps at 5 degrees knee flexion. The value decreased with the increase in the angle of knee flexion. The mean angle at which the anterior drawer force became zero was 45.3 degrees +/- 12.5 degrees. When the angle was increased further, the posterior drawer force gradually increased. In separate isometric contractions of the hamstrings, the posterior drawer force was exerted at all angles of flexion. Thus, during the early stage of rehabilitation after the anterior cruciate ligament injury, the quadriceps exercise by isometric muscle contraction should be performed with the knee flexion at more than 70 degrees (mean +/- 1.96). Exercise of the hamstrings by isometric muscle contractions can be carried out regardless of flexion angle.
The effect of bran ingestion on the flora of the human digestive tract was studied using two methods: quantitative enumeration of various microbial populations of the faecal flora, and a demonstration of the antagonistic effect exerted by the faecal flora against various potentially pathogenic bacteria of the environment. Since this latter study cannot be effected in human subjects, we used a model constituted by axenic mice inoculated with patients' flora. Faecal samples from 3 human donors receiving bran-containing diets were obtained prior to treatment and 30 days thereafter. These faecal samples were inoculated into axenic mice fed a diet with or without bran. The dominant floras of the human donors, before and after bran ingestion, were highly similar. The faecal floras of the gnotoxenic mice resembled those of the donors and no change resulting from the presence of bran in the diet could be observed. The drastic or permissive barrier effects exerted in the gnotoxenic mice by the human donors against Clostridium perfringens, Staphylococcus aureus, Candida albicans and Pseudomonas aeruginosa were not modified by the presence of bran in the diet. The large variability between animals in the barrier effect against Clostridium difficile masked any possible role of the bran. Study of the transit of Bacillus spores in the digestive tract of various mouse groups showed the existence of differences according to the origin of the inoculated floras, but not according to the presence or absence of bran in the diet.
B73.1-positive natural killer (NK) cells were separated from B73.1- cells by fluorescent-activated cell sorting and used for the generation of cytotoxic clones. The B73.1+ and B73.1- cells were cultured at one responder cell per well in medium with feeder cells and interleukin 2 but without lectins. The plating efficiency of B73.1- cells (about 4%) but not of B73.1+ cells was increased 3- to 7-fold by addition of lectin. All B73.1+ clones showed a high cytolytic activity against a wide variety of human NK-susceptible target cells, such as K562, MOLT-4 and HSB, but not against murine cell lines (P815). They also lysed several NK-insensitive Epstein-Barr virus-transformed B cell lines (B-LCLs), Daudi cells, the bladder tumor cell line T24 and melanoma tumor cells. B73.1+ clones also exerted antibody-dependent cellular cytotoxicity. Only 1 of 20 clones derived from the B73.1- fraction showed a similar pattern of cytolytic activity. In addition, some clones derived from both B73.1+ and B73.1- fractions were able to exert lectin-dependent cellular cytotoxicity.
The biological activities exerted in mouse skin by three closely related phorbol esters were compared with the effects of these compounds on HeLa cells. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate has been shown previously to influence various cell cycle parameters of these cells, thereby mimicking X-irradiation [Kinzel, V., Richards, J., and Stöhr, M. Science (Wash. D. C.), 210: 429-431, 1980]. Qualitatively similar effects were exerted by the mitogenic and irritant but almost nonpromoting "incomplete" phorbol esters 12-O-tetradeca-2-cis-4-trans-6,8-tetraenoylphorbol-13-acetate and 12-O-retinoylphorbol-13-acetate. Cell cycle parameters were analyzed by measuring thymidine incorporation rates, labeling indices, DNA histograms gained through flow cytometry, and mitotic activity. In every case, 12-O-tetradecanoylphorbol-13-acetate was more effective than 12-O-tetradeca-2-cis-4-trans-6,8-tetraenoylphorbol-13-acetate or 12-O-retinoylphorbol-13-acetate. The analysis of the influence of phorbol esters in G2 phase showed that, in order to reach the effectiveness of 10(-8) M 12-O-tetradecanoylphorbol-13-acetate, approximately 10 times the concentration of either 12-O-tetradeca-2-cis-4-trans-6,8-tetraenoylphorbol-13-acetate or 12-O-retinoylphorbol-13-acetate has to be applied. Therefore, the susceptibility of replicating HeLa cells to these phorbol derivatives reflects the promoting rather than the mitogenic and irritant capacity of these compounds.
