Differences in phenotype and cell replicative behavior of hepatic tumors induced by dichloroacetate (DCA) and trichloroacetate (TCA)

Dichloroacetate (DCA) and trichloroacetate (TCA) are two hepatocarcinogenic by-products of water chlorination. To compare the effects of DCA and TCA on cell replication in the nodules and tumors they induce, male B6C3F1 mice were administered 2.0 g/L DCA or TCA in their drinking water for 38 or 50 weeks, respectively. The pretreated mice were then given water containing 0, 0.02, 0.5, 1.0, or 2.0 g/L DCA or TCA for two additional weeks to determine whether cell proliferation in the normal liver or tumors that had been induced by DCA or TCA was dependent on continued treatment. Prior to sacrifice the mice were subcutaneously implanted with mini-osmotic pumps to label DNA in dividing cells with 5-bromo-2'-deoxyuridine (BrdU). Serial sections of nodules/tumors and normal liver were stained immunohistochemically for BrdU, the oncoproteins c-Jun and c-Fos, and hematoxylin and eosin (H & E); or with Periodic acid-Schiff (PAS) stain, BrdU, and H & E, respectively. DCA and TCA transiently stimulated the division of normal hepatocytes relative to rates observed in the livers of control mice. However, at 40 and 52 weeks of treatment, replication of normal hepatocytes was substantially inhibited by DCA and TCA, respectively. Cell division within DCA-induced lesions that were identified macroscopically was significantly higher with increasing dose of DCA administered in the last 2 weeks of the experiment. DCA-induced lesions were found to display immunoreactivity to anti-c-Jun and anti-c-Fos antibodies, were predominantly basophilic, and contained very little glycogen relative to surrounding hepatocytes. In contrast, rates of cell division within TCA-induced altered hepatic foci and tumors were very high and appeared to be independent of continued treatment. TCA-induced lesions did not display immunoreactivity to either c-Jun or c-Fos antibodies. Results from this study suggest that the mechanisms by which DCA and TCA induce hepatocarcinogenesis in the male B6C3F1 mouse differ.     

Directional coronary atherectomy for the treatment of Palmaz-Schatz in-stent restenosis

Management of in-stent restenosis has become a significant challenge in interventional cardiology. The results of balloon angioplasty have been disappointing due to the high recurrence of restenosis at follow-up. Debulking of the restenotic tissue within the stents using directional coronary atherectomy (DCA) may offer a therapeutic advantage. We report the immediate clinical and angiographic outcomes and long-term clinical follow-up results of 45 patients (46 lesions), mean age 63+/-12 years, 73% men, with a mean reference diameter of 2.9+/-0.6 mm, treated with DCA for symptomatic Palmaz-Schatz in-stent restenosis. DCA was performed successfully in all 46 lesions and resulted in a postprocedural minimal luminal diameter of 2.7+/-0.7 mm and a residual diameter stenosis of 17+/-10%. There were no in-hospital deaths, Q-wave myocardial infarctions, or emergency coronary artery bypass surgeries. Four patients (9%) suffered a non-Q-wave myocardial infarction. Target lesion revascularization was 28.3% at a mean follow-up of 10+/-4.6 months. Kaplan-Meier event-free survival (freedom from death, myocardial infarction, and repeat target lesion revascularization) was 71.2% and 64.7% at 6 and 12 months after DCA, respectively. Thus, DCA is safe and efficacious for the treatment of Palmaz-Schatz in-stent restenosis. It results in a large postprocedural minimal luminal diameter and a low rate of both target lesion revascularization and combined major clinical events at follow-up.     

