Impairment of mitochondrial respiration after cerebral hypoxia-ischemia in immature rats: relationship to activation of caspase-3 and neuronal injury

Mitochondrial damage may play a key role in the development of necrotic and apoptotic hypoxic-ischemic (HI) brain damage. It has previously been shown that mitochondrial respiration is depressed in the cerebral cortex after HI in neonatal animals. The aim of the present study was to further characterize the time course of the mitochondrial impairment during reperfusion and the correlation between the respiratory control ratio and brain injury and activation of caspase-3. Rat pups were subjected to unilateral carotid artery ligation and exposed to hypoxia (7.7% oxygen). Mitochondrial respiration was measured 0-72 h after HI in a mitochondrial fraction isolated from cerebral cortex. Microtubule associated protein-2 (MAP2) and caspase-3 were analyzed with immunoblotting in cerebral cortex homogenates. In addition, the time course of caspase-3 activation was measured as DEVD cleavage. The mitochondrial respiratory control ratio in cerebral cortex decreased immediately after HI followed by a partial recovery at 3-8 h. Thereafter, a secondary drop occurred with a minimum reached at 24 h of reperfusion. The secondary loss of respiratory function was accompanied by depletion of MAP2, cleavage of caspase-3 and an increased caspase-3 -like activity at 3-24 h after the insult. In conclusion, the primary phase of mitochondrial dysfunction was paralleled by a moderate decrease of MAP2 and a limited activation of caspase-3. The secondary mitochondrial impairment was associated with neuronal injury and pronounced activation of caspase-3.     

Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD

OBJECTIVE AND BACKGROUND: To investigate the CSF levels of tau and the light neurofilament protein (NFL) in patients with frontotemporal dementia (FTD) and other common dementia disorders as well as normal control subjects. Both proteins have been implicated in the pathophysiology of FTD. METHODS: CSF levels of tau and NFL were investigated in 18 patients with FTD, 21 patients with early-onset AD (EAD), 21 patients with late-onset AD (LAD), and 18 age-matched control subjects. RESULTS: Mean +/- SD CSF NFL levels were increased in patients with FTD (1442 +/- 1183 pg/mL; p < 0.05) and LAD (1006 +/- 727 pg/mL; p < 0.001) compared with control subjects (241 +/- 166 pg/mL) and in LAD compared with EAD (498 +/- 236 pg/mL; p < 0.05), and tended to be increased in FTD compared with EAD. CSF tau levels were increased in EAD (751 +/- 394 pg/mL; p < 0.01) and LAD (699 +/- 319 pg/mL; p < 0.01) compared with control subjects (375 +/- 170 pg/mL), and in EAD (p < 0.001) and LAD (p < 0. 01) compared with FTD (354 +/- 140 pg/mL). CSF NFL correlated positively with degree of cognitive impairment in FTD (r = 0.59; p < 0.05) and LAD (r = 0.61; p < 0.01). No significant differences were found in CSF NFL or CSF tau when comparing patients who did and did not possess the APOE-epsilon4 allele within each diagnostic group. CONCLUSION: The results suggest a differential involvement of these cytoskeleton proteins in FTD and EAD, with NFL primarily involved in the pathophysiology of FTD and tau in that of EAD. The increase in CSF NFL found in LAD might reflect the white-matter degeneration found in a proportion of LAD cases.     

Increased mRNA expression levels of ERCC1, OGG1 and RAI in colorectal adenomas and carcinomas

Background  

The majority of colorectal cancer (CRC) cases develop through the adenoma-carcinoma pathway. If an increase in DNA repair expression is detected in both early adenomas and carcinomas it may indicate that low repair capacity in the normal mucosa is a risk factor for adenoma formation.     

Short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) as second-line therapy in patients with advanced colorectal cancer after failure to irinotecan and 5-fluorouracil.

BACKGROUND: The efficacy of oxaliplatin combined with capecitabine (XELOX) as second-line therapy in patients with advanced colorectal cancer (ACRC) resistant to irinotecan is not well established. Oxaliplatin induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2-h infusion is recommended. PATIENTS AND METHODS: For practical and economic reasons, but also for patient's convenience, we performed a phase II study to examine XELOX30 (capecitabine 1000 mg/m2 orally twice daily on days 1-14 and oxaliplatin 130 mg/m2 as a 30 min infusion on day 1) in patients with ACRC resistant to irinotecan. In addition the pharmacokinetics of oxaliplatin was studied. RESULTS: From November 2002 to September 2003, 70 patients with ACRC were treated with XELOX30. Median age was 62 (range 33-74 years) years and median performance status was 1 (range 0-2). The median number of courses was four (range 1-12) and median cumulative dose of oxaliplatin was 530 (range 125-1560) mg/m2. The response rate was 17% (95% CI 10-23), median time to progression (TTP) was 5.4 months (95% CI 4.6-6.4) and median survival 9.5 months (95% CI 8.5-11.2). White blood cell count (WBC) and performance status were significantly correlated to TTP. Neurotoxicity was moderate: grade 1 56%, grade 2 17% and grade 3 6%. Other grade 3 toxicities were nausea/vomiting 9%, diarrhoea 14% and PPE 8%. The maximum blood concentration and total body clearance of oxaliplatin was higher than previously reported in studies examining 2-h infusions, but the volume of distribution and terminal half-life was in close agreement with previous results. CONCLUSION: XELOX30 is a very convenient second-line regimen in ACRC with an activity and safety profile similar to other oxaliplatin schedules.     