The delayed onset of action of antipsychotic drugs (APDs) during the treatment of schizophrenia has been hypothesized to temporally correlate with the induction of depolarization block in rat mesencephalic dopamine (DA) cell groups. Nevertheless, it is unknown whether these drugs also exert a delayed action on the dopaminoceptive postsynaptic target cells in the striatal complex. Using in vivo intracellular recording and dye labeling techniques, the effects of APDs on dye coupling were examined in subregions of the striatal complex defined by double staining for calbindin immunoreactivity. Rats treated repeatedly with APDs were found to exhibit a 66-71% higher incidence of coupling that occurred in a drug- and a region-specific manner, that is, both drug treatments increased dye coupling in the limbic-associated accumbens shell region whereas only haloperidol increased dye coupling in the motor-related striatal matrix and accumbens core regions. In addition, cells located in regions in which dye coupling was altered also showed significantly higher input resistance. These changes were not observed in response to DA receptor blockade by acute drug administration or when haloperidol was administered for a period sufficient to induce DA receptor supersensitivity but not DA cell depolarization block (i.e., 2 weeks). Therefore, alteration in dye coupling appears to be correlated temporally with the induction of DA cell depolarization block. The finding that both APDs exert a common action on neurons in the accumbens shell region is consistent with its identification as the site of therapeutic drug actions, whereas the capacity of haloperidol to also affect cells in the motor-related matrix and core regions correlates with its high propensity to induce extrapyramidal side effects.
Affinity-purified human polyclonal anti-double-stranded DNA antibodies (anti-dsDNA) exerted a cytostatic effect towards human and rat glomerular mesangial cells (MC). In order to identify the cognate antigens for anti-dsDNA on the surface of MC, we used these autoantibodies to probe a human renal lambda gt11 cDNA expression library. Two cDNA clones encoding the cognate proteins for the autoantibodies were isolated. Sequencing analysis of the two cDNA showed that they had 98.6% homology with the gene of the P0 and 99.2% homology with the gene of the P1 human acidic ribosomal phosphoproteins (P protein). Two galactosidase fusion proteins (125,000 and 150,000 MW) derived from the two cDNA inserts expressed in lysogenic Escherichia coli Y1089 could react with the original screening antibodies in an immunoblotting analysis. After transformation and expression of the full-length P1 clone in prokaryotic cells, the purified P1 protein was able to react with anti-dsDNA. In a cross-inhibition experiment, the dsDNA binding activity of anti-dsDNA was inhibited by a synthetic polypeptide corresponding to the carboxyl-terminal 20 amino acids of P protein and purified P1 protein in a dose-dependent manner, but this was less potent than the inhibition caused by calf thymus dsDNA. By use of well-defined systemic lupus erythematosus (SLE) sera, we found only sera containing a high titre of anti-dsDNA activity (> 300 IU/ml) reacted with P1 of rat MC lysate. Furthermore, the 38,000 and 19,000 MW macromolecules were proved to be the cognate antigens for anti-dsDNA expression on the surface of the MC, by Western blot of the MC plasma membrane lysates. These results suggest that anti-dsDNA may cross-react with ribosomal P proteins expressed on the surface of the MC and exert cytostasis towards these cells.
A 63 year old woman presented with a 3 year history of exertional dyspnoea. Spirometry suggested extrathoracic airway obstruction (decreased inspiratory flow and saw-tooth pattern of flow-volume curves), and bronchoscopy revealed structural lesions and a trembling motion in the arytenoid region, causing upper airway obstruction on forced respiratory efforts. As there were no abnormal findings other than the lesions, the exertional dyspnoea was probably caused by impaired movement of the arytenoid region.