Effects of dichloroacetate on glycogen metabolism in B6C3F1 mice

Dichloroacetate (DCA) is a by-product of drinking water chlorination. Administration of DCA in drinking water results in accumulation of glycogen in the liver of B6C3F1 mice. To investigate the processes affecting liver glycogen accumulation, male B6C3F1 mice were administered DCA in drinking water at levels varying from 0.1 to 3 g/l for up to 8 weeks. Liver glycogen synthase (GS) and glycogen phosphorylase (GP) activities, liver glycogen content, serum glucose and insulin levels were analyzed. To determine whether effects were primary or attributable to increased glycogen synthesis, some mice were fasted and administered a glucose challenge (20 min before sacrifice). DCA treatments in drinking water caused glycogen accumulation in a dose-dependent manner. The DCA treatment in drinking water suppressed the activity ratio of GS measured in mice sacrificed at 9:00 AM, but not at 3:00 AM. However, net glycogen synthesis after glucose challenge was increased with DCA treatments for 1-2 weeks duration, but the effect was no longer observed at 8 weeks. Degradation of glycogen by fasting decreased progressively as the treatment period was increased, and no longer occurred at 8 weeks. A shift of the liver glycogen-iodine spectrum from DCA-treated mice was observed relative to that of control mice, suggesting a change in the physical form of glycogen. These data suggest that DCA-induced glycogen accumulation at high doses is related to decreases in the degradation rate. When DCA was administered by single intraperitoneal (i.p.) injection to na?ve mice at doses of 2-200 mg/kg at the time of glucose challenge, a biphasic response was observed. Doses of 10-25 mg/kg increased both plasma glucose and insulin concentrations. In contrast, very high i.p. doses of DCA (> 75 mg/kg) produced progressive decreases in serum glucose and glycogen deposition in the liver. Since the blood levels of DCA produced by these higher i.p. doses were significantly higher than observed with drinking water treatment, we conclude that apparent differences with data of previous investigations is related to substantial differences in systemic dose and/or dose-time relations.     

Effect of perchloroethylene and its metabolites on intercellular communication in clone 9 rat liver cells

Gap junction intercellular communication (IC) is thought to be important in chemical carcinogenesis as abnormalities in IC have been found in cancer cells. Perchloroethylene (PERC) is metabolized in rodent liver to dichloroacetic acid (DCA) and trichloroacetic acid (TCA), which are rodent liver carcinogens. Chloral hydrate (CH) and trichloroethanol (TCEth) are kidney metabolites. We used Lucifer yellow scrape-load dye transfer as a measure of IC to look at the effect of PERC, DCA, TCA, CH, and TCEth on Clone 9 cell cultures (normal rat liver cells). Four independent experiments were performed for each chemical using exposure times of 1, 4, 6, 24, 48, and 168 h. Concentrations for each chemical varied and were based on preliminary data on effect and cytotoxicity. To compare the relative effectiveness of each chemical to cause biological change, we identified the lowest concentration and shortest time to significantly reduce dye transfer. DCA caused a significant change at 10 mM at 6 h; TCA, 1 mM at 1 h; CH and TCEth, 1 mM at 24 h; and PERC, 0.01 mM at 48 h. Over a 24-h treatment period, the relative efficiencies, as defined by the concentration needed to produce 50% reduction in IC, were PERC (0.3 mM) > TCA (3.8 mM) > TCEth (6.6 mM) = CH (7.0 mM) > DCA (41 mM). Time-course data indicated that PERC, DCA, and TCA produced reduction in IC in a similar fashion, but 5 mM CH or TCEth exhibited variances from these results and may indicate specific cell responses to these chemicals. The mechanism(s) responsible for inhibition of IC by these structurally related chemicals needs to be established.     

Age-related differences in the effect of dichloroacetate on postischemic lactate and acid clearance measured in vivo using magnetic resonance spectroscopy and microdialysis

Numerous studies using adult animal models suggest that dichloroacetate (DCA) may have neuroprotective properties by virtue of its ability to increase rates of metabolism and, therefore, clearance of brain lactic acidosis, which may accumulate during cerebral ischemia. We tested the hypothesis that postischemic DCA administration affects lactate and acid clearance to different extents in immature versus mature brain. 31P and 1H magnetic resonance spectroscopy were used to measure intracellular acid and lactate clearance rates in vivo in newborn and 1-month-old swine after a 14-min episode of transient near-complete global ischemia. Simultaneous monitoring of extracellular lactate efflux and clearance was measured in the same animals by in vivo microdialysis. Plasma glucose concentrations were elevated in order to study animals with severe cerebral lactic acidosis. Maximal levels of brain lactosis (16-20 micromol/g) and acidosis (PHintracellular 5.8-6.0) were reached during the first 10 min of recovery and were the same in age groups and in subgroups either acting as controls or treated with DCA (200 mg/kg) given from the last minute of ischemia to 5-7 min after ischemia. For newborns, DCA administration improved the postischemic clearance rate of cerebral acidosis and cerebral phosphocreatine, with similar trends for the clearance of lactosis and increased rates of recovery of nucleotide triphosphates, compared with controls. In contrast, DCA administration in 1-month-olds resulted in a modest trend for improvement of cerebral lactate clearance, but did not affect acid clearance or the recovery rate of phosphocreatine or nucleotide triphosphates. Extracellular brain lactate concentrations had similar relative increases and rates of decline for subgroups of either age treated with DCA versus controls. The results of this study indicate that postischemic DCA administration helps to resolve cerebral acidosis to a greater degree in immature than more mature brain, suggesting that DCA may have cerebroprotective properties for neonatal hypoxic-ischemic encephalopathy.     