Both total and phosphorylated tau are increased in Alzheimer's disease

BACKROUND: Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES: To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS: Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS: Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p<0.001), SAE (p<0.001), PD (p<0.001), and controls (p<0.001). CSF phosphotau was increased in possible AD compared with FTD (p<0.001) and SAE (p<0.001). CSF tau and CSF phosphotau were positively correlated in all the groups. Molecular weight forms of tau ranging from 25 kDa to 80 kDa were found in the CSF CONCLUSION: Both phosphorylated and unphosphorylated tau isoforms were present in the CSF, and tau protein appeared in both truncated and full length forms. The results suggest that the CSF concentrations of tau and phosphotau are increased in about two thirds of patients with probable AD and in half of those with possible AD but are normal in FTD, SAE, and PD compared with normal aging. Values in the normal range do not exclude AD.     

Inclusion of lignocaine base into a polar lipid formulation--in vitro release, duration of peripheral nerve block and arterial blood concentrations in the rat

BACKGROUND: Slow-release formulations of local anaesthetics may produce nerve blocks of long duration. The present study aimed at investigating the in vitro and in vivo properties of a polar lipid formulation for slow release of lignocaine and the effects on nerve block duration by inclusion of dexamethasone into the system. METHODS: In vitro release of lignocaine from the lipid formulation was studied in a US Pharmacopoeia rotating apparatus. Sciatic nerve blocks were induced in rats by 0.1 ml of test formulations containing lignocaine HCl 20 mg. ml-1 in aqueous solution, lignocaine base 20, 100 or 200 mg. ml-1 in lipid formulation or the last formulation with dexamethasone 0.05, 0.5 or 5 mg. ml-1. The durations of sensory and motor block and the arterial blood concentrations of lignocaine were investigated. RESULTS: In vitro there was a sustained release of lignocaine from the lipid formulation, with 50% release at around 48 h. In vivo lignocaine base 20 mg. ml-1 in lipid formulation produced sciatic nerve blocks of significantly shorter duration than lignocaine HCl 20 mg. ml-1 in aqueous solution, while lignocaine base 100 and 200 mg. ml-1 in lipid formulation produced blocks lasting two and three times longer, respectively, than the lignocaine HCl solution. Addition of dexamethasone did not affect the duration of nerve block. Following administration of lignocaine base 200 mg. ml-1 in lipid formulation, as compared to lignocaine HCl 20 mg. ml-1 in aqueous solution, the maximal blood concentration of lignocaine was only three times higher in spite of the ten-fold difference in dose, and the mean terminal half-life was three times longer, reflecting the slow release from the formulation. CONCLUSIONS: Our findings indicate that lignocaine base in polar lipids acts as a slow-release preparation of local anaesthetic both in vitro and in vivo.     

Multiple sclerosis in North African migrants to France

Among some 7500 respondents with known place of birth who had completed a nationwide questionnaire survey for multiple sclerosis (MS) in France in 1986, there were 260 born in former French North Africa (Algeria, Morocco, Tunisia). They had migrated to France between 1923 and 1986, but 66% came between 1956 and 1964. Two-thirds were from Algeria, where virtually the entire European population had emigrated in 1962 at the end of the Algerian war for independence. The migrants were younger at prevalence day (mean 43.4 years) and at onset (29.4 years) than the French-born MS (46.6; 31.3 years). Eight migrants lacked age information. The 225 migrants with onset more than 1 year after immigration presumably acquired their MS in France. They provided an age adjusted (US 1960) MS prevalence rate 1.54 times that for all France. If the latter is taken at 50 per 100,000 population their estimated adjusted rate is 76.8 with 95% confidence interval of 67.1 to 87.5. The other 27 with presumed acquisition in North Africa gave an estimated adjusted prevalence of 16.6 per 100,000 (95% CI 10.9-24.1). For those migrants with acquisition in France there was a mean interval of 13 years between immigration or age 11 and clinical onset, with a minimum of 3 years. This series provides further support for the theses: 1) that MS is primarily an environmental disease acquired after childhood; 2) that acquisition requires prolonged or repeated exposure (here 3 years for these medium-to-high MS risk migrants) followed by a prolonged latent or incubation period between acquisition and symptom onset (here 10 years); and 3) that this disease is most likely a widespread but unknown persistent infection which results in clinical MS in only a small proportion of those affected.     

Time course and duration of bronchodilatation with formoterol dry powder in patients with stable asthma.

BACKGROUND--Formoterol, a new beta 2 agonist, is long and fast acting when given as an aerosol. The aim was to determine the onset and duration of bronchodilatation with formoterol as a dry powder compared with salbutamol dry powder and with placebo. METHODS--Fifteen patients with stable asthma with a reversibility of 15% or more participated in a double blind, within patient study. On five different days the patients received formoterol 6 micrograms, 12 micrograms, or 24 micrograms, salbutamol 400 micrograms, or placebo in random order. Forced expiratory volume in one second (FEV1) was measured 10 minutes before, 30 minutes after, and then every hour for up to 12 hours after treatment. Specific airway resistance (sRaw) and specific airway conductance (sGaw) were measured immediately before and one, three, five, 10, 15, and 30 minutes after treatment. RESULTS--Formoterol 12 micrograms and 24 micrograms caused bronchodilatation as rapidly as salbutamol 400 micrograms. Peak values were not significantly different in the active treatments. The duration of action, calculated as median time with 20% or more of the maximum achieved increase in FEV1, was sustained for 9 hours and 16 minutes with salbutamol 400 micrograms, for 9 hours and 45 minutes with formoterol 6 micrograms, for 11 hours and 22 minutes with formoterol 12 micrograms, and for 11 hours and 42 minutes with formoterol 24 micrograms. CONCLUSIONS--Formoterol as a dry powder at doses of 12 micrograms and 24 micrograms produces a rapid onset of action and has a bronchodilator effect comparable with salbutamol 400 micrograms as a dry powder. The bronchodilatation was sustained for 11-12 hours. Formoterol 6 micrograms caused similar bronchodilatation but more slowly and for a shorter time.