A multicentre, open, crossover study in 27 patients with exertional angina compared the efficacy of verapamil LP 120 mg twice a day (VP LP 120) with that of verapamil LI 120 mg 3 times a day (VP LI 120) by means of stress tests. The study procedure was as follows: 7-day selection period during which the patient received placebo, and two 21-day treatment periods by VP LI 120 or VP LP 120 according to the crossover principle. At the end of each treatment phase, a stress test was performed at the trough serum concentration for each substance. VP LP 120 mg and VP LI 120 mg both improved exercise capacity compared to placebo. Comparison of VP LP 120 and VP LI 120 did not reveal any significant difference for stress test parameters (total duration of effort: 12 +/- 3.2 min with placebo, 13.3 +/- 3.7 min for the VP LI phase, 13.9 +/- 3.2 min for the VP LP phase; % FMT reached: 87.2% +/- 7.2 for VP LI, 89% +/- 7.3 for VP LP; time to onset of significant ST depression: 10 min +/- 2.9 for VP LI, 11 min 3.6 for VP LP). The efficacy of VP LP 120 in exertional angina is therefore identical to that of VP LI 120, despite a reduction of the total dose and serum levels.
This investigation examined using heart rate (HR), central rating of perceived exertion (C-RPE) and peripheral rating of perceived exertion (P-RPE) values obtained during a graded exercise test (GXT) for monitoring intensity during a 5000 m field run. Ten trained runners performed a GXT to determine HR, C-RPE and P-RPE values at a blood lactate concentration ([La]) > or = 4.0 mM. Three randomly assigned 5000 m runs were performed on an outdoor track using the HR, C-RPE and P-RPE values from the GXT. [La] was assessed at 1000 m, 3000 m and 5000 m and running velocity (RV) at each 1000 m interval. No significant interaction effect was observed for [La] or RV among trials. A significant time effect was found among trials for [La] and RV. The 5000 m [La] was significantly different from the GXT for the C-RPE and P-RPE trials, but not the HR trial. The 1000 m RV for each trial was significantly different from the RV of the GXT. The 2000 m and 5000 m RV for P-RPE were significantly different from the RV of the GXT. The data indicate that using HR values from a GXT were better than using RPE values for maintaining exercise intensity at a [La] of 4.0 mM during a 5000 m field run in trained runners.
The purpose of this study was to determine whether specific angiotensin II (AII) type 1 receptor blockade with losartan would affect arrhythmia generation in an isolated guinea pig ventricular model of simulated ischemia and reperfusion. Effects of losartan were evaluated in the presence and absence of exogenous AII. Transmembrane potentials and an electrocardiogram were recorded during perfusion with normal Tyrode's solution, exposure to simulated ischemia for 15 min (hypoxia, acidosis, lactate, hyperkalemia, glucose-free) and reperfusion for 30 min. Under normal conditions, losartan did not affect endocardial or transmural conduction times, action potential duration at 90% repolarization or effective refractory period (ERP). However, losartan and AII each had significant effects on electrophysiological parameters during simulated ischemia and reperfusion. Further, losartan and AII, both independently and in combination, exerted antiarrhythmic effects in early reperfusion. Neither losartan nor AII affected action potential duration at 90% repolarization during simulated ischemia or reperfusion. However, AII exerted antiarrhythmic effects by preventing pronounced shortening of ERP in simulated ischemia and early reperfusion. Losartan by itself had no effect on ERP, but completely blocked the antiarrhythmic action of AII on ERP. Nevertheless, losartan preserved antiarrhythmic efficacy by attenuating prolongation of transmural conduction times in stimulated ischemia and early reperfusion. This antiarrhythmic action occurred in the absence or presence of AII. Our results indicate that losartan has antiarrhythmic efficacy which is independent of AII type 1 receptor blockade.