Improvement of lesions shown on MRI and CT scan by administration of dichloroacetate in patients with Leigh syndrome

Brain lesions exhibited on MRI and CT scan in 2 patients with mitochondrial encephalomyelopathy representing Leigh syndrome were improved by administration of dichloroacetate (DCA). One patient had pyruvic acid dehydrogenase complex (PDHC) deficiency, the other had complex I deficiency. The efficacy of DCA was transient in the patient with the PDHC deficiency, lasting for about 2.5 months. The patient died at the age of 6, about 2 years after the initiation of DCA treatment. DCA administration was started in the patient with complex I deficiency when he was 15 months old and it is still effective at his present age of 24 months. His motor ability is developing, and he could walk without support at the age of 19 months. DCA administration should be tried in patients with mitochondrial diseases.     

Enrichment of the more hydrophilic bile acid ursodeoxycholic acid in the fecal water-soluble fraction after feeding to rats with colon polyps

We recently showed that feeding the cytoprotective bile acid ursodeoxycholic acid (UDCA) to rats resulted in significant reduction in polyps and especially cancers, both in number and size (D. L. Earnest et al., Cancer Res., 54: 5071-5074, 1994). Because fecal secondary bile acids [particularly deoxycholic acid (DCA)] are considered to promote formation of colon adenomas and cancer, we have now attempted to find a relationship between polyp reduction and fecal secondary bile acids after feeding UDCA to these rats. We examined the fecal bile acids in rats with polyps and compared them with fecal bile acids in control rats and also determined the bile acid composition in fecal aqueous phase, which is in direct contact with the colon epithelium and may be physiologically more active. Treatment with azoxymethane did not significantly alter fecal bile acid composition in the rats. Cholic acid feeding resulted in greatly increased proportions of DCA (82% of total bile acids versus 18% in control rats). On the other hand, UDCA feeding significantly reduced the proportion of fecal DCA (2% in control rats fed UDCA and 3% in rats also treated with azoxymethane). In control rats, 96% of the bile acids were present in the water-insoluble fraction and 4% in the water-soluble fraction. The major insoluble bile acids included DCA and hyodeoxycholic acid (73% of total bile acids). In contrast, the muricholic acids were concentrated in the soluble fraction (37%). When 0.4% UDCA was added to the diet, lithocholic acid increased in the insoluble fraction (40 versus 1%), but the hydrophilic UDCA and muricholic acids were enriched in the water-soluble fraction (37 and 43%, respectively). Thus, the hydrophobic bile acids were distributed predominantly in the water-insoluble fraction, whereas the hydrophilic bile acids were distributed preferentially in the water-soluble fraction. These data suggest that UDCA may prevent colon tumors and polyps by countering the toxic effect of DCA and enhancing the possible cytoprotective effects of UDCA and muricholic acids in the water-soluble fraction in the feces of rat.     

Are directional coronary atherectomy and Palmaz-Schatz stent more efficacious than conventional balloon angioplasty for treating de novo coronary artery lesions?

It is unclear whether new devices such as directional coronary atherectomy (DCA) or Palmaz-Schatz stent implantation improve long-term outcomes compared with conventional balloon angioplasty in patients with stable angina and de novo coronary artery lesions of type A or type B except for complete occlusive lesions investigated by the American College of Cardiology/American Heart Association task force on percutaneous transluminal coronary angioplasty. A total of 146 patients with stable angina and simple lesions were assigned to either conventional balloon angioplasty (62 patients), DCA (50 patients), or Palmaz-Schatz implantation (34 patients). The acute results and late outcomes were assessed by coronary angiography. The results of the three procedures were similar with respect to procedural success and complications. Patients who underwent stenting or DCA had a larger immediate increase in the diameter of the lumen and a larger luminal diameter immediately after the procedure than those who underwent balloon angioplasty. At six months follow-up, the patients treated by stenting continued to have a larger luminal diameter and a lower rate of restenosis than those treated with balloon angioplasty (2.30 +/- 0.66 vs 1.85 +/- 0.83 mm, p < 0.005; 5.9% vs 29%, p < 0.05) and DCA (2.30 +/- 0.66 vs 1.90 +/- 0.96 mm, p < 0.05; 5.9% vs 24%, NS). The patients treated with balloon angioplasty had a smaller late loss than those treated with DCA or Palmaz-Schatz stent. The patients treated with DCA had a larger loss index than those treated with balloon angioplasty or Palmaz-Schatz stent. Stenting was a significant factor in decreasing the rate of restenosis by logistic regression analysis, compared with balloon angioplasty. The angiographic outcomes were better in patients who received a stent than in those who received other treatments. This study suggests that even lesions stable for treatment by balloon angioplasty and DCA can also be treated with Palmaz-Schatz stents.     

Results of directional coronary atherectomy in Northern New England. Northern New England Cardiovascular Disease Study Group

The role of directional coronary atherectomy (DCA) in interventional cardiology remains uncertain. We report the Northern New England regional experience with DCA from 1991 to 1994. Data were collected on 11,178 patients having had an intervention on a single lesion in a single vessel (798 DCAs; 10,380 percutaneous transluminal angioplasties [PTCA]). The use of DCA increased from 1.8% of interventions in 1991 to 10% in 1994. Compared with PTCA, DCA patients were younger, more often men, had more 1-vessel disease and more coronary artery bypass surgery (CABG). DCA was more often used in the left anterior descending artery, in vein grafts, for restenoses, for subtotal occlusions, and with type A lesions. Angiographic success (96.7%) and clinical success (93%) were good. Adverse events were rare: mortality 0.9%, emergent CABG 2.2%, nonfatal myocardial infarction 2.8%. After adjusting for case-mix, there was no difference between DCA and PTCA for in-hospital mortality (odds ratio [OR] = 1.03, 95% confidence interval [CI] 0.44 to 2.43, p = 0.95) or need for emergent CABG (OR = 1.27, 95% CI 0.77 to 2.10, p = 0.34). Atherectomy patients were more likely to have a nonfatal myocardial infarction (OR = 2.0, 95% CI 1.26 to 3.20, p <0.01), to sustain an injury to the femoral or brachial artery (OR = 2.89, 95% CI 1.52 to 5.51, p <0.01), and to have a clinically successful procedure (OR = 1.37, 95% CI 1.01 to 1.88, p = 0.05). Our results support the relative safety and effectiveness of DCA as its use disseminated into the region.     

Dichloroacetate enhanced myocardial functional recovery post-ischemia : ATP and NADH recovery

This study was undertaken to determine the effect of dichloroacetate (DCA) on myocardial functional and metabolic recovery following global ischemia. Isolated rabbit hearts were subjected to 120 min of mildly hypothermic (34 degrees C), cardioplegic arrest with multidose, modified St. Thomas' cardioplegia. Hearts were reperfused with either physiologic salt solution (PSS) as controls, (CON, n = 10) or PSS containing DCA (DCA, n = 6) at a concentration of 1 mM. Functional and metabolic indices were determined at baseline and at 15, 30, and 45 min of reperfusion. In four DCA and four CON hearts, myocardial biopsies were taken at baseline, end-ischemia, 15 and 45 min for nucleotide levels. Functional recovery was significantly better in hearts reperfused with DCA as demonstrated by recovery of baseline developed pressure (DCA = 69 +/- 5%, CON = 45 +/- 9%) and dP/dt (DCA = 64% +/- 10% versus CON = 48% +/- 10%). Coronary blood flow was not different between groups either at baseline or during reperfusion, but myocardial oxygen consumption (MVO2) was increased in the DCA versus CON hearts (79% +/- 20% of baseline vs 50% +/- 18%). Recovery of myocardial adenylate energy status was improved in the DCA versus CON hearts (ATP recovered to 45% +/- 20% versus 8% +/- 6% of baseline). Coronary sinus lactate concentration was decreased in DCA perfused hearts at 45 min of reperfusion. Percent of baseline NADH values was similar at 15 min of reperfusion, but at 45 min, DCA hearts showed a decrease in NADH levels, while CON hearts showed an increase (DCA = 48%; CON = 121%). The enhanced myocardial function and improved metabolic status noted with DCA may result from increased oxidative phosphorylation due to altered pyruvate dehydrogenase (PDH) activity.     