Bcr-Abl expression in leukemic cells is known to exert a potent effect against apoptosis due to antileukemic drugs, but its mechanism has not been elucidated. Recent reports have indicated that a variety of apoptotic stimuli cause the preapoptotic mitochondrial release of cytochrome c (cyt c) into cytosol, which mediates the cleavage and activity of caspase-3 involved in the execution of apoptosis. Whether Bcr-Abl exerts its antiapoptotic effect upstream to the cleavage and activation of caspase-3 or acts downstream by blocking the ensuing degradation of substrates resulting in apoptosis, has been the focus of the present studies. In these, we used (1) the human acute myelogenous leukemia (AML) HL-60 cells that are stably transfected with the bcr-abl gene (HL-60/Bcr-Abl) and express p185 Bcr-Abl; and (2) the chronic myelogenous leukemia (CML)-blast crisis K562 cells, which have endogenous expression of p210 Bcr-Abl. Exposure of the control AML HL-60 cells to high-dose Ara-C (HIDAC), etoposide, or sphingoid bases (including C2 ceramide, sphingosine, or sphinganine) caused the accumulation of cyt c in the cytosol, loss of mitochondrial membrane potential (MMP), and increase in the reactive oxygen species (ROS). These preapoptotic events were associated with the cleavage and activity of caspase-3, resulting in the degradation of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) and DNA fragmentation factor (DFF), internucleosomal DNA fragmentation, and morphologic features of apoptosis. In contrast, in HL-60/Bcr-Abl and K562 cells, these apoptotic stimuli failed to cause the cytosolic accumulation of cyt c and other associated mitochondrial perturbations, as well as the failure to induce the activation of caspase-3 and apoptosis. While the control HL-60 cells showed high levels of Bcl-2 and barely detectable Bcl-xL, HL-60/Bcr-Abl cells expressed high levels of Bcl-xL and undetectable levels of Bcl-2, a pattern of expression similar to the one in K562 cells. Bax and caspase-3 expressions were not significantly different between HL-60/Bcr-Abl or K562 versus HL-60 cells. These findings indicate that Bcr-Abl expression blocks apoptosis due to diverse apoptotic stimuli upstream by preventing the cytosolic accumulation of cyt c and other preapoptotic mitochondrial perturbations, thereby inhibiting the activation of caspase-3 and execution of apoptosis.
Activation of the mitogen-activated protein kinase (Erk) and c-Jun terminal kinase is a well-documented mechanism for the seven transmembrane spanning receptors. We have previously shown that thrombin stimulation of the T-leukemic cell line Jurkat induced a transient increase in [Ca2+]i and tyrosine phosphorylation of several cellular proteins. Here, we have analyzed p42-44 MAPK, JNK and p38 MAPK activation using Jurkat T-cell lines deficient in either the tyrosine kinase p56Lck (JCaM1) or the tyrosine phosphatase CD45 (J45.01). Our results demonstrate that p56Lck and CD45 exert a negative control on thrombin-induced p38 MAPK activation and [Ca2+]i release in Jurkat cells. Thrombin receptor expression was identical on the different cell lines as assessed by FACS analysis. Tyrosine phosphorylation of p38 MAPK was drastically increased after thrombin stimulation of JCaM1 or J45.01 cells, as compared with parental cells (JE6.1). P42-44 MAPK and JNK activity also enhanced after thrombin treatment of JE6.1 and JCaM1 cell lines, whereas basal kinase activity was higher in J45.01 cells and was not further stimulated by thrombin. Thrombin and thrombin receptor agonist peptide-induced [Ca2+]i mobilization paralleled p38 MAPK activation in JCaM1 and J45.01 cells. Moreover, reconstitution of J45.01 and JCaM1 cell lines with either CD45 or Lck is accompanied by restoration of a normal thrombin-induced [Ca2+]i response and p38MAPK phosphorylation. These data show that a component of the T-cell receptor signaling pathway exerts a negative control on thrombin-induced responses in Jurkat T cells. Accordingly, we found that thrombin enhanced tyrosine phosphorylation of p56Lck and decreased p56Lck kinase activity in J45.01 cells. Our results are consistent with a negative role for p56Lck on thrombin-induced [Ca2+]i release and p38 MAPK activation in Jurkat T-cell lines.
Glial cell line-derived neurotrophic factor (GDNF) exhibits potent effects on survival and function of midbrain dopaminergic (DA) neurons in a variety of models. Although other growth factors expressed in the vicinity of developing DA neurons have been reported to support survival of DA neurons in vitro, to date none of these factors duplicate the potent and selective actions of GDNF in vivo. We report here that neurturin (NTN), a homolog of GDNF, is expressed in the nigrostriatal system, and that NTN exerts potent effects on survival and function of midbrain DA neurons. Our findings indicate that NTN mRNA is sequentially expressed in the ventral midbrain and striatum during development and that NTN exhibits survival-promoting actions on both developing and mature DA neurons. In vitro, NTN supports survival of embryonic DA neurons, and in vivo, direct injection of NTN into the substantia nigra protects mature DA neurons from cell death induced by 6-OHDA. Furthermore, administration of NTN into the striatum of intact adult animals induces behavioral and biochemical changes associated with functional upregulation of nigral DA neurons. The similarity in potency and efficacy of NTN and GDNF on DA neurons in several paradigms stands in contrast to the differential distribution of the receptor components GDNF Family Receptor alpha1 (GFRalpha1) and GFRalpha2 within the ventral mesencephalon. These results suggest that NTN is an endogenous trophic factor for midbrain DA neurons and point to the possibility that GDNF and NTN may exert redundant trophic influences on nigral DA neurons acting via a receptor complex that includes GFRalpha1.