New mycalolides from the marine sponge Mycale magellanica and their interconversion

We report a case of spontaneous rupture of oesophagus revealed by a severe asthma attack, in a 78-year-old woman, with continuous dyspneic asthma treated with corticosteroids. We discuss the diagnostic difficulties in spontaneous oesophageal rupture, and emphasize the necessity for always looking for a triggering factor in case of severe attacks of asthma not responding to treatment.     

Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy

A therapeutic trial with polyvitamins and dichloroacetate (DCA) in combination with thiamine in a 13-year-old girl with complex I deficiency is reported. The polyvitamin therapy included thiamine, riboflavin, ascorbate, coenzyme Q 10 and carnitine. This therapeutic regine was used over a period of 17 months without any effect. Although DCA lowered the lactate concentration in blood and CNS--measured by magnetic resonance spectroscopy--no clinical benefit was achieved. After 20 weeks of DCA therapy a distal polyneuropathy with areflexia developed although 100 mg thiamine daily as comedication was given from the beginning of DCA therapy. Nerve conduction velocity of the peroneal nerve was not detectable, sensible evoked potentials of the tibialis posterious nerve were normal. This side-effect resolved completely within 6 months after omission of DCA. Our observation suggests a direct toxic effect of DCA only on the peripheral nervous system in our patient since several cerebral MRI and magnetic resonance spectroscopy studies showed no abnormalities. CONCLUSION. DCA lowers the lactate concentration in children with complex I deficiency of the respiratory chain in a dose of 100 mg/kg body weight without clinical benefit. Reversible peripheral polyneuropathy may develop under DCA therapy despite thiamine medication.     

Predictors and sequelae of distal embolization during saphenous vein graft intervention from the CAVEAT-II trial. Coronary Angioplasty Versus Excisional Atherectomy Trial

BACKGROUND: The purpose of this study was to identify the predictors and sequelae of distal embolization from a multicenter, randomized trial of saphenous vein graft intervention. The CAVEAT-II trial demonstrated that saphenous vein graft directional coronary atherectomy (DCA) was associated with greater angiographic success and less need for repeat intervention compared with percutaneous transluminal coronary angioplasty (PTCA) but at the cost of more acute complications--notably distal embolization. METHODS AND RESULTS: In CAVEAT-II, 305 patients were randomly assigned to DCA (149 patients) or PTCA (156 patients) for lesions with > 60% diameter stenosis in vein grafts > or = 3 mm in diameter. Distal embolization occurred in 20 patients (13.4%) assigned to DCA and 8 patients (5.1%) assigned to PTCA (P = .011). Independent predictors of distal embolization were use of DCA (71% in distal embolization patients versus 47% in patients without distal embolization, P = .011) and presence of thrombus (39% in distal embolization patients versus 14% in patients without distal embolization, P < .00). In-hospital adverse events were more frequent after distal embolization; 71% versus 20%, odds ratio plus (95% confidence intervals) 9.87 (4.65, 20.94). At 12-month follow-up, adverse event rates were also higher in patients with distal embolization (odds ratio, 3.05 [1.95, 4.76]). CONCLUSIONS: In this first prospective multicenter trial of saphenous vein graft intervention, distal embolization was more common after DCA than PTCA and in lesions containing thrombus. It also was associated with worse in-hospital and 12-month outcomes. The risk and sequelae of distal embolization should be considered when choosing a treatment strategy for vein graft disease.     

Interpreting indirect replies

PROBLEM/CONDITION: Asthma is one of the most common chronic diseases in the United States, and it has increased in importance during the preceding 20 years. Despite its importance, no comprehensive surveillance system has been established that measures asthma trends at the state or local level. REPORTING PERIOD: This report summarizes and reviews national data for specific end-points: self-reported asthma prevalence (1980-1994), asthma office visits (1975-1995), asthma emergency room visits (1992-1995), asthma hospitalizations (1979-1994), and asthma deaths (1960-1995). DESCRIPTION OF SYSTEM: The National Center for Health Statistics (NCHS) annually conducts the National Health Interview Survey, which asks about self-reported asthma in a subset of the sample. NCHS collects physician office visit data with the National Ambulatory Medical Care Survey, emergency room visit data with the National Hospital Ambulatory Medical Care Survey, and hospitalization data with the National Hospital Discharge Survey. NCHS also collects mortality data annually from each state and produces computerized files from these data. We used these datasets to determine self-reported asthma prevalence, asthma office visits, asthma emergency room visits, asthma hospitalizations, and asthma deaths nationwide and in four geographic regions of the United States (i.e., Northeast, Midwest, South, and West). RESULTS: We found an increase in self-reported asthma prevalence rates and asthma death rates in recent years both nationally and regionally. Asthma hospitalization rates have increased in some regions and decreased in others. At the state level, only death data are available for asthma; death rates varied substantially among states within the same region. INTERPRETATION: Both asthma prevalence rates and asthma death rates are increasing nationally. Available surveillance information are inadequate for fully assessing asthma trends at the state or local level. Implementation of better state and local surveillance can increase understanding of this disease and contribute to more effective treatment and prevention strategies.     

Effects of sodium selenite on deoxycholic acid-induced hyperproliferation of human colonic mucosa in short-term culture

It has been shown that in vitro incubation of human colonic biopsies with the secondary bile acid deoxycholic acid (DCA) leads to the hyperproliferation of colonic crypt cells with an expansion of the proliferative zone, which is regarded as a biomarker of increased cancer risk. Sodium selenite (SSE), on the other hand, has been implicated as a protective agent in experimental studies, but toxic effects were reported as well, depending on the dose of SSE. To elucidate the effects of SSE on human colonic mucosa, biopsies from endoscopically normal sigmoid colon tissue of 30 subjects were incubated with 5 microM DCA or a combination of 5 microM DCA and SSE in concentrations of 5, 10, 20, 50, 80, and 100 microM, respectively. Equimolar NaCl incubations served as a control. Proliferating cells were labeled by bromodeoxyuridine immunohistochemistry, and the labeling index (LI) was computed. In the experiments using 5, 10, and 20 microM SSE, the whole crypt LI was significantly lower after DCA + SSE incubation (0.136, 0.118, and 0.110, respectively) compared to that after incubation with DCA alone (0.172, 0.157, and 0.165, respectively; P < 0.01). The corresponding LIs during DCA + SSE incubation were comparable to the LIs obtained after NaCl incubation (average LI = 0.14). Contrary to this finding, severe cell damage was observed in the biopsies that were incubated with the higher SSE concentrations of 50 microM and above. The antiproliferative effects of SSE may indicate a possible protective effect in the prevention of human colon cancer development. However, the observed toxic effects of higher SSE concentrations strongly suggest the need for additional studies before general recommendations for the use of SSE in colon cancer prevention can be made.     

Electrospray analysis of biological samples for trace amounts of trichloroacetic acid, dichloroacetic acid, and monochloroacetic acid

Trichloroethylene (TCE) has been identified as a widespread groundwater contaminant. Trichloroacetic acid (TCA) and dichloroacetic acid (DCA) are toxicologically relevant metabolites of TCE that produce tumors in B6C3F1 mice. A sensitive method for measuring these metabolites in plasma has been developed to obtain pharmacokinetic data from TCE exposure. This is particularly important because DCA is more potent at producing hepatoproliferative lesions than TCA. At present, it is unclear whether DCA is produced by humans. Existing gas chromatographic methods cannot detect DCA at low nanogram-per-milliliter levels. A Finnigan TSQ 700 mass spectrometer (MS) with electrospray ionization was used to measure TCA, DCA, and monochloroacetic acid (MCA) in plasma. The MS was operated in negative ion tandem MS mode. The limit of detection for TCA and DCA was 4 ng/ml, and the limit of detection for MCA was 25 ng/mL. Plasma samples from human subjects exposed to 100 ppm TCE for 4 h contained TCA at concentrations as high as 10 micrograms/mL. DCA concentrations were less than 5 ng/mL, and MCA was not detected (less than 25 ng/mL).     