Three cases of exertional haemoglobinuria are described. So far, the cause of the underlying haemolysis in this condition has not been satisfactorily explained, but in the cases described, the haemoglobinuric episodes appeared to be related to traumatic damage to the soles of the feet. Experimental studies support the hypothesis that the intravascular haemolysis results from mechanical damage to red cells in the soles of the feet. Furthermore, since adopting remedial measures, haemoglobinuria has not recurred in any of the patients, although they have continued to pursue their strenuous athletic activities.
This study was conducted to determine, on a prospective basis, the incidence of acute exertional rhabdomyolysis (AER) among recruits at the Marine Corps Recruit Depot, San Diego, Calif. Blood samples were taken from each of 337 volunteer recruits on each of their first six days of regularly scheduled training. Serum myoglobin, serum creatine phosphokinase, lactic dehydrogenase, and serum glutamic oxaloacetic transaminase values were used as indicators of muscle injury. Substantial elevations of serum enzyme activity were observed throughout the study population. Of the study population, 39.2% had serum myoglobin levels that ranged from 0.37 mug/ml to 21.9 mug/ml during the study interval. Six subjects had serum myoglobin levels consistent with those reported in clinical cases of AER. It is concluded that, in a recruit population, large numbers of men may have myoglobinemia but not be seen initially as clinical cases.
Five cases of exertional disruption of the axillary anastomosis occurred at intervals of 13 to 30 days after axillofemoral polytef (polytetrafluoroethylene [PTFE]) graft insertion. Graft evulsion was preceded by effort and heralded by axillary pain, an expanding hematoma, and a pseudoaneurysm formation. Proximal control of the subclavian artery by a supraclavicular approach or balloon allowed safe wound exploration. Successful reconstruction required lengthening of the graft or replacement. Secondary disruption occurred with simple repair. Although temporary postoperative brachial plexus neuropathy was common, no significant hand ischemia was noted. Twenty-two reports of axillary anastomotic disruption were made to the Food and Drug Administration, Washington, DC, during a 2-year period, and one manufacturer of polytef grafts provided data on 10 reports received throughout 7 years. Surface anatomy measurements in 20 control patients demonstrated that arm abduction and lateral flexion of the body increased the distance between the axillary and femoral arteries by a mean of 15.5%. Similar measurements taken from the proximal axillary artery showed a mean length increase of less than 10%. This complication may be avoided by inserting the polytef graft with several centimeters of excess length and positioning the axillary anastomosis medial to the pectoralis minor muscle.
The efficacy and safety of high-dose verapamil (480 mg/day) and diltiazem therapy (360 mg/day) were compared in separate cohorts of 26 and 20 patients, respectively. All patients had stable exertional angina and underwent an initial 6-week double-blind, placebo-controlled, randomized phase followed by a 12-month open-label period. Angina attacks were reduced by verapamil (6.3 +/- 7.5 to 2.5 +/- 4.1 attacks per week, p less than 0.001) and by diltiazem (9.2 +/- 7.5 to 3.0 +/- 3.1 attacks per week, p less than 0.001), while treadmill time increased with both verapamil (372 +/- 132 to 444 +/- 108 s, p less than 0.001) and diltiazem (412 +/- 175 to 536 +/- 164 s, p less than 0.001) during the short-term study. Both agents continued to show similar salutory effects at the end of one year. The beneficial effects of both drugs appeared to be related in part to a reduction of the rate-pressure product during submaximal exercise (12% by verapamil, 7% by diltiazem, both p less than 0.05). Adverse effects were few and consisted primarily of mild constipation in six patients taking verapamil, and pedal edema and transient flushing in 2 patients each using diltiazem. Thus, high-dose verapamil and diltiazem have similar beneficial effects and are safe for the long-term treatment of effort-related angina pectoris.