Radiotherapy results in early stage low grade nodal non-Hodgkin''s lymphoma

Severe lactic acidosis usually accompanies intense endurance exercise. It has been postulated that glycogen depletion working in concert with elevated muscle and plasma lactate levels lead to a concomitant reduction in pH. Their cumulative effect during prolonged physical exertion now leads to muscular fatigue and eventually limit endurance capacity. Therefore in the present study, dichloroacetate (DCA), a compound which enhances the rate of pyruvate oxidation thus reducing lactate formation, has been evaluated in a validated rat model of sub-maximal exercise performance. Male rats (350 g) were divided into two groups (control-saline, i.v. and DCA 5 mg/kg, i.v.) and were exercised to exhaustion in a chamber (26 degrees C) on a treadmill (11 m/min, 6 degrees incline). When compared to controls, the DCA-treated rats had longer run times (169 vs 101 min) and a decreased heating rate (0.020 vs 0.029 degrees C/min). In addition, DCA attenuated the increase in plasma lactate (28 vs 40 mg/dl) and significantly reduced both the rate and absolute amount of depletion of muscle glycogen stores. These results suggest that the activation of pyruvate dehydrogenase activity by DCA resulted in a reduction in the rate of glycogenolysis in addition to decreasing lactate accumulation by presumably limiting the availability of pyruvate for conversion to lactate, therefore increasing muscle carbohydrate oxidation via the TCA cycle. Thus DCA effected a significant delay in muscle fatigue.     

Aromatase cytochrome P450 transcripts are detected in fractured human bone but not in normal skeletal tissue

Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolites of the industrial solvent and environmental contaminant trichloroethylene (TCE), as well as contaminants of chlorinated drinking water. Human exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence in mice. Differences in dose-response curves, progression to cancer, and postexposure regression of lesions suggest that TCA and DCA work through different mechanisms. The purpose of this study was to further characterize the proliferative hepatocellular lesions promoted by TCA and DCA using biomarkers of cell growth, differentiation, and metabolism in liver sections to better delineate the distinctions in the mechanism of the two chloroacetates. Fifteen-day-old female mice were initiated with 25 mg/kg N-methyl-N-nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmol/L) in drinking water from age 49 days until euthanasia at age 413 days. The pathologic assessment showed that the foci of altered hepatocytes and tumors occurring in the animals promoted with DCA were eosinophilic and positive immunohistochemically for TGF-alpha, c-jun, c-myc, CYP 2E1, CYP 4A1, and glutathione S-transferase-pi (GST-pi). The DCA lesions also were essentially negative for c-fos and TGF-beta, but nontumor hepatocytes were consistently TGF-beta-positive. In contrast, tumors promoted by TCA were predominantly basophilic, lacked GST-pi, and stained variably; usually, more than 50% of the tumor hepatocytes were essentially negative for the other biomarkers. This study demonstrates some striking differences in certain molecular biomarkers of cell growth, differentiation, and metabolism between DCA and TCA. The results also suggest some potential growth signal transduction pathways that may contribute to the DCA promotion of tumors, further support the premise that these two chloroacetates promote hepatocarcinogenesis in different ways, and provide a rational basis for a similar comparison with TCE. Such a comparison should give some insight as to whether DCA, TCA, or both are playing a significant role in the murine liver carcinogenesis of the parent compound, TCE.     

Differences between asthma exacerbations and poor asthma control

BACKGROUND: Increased variation in peak expiratory flow (PEF) is characteristic of poorly controlled asthma, and measurement of diurnal variability of PEF has been recommended for assessment of asthma severity, including during exacerbations. We aimed to test whether asthma exacerbations had the same PEF characteristics as poor asthma control. METHODS: Electronic PEF records from 43 patients with initially poorly controlled asthma were examined for all exacerbations that occurred after PEF reached a plateau with inhaled corticosteroid treatment. Diurnal variability of PEF was compared during exacerbations, run-in (poor asthma control), and the period of stable asthma before each exacerbation. FINDINGS: Diurnal variability was 21.3% during poor asthma control and improved to 5.3% (stable asthma) with inhaled corticosteroid treatment. 40 exacerbations occurred in 26 patients over 2-16 months; 38 (95%) of exacerbations were associated with symptoms of clinical respiratory infection. During exacerbations, consecutive PEF values fell linearly over several days then improved linearly. However, diurnal variability during exacerbations (7.7%) was not significantly higher than during stable asthma (5.4%, p=0.1). PEF data were consistent with impaired response to inhaled beta2-agonist during exacerbations but not during poorly controlled asthma. INTERPRETATION: Asthmatics remain vulnerable to exacerbations during clinical respiratory infections, even after asthma is brought under control. Calculation of diurnal variability may fail to detect important changes in lung function. PEF variation is strikingly different during exacerbations compared with poor asthma control, suggesting differences in beta2-adrenoceptor function between these conditions.